keto research

Diet Review: Ketogenic Diet for Weight Loss

Finding yourself confused by the seemingly endless promotion of weight-loss strategies and diet plans? In this series , we take a look at some popular diets—and review the research behind them .

What is it?

The ketogenic or “keto” diet is a low-carbohydrate, fat-rich eating plan that has been used for centuries to treat specific medical conditions. In the 19 th century, the ketogenic diet was commonly used to help control diabetes. In 1920 it was introduced as an effective treatment for epilepsy in children in whom medication was ineffective. The ketogenic diet has also been tested and used in closely monitored settings for cancer, diabetes, polycystic ovary syndrome, and Alzheimer’s disease.

However, this diet is gaining considerable attention as a potential weight-loss strategy due to the low-carb diet craze, which started in the 1970s with the Atkins diet (a very low-carbohydrate, high-protein diet, which was a commercial success and popularized low-carb diets to a new level). Today, other low-carb diets including the Paleo, South Beach, and Dukan diets are all high in protein but moderate in fat. In contrast, the ketogenic diet is distinctive for its exceptionally high-fat content, typically 70% to 80%, though with only a moderate intake of protein.

How It Works

The premise of the ketogenic diet for weight loss is that if you deprive the body of glucose—the main source of energy for all cells in the body, which is obtained by eating carbohydrate foods—an alternative fuel called ketones is produced from stored fat (thus, the term “keto”-genic). The brain demands the most glucose in a steady supply, about 120 grams daily, because it cannot store glucose. During fasting, or when very little carbohydrate is eaten, the body first pulls stored glucose from the liver and temporarily breaks down muscle to release glucose. If this continues for 3-4 days and stored glucose is fully depleted, blood levels of a hormone called insulin decrease, and the body begins to use fat as its primary fuel. The liver produces ketone bodies from fat, which can be used in the absence of glucose. [1]

When ketone bodies accumulate in the blood, this is called ketosis. Healthy individuals naturally experience mild ketosis during periods of fasting (e.g., sleeping overnight) and very strenuous exercise. Proponents of the ketogenic diet state that if the diet is carefully followed, blood levels of ketones should not reach a harmful level (known as “ketoacidosis”) as the brain will use ketones for fuel, and healthy individuals will typically produce enough insulin to prevent excessive ketones from forming. [2] How soon ketosis happens and the number of ketone bodies that accumulate in the blood is variable from person to person and depends on factors such as body fat percentage and resting metabolic rate. [3]

What is ketoacidosis?

There is not one “standard” ketogenic diet with a specific ratio of macronutrients ( carbohydrates , protein , fat ). The ketogenic diet typically reduces total carbohydrate intake to less than 50 grams a day—less than the amount found in a medium plain bagel—and can be as low as 20 grams a day. Generally, popular ketogenic resources suggest an average of 70-80% fat from total daily calories, 5-10% carbohydrate, and 10-20% protein. For a 2000-calorie diet, this translates to about 165 grams fat, 40 grams carbohydrate, and 75 grams protein. The protein amount on the ketogenic diet is kept moderate in comparison with other low-carb high-protein diets, because eating too much protein can prevent ketosis. The amino acids in protein can be converted to glucose, so a ketogenic diet specifies enough protein to preserve lean body mass including muscle, but that will still cause ketosis.

Many versions of ketogenic diets exist, but all ban carb-rich foods. Some of these foods may be obvious: starches from both refined and whole grains like breads, cereals, pasta, rice, and cookies; potatoes, corn, and other starchy vegetables; and fruit juices. Some that may not be so obvious are beans , legumes, and most fruits. Most ketogenic plans allow foods high in saturated fat, such as  fatty cuts of meat , processed meats, lard, and butter, as well as sources of unsaturated fats , such as nuts, seeds, avocados, plant oils, and oily fish. Depending on your source of information, ketogenic food lists may vary and even conflict.

• Strong emphasis on fats at each meal and snack to meet the high-fat requirement. Cocoa butter, lard, poultry fat, and most plant fats (olive, palm, coconut oil) are allowed, as well as foods high in fat, such as avocado, coconut meat, certain nuts (macadamia, walnuts, almonds, pecans), and seeds (sunflower, pumpkin, sesame, hemp, flax).
• Some dairy foods may be allowed. Although dairy can be a significant source of fat, some are high in natural lactose sugar such as cream, ice cream, and full-fat milk so they are restricted. However, butter and hard cheeses may be allowed because of the lower lactose content.
• Protein stays moderate. Programs often suggest grass-fed beef (not grain-fed) and free-range poultry that offer slightly higher amounts of omega-3 fats, pork, bacon, wild-caught fish, organ meats, eggs, tofu, certain nuts and seeds.
• Most non-starchy vegetables are included: Leafy greens (kale, Swiss chard, collards, spinach, bok choy, lettuces), cauliflower, broccoli, Brussels sprouts, asparagus, bell peppers, onions, garlic, mushrooms, cucumber, celery, summer squashes.
• Certain fruits in small portions like berries. Despite containing carbohydrate, they are lower in “net carbs”* than other fruits.
• Other: Dark chocolate (90% or higher cocoa solids), cocoa powder, unsweetened coffee and tea, unsweetened vinegars and mustards, herbs, and spices.

Not Allowed

• All whole and refined grains and flour products, added and natural sugars in food and beverages, starchy vegetables like potatoes, corn, and winter squash.
• Fruits other than from the allowed list, unless factored into designated carbohydrate restriction. All fruit juices.
• Legumes including beans, lentils, and peanuts.
• Although some programs allow small amounts of hard liquor or low carbohydrate wines and beers, most restrict full carbohydrate wines and beer, and drinks with added sweeteners (cocktails, mixers with syrups and juice, flavored alcohols).

*What Are Net Carbs? “Net carbs” and “impact carbs” are familiar phrases in ketogenic diets as well as diabetic diets. They are unregulated interchangeable terms invented by food manufacturers as a marketing strategy, appearing on some food labels to claim that the product contains less “usable” carbohydrate than is listed. [6] Net carbs or impact carbs are the amount of carbohydrate that are directly absorbed by the body and contribute calories. They are calculated by subtracting the amount of indigestible carbohydrates from the total carbohydrate amount. Indigestible (unabsorbed) carbohydrates include insoluble fibers from whole grains, fruits, and vegetables; and sugar alcohols, such as mannitol, sorbitol, and xylitol commonly used in sugar-free diabetic food products. However, these calculations are not an exact or reliable science because the effect of sugar alcohols on absorption and blood sugar can vary. Some sugar alcohols may still contribute calories and raise blood sugar. The total calorie level also does not change despite the amount of net carbs, which is an important factor with weight loss. There is debate even within the ketogenic diet community about the value of using net carbs.

Programs suggest following a ketogenic diet until the desired amount of weight is lost. When this is achieved, to prevent weight regain one may follow the diet for a few days a week or a few weeks each month, interchanged with other days allowing a higher carbohydrate intake.

The Research So Far

The ketogenic diet has been shown to produce beneficial metabolic changes in the short-term. Along with weight loss, health parameters associated with carrying excess weight have improved, such as insulin resistance, high blood pressure, and elevated cholesterol and triglycerides. [2,7] There is also growing interest in the use of low-carbohydrate diets, including the ketogenic diet, for type 2 diabetes. Several theories exist as to why the ketogenic diet promotes weight loss, though they have not been consistently shown in research: [2,8,9]

• A satiating effect with decreased food cravings due to the high-fat content of the diet.
• A decrease in appetite-stimulating hormones, such as insulin and ghrelin, when eating restricted amounts of carbohydrate.
• A direct hunger-reducing role of ketone bodies—the body’s main fuel source on the diet.
• Increased calorie expenditure due to the metabolic effects of converting fat and protein to glucose.
• Promotion of fat loss versus lean body mass, partly due to decreased insulin levels.

The findings below have been limited to research specific to the ketogenic diet: the studies listed contain about 70-80% fat, 10-20% protein, and 5-10% carbohydrate. Diets otherwise termed “low carbohydrate” may not include these specific ratios, allowing higher amounts of protein or carbohydrate. Therefore only diets that specified the terms “ketogenic” or “keto,” or followed the macronutrient ratios listed above were included in this list below. In addition, though extensive research exists on the use of the ketogenic diet for other medical conditions, only studies that examined ketogenic diets specific to obesity or overweight were included in this list. ( This paragraph was added to provide additional clarity on 5.7.18. )

• A meta-analysis of 13 randomized controlled trials following overweight and obese participants for 1-2 years on either low-fat diets or very-low-carbohydrate ketogenic diets found that the ketogenic diet produced a small but significantly greater reduction in weight, triglycerides, and blood pressure, and a greater increase in HDL and LDL cholesterol compared with the low-fat diet at one year. [10] The authors acknowledged the small weight loss difference between the two diets of about 2 pounds, and that compliance to the ketogenic diet declined over time, which may have explained the more significant difference at one year but not at two years (the authors did not provide additional data on this).
• A systematic review of 26 short-term intervention trials (varying from 4-12 weeks) evaluated the appetites of overweight and obese individuals on either a very low calorie (~800 calories daily) or ketogenic diet (no calorie restriction but ≤50 gm carbohydrate daily) using a standardized and validated appetite scale. None of the studies compared the two diets with each other; rather, the participants’ appetites were compared at baseline before starting the diet and at the end. Despite losing a significant amount of weight on both diets, participants reported less hunger and a reduced desire to eat compared with baseline measures. The authors noted the lack of increased hunger despite extreme restrictions of both diets, which they theorized were due to changes in appetite hormones such as ghrelin and leptin, ketone bodies, and increased fat and protein intakes. The authors suggested further studies exploring a threshold of ketone levels needed to suppress appetite; in other words, can a higher amount of carbohydrate be eaten with a milder level of ketosis that might still produce a satiating effect? This could allow inclusion of healthful higher carbohydrate foods like whole grains, legumes, and fruit. [9]
• A study of 39 obese adults placed on a ketogenic very low-calorie diet for 8 weeks found a mean loss of 13% of their starting weight and significant reductions in fat mass, insulin levels, blood pressure, and waist and hip circumferences. Their levels of ghrelin did not increase while they were in ketosis, which contributed to a decreased appetite. However during the 2-week period when they came off the diet, ghrelin levels and urges to eat significantly increased. [11]
• A study of 89 obese adults who were placed on a two-phase diet regimen (6 months of a very-low-carbohydrate ketogenic diet and 6 months of a reintroduction phase on a normal calorie Mediterranean diet) showed a significant mean 10% weight loss with no weight regain at one year. The ketogenic diet provided about 980 calories with 12% carbohydrate, 36% protein, and 52% fat, while the Mediterranean diet provided about 1800 calories with 58% carbohydrate, 15% protein, and 27% fat. Eighty-eight percent of the participants were compliant with the entire regimen. [12] It is noted that the ketogenic diet used in this study was lower in fat and slightly higher in carbohydrate and protein than the average ketogenic diet that provides 70% or greater calories from fat and less than 20% protein.

Potential Pitfalls

Following a very high-fat diet may be challenging to maintain. Possible symptoms of extreme carbohydrate restriction that may last days to weeks include hunger, fatigue, low mood, irritability, constipation, headaches, and brain “fog.” Though these uncomfortable feelings may subside, staying satisfied with the limited variety of foods available and being restricted from otherwise enjoyable foods like a crunchy apple or creamy sweet potato may present new challenges.

Some negative side effects of a long-term ketogenic diet have been suggested, including increased risk of kidney stones and osteoporosis, and increased blood levels of uric acid (a risk factor for gout). Possible nutrient deficiencies may arise if a variety of recommended foods on the ketogenic diet are not included. It is important to not solely focus on eating high-fat foods, but to include a daily variety of the allowed meats, fish, vegetables, fruits, nuts, and seeds to ensure adequate intakes of fiber, B vitamins, and minerals (iron, magnesium, zinc)—nutrients typically found in foods like whole grains that are restricted from the diet. Because whole food groups are excluded, assistance from a registered dietitian may be beneficial in creating a ketogenic diet that minimizes nutrient deficiencies.

Unanswered Questions

• What are the long-term (one year or longer) effects of, and are there any safety issues related to, the ketogenic diet?
• Do the diet’s health benefits extend to higher risk individuals with multiple health conditions and the elderly? For which disease conditions do the benefits of the diet outweigh the risks?
• As fat is the primary energy source, is there a long-term impact on health from consuming different types of fats (saturated vs. unsaturated) included in a ketogenic diet?
• Is the high fat, moderate protein intake on a ketogenic diet safe for disease conditions that interfere with normal protein and fat metabolism, such as kidney and liver diseases?
• Is a ketogenic diet too restrictive for periods of rapid growth or requiring increased nutrients, such as during pregnancy, while breastfeeding, or during childhood/adolescent years?

Bottom Line

Available research on the ketogenic diet for weight loss is still limited. Most of the studies so far have had a small number of participants, were short-term (12 weeks or less), and did not include control groups. A ketogenic diet has been shown to provide short-term benefits in some people including weight loss and improvements in total cholesterol, blood sugar, and blood pressure. However, these effects after one year when compared with the effects of conventional weight loss diets are not significantly different. [10]

Eliminating several food groups and the potential for unpleasant symptoms may make compliance difficult. An emphasis on foods high in  saturated fat  also counters recommendations from the Dietary Guidelines for Americans and the American Heart Association and may have adverse effects on blood LDL cholesterol. However, it is possible to modify the diet to emphasize foods low in saturated fat such as olive oil, avocado, nuts, seeds, and fatty fish.

A ketogenic diet may be an option for some people who have had difficulty losing weight with other methods.  The exact ratio of fat, carbohydrate, and protein that is needed to achieve health benefits will vary among individuals due to their genetic makeup and body composition. Therefore, if one chooses to start a ketogenic diet, it is recommended to consult with one’s physician and a dietitian to closely monitor any biochemical changes after starting the regimen, and to create a meal plan that is tailored to one’s existing health conditions and to prevent nutritional deficiencies or other health complications. A dietitian may also provide guidance on reintroducing carbohydrates once weight loss is achieved.

A modified carbohydrate diet following the Healthy Eating Plate model may produce adequate health benefits and weight reduction in the general population. [13]

• Low-Carbohydrate Diets
• David Ludwig clears up carbohydrate confusion
• The Best Diet: Quality Counts
• Other Diet Reviews
• Paoli A, Rubini A, Volek JS, Grimaldi KA. Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets. Eur J Clin Nutr . 2013 Aug;67(8):789.
• Paoli A. Ketogenic diet for obesity: friend or foe?. Int J Environ Res Public Health . 2014 Feb 19;11(2):2092-107.
• Gupta L, Khandelwal D, Kalra S, Gupta P, Dutta D, Aggarwal S. Ketogenic diet in endocrine disorders: Current perspectives. J Postgrad Med . 2017 Oct;63(4):242.
• von Geijer L, Ekelund M. Ketoacidosis associated with low-carbohydrate diet in a non-diabetic lactating woman: a case report. J Med Case Rep . 2015 Dec;9(1):224.
• Shah P, Isley WL. Correspondance: Ketoacidosis during a low-carbohydrate diet. N Engl J Med . 2006 Jan 5;354(1):97-8.
• Marcason W. Question of the month: What do “net carb”, “low carb”, and “impact carb” really mean on food labels?. J Am Diet Assoc . 2004 Jan 1;104(1):135.
• Schwingshackl L, Hoffmann G. Comparison of effects of long-term low-fat vs high-fat diets on blood lipid levels in overweight or obese patients: a systematic review and meta-analysis. J Acad Nutr Diet . 2013 Dec 1;113(12):1640-61.
• Abbasi J. Interest in the Ketogenic Diet Grows for Weight Loss and Type 2 Diabetes. JAMA . 2018 Jan 16;319(3):215-7.
• Gibson AA, Seimon RV, Lee CM, Ayre J, Franklin J, Markovic TP, Caterson ID, Sainsbury A. Do ketogenic diets really suppress appetite? A systematic review and meta‐analysis. Obes Rev . 2015 Jan 1;16(1):64-76.
• Bueno NB, de Melo IS, de Oliveira SL, da Rocha Ataide T. Very-low-carbohydrate ketogenic diet v. low-fat diet for long-term weight loss: a meta-analysis of randomised controlled trials. Br J Nutr . 2013 Oct;110(7):1178-87.
• Sumithran P, Prendergast LA, Delbridge E, Purcell K, Shulkes A, Kriketos A, Proietto J. Ketosis and appetite-mediating nutrients and hormones after weight loss. Eur J Clin Nutr . 2013 Jul;67(7):759.
• Paoli A, Bianco A, Grimaldi KA, Lodi A, Bosco G. Long term successful weight loss with a combination biphasic ketogenic mediterranean diet and mediterranean diet maintenance protocol. Nutrients . 2013 Dec 18;5(12):5205-17.
• Hu T, Mills KT, Yao L, Demanelis K, Eloustaz M, Yancy Jr WS, Kelly TN, He J, Bazzano LA. Effects of low-carbohydrate diets versus low-fat diets on metabolic risk factors: a meta-analysis of randomized controlled clinical trials. Am J Epidemiol . 2012 Oct 1;176(suppl_7):S44-54.

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Review article, ketogenic diets and chronic disease: weighing the benefits against the risks.

• 1 Physicians Committee for Responsible Medicine, Washington, DC, United States
• 2 Brenda Davis Nutrition Consulting, Kelowna, BC, Canada
• 3 Department of Medicine, New York University Grossman School of Medicine, New York, NY, United States
• 4 Department of Medicine, New York City Health + Hospitals/Bellevue, New York, NY, United States
• 5 College of Liberal and Professional Studies, University of Pennsylvania, Philadelphia, PA, United States
• 6 School of Public Health, Loma Linda University, Loma Linda, CA, United States
• 7 Adjunct Faculty, Department of Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, United States

Very-low-carbohydrate ketogenic diets have been long been used to reduce seizure frequency and more recently have been promoted for a variety of health conditions, including obesity, diabetes, and liver disease. Ketogenic diets may provide short-term improvement and aid in symptom management for some chronic diseases. Such diets affect diet quality, typically increasing intake of foods linked to chronic disease risk and decreasing intake of foods found to be protective in epidemiological studies. This review examines the effects of ketogenic diets on common chronic diseases, as well as their impact on diet quality and possible risks associated with their use. Given often-temporary improvements, unfavorable effects on dietary intake, and inadequate data demonstrating long-term safety, for most individuals, the risks of ketogenic diets may outweigh the benefits.

Introduction

Very-low-carbohydrate (ketogenic) diets have been promoted for weight loss and, less commonly, for other health reasons. This review summarizes the effects of a ketogenic diet on health conditions for which it has been promoted, as well as potential long-term effects on health.

The term “ketogenic diet” generally refers to a diet that is very low in carbohydrate, modest in protein, and high in fat. This mix of fuels aims to induce ketosis , or the production of ketone bodies that serve as an alternate energy source for neurons and other cell types that cannot directly metabolize fatty acids. Urinary ketone levels are often used as an indicator of dietary adherence ( 1 ).

Various ketogenic diets have been studied, as shown in Table 1 . The best defined and studied is sometimes called a “classic” ketogenic diet, referring to a very-low-carbohydrate diet that is generally medically supervised, with a 4:1 or 3:1 ratio, by weight, of dietary fat to combined dietary protein and carbohydrate ( 2 ).

Table 1 . Macronutrient composition of ketogenic diets.

Other variants allow more protein or carbohydrate ( 2 ). Ketogenic diets as typically implemented in scientific studies limit dietary carbohydrate to <50 g per day with varying amounts of fat and protein ( 3 , 4 ). “Low-carbohydrate diets” refer to carbohydrate intake below the recommended dietary allowance of 130 g/day ( 3 ), which may not be low enough to induce ketosis ( 5 ).

Effects on Nutrient Metabolism

During prolonged fasting, some tissues, such as muscle, can directly metabolize free fatty acids released from adipose stores. However, much of this fatty acid is converted into ketones in the liver, which can fuel otherwise-obligate glucose consumers like neurons, minimizing mobilization of body protein for gluconeogenesis. However, to induce the liver to make ketones in the fed state, carbohydrate intake must be minimized and fat intake increased. Protein utilization is also altered on a ketogenic diet; the body shunts as much protein as possible to gluconeogenesis, while the minimum necessary amount is used for tissue repair.

Effects on Diet Quality

Extreme carbohydrate restriction can profoundly affect diet quality, typically curtailing or eliminating fruits, vegetables, whole grains, and legumes and increasing consumption of animal products. Very-low-carbohydrate diets may lack vitamins, minerals, fiber, and phytochemicals found in fruits, vegetables, and whole grains ( 6 – 8 ). Low-carbohydrate diets are often low in thiamin, folate, vitamin A, vitamin E, vitamin B6, calcium, magnesium, iron, and potassium ( 9 ). In the absence of multivitamin supplements, individuals on low-carbohydrate diets are at risk of frank nutritional deficiencies ( 10 ). Even when consuming only nutrient-dense foods, a 4:1 ketogenic diet is reported to have multiple micronutrient shortfalls, often lacking in vitamin K, linolenic acid, and water-soluble vitamins excluding vitamin B12 ( 11 ).

Ketogenic diets are typically low in fiber needed not only for healthful intestinal function but also for microbial production of beneficial colonic short-chain fatty acids ( 12 ), which enhance nutrient absorption, stimulate the release of satiety hormones, improve immune function, and have anti-inflammatory and anti-carcinogenic effects ( 13 , 14 ). Inadequate intake of these microbiota-accessible carbohydrates found in plant cell walls also increases gut permeability, as bacteria extract the carbon they need from the mucus membrane that protects the gastrointestinal tract instead of fiber ( 15 ). The relative abundance of certain health-promoting, fiber-consuming bacteria has been found to be reduced in children consuming a ketogenic diet for epilepsy ( 16 ). It has been suggested that supplementation of ketogenic diets with fiber and non-digestible carbohydrates might be advisable ( 16 ), although data to confirm that supplementation could counteract the effects of very-low-carbohydrate diets on the gut microbiota are lacking.

Intake of other protective dietary components may also be insufficient, such as phytochemicals (e.g., flavanones and anthocyanins), which are not typically included in multivitamins and for which specific intake targets have not been established. Low-carbohydrate diets are also typically high in saturated fat and cholesterol ( 10 ).

Effects of Ketogenic Diets by Condition

Seizure disorders.

Worldwide, the lifetime prevalence of epilepsy is 7.6 per 1,000 people ( 17 ). According to a 2018 Cochrane Review, most affected individuals can eliminate seizures with medication, but about 30% cannot. Some one-third to one-half of people with drug-resistant epilepsy can reduce seizure frequency by at least 50% with a ketogenic diet ( 18 ). The lack of glucose available to fuel neurons is a possible mechanism for action ( 19 ).

Long-term adherence is challenging, as food choices are limited and adverse effects are common ( 18 ). Micronutrient supplementation is required. Potential health risks accompany the long-term use of such a diet, as described below. Research has shown that modified versions of the ketogenic diet allowing for more carbohydrates have also been somewhat effective in seizure reduction ( 19 ). Most studies have not been long term, large scale, nor conducted with adult participants; therefore, more research is needed.

Obesity and Weight Management

Ketogenic diets can induce weight loss ( 20 – 23 ). In a 2020 meta-analysis of 38 studies lasting 6–12 months and including 6,499 participants, low-carbohydrate diets, defined here as <40% of energy from carbohydrate, led to a small weight loss, compared with low-fat diets, defined as <30% of energy from fat (mean difference −1.30 kg; 95% CI, −2.02 to −0.57), with considerable variability between individuals and between studies. More than half of included studies met criteria for a general ketogenic diet, as defined in Table 1 , for part or all of the low-carbohydrate intervention ( 24 ).

It has been proposed that weight loss on ketogenic diets may be due to reduced appetite ( 25 ), an effect also seen in those following balanced, very-low-energy diets (<800 kcal/day). Since ketosis occurs on both types of diets, though to a lesser degree with very-low-energy diets, it is speculated that ketosis itself may decrease hunger ( 26 ). However, findings from a recent trial by Hall et al. suggest that a low-fat vegan diet (10% energy from fat) may be more effective than a ketogenic diet in suppressing appetite ( 27 ). Energy expenditure has also been shown to increase on a ketogenic diet, at least in short-term studies ( 27 , 28 ).

In controlled trials, low-carbohydrate diets appear no more effective than other diets that similarly restrict calories ( 29 ), nor are they more effective than other dietary interventions, such as low-fat vegetarian diets, at inducing weight loss ( 30 , 31 ). A 2013 meta-analysis of randomized controlled trials testing very-low-carbohydrate ketogenic diets (≤50 g carbohydrate/day or ≤10% kcal from carbohydrates) against diets based on modest reductions in fat intake (<30% kcal from fat) for at least 1 year found that ketogenic diets led to marginally more weight loss than reduced-fat diets (weighted mean difference: −0.91 kg; 95% CI, −1.65 kg to −0.17 kg, p = 0.02). However, no statistically significant difference in amount of weight lost was seen between the 2 diets in trials following people for at least 2 years ( 3 ).

A 2017 meta-analysis of 9 trials echoed these findings. In studies <12 months long, low-carbohydrate diets (<130 g carbohydrate/day or <26% kcal from carbohydrates) were seen to lead to greater weight loss in people with type 2 diabetes relative to normal- or high-carbohydrate control diets (weighted mean difference: −1.18 kg; 95% CI, −2.32 kg to −0.04 kg; p = 0.04). No advantage was seen relative to control diets in studies of longer duration (weighted mean difference: −0.24 kg; 95% CI, −2.18 kg to 1.7 kg; p = 0.81) ( 32 ).

At least initially, ketogenic diets may slow fat loss. In a 2016 metabolic ward study by Hall et al., 17 overweight or obese men were provided a baseline diet (50% carbohydrate, 35% fat, and 15% protein, as a percent of energy) for 4 weeks, then a ketogenic diet (5% carbohydrate, 80% fat, 15% protein) for 4 weeks. For 2 weeks after switching from the baseline diet to the ketogenic diet, participants' weight loss accelerated—but fat loss slowed. The authors attributed the additional weight loss primarily to loss of body water. However, loss of body protein may have contributed; urinary nitrogen levels increased through day 11 on the ketogenic diet. In the final 2 weeks on the ketogenic diet, participants' rates of body weight and fat loss rebounded to a rate comparable to that on the baseline diet. As a result, study participants required 4 weeks on a ketogenic diet to lose the same average 0.5 kg of fat lost in the final 2 weeks on a baseline diet. It is not clear whether these effects have longer-term consequences ( 28 ).

The 2021 metabolic ward study by Hall et al. tested the effects of both an animal-based ketogenic diet (76% energy from fat, 10% carbohydrate) and a plant-based, low-fat diet (75% carbohydrate, 10% fat) on 20 weight-stable adults, mean age 29.9 years, mean BMI 27.8 kg/m 2 ( 27 ). Participants were randomized to each diet, which they consumed ad libitum for 2 weeks before immediately crossing over to the other diet. Ad libitum energy intake was 689 kcal/day lower on the low-fat, plant-based diet as compared to the ketogenic diet ( p < 0.0001). Reported hunger and satisfaction were similar between groups. Both diets induced weight loss: 1.77 ± 0.32 kg ( p < 0.0001) for the ketogenic diet vs. 1.09 ± 0.32 kg ( p = 0.003) for the low-fat diet. However, most of the weight lost on the ketogenic diet came from fat-free mass (-1.61 ± 0.27 kg; p < 0.0001); this was not the case with the low-fat diet (−0.16 ± 0.27 kg; p = 0.56). Fat mass did not significantly change during either the first or second week of the ketogenic diet, while the low-fat diet led to significant losses in body fat after both the first and second weeks. This suggests that low-fat, plant-based diets may control appetite better than ketogenic diets. These results also add to evidence suggesting that the rapid initial weight loss observed on ketogenic diets is due predominantly to loss of fat-free mass (e.g., body water, glycogen, protein, and contents of the gastrointestinal tract) ( 27 ).

Type 1 Diabetes

Although ketogenic diets can improve glycemia in pediatric patients with type 1 diabetes, they are generally not used in this population due to the risk of malnutrition, failure to thrive, reduced bone density, hyperlipidemia, poor sleep, amenorrhea, and hypoglycemia. In addition, mood and behavior may be adversely affected ( 33 ).

In adults with type 1 diabetes, both favorable and unfavorable outcomes have been observed. A small study of 11 adults with type 1 diabetes reported that a ketogenic diet improved blood glucose control ( 34 ). However, the ketogenic diet triggered more frequent and extreme hypoglycemic episodes (6.3 episodes per week compared to 1–2 episodes per week typically reported for those following conventional or otherwise unspecified diets). The majority of participants also developed dyslipidemia. Lipid changes are of particular concern in individuals with diabetes, who are already at heightened risk of cardiovascular events ( 34 ).

A comprehensive review strongly discouraged sustained ketosis or hyperketonemia in individuals with type 1 diabetes ( 35 ). Due to metabolic irregularities associated with type 1 diabetes, ketone production is elevated, and ketone clearance is diminished. Individuals with elevated ketones are at increased risk for complications of the microvasculature, brain, kidney, and liver compared to those with normal ketone levels. In type 1 diabetes, hyperketonemia is associated with oxidative stress, inflammation, non-alcoholic fatty liver disease, and insulin resistance ( 35 ).

Type 2 Diabetes

Ketogenic diets depress appetite, promote weight loss, reduce blood glucose values, and decrease HbA1c in the short term ( 21 , 36 – 43 ). Some studies have reported improved insulin sensitivity ( 40 ); the effect appears to be dependent on loss of fat mass ( 44 ). In the abovementioned metabolic ward study in which 17 overweight or obese men were provided a baseline diet (50% carbohydrate) for 4 weeks and then a ketogenic diet (5% carbohydrate) for 4 weeks, during the ketogenic diet phase, total cholesterol, low-density lipoprotein cholesterol (LDL-C), and C-reactive protein increased significantly, while fasting insulin and triglycerides decreased. While on the ketogenic diet, insulin sensitivity was impaired when participants were challenged with a baseline diet meal (50% carbohydrates) ( 45 ).

In the 2021 metabolic ward trial by Hall et al. comparing the effects of an animal-based ketogenic diet and a plant-based, low-fat diet, the plant-based diet had a greater glycemic load and predictably resulted in higher postprandial glucose and insulin levels than the ketogenic diet. However, glucose tolerance, as determined by an oral glucose tolerance test at the end of each phase, was compromised during the ketogenic phase (average 2-h glucose was 142.6 mg/dL) compared to the plant-based phase (average 2-h blood glucose was 108.5 mg/dL). In addition, high-sensitivity C-reactive protein, a marker of inflammation, was substantially higher while on the ketogenic diet compared to the plant-based diet (2.1 vs. 1.2 mg/L; p = 0.003), although not significantly different from baseline ( 27 ).

Another low-carbohydrate diet trial that followed individuals for 1 year found that insulin sensitivity was improved at 6 months but returned to baseline at 1 year ( 22 ). In healthy men, a ketogenic diet (83% fat and 2% carbohydrate) reduced insulin's ability to suppress endogenous glucose production ( 46 ).

A recent meta-analysis showed that reductions in hemoglobin A1c achieved with carbohydrate-restricted diets typically wane after a few months and that such diets are not more effective than other diets ( 47 ).

In other clinical trials with ketogenic diets, diabetes medications are frequently reduced or eliminated ( 21 , 36 – 43 ). The beneficial effects of ketogenic diets for people with type 2 diabetes are attributable primarily to weight loss, with benefits appearing to wane over time ( 48 , 49 ). Few additional negative impacts on global measures of health have been reported in short-term studies on type 2 diabetes ( 21 , 37 , 40 ). Long-term effects have not been elucidated ( 49 ).

The prospective Nurses' Health Study found no link between diets lower in carbohydrate and incident type 2 diabetes in women, although those consuming the most vegetable protein and fat had an 18% lower risk ( 50 ). The Health Professionals Follow-Up Study found that men consuming diets low in carbohydrate and high in animal protein and fat had a 37% higher risk of being diagnosed with type 2 diabetes than those who scored lowest for this diet style. Those emphasizing vegetable protein and fat on low-carbohydrate diets did not experience increased risk, and for men under 65 years of age, diabetes risk was 22% lower ( 51 ).

Dietary staples in ketogenic diets include concentrated fats, meat, poultry, fish, eggs, and cheese, all of which have been associated with increased diabetes risk ( 52 – 56 ). These foods can be high in saturated fat, cholesterol, chemical contaminants, pro-oxidants such as heme iron, and inflammatory compounds such as N-glycolylneuraminic acid (Neu5Gc) and endotoxins. Conversely, foods consistently associated with reduced diabetes risk, including fruits, legumes, whole grains, and several vegetables, are minimized or eliminated ( 52 – 56 ).

Non-alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is a serious condition where excess fat is stored in hepatocytes, causing steatosis, which can progress to non-alcoholic steatohepatitis and increase the risk of hepatocellular carcinoma ( 57 – 60 ). Worldwide, the prevalence of NAFLD in adults is estimated to be 25.2%, ranging from a low of 13.5% in Africa to a high of 31.8% in the Middle East, with North America at 24.1% ( 61 ). The risk of NAFLD is significantly higher in individuals who have obesity or type 2 diabetes (43–92%) ( 57 , 58 , 62 ).

Hepatic triacylglycerol comes from three sources: de novo lipogenesis, primarily from glucose; lipolysis of stored triglyceride from adipose tissue; and diet-derived fats ( 58 ). Most (60–80%) triglyceride is from adipose tissue, 15% is from diet, and 5% is from de novo lipogenesis in healthy people. Triglyceride from de novo lipogenesis is much higher (26%) in individuals with NAFLD ( 63 ). Fat derived from de novo lipogenesis and adipose tissue is accelerated by insulin resistance ( 63 ).

Several clinical trials have compared low-fat and low-carbohydrate hypocaloric diets in overweight or obese adults and found similar reductions in intrahepatic fat ( 64 – 66 ). Ketogenic diets typically increase intake of saturated fat, cholesterol, and animal protein, all of which are associated with insulin resistance, oxidative stress, and an exacerbated flow of free fatty acids to hepatocytes ( 57 , 62 , 63 , 67 ).

In epidemiological studies, diets high in saturated fat, trans fat, simple sugars, and animal protein (especially from red and processed meat) ( 57 ) and low in dietary fiber and omega-3 fatty acids ( 62 , 68 ) are thought to contribute to NAFLD. In the Rotterdam Study, those consuming the most animal protein were 54% more likely to have NAFLD than those consuming the least (OR 1.54, 95% CI, 1.20–1.98) ( 68 ). Dietary components associated with reduced NAFLD risk include whole grains, nuts and seeds, monounsaturated fats, omega-3 fatty acids, vegetable protein, prebiotic fiber, probiotics, resveratrol, coffee, taurine, and choline ( 57 ). In the Tzu Chi Health Study, replacing one serving of soy with fish (or meat) was associated with a 12–13% increased risk of NAFLD. Whole grain intake had an inverse relationship with NAFLD, and those following a vegetarian diet had a 21% lower risk of NAFLD ( 69 ).

Lifestyle modifications, particularly diet change, weight loss, and exercise, are the primary modality for treating NAFLD ( 57 , 62 , 63 ). Lifestyle interventions that promote weight loss have been found to reduce liver fat and improve aminotransferase concentrations and insulin sensitivity ( 48 , 57 , 58 , 62 , 63 , 68 ). It has been suggested that achieving ketosis may have a benefit in ameliorating fatty liver ( 63 ), but the studies supporting this are limited and typically also restrict energy intake. Long-term safety and specific clinical outcomes have not been determined.

Some have suggested ketogenic diets for cancer patients ( 70 ) based on the so-called “Warburg effect,” whereby cancer cells increase glucose uptake and upregulate glycolysis even in the presence of oxygen, preferentially fermenting glucose to lactate ( 71 ). By nearly eliminating available glucose, ketogenic diets theoretically stress cancer cells.

Few clinical trials have tested this. A 2018 systematic review of ketogenic diets for the management of gliomas found no randomized clinical trials and just 6 published case series/reports. While the authors could not evaluate the effectiveness of ketogenic diets for cancer survival, they noted that minimal adverse events were reported, suggesting ketogenic diets may be safe in this population ( 72 ).

A 2020 systematic review analyzed 13 studies of ketogenic diets as a complementary therapy for standard treatments in a variety of cancers. Studies analyzed were small ( n = 2–44); 9 were prospective and 6 were controlled, but just 2 were randomized, and ketogenic diet prescriptions differed between studies. Diet-related adverse events were uncommon and mostly minor, and the diet had a beneficial effect on body composition. Findings were mixed for both overall survival and progression-free survival; beneficial effects were seen in four studies ( 73 ). A possible explanation for the lack of a consistent survival benefit is demonstrated in in vitro research suggesting that ketone utilization by cancer cells increases expression of genes associated with high metastatic potential ( 74 ). Given potential benefits for body composition, large, well-designed, randomized clinical trials are needed to determine the safety and effectiveness of ketogenic diets in cancer treatment ( 72 , 73 ).

Long-term data on cancer outcomes with ketogenic diets are lacking. However, food components typical of a ketogenic diet, such as red and processed meats, are linked to increased cancer risk ( 75 – 77 ). Whole grains, fruits, and vegetables are linked to a lower risk of both cancer and all-cause mortality ( 78 , 79 ), yet, with the exception of non-starchy vegetables, these foods are commonly avoided on ketogenic diets. For example, in one study of a ketogenic diet for type 2 diabetes, researchers encouraged unlimited meat, poultry, seafood, and eggs, while cutting intake of whole grains, fruits, and starchy vegetables and limiting intake of salad vegetables and non-starchy vegetables ( 21 ).

Alzheimer's Disease

By 2050, it is projected that 13.8 million people in the U.S. will have Alzheimer's disease (AD) ( 80 ). Given the brain's inability to efficiently utilize glucose in AD, some have proposed ketones as an alternate fuel source for these individuals ( 81 ). As reviewed by Włodarek in 2019, small trials have found that increasing blood ketones by supplementing with medium-chain triglycerides does improve some measures of cognitive function in AD, although not necessarily in those with the APOEε4 genotype ( 82 ).

No long-term data on ketogenic diets for AD are available, although small, short-term trials have been conducted. A 3-month, weight-maintaining ketogenic diet intervention improved cognition in subjects with mild-to-moderate AD ( n = 15), but improvements were lost after a 1-month washout period ( 83 ). A 6-week trial of a ketogenic diet in subjects with mild cognitive impairment led to improved memory relative to a control diet (50% of energy from carbohydrates); follow-up data were not available. However, the ketogenic diet was substantially lower in calories, which may have independently reduced insulin resistance ( 84 ). In a 2020 review of short-term ketogenic diet and ketone supplement studies in older adults, including those with no dysfunction, mild cognitive impairment, and AD, 6 of 9 controlled trials with clinical endpoints found significant cognitive improvements in the intervention groups, while other trials did not. Whether cognitive gains would be maintained upon discontinuation of the diet/supplement remains unknown due to lack of long-term follow-up ( 85 ).

Saturated fat intake, which typically increases on a ketogenic diet, is strongly associated with AD risk. In the Chicago Health and Aging Project, high saturated fat intake was linked to a 2- to 3-fold increased risk of incident AD ( 86 ). A 2016 review of international data found that consuming meats, eggs, high-fat dairy such as butter and cheese, and sweets was linked to an increased risk of AD ( 87 ). Aside from sweets, consumption of these foods generally increases on a ketogenic diet.

Polyphenol-rich plant foods such as fruits and vegetables are associated with lower AD risk ( 88 ) and diets focusing on whole plant foods and limiting animal foods and processed foods, such as the MIND diet, are proven to reduce AD risk ( 89 ). Thus, by providing ketones that can be metabolized by neurons in AD, a ketogenic diet could improve symptoms in the short term, but the diet's nutritional profile could increase risk over the long-term in healthy individuals.

Cardiovascular Disease

The effect of low-carbohydrate diets on plasma lipid concentrations is a major concern. It has long been established that weight loss by any means causes a reduction in total cholesterol of about 2 mg/dL per kilogram lost ( 90 ). However, low-carbohydrate diets are often an exception to that rule. In a 2002 6-month study of a very-low-carbohydrate “Atkins” diet by Westman et al., 12 (29%) of the 41 participants had LDL-C elevations. The average increase was 18 mg/dL ( 91 ). In a similar 6-month study by Yancy, 30% of participants had LDL-C increases > 10% ( 92 ).

In a trial published in 2003 by Foster et al., LDL-C rose 6.2% in a group of low-carbohydrate dieters at 3 months ( 22 ). For comparison, LDL-C dropped by 11.1% during this same time period in participants following a conventional low-calorie diet. In a 2004 1-year study, those on a low-carbohydrate diet increased their mean LDL-C from 112 to 120 mg/dL ( 93 ). In 2018, Hallberg ( 94 ) reported a mean 10% rise in LDL-C in individuals following low-carbohydrate diets, an elevation that persisted during 2 years of follow-up ( 95 ). A recent meta-analysis of 5 studies showed that, in individuals with type 2 diabetes, ketogenic diets led to, on average, no substantial change in LDL-C ( 96 ).

It is important to note that changes reported in group means do not reflect the change for any given individual. In the 2002 study cited above, while the mean LDL-C increase was 18 mg/dL, one participant's LDL-C concentration increased from 123 to 225 mg/dL ( 91 ). In the Yancy study, one participant's LDL-C increased from to 219 mg/dL. Another experienced an LDL-C rise from 184 to 283 mg/dL, and a third developed chest pain and was subsequently diagnosed with coronary heart disease ( 92 ). In the Foster study, the standard deviation for the change in LDL-C was 20.4%, indicating that while LDL-C decreased for some, for many participants, LDL-C rose dramatically ( 22 ).

Negative effects on blood lipids have also been seen in healthy individuals. A 2018 pilot study of young, fit adults (average age 31) found that 12 weeks on a ketogenic diet led to a weight loss of 3.0 kg in the ketogenic group, with no significant weight change in the control group. However, despite significant weight loss, LDL-C increased by 35% in the ketogenic group ( p = 0.048), from 114 mg/dL at baseline to 154 mg/dL at 12 weeks ( 97 ).

Some have suggested that LDL-C or LDL particle concentration elevations are of no concern if the increase is mainly in larger LDL particles. There are two problems with this rationale: First is the problem of heterogeneity noted above (i.e., individuals may have significant worsening of their lipid profiles that are not reflected by mean figures). Second, LDL is potentially atherogenic regardless of particle size ( 98 , 99 ). Data supporting this concern come from the Women's Health Study, a randomized, placebo-controlled trial of low-dose aspirin and vitamin E. As part of the study, LDL particle size was assessed. The hazard ratio for incident cardiovascular disease associated with large LDL particles was 1.44 (indicating a 44% increased risk). For small LDL, it was 1.63 (a 63% increased risk). Both were highly statistically significant. In other words, large LDL particles were strongly atherogenic, albeit less so than small LDL ( 100 ).

It has also been proposed that the risk elevation associated with increased LDL-C concentrations may be neutralized to the extent that high-density lipoprotein cholesterol (HDL-C) also rises. However, both Mendelian randomization trials and studies using HDL-elevating agents have not shown benefit regarding cardiovascular risk. In the former category are studies that have examined individuals with naturally occurring genetic variants associated with elevated plasma HDL-C concentrations. These genetic traits are not associated with reduced risk of myocardial infarction unless they also reduce LDL-C ( 101 ).

Treatment-induced HDL-C elevations were examined in a meta-analysis of 108 studies including 299,310 participants, which found no associated reduction in the risk of coronary heart disease events, coronary disease mortality, or total mortality ( 102 ). The LDL-C/HDL-C ratio was not a better predictor of cardiovascular outcomes than LDL-C alone, and the authors recommended using LDL-C, rather than HDL-C or a ratio of the two, as the therapeutic target.

Kidney Health

The evidence of the renal-specific effects of ketogenic diets is limited but worth noting, especially in the context of the unclear long-term benefits of such diets for diabetes and obesity ( 103 ). For those without chronic kidney disease (CKD), one of the biggest potential risks of the ketogenic diet is the development of kidney stones, a finding that has been frequently noted in the pediatric epilepsy literature ( 104 , 105 ). The ketogenic diet's emphasis on high-fat, animal-based foods while excluding many fruits and vegetables promotes a urinary milieu for kidney stones. Dietary animal protein consumption is a well-established promoter of kidney stones ( 106 ). The acidosis caused by the ketogenic diet may also encourage stone formation by lowering urinary citrate and pH levels while increasing urinary calcium levels.

Another potential risk of animal-based ketogenic diets for those without CKD is the development of CKD through the consumption of animal fat and protein. In observational studies of populations eating Western diets, high animal fat consumption, as is common with ketogenic diets, has been associated with increased risk of developing albuminuria ( 107 ). In a prospective study of nearly 12,000 people over 23 years, high animal protein consumption was associated with a 23% increased hazard ratio of incident CKD ( 108 ). Other observational studies of animal protein have shown similar findings ( 109 , 110 ).

For those with CKD, the high protein content in some ketogenic diets is of concern. While “classic” ketogenic diets are not necessarily high in protein, those used for weight loss often meet the definition of a high-protein diet (>1.5 g/kg/d) by encouraging dieters to consume 1.2–2.0 g/kg/d. Compared to control diets with higher protein content, low protein consumption has been associated with a reduction in the rate of kidney function decline in a meta-analysis of 14 randomized controlled trials ( 111 ). High protein consumption facilitates hyperfiltration, a phenomenon of increased blood flow to the glomerulus, which is thought to lead to long-term damage in those with CKD ( 112 ). Finally, the acid load from the ketogenic diet may worsen metabolic acidosis and kidney disease in those with CKD ( 113 ). The ketogenic diet's acid load comes from the foods consumed (especially those from animal-based sources), ketoacids associated with ketone production, and from the lack of natural alkali found in fruits and vegetables that are often avoided in the ketogenic diet. As such, the ketogenic diet requires further research regarding its long-term renal safety in those with and without CKD.

Pre-pregnancy and Pregnancy

Approximately 40% of pregnancies in the United States are unplanned ( 114 ). Low-carbohydrate diets followed prior to conception or during the periconceptual period are associated with an increased risk of birth defects and gestational diabetes, respectively.

The National Birth Defects Prevention Study found that women who reported consuming low-carbohydrate diets in the year prior to conception (daily carbohydrate intake ≤5th percentile of control mothers, or ~95 g carbohydrate/day) were 30% more likely to have an infant with a neural tube defect (95% CI, 1.02–1.67), specifically anencephaly (OR 1.35; 95% CI, 0.90–2.02) and spina bifida (OR 1.28; 95% CI, 0.95–1.72) ( 115 ). For unplanned pregnancies in particular, effect estimates for carbohydrate-restricted diets showed an 89% increased risk of neural tube defects (95% CI, 1.28–2.79) ( 115 ).

Use of folate supplements may not mitigate the risk seen with low-carbohydrate diets. In the above study, there was no effect measure modification by folic acid supplement use ( 115 ). A 2019 study conducted using data that predated the era of folate-fortified grain products also found an increase in neural tube defects in the offspring of women consuming low-carbohydrate diets in the periconceptual period (OR 2.0; 95% CI, 1.2–3.4), suggesting other factors were contributing ( 116 ).

A prospective cohort study evaluating gestational diabetes risk scored women's diets for adherence to a low-carbohydrate diet pattern and dietary fat source. After adjusting for multiple variables including BMI, women consuming the least carbohydrate had a 27% higher risk of gestational diabetes compared to those consuming the most (RR 1.27; 95% CI, 1.06–1.51, p = 0.03). A stronger association was seen for women following a low-carbohydrate diet pattern high in animal products; they had a 36% higher risk of gestational diabetes (RR 1.36; 95% CI, 1.13–1.64, p = 0.003). A vegetable-based low-carbohydrate dietary pattern was not associated with increased risk ( 117 ).

Adverse Effects of Ketogentic Diets

The most restrictive ketogenic diets used for epilepsy can cause fatigue, headache, nausea, constipation, hypoglycemia, and acidosis, especially within the first few days to weeks of following the diet ( 2 ). Dehydration, hepatitis, pancreatitis, hypertriglyceridemia, hyperuricemia, hypercholesterolemia, hypomagnesemia, and hyponatremia can also occur ( 82 , 118 ).

A study of 300 users of online forums found that self-administered ketogenic diets may be accompanied by a temporary cluster of symptoms frequently termed “keto flu,” which includes headache, fatigue, nausea, dizziness, “brain fog,” gastrointestinal discomfort, decreased energy, feeling faint, and heartbeat alterations ( 119 ). In endurance athletes, 3.5 weeks on a ketogenic diet led to unfavorable effects on markers of bone modeling and remodeling ( 120 ).

Longer-term effects can include decreased bone mineral density, nephrolithiasis, cardiomyopathy, anemia, and neuropathy of the optic nerve ( 82 , 121 ). Ketogenic diets have low long-term tolerability, and are not sustainable for many individuals ( 48 , 49 ). Diets low in carbohydrate have also been associated with an increased risk of all-cause mortality ( 122 ), although recent data suggest that lower-carbohydrate diets can be linked to either higher or lower mortality risk, depending on the quality of the carbohydrate they contain and whether they rely more on animal protein and saturated fat or plant protein and unsaturated fat, respectively ( 123 ).

Ketogenic diets reduce seizure frequency in some individuals with drug-resistant epilepsy. These diets can also reduce body weight, although not more effectively than other dietary approaches over the long term or when matched for energy intake. Ketogenic diets can also lower blood glucose, although their efficacy typically wanes within the first few months.

Very-low-carbohydrate diets are associated with marked risks. LDL-C can rise, sometimes dramatically. Pregnant women on such diets are more likely to have a child with a neural tube defect, even when supplementing folic acid. And these diets may increase chronic disease risk: Foods and dietary components that typically increase on ketogenic diets (eg, red meat, processed meat, saturated fat) are linked to an increased risk of CKD, cardiovascular disease, cancer, diabetes, and Alzheimer's disease, whereas intake of protective foods (eg, vegetables, fruits, legumes, whole grains) typically decreases. Current evidence suggests that for most individuals, the risks of such diets outweigh the benefits.

Author Contributions

LC and NDB contributed to the organization of the manuscript, reviewed, and approved the submitted version. LC composed the outline and drafted the manuscript. LC, BD, SJ, MJ, JP, MN, and NDB wrote sections of the manuscript. All authors had full access to data and revised and approved the manuscript for publication.

This work was funded by the Physicians Committee for Responsible Medicine.

Conflict of Interest

LC is an employee of the Physicians Committee for Responsible Medicine in Washington, DC, a non-profit organization providing educational, research, and medical services related to nutrition. LC also declares that a trust for her benefit previously held stock in 3M, Abbot Labs, AbbVie, Johnson and Johnson, Mondelez, Nestle, and Walgreens; she is the author of a food and nutrition blog, Veggie Quest; and she is former publications editor and current chair for the Women's Health Dietetic Practice Group within the Academy of Nutrition and Dietetics. MJ and JP received compensation from the Physicians Committee for Responsible Medicine while working on this manuscript. MN is an employee of the Physicians Committee for Responsible Medicine. NDB is an Adjunct Professor of Medicine at the George Washington University School of Medicine. He serves without compensation as president of the Physicians Committee for Responsible Medicine and Barnard Medical Center in Washington, DC, non-profit organizations providing educational, research, and medical services related to nutrition. He writes books and articles and gives lectures related to nutrition and health and has received royalties and honoraria from these sources.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Keywords: ketogenic diet, very-low-carbohydrate diet, low-carbohydrate diet, obesity, disease prevention

Citation: Crosby L, Davis B, Joshi S, Jardine M, Paul J, Neola M and Barnard ND (2021) Ketogenic Diets and Chronic Disease: Weighing the Benefits Against the Risks. Front. Nutr. 8:702802. doi: 10.3389/fnut.2021.702802

Received: 29 April 2021; Accepted: 10 June 2021; Published: 16 July 2021.

Reviewed by:

Copyright © 2021 Crosby, Davis, Joshi, Jardine, Paul, Neola and Barnard. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Lee Crosby, LCrosby@pcrm.org

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• Published: 17 January 2022

Ketogenic diet for human diseases: the underlying mechanisms and potential for clinical implementations

• Huiyuan Zhu 1   na1 ,
• Dexi Bi 1   na1 ,
• Youhua Zhang 1   na1 ,
• Cheng Kong 2 , 3   na1 ,
• Jiahao Du 2 ,
• Xiawei Wu 2 , 4 ,
• Qing Wei 1 &
• Huanlong Qin 2 , 3  

Signal Transduction and Targeted Therapy volume  7 , Article number:  11 ( 2022 ) Cite this article

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The ketogenic diet (KD) is a high-fat, adequate-protein, and very-low-carbohydrate diet regimen that mimics the metabolism of the fasting state to induce the production of ketone bodies. The KD has long been established as a remarkably successful dietary approach for the treatment of intractable epilepsy and has increasingly garnered research attention rapidly in the past decade, subject to emerging evidence of the promising therapeutic potential of the KD for various diseases, besides epilepsy, from obesity to malignancies. In this review, we summarize the experimental and/or clinical evidence of the efficacy and safety of the KD in different diseases, and discuss the possible mechanisms of action based on recent advances in understanding the influence of the KD at the cellular and molecular levels. We emphasize that the KD may function through multiple mechanisms, which remain to be further elucidated. The challenges and future directions for the clinical implementation of the KD in the treatment of a spectrum of diseases have been discussed. We suggest that, with encouraging evidence of therapeutic effects and increasing insights into the mechanisms of action, randomized controlled trials should be conducted to elucidate a foundation for the clinical use of the KD.

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Introduction.

The KD comprises a high-fat component, very low carbohydrates, and adequate proteins (Fig. 1 ), 5 , 6 , 7 and has been clinically used since the early 1920s to control seizures in patients with epilepsy, especially those who do not respond adequately to antiepileptic medication. 7 , 8 , 9 The history of dietary interventions used as “cures” for epilepsy possibly dates back to 500 before christ, whereas fasting has been recognized as an effective therapy against epilepsy and has even been recorded in the Hippocratic collection. 8 Modern implementation of fasting as an antiepileptic treatment began in 1911, 8 when it was noted that a diet containing few carbohydrates but a high proportion of fat could produce acetone and beta-hydroxybutyric acid (β-HB), similar to what is seen with starvation, 10 and that alternative ketonemia-producing approaches might achieve effects similar to that of fasting. 5 In 1921, Russel Wilder first proposed that a ketone-producing diet could be as effective as fasting for the treatment of epilepsy, and coined the term “ketogenic diet”. 8 In particular, the KD can mimic the metabolic effects of fasting without significant calorie deprivation. The KD enjoyed wide popularity as a medical approach for treating epilepsy for nearly a decade before the introduction of antiepileptic agents, such as diphenylhydantoin. 8 The KD re-emerged in the 1990s and became well established as an option for drug-resistant epilepsy. 8 , 9 , 11 , 12 In the past few decades (Fig. 1 ), the KD has received extensive interest because of its beneficial effects in a number of diseases, such as neurological disorders, obesity, type 2 diabetes mellitus (T2DM), cancer, intestinal disorders, and respiratory compromise. 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 Here, we provide a comprehensive review of the KD, covering the therapeutic effects, relevant mechanisms, and clinical evidence underlying the implementation of the KD in various diseases.

The composition and metabolic effects of the ketogenic diet, which have increasingly generated interest. a The compositional features of the classic KD and its variants are shown. b The number of publications obtained for the search term “ketogenic diet” in PubMed is shown by the year of publication. Articles published before 1931 were not included due to the unavailability of PubMed records predating this timepoint

Types of the ketogenic diet

The KD is characterized as a high-fat, very-low-carbohydrate diet. Several variant KD that show similar efficacy to that of the original form has been developed to date, and offer flexibility to increase compliance with the regimens. 24 , 25 There are four major types of the KD with proven efficacy: the classic long-chain triglyceride (LCT) KD, medium-chain triglyceride (MCT) KD, modified Atkins diet (MAD), and low glycemic index treatment (Fig. 1 ). 24

The classic LCT KD is the most traditional type of the KD, is widely used in the clinical setting, and incorporates a 4:1 ratio of fat (in grams) to protein plus carbohydrate (in grams). 26 , 27 Fat provides 90% calories, and its predominant source is food-derived LCT, and a 3:1 or lower ratio may be used. 24 Moreover, the low ratios are appropriate for the KD initiation in infants, whereas in older children, initiation with a 4:1 ratio, followed by a reduced ratio may be more effective. 24 , 28 Furthermore, there is evidence that calorie and fluid restriction is unnecessary as no beneficial effect was proved with these two factors. 24 , 29

Due to the severe carbohydrate restriction, the LCT KD is unpalatable, difficult to prepare, and, therefore, difficult to maintain. 30 In 1971, the MCT (C6-C12) KD was devised. 30 The dietary use of MCT oil is more acceptable and is more ketogenic than LCTs. 30 , 31 , 32 , 33 The MCT KD has better flexibility in diet ratios than the LCT KD, and the calorie intake is calculated based on the percentage of energy derived from MCT. 24 , 31 In addition, there is clinical evidence of the equivalent efficacy of the MCT and LCT KD. 12 , 32 However, the MCT KD is frequently associated with gastrointestinal side effects. 24 , 31

The MAD is based on the Atkins diet, which was popularly used in weight loss 34 , 35 , 36 and shares similar food choices with the classic KD, but without the need for precise weighing of ingredients. The MAD does not have a strict ketogenic ratio, which typically ranges from 1:1 to 1.5:1 and, sometimes, can reach 4:1. 35 Moreover, the MAD does not include protein, fluid, or calorie restrictions. Carbohydrate intake in the MAD is restricted to 10–15 g/day in the first month and can be subsequently increased to 20 g/day. 37 , 38 There is clinical evidence supporting the efficacy of the MAD in children with intractable epilepsy. 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44

The low glycemic index treatment is based on the concept that the protective effect of the KD relies on stable glucose levels, 45 but has a liberalized regimen with low-carbohydrate composition to minimize glycemic increases (glycemic indices <50), 45 and is an effective antiepileptic intervention in children with intractable epilepsy. 44 , 45 , 46 , 47 , 48 , 49

Despite the abovementioned evidence that suggests the similar efficacy of the four types of KD, it is unclear whether the mechanisms of action of these diets differ.

The impact of the ketogenic diet on metabolism

Lipid metabolism.

The metabolism of blood lipids during KD is often a concern. In the presence of oxygen, most cellular energy originates, through glycolysis, from glucose-metabolized pyruvate, which then undergoes oxidative phosphorylation within mitochondria. In the absence of glucose, cellular energy is produced by the degradation of fatty acids. 50 A low-carbohydrate, high-protein, and high-fat diet can be unhealthy as it may lead to an increase in the circulating low-density lipoprotein (LDL), cholesterol, and triglyceride (TG) concentrations. As for liver fat metabolism, from the perspective of diet metabolism, a low total and saturated fat/high-carbohydrate diet can effectively manage liver fat storage by limiting exogenous fats. 51 However, the KD has potential health benefits with regard to these cardiovascular risk factors, and recent animal and clinical studies provided ample evidence that cutting carbs can actually lower total cholesterol, increase high-density lipoprotein (HDL), and reduce blood TG levels. 52 , 53 With the premise of ensuring constant total calorie intake, the KD reduces carbohydrate intake, lowers serum insulin levels, increases insulin sensitivity, and enhances fat catabolism, thus reducing blood lipids. 14 Due to increased de novo lipogenesis and decreased fatty acid oxidation and/or ketone production, higher carbohydrate intake may be detrimental to the net loss of liver fat. In contrast, low-carbohydrate/high-fat KD significantly increases the rate of whole-body fatty acid oxidation and liver ketogenesis. 54 , 55 Therefore, KD has been shown to reduce liver fat. 56 , 57 Moreover, the KD induces the expression of fibroblast growth factor-1 and promotes the hepatic clearance of TGs. 58 In addition, the KD can increase the size and volume of LDL-C particles, 59 which is believed to reduce the risk of cardiovascular disease, as smaller LDL particles have higher atherogenic activity. Furthermore, the KD affects endogenous cholesterol synthesis. β-Hydroxy β-methylglutaryl-CoA reductase, a key enzyme in cholesterol biosynthesis, is activated by insulin. Therefore, increased blood glucose concentrations and higher insulin levels lead to increased endogenous cholesterol synthesis. Thus, reducing dietary carbohydrates and proper cholesterol intake will lead to the inhibition of cholesterol biosynthesis.

Glucose metabolism

There are two sources of glucose in humans: glycogenic amino acids and glycerol that are released by TG lysis. 60 , 61 The importance of the latter source increases during ketosis. In the first few days of the KD, glycogenesis from amino acids is the main source of glucose. Subsequently, the contribution of amino acids is reduced, whereas the amount of glucose obtained from glycerol increases. In fact, TG-hydrolysis-induced glycerol can generate more than 16% glucose in the liver during the KD, compared to 60% glucose after several days of complete fasting. 62 The effect of the KD on blood sugar levels remains controversial. After fasting for several days or restricting carbohydrate intake, the glucose reserves in the body are insufficient to produce oxaloacetate in the Krebs cycle for normal fat oxidation and supply of glucose to the central nervous system. 63 Thus, most studies believe that the KD leads to decreased blood sugar concentration and a lower insulin-to-glucagon ratio, which is beneficial for glycemic control in individuals with diabetes. 20 , 64 Elevated glucagon levels are associated with hepatic glucose mobilization. A recent study analyzed the effects of KDs in exercising and sedentary rats. 65 After 6 weeks, KD decreased insulin levels by 80%, blood sugar by 50%, TGs by 55%, and cholesterol by 20%, compared to the standard feed, whereas exercising did not bring benefits. Furthermore, a 5-year prospective study that included a total of 27,799 men and 36,875 women in Japan showed that LCDs are significantly associated with a reduced risk of type 2 diabetes in women, whereas high-fat and high-protein diets are protective factors against diabetes in Japanese women. 66 However, Delahanty et al. arrived at the opposite conclusion. Independent of exercise and body mass index, patients with type 1 diabetes who consume high fat and LCDs have higher glycosylated hemoglobin and poorer blood sugar control. 67 Some animal experiments have shown that glucose tolerance decreases in mice that are fed KD for 22 weeks. 68 The KD did not prevent the decline in β-cell function, nor did it improve insulin secretion. Therefore, individual differences and treatment conditions should be considered in the clinical application of the KD.

Ketogenic process

In the liver, excessive production of acetyl coenzyme A (acetyl-CoA) and oxidation of fatty acids leads to the production of Ketone Bodies (KBs). 69 The acetyl-CoA molecule can be utilized in the Krebs cycle or to produce acetoacetate, which is then spontaneously converted to acetone or 3-β-hydroxybutyrate by 3-β-hydroxybutyrate dehydrogenase. 70 , 71 The KBs then enter the bloodstream and can be utilized by the brain, heart, and muscle, where they produce cellular energy in mitochondria. 7 , 72 , 73 Higher circulating KB levels lead to ketonemia and ketonuria. 74 Under physiological conditions, the blood concentration of KBs during prolonged fasting usually is 5–7 mM, while the glucose concentration could be lowered to below 1 mM without either convulsions or any impairment of cognitive function. 75 In diabetic ketoacidosis, the plasma KB levels can increase up to 25 mM due to insulin deficiency, with a consequent increase in the plasma glucose concentration and decreased blood pH. 74 The KBs constitute a more efficient energy source than glucose, metabolize faster than glucose, and can bypass the glycolytic pathway by directly entering the Krebs cycle, whereas glucose needs to undergo glycolysis. 76 Moreover, KBs cause fatty acid-mediated activation of peroxisome proliferator-activated receptor α as well as the inhibition of glycolysis and fatty acids. 77 Therefore, KBs reduce the production of glycolytic adenosine triphosphate (ATP) and increase mitochondrial oxidation-induced ATP generation, 71 thereby promoting mitochondrial oxidative metabolism, with resultant beneficial downstream metabolic changes.

Ketogenic diet and gut microbiota

The effects of the KD on the gut microbiome have been reported in many murine and human studies (Table 1 ). Mice that were fed a 4-day KD showed significant changes in gut bacterial composition, which was characterized by an increase in Akkermansia and Parabacteriodes populations that induced an anti-seizure effect in germ-free or antibiotic-treated mice. 78 The increased gut populations of these two bacterial genera decrease the γ-glutamyl transpeptidase level, which catalyzes the transfer of functional groups of γ-glutamyl from glutathione to an amino acid acceptor that may produce glutamate. 79 In addition, ketogenic γ-glutatamylated amino acids decreased in the gut and in the blood, which supports the key anti-seizure effects of KD-associated microbiota. 78 In the human gut, the post-KD production of KB by the host can partially drive gut microbial shifts, which reduces the number of intestinal Th17 cells. 19 Similarly, using a murine model, Kong et al. demonstrated that an increase in Akkermansia muciniphila, Lactobacillus , and Roseburia following a KD plays a potential anti-colitis effect. 20 The potential protective effects on intestinal barrier function may be related to the production of RORγt + CD3 - group 3 innate lymphoid cells and related inflammatory cytokines (IL-17α, IL-18, IL-22, CCL-4). 20 Another study of a 16-week KD revealed beneficial effects of the ketogenic-induced microbiota, including improved neurovascular functions in mice and reduced risk of Alzheimer’s disease. 80 These beneficial effects may be related to changes in the gut microbiota composition, including an increase in the beneficial bacteria Akkermansia muciniphila and Lactobacillus , which produce short-chain fatty acids. Interestingly, Ma et al. also found a decrease in the numbers of pro-inflammatory microbes, such as Desulfovibrio and Turicibacter . Furthermore, the KD improves the gut microbiome in a murine model of autism, 81 and Newell et al. observed an overall reduction in the microbial richness of the cecum and feces and an increased ratio of Firmicutes and Bacteroides after the administration of the KD. As carbohydrates are the basic blocks that the microbes break down to produce energy, the lower carbohydrate content in the KD results in a decline in overall microbial diversity. 82 Furthermore, in treatment-refractory epilepsy, the KD significantly reduced the abundance of pathogenic proteobacteria ( Escherichia , Salmonella , and Vibrio ), whereas Bacteroidetes populations increased. 83 Notably, Bacteroidetes are closely involved in the digestion and metabolism of high-fat nutrients, regulation of interleukin secretion in dendritic cells, and are associated with seizure effects in epileptic patients. 84 Another study found differences in the gut microbiota between responders (reduced seizure frequency or seizure cessation) and non-responders (no effect on seizure) among children who received a KD and noted that an increase in Bacteroides and a decrease in Firmicutes and Actinomycetes populations in the responders. 85 On the other hand, populations of Clostridia , Ruminococcus , and Lachnospiraceae ( Firmicutes phylum) increased in non-responders. These data suggest that the KD-induced gut microbiota changes should be considered as a potential biomarker for the efficacy of antiepileptic therapy. Moreover, an updated study showed that KD potentiates cognitive impairment induced by intermittent hypoxia in mice and increases the risk-associated Bilophila wadsworthia. 86 Inhibiting Th1 cell development abrogates the adverse effects of both B. wadsworthia and environmental risk factors on cognitive impairment. 86 Taken together, these findings identify the potential select gut bacteria that contribute to KD effects on target site in mice and humans.

In the potential physiological application of the ketogenic diet, some studies have found that KD could extend longevity and reduce midlife mortality in the mouse model. 87 , 88 In fact, the mechanism of how KD works in our body from the intestine to the target site is still controversial. Based on the gut microbiota, the ketone body itself can selectively inhibit the growth of bifidobacteria , thereby reducing the level of intestinal pro-inflammatory Th17 cells. 19 The ketone bodies are also involved in multiple metabolic pathways, and protective effects of ketone bodies may lead to improvement in health status and delay both aging and the development of related diseases through improving mitochondrial function, antioxidant and anti-inflammatory effects, histone and non-histone acetylation, β-hydroxybutyrylation of histones, modulation of neurotransmitter systems and RNA functions. 89 Thus, the accumulation of ketone bodies can at least partly explain the influence of the gut microbiota by KD, 20 which thereby inhibiting colitis, improving several diseases such as epilepsy. The summary of changes in metabolism and gut microbiota induced by the ketogenic diet is shown in Fig. 2 .

Summary of KD-induced changes in metabolism and gut microbiota. a , b The KD increases the levels of FA and KBs and decreases plasma glucose concentrations through different pathways. c The KD alters the composition and diversity of microbiota as follows: the increased abundance of Akkermansia muciniphila , Parabacteriodes , Lactobacillus , Ruminococcaceae , Bacteroidetes , and Roseburia , and reduced populations of Bifidobacteria , Desulfovibrio , Turicibacter , Escherichia , Salmonella , and Vibrio

Function in endocrine and metabolic disorders

Type 2 diabetes mellitus.

T2DM is characterized by chronic hyperglycemia with fasting plasma glucose concentrations ≥126 mg/dL and glycated hemoglobin (HbA1c) ≥6.5%. 90 As dietary carbohydrates are the major macronutrients that increase glycemic levels, 91 it is logical to reduce the dietary carbohydrate intake to treat T2DM. Researchers have found that carbohydrate restriction has the greatest effect on reducing postprandial and overall glucose concentrations and the HbA1c. 92 , 93 , 94 , 95 , 96 For example, in a study comparing the effect of a very-low-carbohydrate ketogenic diet (VLCKD) and a low-calorie diet on blood glucose levels in diabetic patients, the decrease in blood glucose concentrations was greater in the VLCKD group than in the low-calorie diet group for 24 weeks. More importantly, the blood glucose level of the VLCKD group was ~1 mM lower than that of the low-calorie diet group and reverted to a normal level after 24 weeks. However, the blood glucose level of the low-calorie group leveled out at 16 weeks and remained elevated thereafter. At 24 weeks, the HbA1c level in the VLCKD group decreased to 6.2%, compared to >7.5% in the low-calorie diet group. 96 Similarly, a meta-analysis revealed that VLCKD resulted in a significant decrease in HbA1c and weight loss after 3 months and after 6 months, however, it was not better after 12 months compared to a control diet. 97 VLCKD showed more beneficial effects on serum triglycerides and high-density lipoprotein cholesterol levels and reducing antidiabetic medications for up to 12 months. 97

Hyperglycemia is the most frequent characteristic of T2DM; however, the pathophysiology of T2DM involves insulin resistance and hyperinsulinemia. Therefore, reducing insulin levels should be a therapeutic target in the treatment of T2DM. The homeostatic model assessment of insulin resistance is an indicator for evaluating insulin resistance. The consumption of the KD decreased the homeostatic model assessment of insulin resistance in patients with T2DM from −0.4 to −3.4. 98 , 99 , 100 , 101 A systematic meta-analysis that included 13 studies showed that the KD not only guarantees the basic supply of nutrients but also maintains a negative balance of energy, thereby decreasing the fluctuation and reduction of insulin secretion caused by reduced carbohydrate intake as well, which eventually leads to increased insulin sensitivity. 102 Thus, KD improves glycemic control in T2DM patients by reducing glucose uptake and improving systemic insulin sensitivity (Fig. 3 ).

Possible mechanisms whereby the ketogenic diet ameliorates metabolic disorders. The mechanisms, through which the ketogenic diet ameliorates endocrine and metabolic disorders, including T2DM, obesity, NAFLD, and PCOS, are shown. Ketogenic diets exert therapeutic effects on metabolic disorders through various mechanisms, including reduction of plasma glucose, glycated hemoglobin levels, and serum insulin levels; improvement of insulin sensitivity; increased satiety; and decreased inflammation

The molecular mechanism underlying the KD-induced improvement of T2DM clinical outcomes has been investigated in both the system biology approach and mouse model studies. Using a cell network-analysis approach, researchers identified a strong correlation between insulin resistance and the main pathways of ketosis. Glucose transporter type 4, an effector protein of the insulin-resistance pathway, directly correlates with proteins, such as Hydroxyacy1-CoA dehydrogenase 1 and Acyl-coenzyme A oxidase 1, that are involved in the KD-induced pathways. 103 In ob/ob mice studies, several molecules are involved in the improvement of hyperglycemia and hyperinsulinemia during the KD. The expression of certain O-GlcNAc-modified proteins is altered when the KD improves hyperglycemia. 104 Fatty acid synthase and acetyl-CoA carboxylase 1, which are two key enzymes that are involved in hepatic lipogenesis, are present in regular diet fed-ob/ob mice but absent in the KD-fed mice. 105 KD administration decreased liver mRNA expression of Glucose transporter type 2 while increased that of Fibroblast growth factor 21 in diabetic mice. 106 Glucose transporter type 2 plays an important role in glucose induced-insulin secretion in pancreatic β cells 107 thus decreased Glucose transporter type 2 expression suggests a decreased insulin level and improved insulin resistance in T2DM. Fibroblast growth factor 21 is an important target gene of peroxisome proliferator-activated receptor α, which promotes lipid catabolism and improves insulin resistance. 108 Moreover, the β-HB could inhibit nuclear factor κB (NF-κB) signaling, 109 an upregulated inflammatory pathway associated with the pathogenesis of T2DM. 110

Caution should be exercised when prescribing the KD to T2DM patients on other drug treatments, such as sodium glucose cotransporter 2 (SGLT2) inhibitors and insulin. SGLT2 inhibitors, which confer cardiovascular benefits in T2DM patients, can also exert pro-ketogenic effects by mediating a metabolic switch from glucose to lipid utilization. Thus, T2DM patients who are already receiving SGLT2 inhibitors will have a significantly higher risk of developing euglycemic diabetic ketoacidosis if placed on the KD; therefore, the KD should not be prescribed to T2DM patients receiving SGLT2 inhibitors. 111 Carbohydrate restriction may increase the risk of hypoglycemia in patients receiving insulin and insulin secretagogues; thus, it is recommended that the drug dosage should be modified based on the goal of glycemic control and the type of antidiabetes therapy when prescribing the KD to T2DM patients. 112

With the increasing prevalence of obesity, the 21st century has witnessed the emergence of various diet programs, with the KD at the forefront, for promoting weight loss and enhancing physical performance. Many studies have demonstrated that the KD is a potentially promising diet for reducing obesity while maintaining the capacity for physical activity. A study conducted in 2016 showed that short-term KD followed by an almost carbohydrate-free diet effectively reduced body weight, waist circumference, blood pressure, and insulin resistance in clinically healthy morbidly obese adults with body mass index (BMI) ≥ 45 kg/m. 2 , 113 In a long-term study, the KD significantly decreased BMI, blood cholesterol, and plasma glucose, and increased weight loss, thereby reducing the risk factors for various obesity-associated chronic diseases, in obese hypercholesterolemic patients with BMI > 35 kg/m 2 without any side effects. 114 In a controlled study enrolling 20 participants who received the VLCKD, a significant improvement in biochemical parameters was observed after 8 weeks of KD adherence, which included a reduction in BMI, LDL-C, TGs, insulinemia, and liver transaminases.

In addition, KD has a more beneficial effect on obesity than other diets. In a meta-analysis of 11 studies, significant weight reductions were reported in the LCD group when compared to the low-fat diet group. Interestingly, the authors attributed this effect to a lower energy intake rather than the macronutrient composition. 115 In individuals assigned to a VLCKD, the body weight (weighted mean difference [WMD]−0.91 kg, 1,415 patients), TG (WMD 0.18 mmol/l, 1,258 patients), and diastolic blood pressure (WMD-1.43 mmHg, 1,298 patients) decreased, whereas HDL-C (WMD 0.09 mmol/l, 1,257 patients) and LDL-C (WMD 0.12 mmol/l, 1,255 patients) increased, and resulted in a greater weight loss than in those assigned to a low-fat diet in the long term; thus, a VLCKD may be an alternative option in obesity. 116 Similarly, a meta-analysis of randomized controlled trials (RCTs) demonstrated that, compared to low-fat diets, KD more effectively improved the metabolic parameters associated with glycemic, weight, and lipid control in obese participants, especially those with preexisting diabetes. 117

Plasma lipids constitute the main exigent concern with the KD in the treatment of obesity. The general opinion is that a low-carbohydrate, high-protein, and high-fat diet is potentially unhealthy because it may increase LDL-C and TGs, which is an especially important issue in obese individuals. However, several lines of evidence support the positive effects of the KD on these cardiovascular risk factors. The majority of studies amply demonstrate that reduced carbohydrate uptake can decrease total cholesterol and TG levels and increase the HDL-C level. 116 , 118 Furthermore, KD increase the size and volume of LDL-C particles 59 which could alleviate the risk of cardiovascular disease that is attributable to the higher atherogenicity of smaller LDL particles. In addition, KD influence endogenous cholesterol synthesis, whereby an increase in blood glucose and insulin levels increases endogenous cholesterol synthesis. In turn, reduced carbohydrate uptake accompanied by proper cholesterol intake inhibits cholesterol biosynthesis.

The KD is obviously effective in the weight control of obese individuals; however, the underlying mechanism is incompletely understood. Researchers have proposed several mechanisms for the KD effect on weight loss including: (1) reduced appetite due to the higher satiety effect of proteins (by increasing the concentrations of “satiety” hormones, such as glucagon-like peptide-1, cholecystokinin, and ghrelin), 119 , 120 effect on appetite-control hormones, 121 and a possible direct suppression of appetite by KBs, such as β-HB, which act both in energy/satiety signaling and in mediating the central satiety signal; 122 , 123 (2) reduced lipogenesis due to improved insulin resistance 124 and increased lipolysis due to increased expression of lipolytic enzymes, such as adipose triglyceride lipase, hormone-sensitive lipase, and lipoprotein lipase; 125 (3) higher metabolic efficiency in consuming fats that is indicated by the reduction in the resting respiratory quotient; 126 , 127 and (4) increased energy consumption due to increased gluconeogenesis, which is an energy-intensive process that costs ~400–600 Kcal/day and the thermic effect of protein, which has the highest energy cost among all the three macronutrients (Fig. 3 ). 128 , 129

Besides fat and weight loss, the KD can exert a series of other beneficial effects on obesity. Insulin resistance is common in obese patients. Very-low-carbohydrate diets could improve glycemic control, HbA1c levels, and lipid markers in obese individuals before obvious weight loss occur, which indicates that the KD could improve metabolic markers independent of weight loss. Moreover, in isocaloric experiments, the KD showed a dramatic improvement of metabolic markers than a low-fat diet in obese participants with insulin resistance. 130 The KD may protect against obesity-induced cognitive damage 131 and confer positive effects on mood in obese participants. 132 , 133 Another postulated beneficial effect of KD is related to longevity. Although restricted to animal studies, the KD is related to several pathways in metabolic syndrome and cancer, including increased 5′ adenosine monophosphate-activated protein kinase (AMPK) activity, inhibition of the mTOR/AKT pathway, 134 lowering the serum ratio of insulin-like growth factor/IGF-binding protein 3 135 and increasing peroxisome proliferator-activated receptor-γ coactivator-1α expression (a master mitochondrial metabolic regulator that can increase mitochondrial biogenesis). 136

Nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent disease that is characterized by hepatic adiposity, which comprises fatty liver, fibrosis, and inflammation. The earliest stage of NAFLD is hepatic steatosis, wherein TG accumulate in >5% of hepatocytes or the intrahepatic TG concentrations exceed 55 mg/g liver (5.5%). 137 , 138 Weight loss is recommended for the general clinical management of NAFLD.

The LCDs, especially those with high-fat content, are reported to have a worsening effect on hepatic steatosis due to the influence on cholesterol levels and hepatic function. However, the beneficial effects of KD on NAFLD have been widely reported. A meta-analysis of ten studies examining the effects of LCDs on NAFLD revealed that participants with NAFLD who followed LCDs exhibited a significant reduction in intrahepatic lipid content; however, there was no significant alteration in the concentration of liver enzymes. 139 Moreover, the KD exerts a more beneficial effect on NAFLD parameters than interventions such as calorie-restricted and low-fat diets. A small clinical trial revealed a greater reduction in intrahepatic TGs in patients with NAFLD after a 2-week carbohydrate-restricted diet without calorie restriction than in patients who received a calorie-restricted diet, without any significant weight-loss differences in the two treatment groups. 140 Consistently, a 2-year multicenter trial that included more than 300 patients who enrolled in a comprehensive lifestyle modification regimen demonstrated similar weight-loss patterns with low-fat diets and LCDs, although the LCD group displayed superior HDL-C profiles. 141

The KD might protect against NAFLD through several mechanisms 142 (Fig. 3 ). On one hand, due to its low-carbohydrate content, the KD could decrease insulin levels, with a consequent increase in fat oxidation and reduced lipogenesis, 143 and induce a microbiome shift, with increased folate production and limited inflammatory and oxidative stress. 54 On the other hand, the KD-induced KBs may result in (1) satiety, which limits food intake and facilitates weight loss; 144 and (2) epigenetic modifications, which play an important role in NAFLD pathogenesis. For example, β-HB increases the histone acetylation of genes that encode resistance factors against oxidative stress; 145 (3) activates GPR109A, which is widely expressed in various types of immune cells and exerts anti-inflammatory effects in many diseases, including obesity, inflammatory bowel disease, and cancer; 109 , 146 (4) inhibits NLRP3, 147 a key inflammasome that activates pro-inflammatory cytokines, such as IL-1β and IL-18, which closely correlate with obesity and T2DM pathogenesis. 148

Polycystic ovarian syndrome

The polycystic ovarian syndrome (PCOS) is closely related to other metabolic and endocrinological abnormalities, including insulin resistance, hyperinsulinemia, T2DM, dyslipidemia, and hyperandrogenism, and is characterized by insulin resistance, androgen excess, and abnormal gonadotropin dynamics. Therefore, the treatment goal is to improve insulin resistance and weight loss and decrease luteinizing hormone (LH)/follicle-stimulating hormone (FSH) ratios and excess androgen levels (Fig. 3 ).

The KD has been postulated to have a positive impact on women with PCOS. A study implemented a 6-month period of the KD for women diagnosed with PCOS, with BMI greater than 27 kg/m 2 , and no other serious medical conditions. After 24 weeks, women with PCOS showed a significant decrease in fasting serum insulin (pre, post-design: 23.5 to post-design: 8.2), in the LH/FSH ratio (2.23 to 1.21), and the free testosterone level (2.19 to 1.70). Furthermore, participants had an overall mean weight loss of 12.1% and a mean 4.0 kg/m 2 decrease in BMI. 149 A crossover study compared the effects of a standard diet and an LCD on PCOS and showed that the LCD decreased glycemia, fasting serum insulin, and testosterone, and increased insulin sensitivity. 150 Paoli et al. reported similar results, with significant reductions in BMI, glycemia, insulin, LDL-C, HDL-C, TGs, LH, testosterone, and dehydroepiandrosterone sulfate. The initial reversal of the LH/FSH ratio did not persist after 12 weeks. 151 Although these studies demonstrated a beneficial effect of the KD on PCOS, they have limitations such as small sample size, broad age range, single-arm design, and a short intervention time interval.

The exact mechanism by which the KD achieves therapeutic benefits in PCOS remains unclear. The exact mechanism by which KD achieves therapeutic benefit on PCOS remains unclear. A variety of studies identify a central role of insulin resistance in the pathogenesis of PCOS. Fasting insulin shows a positive correlation with androgen levels in women with PCOS. 152 Insulin stimulates increased production of androgens in theca cells isolated from women with PCOS, which effect is mediated by the insulin receptor. 153 Furthermore, excess insulin inhibits liver sex hormone-binding globulin synthesis, which increased the delivery of free androgens to target tissue. It has also been reported that AMPK, a regulator of cellular metabolism and energy balance, plays an essential role in the improvements of KD toward PCOS. 154

Function in neurodegenerative diseases

Alzheimer’s disease.

Alzheimer’s disease (AD) affects ~50 million people worldwide and is characterized by cognitive impairment that is associated with a progressive decline in memory, impaired self-care, disorientation, and personality changes. 14 AD induces changes in amyloid precursor protein cleavage and production of the amyloid precursor protein fragment beta-amyloid (Aβ) along with hyperphosphorylated tau protein aggregation. 155 Patients with AD have mitochondrial dysfunction and metabolic changes, such as impaired glucose utilization in the brain. 156 During the past decades, changes in dietary patterns and lifestyle modifications have had potential application in the treatment of AD and have received extensive attention in AD research, including calorie restriction, dietary approaches to stop hypertension, Mediterranean diet, and the KD. 157

The KD is a biochemical model of fasting or starvation, which promotes the utilization of KBs as the dominant fuel source to replace glucose in the central nervous system. 158 This may modulate the neuropathological and biochemical changes observed in AD, and the KD can directly reduce the accumulation of amyloid plaques while reversing Aβ toxicity; furthermore, KBs may protect against Aβ neurotoxicity. 159 Kashiwaya et al. treated cultured rat hippocampal cells with Aβ, β-HB, or both Aβ plus β-HB. Treatment with Aβ alone resulted in reduced neurite numbers and length compared to controls, and the additional treatment with β-HB reversed Aβ toxicity, suggesting that β-HB could potentially play a neuroprotective role against Aβ toxicity. 160

In addition, the development of AD is associated with hypometabolism, mitochondrial dysfunction, oxidative stress, and inflammation (Fig. 4 ). 161 , 162 , 163 , 164 Impaired glucose uptake and utilization in regional brain energy-substrate hypometabolism may be one of the earliest hallmarks of AD and suggests a potential avenue for compensating the brain energy deficit in AD dementia with ketones. 165 Both β-HB and acetoacetate bypass glycolysis to reduce acetyl-CoA, which can then be channeled into the Krebs cycle, and can thus increase energy availability in the brain. 166 In AD, brain ketone uptake is unimpaired, which makes KBs a viable alternative energy source.

Mechanisms of the KD on neuromuscular and neurodegenerative diseases, including AD, PD, ALS, and epilepsy. Ketogenic diets altered the neuropathological and biochemical behavior through a variety of mechanisms including increasing mitochondrial function and ATP producing, decreasing oxidation stress and inflammation in the brain, and improving motor function and motor neuron survival

Mitochondrial dysfunction and oxidative stress play significant roles in neurodegenerative diseases, and both generate high levels of reactive oxygen species (ROS), which are harmful to all cellular macromolecules. 167 Importantly, the KD could improve mitochondrial numbers and function by inhibiting glycolysis and increasing KB formation to provide neuroprotective benefits in the neuronal cell line (SH-SY5Y). 168 In addition, KBs may regulate the homeostatic status of mitochondria by modulating calcium-induced membrane permeability transition. 169 Moreover, the KD elevates brain ATP and induces a higher phosphocreatine/creatine ratio and glutamate levels, but decreases glycogen levels. 170 Lu et al. reported that the KD increased superoxide dismutase activity and attenuated oxidative stress by activating Nrf2. 171

Furthermore, the KD reduces inflammation through established effects. The β-HB receptor HCA2 could activate a neuroprotective phenotype of macrophages depending on PGD2 production by COX1 and hematopoietic PGD2 synthase. 172 Pretreatment with the KD is associated with a reduction of pro-inflammatory cytokines, such as IL-1β and tumor necrosis factor alpha (TNF-α), which are induced by lipopolysaccharide injection, thereby suggesting that KD has anti-inflammatory properties. 173 Another mechanism of KD is the inhibition of histone deacetylases (HDACs) by the β-HB. 163 HDACs are a kind of protease that alters chromatin structure, and accessibility. HDACs are inhibited by β-HB, which improves memory function and synaptic plasticity. 170 , 174 Moreover, the KD inhibits the activation of NF-κB in activated B cells and downregulates COX2. 77 Thus, the KD could regulate dysregulated brain metabolism, mitochondrial homeostasis, and inflammation in AD.

In a transgenic mouse model of AD, the KD reduced the level of soluble Aβ deposits in the brain by 25% after only 40 days. 175 In addition, treatment with the KD, exogenous β-HB, and MCT reduced brain Aβ levels and improved cognitive ability. 176 When a mouse model of AD was fed a KD for 43 days, serum levels of the KB β-HB increased, total Aβ levels decreased, mitochondrial function improved, and oxidative stress decreased compared to controls. 177 Aged dogs receiving MCT showed dramatically improved mitochondrial function and decreased oxidative damage compared to age-matched controls. 178 In aged rats, the KD improved cognitive performance due to increased angiogenesis and capillary density, supporting the theory that diet-induced ketosis is beneficial in the treatment of neurodegenerative conditions. 179

Clinical data show that significant increases in β-HB levels and improved memory were observed in 20 participants with AD or mild cognitive impairment when they were administered MCT. 180 A randomized, double-blind, placebo-controlled, multicenter trial compared the effects of MCT on memory and cognition and demonstrated that elevated serum β-HB levels improved cognitive function and memory. Phillips et al. conducted a randomized crossover trial of a modified ketogenic diet in the treatment of Alzheimer’s disease. The results showed that patients achieved sustained physiological ketosis (12-week mean beta-hydroxybutyrate level: 0.95 ± 0.34 mmol/L). Compared with the usual diet, patients on the ketogenic diet increased their mean within-individual ADCS-ADL ( P  = 0.0067) and QOL-AD ( P  = 0.023) scores. 181 Another study compared an LCD with a high-carbohydrate diet in 23 adult patients treated with MCTs for 6 weeks. The LCD showed better memory performance and was positively correlated with levels of KBs. 182 Krikorian et al. reported maximum cognitive benefit of KD treatment in ApoE4(−) patients after 24-week treatment with MCT or a ketogenic product compared to placebo. 183 This observational study was limited to ApoE4(−) patients with mild AD. In a recent study, MCT was administered to 20 Japanese patients with mild to moderate AD over 12 weeks, and 120 min after MCT intake, the level of KBs increased; after 8 weeks, the patients demonstrated significant improvement in their immediate and delayed memory tests compared to their baseline scores. Additional research is warranted to determine the therapeutic benefits of MCT in patients with AD and to ascertain how APOE-4 status may mediate β-HB efficacy.

Parkinson’s disease

Parkinson’s disease (PD) is the commonest serious movement disorder worldwide and affects ~1% of adults who are older than 60 years. 184 PD is characterized by the loss of nigrostriatal dopaminergic neurons and a deficit in mitochondrial respiration. α-Synuclein is an overexpression protein in PD while its relationship with PD is unknown. The knockout of α-Synuclein only increased the number of dopamine neurons which suggested that the loss of synucleins does not produce parkinsonism. 185 In recent years, animal and in vitro studies have demonstrated the beneficial effect of KBs on the course of PD due to their function in mitochondrial homeostasis.

Joniec-Maciejak et al. observed that the administration of octanoic acid induced the inhibition of the neurodegenerative processes seen after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration and was related to increased metabolic activity in striatal mitochondria. 186 One of the important factors that cause PD is DNA oxidative damage mediated by reactive oxygen species. It has been discussed that the injury of the respiratory chain and the mutations of mitochondrial DNA found in patients with PD suggest the importance of oxidative stress in PD. 187 The accumulation of hydroxyl radicals in the brain may lead to increased dopamine metabolism and, at the same time, to the accumulation of iron in the redox form of neurons. 188 KBs produced by liver metabolism not only promote mitochondrial respiration by increasing ATP production, but also reduce free radical production by increasing the efficiency of the mitochondrial respiratory chain complex (increasing NADH oxidation and inhibiting mitochondrial permeability conversion). An increase in anti-peroxidase in the hippocampus protects the central nervous system from degenerative changes. 13 , 189 Other studies showed that the KD exerted anti-inflammatory effects by decreasing the levels of pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α, in the substantial nigra. 190 Cheng et al. found that β-HB could inhibit the apoptosis of dopaminergic cells that were exposed to MPTP in relation to the upregulation of Bcl-2/Bax mRNA. 191 A summary of the KD-induced changes in PD is shown in Fig. 4 .

In a rat model of PD, the KD, via glutathione activity, protected dopaminergic neurons of the substantia nigra against 6-hydroxydopamine neurotoxicity. 192 In mice, β-HB infusion confers partial protection against MPTP-induced dopaminergic neurodegeneration and motor deficits. 193 These effects appear to be mediated by a Complex II-dependent mechanism that improves mitochondrial respiration and ATP production. Shaafi et al. observed a beneficial influence of the KD on motor function in a rat model of PD and confirmed that, when coadministered, the KD potentiated the efficacy of pramipexole. 194

In a clinical study, five patients with PD who consented to adhere to KD rules in their home environments were observed for 28 days and exhibited some improvements in the Unified Parkinson’s Disease Rating Scale. 195 In another pilot RCT, the effect of a low-fat diet versus the KD in 47 PD patients was assessed; 44 participants commenced the diets, and 38 completed the study (86% completion rate). The KD group maintained physiological ketosis. Both groups showed significantly decreased MDS-Unified Parkinson’s Disease Rating Scale scores, but the KD group showed a greater decrease in Part 1 (−4.58 ± 2.17 points; 41% improvement in baseline Part 1 scores) compared to the low-fat group (−0.99 ± 3.63 points; 11% improvement) ( P  < 0.001); the largest intergroup differences in decreases were observed for urinary problems, pain and other sensations, fatigue, daytime sleepiness, and cognitive impairment. The results of the study indicated that it is plausible and safe for PD patients to maintain a low-fat diet or KD for 8 weeks. Both diet groups showed significant improvements in motor and nonmotor symptoms; however, the ketogenic group showed greater improvements in nonmotor symptoms. 196

Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by the death of motor neurons in the spinal cord and brainstem, resulting in death within 2–5 years of symptom onset and respiratory paralysis. The accepted hypothesis of ALS pathogenesis includes loss of oxidative control with an excessive generation of oxidative free radicals, accumulation of neurofilaments, and excitotoxicity linked to an increase in the neurotransmitter glutamate, with resultant mitochondrial membrane dysfunction. 197 Furthermore, at least 20 genes are associated with ALS. Most familial and sporadic cases of ALS are caused by variants of the superoxide dismutase 1 (SOD1), C9orf72, FUS, and TARDBP genes. 198 To date, there are no effective treatments for ALS. The only US FDA-approved pharmacological therapy is riluzole, which could prolong survival by ~2 months in ALS patients. 199

Mitochondrial dysfunction may play an important role in the pathogenesis of ALS, which makes it a potential novel therapeutic target of intervention for ALS. Kong showed that KD can increase antioxidant power and attenuate oxidative stress in spinal cord injury by suppressing class I histone deacetylases. 200 Mutations in the gene encoding Cu/Zn SOD1 lead to abnormal mitochondrial activity, which is associated with a portion of ALS. 201 In energy alterations secondary to the mitochondrial dysfunction in ALS, the KD increased energy production and regulated mitochondrial activity by restoring the activity of complex I of the electron chain whose function is reduced in ALS (Fig. 4 ). 202

Moreover, the KD improved motor functions, which were associated with increased motor neurons in a mouse model of ALS. In the SOD1-G93A transgenic ALS mouse model, the KD led to higher motor neuron survival and an improvement in motor function compared to KO mice without the KD; furthermore, weight and synthesis of ATP at the mitochondrial level increased. 202 Mice that were fed the KD exhibited better motor performance on all motor function tests at 15 and 16 weeks of age compared to controls and, after the implementation of the Deanna protocol based on the KD, significantly extended the survival time of SOD1-G93A mice; 63% of mice in this group lived beyond 125 days, whereas only 9% of the control animals survived beyond this timepoint. 203 In another study, SOD1-G93A mice were treated with caprylic triglyceride, a medium-chain TG that is metabolized into KBs and can serve as an alternative energy substrate for neuronal metabolism. Treatment with caprylic triglyceride attenuated the progression of weakness, protected spinal cord motor neuron loss, and promoted the mitochondrial oxygen consumption rate in vivo. 204 These studies indicate that KD treatment may have a high impact on the quality of life of ALS patients.

Epilepsy is a chronic brain disorder characterized by recurrent seizures, which are short episodes of involuntary movement that can affect a part or all of the body, and are sometimes accompanied by loss of consciousness or loss of control of bladder or bowel function. The causes of epilepsy include brain tumors, stroke, brain infection, severe head injury, congenital abnormalities associated with brain defects, brain damage due to prenatal or perinatal injuries, and certain genetic syndromes. 205 Although 50–70 million people worldwide suffer from epilepsy, the available pharmacological treatment for epilepsy has limited effectiveness. 206

The KD was first recognized as an effective treatment for epilepsy. Studies have re-emerged that demonstrating the efficacy of KD in patients with drug-resistant epilepsy and some pediatric epilepsy syndromes. 207 The anticonvulsant mechanisms of the KD are incompletely understood, and the potential mechanisms of the KD are based essentially on the role of neurotransmitters, brain energy metabolism, ion channels, and oxidative stress (Fig. 4 ). 7 One study confirmed that norepinephrine and the orexigenic neuropeptide galanin are the two classes of molecules that contribute to the anticonvulsant effect of the KD. 208 However, in children with refractory epilepsy, the KD does not alter the level of norepinephrine but significantly alters the levels of dopamine and serotonin metabolites in the cerebrospinal fluid. 209 And a significant increase in γ-aminobutyric acid (GABA) and agmatine levels, without changes in glutamate levels, was observed in the hippocampus of rats subjected to a KD for 15 days compared to rats on a normal rat chow diet; this supports the notion that the KD modifies different transmitters while favoring inhibitory over excitatory neurotransmitters. 210 Recently, Zarnowski et al. find that the KD plays an important role in the neuroprotection and anti-convulsion via the kynurenine pathway. Kynurenic acid, the metabolite from the kynurenine pathway, participates in epilepsy. KBs, rich in KD, can inhibit glutamate which reduces the production of kynurenic acid. 211 While ATP is produced by mitochondrial respiration, the damaged substance ROS is produced at the same time. The uncoupling proteins, upregulated by mitochondrial respiration, can reduce the production of ROS and increase the resistance towards seizure. Moreover, the KD can also protect the mitochondrial DNA from ROS by improving the glutathione levels. In final, the KD can generate beneficial substances to reduce the happening of epilepsy. 212 , 213 Under KD conditions, the reduction of brain glucose utilization and glycolytic ATP production may induce potassium channels that are sensitive to ATP opening, which leads to the hyperpolarization of the neuronal membrane, 214 consequently reducing the electrical excitability of the brain and increasing the seizure threshold. Moreover, KD treatment increases polyunsaturated fatty acids and induces the expression of neuronal uncoupling proteins, regulates numerous energy metabolism genes, and induces mitochondrial biogenesis, which further limits ROS generation and increases energy production. 215

A meta-analysis reviewed 12 studies using classic KD, MAD, and classic KD in combination with MCT in adults with antiepileptic drug-resistant epilepsy. They found a combined efficacy rate of 52% for classic KD and 34% for MAD. The results indicate that a classical ketogenic diet may be more effective, and adult patients are likely to be less compliant with the KD than with an MAD. 216 In an observational study, at 3 months, 36% of 101 participants responded (≥50% seizure reduction) to diet therapy, and 16% were seizure-free. At 1 year, 30% responded, and 13% were seizure-free. At 4 years, 21% responded, and 7% were seizure-free. This study provided evidence that ketogenic diets may be feasible, effective, and safe in the long-term in adults, although long-term adherence was limited. Thus, adequately controlled studies are necessary to determine the efficacy of ketogenic diets in the treatment of adults with epilepsy. 217 An RCT in Iran compared the proportion of patients with focal or generalized epilepsy achieving ≥50% seizure reduction between 34 patients randomized to 2 months of MAD (22 completed the study), compared to 32 patients randomized to standard medical management, and found 35.5% (12/34) efficacy in the MAD group (intention-to-treat (ITT) analysis) at 2 months compared to 0% in the control group, a difference that was statistically significant. 218 In contrast, an RCT in Norway compared the change in seizure frequency in patients with drug-resistant focal or multifocal epilepsy between 37 patients randomized to 12 weeks of MAD (of whom 28 received the intervention and 24 completed the study) and 38 adults randomized to their habitual diet (of whom 34 received the intervention and 32 completed the study). 219 Overall, ITT data from adult observational studies demonstrate responder rates of 22–70% for classic KD and 12–67% for MAD, with some suggestion of increased efficacy in adults with generalized rather than focal epilepsy. 220 , 221 Additional RCTs with larger sample sizes are warranted to investigate the efficacy of the MAD in different subpopulations of adult patients with epilepsy. Thus, the KD offers a necessary adjunctive strategy for management with the advantages of potentially synergizing concurrent treatments and reducing the need for prolonged use of anesthetic drugs.

Depression is a common kind of mood disorder that involves reduced inhibitory GABA neurotransmission. KD may do a favor to depression via its nutrition and microbiome that attracts more attention from doctors and researchers. The main source of GABA is the glutamate–glutamine cycle which happens to be adequate in KD. Moreover, KD is full of other nutrition such as ω-3s, tryptophan, vitamin B, which may regulate the disorders in both physiology and psychology. 222 The gut–brain axis suggests that the microbiome plays an important role in mental health and an existing study proves that the KD may affect mental health through the gut–brain axis by the gut microbiome. Nagpal et al. find that the KD alters the gut microbiome signature and short-chain fatty acid in association with cerebrospinal fluid AD biomarkers. 223

KD has been reported to exhibit preventative effects on depressive-like behaviors in rodents while its exact mechanism is still unknown. As we noticed before, the adult offspring of pregnant mice fed by KD exhibited less prone to depression behaviors. 224 Recently, Sun et al. find that a ketogenic diet can ameliorate social defeat and lipopolysaccharide-induced depressive-like behaviors by the restoration of microglial inflammatory activation and neuronal excitability. 225 Also, Campbell’s report revealed that a ketogenic diet may lead to mood stabilization. 226 According to the randomized controlled trial, DM. et al. find that the KD group showed lower levels of anxious and mood-disturbed behaviors. 227

Anxiety disorders

Anxiety disorder is an increasingly common mental disorder worldwide, resulting in considerable mental stress for patients, and social medicine and economic burden. According to epidemiological statistical analysis, about one-third of the global population is affected by anxiety disorders during their lifetime. 228 Current treatments including drugs, psychological interventions, and so on still fail to meet the need for a cure. Recently, nutritional therapies such as ketogenic diets are considered promising due to their effectiveness in preventing relapse.

Disorders in the metabolism of neurotransmitters are considered to be a major factor in anxiety disorders. A deficiency of the central inhibitory neurotransmitter GABA has been linked to anxiety, depression and other affective disorders. Due to the decrease of blood glucose level during the implementation of the ketogenic diet, the glycolysis pathway in the brain is significantly inhibited, and the energy supplier of the central nervous system changes from glucose to ketone bodies. Excitation of the steroid pathway enhances the synthesis and transmission of GABA at the synapse, while decreasing the content of aspartic acid and the excitability of neurons. 229 , 230 It is suggested in several studies that the progeny of mice exposed to KD during pregnancy show lower susceptibility to anxiety and depression and significantly improve social and physical activity levels compared to the standard diet group.

On the other hand, bi-directional interactions between the central nervous system and the intestinal microbiome are associated with the development of psychiatric disorders. With the disorder of intestinal microflora, the barrier function of the intestinal epithelium is gradually reduced or even lost with the increased permeability, which then mediates the enhancement of immune response and causes chronic neuritis. Neurotransmitter metabolism, particularly serotonin metabolism, which is closely associated with the onset of anxiety and depression, would be disrupted. 231 Mechanistically, ketones produced by liver metabolism act as both energy supply molecules and signal molecules involved in binding G protein-coupled receptors, inhibiting HDACs, regulating the abundance of intestinal microbiota, improving intestinal barrier function, and reducing the production of ROS and free radicals. 232 , 233 Experiments on mice have demonstrated the positive effects of KD on the intestinal microbiome. 234 Overall, KD has an ideal potential to be further used to the mood disorder and the mechanism behind remains to be explored.

Function in cancer

Cancer is one of the greatest global public health challenges and is a leading cause of global mortality. Complementary approaches to significantly enhance the efficacy of standard anticancer therapies are scarce. The KD appears to sensitize most cancers to standard treatment by exploiting the reprogramming metabolism of cancer cells, making it a promising candidate in adjuvant cancer therapy. 17

Tumor cells use glucose as the primary energy source. To meet the requirements of rapid proliferation, tumor cells utilize glycolysis, even in the presence of oxygen: a phenomenon known as the “Warburg effect”. 235 Thus, any pharmacologic intervention that reduces intratumoral glucose levels may be effective for slowing tumor growth. During KD implementation, tumor cells have limited access to glucose and cannot use KBs as an energy source owing to aberrant mitochondrial function and reduced enzymatic activity for ketone consumption, which makes the KD a promising approach for cancer prevention. Due to a reduction in blood glucose levels, the KD could concurrently affect glucose metabolism and glucose-dependent signaling in tumor cells. 236 Furthermore, glucose starvation leads to a suppressed lactate/pyruvate cycle, which inhibits neovascularization, hypoxia-induced vascular epidermal growth factor activation, and angiogenesis, and causes ultimate necrosis in tumor cells, especially for colon adenocarcinoma xenografts. 237 KBs can inhibit inflammation, which is closely correlated with tumor pathogenesis. By inhibiting the NLRP3 inflammasome, β-HB diminishes the inflammatory microenvironment, which provides ancillary therapeutic benefits for therapeutic interventions in glioblastoma. 238 Interestingly, GPR109A, a receptor for β-HB, is downregulated in cancer. GPR109A, a tumor suppressor, was downregulated when β-HB synthesis was suppressed. Therefore, low levels of β-HB attenuate the tumor-suppressive function of GPR109A in colon cancer cells. 239 Recent studies have extended the tumor-suppressive function of the receptor beyond the colon, as GPR109A suppressed mammary tumorigenesis in a mouse model of breast cancer. 240

Furthermore, the KD could enhance the efficacy of phosphatidylinositol 3 kinase (PI3K) inhibitors and overcome drug resistance, which was confirmed in different mouse cancer models, including pancreatic, bladder, endometrial, and breast cancer, as well as in acute myeloid leukemia. The KD improves the efficacy of anti-PI3K treatment and drug resistance by decreasing hyperglycemia and reducing the insulin-secretory response, and these effects correlated with reduced intratumoral mTORC1 signaling. 241 In a mouse model of melanoma, acceleration of proliferation in BRAF V600E-mutated melanoma cells after the KD treatment was observed because of the selectively increased activation of BRAF V600E-mutant-dependent MEK1 signaling by the KB acetoacetate. In contrast, NRAS Q61K- and Q61R-mutated and BRAF wild-type melanoma cells were unaffected by the KD. 242

Besides slowing tumor growth, KD sensitizes tumor cells to classic chemotherapy or radiotherapy in neuroblastoma, glioma, and lung cancer. 243 , 244 , 245 , 246 For example, the KD supplemented with medium-chain TG enhanced the antitumor and anti-angiogenic efficacy of chemotherapy on neuroblastoma xenografts in a CD1-nu mouse model. 247 In addition, KD showed promising benefits in boosting the effect of anti-PD-1/PD-L1 immunotherapy. Ferrere et al. found that anti-PD-1, alone or in combination with anti-CTLA-4, failed to inhibit tumor growth in mice receiving a standard diet, whereas KD implementation, or oral administration of 3-hydroxybutyrate (3-HB), a principal KB generated in the KD, reestablished therapeutic responses. 248 3-HB prevented the upregulation of PD-L1 on myeloid cells whereas promoting the expansion of CXCR3 + T cells and instituting consequent T cell-mediated tumor immunosurveillance. Similarly, Dai et al. reported that KD treatment decreased PD-L1 protein levels and increased the expression of type-I interferon (IFN) and antigen-presentation genes, leading to the enhanced efficacy of anti-CTLA-4 immunotherapy. 249 The key molecular event of KD treatment in promoting immunotherapy is the activation of AMPK, which phosphorylates PD-L1, resulting in its disrupted interaction with CMTM4 and subsequent PD-L1 degradation, which phosphorylates EZH2, resulting in improper PRC2 function and subsequently enhanced expression of IFN and antigen-presentation gene. 249

Many studies investigating the effect of the KD on tumor metastasis indicate a metastasis-inhibiting effect of the KD. 250 , 251 , 252 An early study reported that KBs could inhibit the growth rate of malignant lymphoblasts (Raji cells) and diet-induced ketosis could reduce the number of B16 melanoma deposits in mouse lung. 251 Combined treatment with the KD and hyperbaric oxygen significantly reduced the tumor-growth rate and diminished metastatic spread, while increasing survival, in the VM-M3 mouse model of metastatic cancer, possibly through induction of ROS production in tumor cells. 250

Apart from preclinical studies, clinical trials have demonstrated the beneficial effects of the KD on antitumor therapy. A clinical trial showed that positron emission tomography revealed an average decrease of 21.8% in glucose uptake at the tumor site in children after 8 weeks of KD implementation. One child displayed significant mood improvement, promotion of skill-learning ability, and remained free of disease progression after continuing the KD for 12 months. All participants remained in remission for 4–5 years after diagnosis, with good quality of life. A prospective feasibility trial applying the MAD to patients with glioblastoma who were not receiving chemotherapy reported that four patients were stable or improved after 16 weeks of dietary intervention. 253 A randomized controlled clinical trial showed that TNF-α decreased significantly after 12 weeks of treatment ( P  < 0.001), while IL-10 increased ( P  < 0.001) in the intervention compared to the control group. Patients in the KD group had lower adjusted serum insulin compared to the control group ( P  < 0.002). KD lead to a reduction in tumor size in the KD compared to the control (27 vs 6 mm, P  = 0.01). Stage decreased significantly in patients with locally advanced disease in the KD group after 12 weeks ( P  < 0.01). 254 A study that investigated the effect of KD in combination with intranasal perillyl alcohol in patients with recurrent glioblastoma found that after 3 months of combined therapy, the KD increased the partial response rate to 77.8%, compared with 25% in the control group. The percentage of tumor progression was 11.1% in the KD group, compared to 50% in the control group. 255 A study among ovarian and endometrial cancer patients reported that the KD improved overall physical health and increased energy in patients without chemotherapy. 256 Therefore, the administration of KD may be a potential approach to enhance the therapeutic efficacy of chemotherapy. In addition, the boundary between a high-fat diet and KD still needs to be further clarified. Recently, Jun Yu’s team found that high-fat diet can drive colorectal tumors by inducing gut microbiota dysbiosis, metabolic changes, and intestinal epithelial barrier dysfunction in mice, and revealed potentially key bacteria and metabolites. Moreover, compared with a high-oleic acid diet, a high-fat diet rich in linoleic acid can specifically promote breast tumor growth. 257

Taken together, the KD has shown benefits in tumor-growth inhibition and enhanced efficacy of multiple antitumor therapies in various types of cancer, including glioblastoma, prostate, colon, pancreatic, and lung cancer (Fig. 5 ). These mechanisms can be attributed to a limited glucose source and reduced inflammation. However, the efficacy of KD could be influenced by cancer type, subtype, genetic features, or tumor-associated syndrome. Future studies should focus on more molecular studies as well as RCTs with heterogeneous study designs and large samples in order to elucidate the mechanisms of the KD in tumor therapy and to evaluate the application of the KD in the clinical setting.

Summary of the potential interplay in the molecular mechanisms of the ketogenic diet (KD) and cancer. The KD exerts a therapeutic effect on tumors such as neuroblastoma, acute myeloid leukemia, glioblastoma, etc., through decreased GPR109A expression, mTORC1 activation, and glucose uptake at the tumor site, which leads to decreased tumor growth, increased survival, and increased chemotherapeutic efficacy

Function in cardiac diseases

Heart failure (HF) is characterized by metabolic abnormalities. Therefore, augmenting cardiac ATP production in a bioenergetically efficient manner is of significant interest to the HF field.

Growing evidence has demonstrated increased ketone body utilization in the failing heart. For example, expression of β-hydroxybutyrate dehydrogenase 1 (a key enzyme in the ketone oxidation pathway) and ketogenic β-hydroxybutyryl-CoA, in association with increased myocardial utilization of β-hydroxybutyrate, is increased in the heart failure samples supported the notion that the hypertrophied and failing heart shifts to ketone bodies as an alternate fuel and myocardial ketone oxidation as a key metabolic adaptation in the failing human heart. 258 , 259 In mice and canine pacing model of progressive heart failure, increased delivery of 3-HB ameliorates pathologic cardiac remodeling and dysfunction. Mice rendered incapable of oxidizing the ketone body 3-HB in the heart exhibits worsened heart failure compared with WT controls. These results indicate that the heart utilizes 3-HB as a metabolic stress defense and suggest that strategies aimed at increasing ketone delivery to the heart could prove useful in the treatment of heart failure. 260 Preclinical and clinical studies also suggest that exogenous delivery of ketones may improve cardiovascular function as well as prevent the development of pathological remodeling en-route to HF. 261 The potential mechanism of ketosis is associated with SGLT2 inhibitors and reductions in HF morbidity and cardiovascular mortality were observed in patients with HF (irrespective of diabetes status) further confirmed the potential benefits of ketones in patients with HF. 262

Zhang et al. have constructed mice with cardiomyocyte-restricted deletion of subunit 1 of MPC (cMPC1 −/− ). The mice develop age-dependent pathologic cardiac hypertrophy, transitioning to a dilated cardiomyopathy and premature death. The KD could increase the availability of non-glucose substrates in vivo and reverse the structural, metabolic, and functional remodeling of non-stressed cMPC1 −/− hearts. Although concurrent short-term KD did not rescue cMPC1 −/− hearts from rapid decompensation and early mortality after pressure overload, 3 weeks of the KD before transverse aortic constriction is sufficient to rescue this phenotype. 263

Although the beneficial effects of β-HB on HF have been acknowledged by numerous reports, its safety on other cardiovascular problems has been challenged by certain lines of evidence. In rat models, KD decreased mitochondrial biogenesis, reduced cell respiration, and increased cardiomyocyte apoptosis and cardiac fibrosis. Mechanistically, the KD increases levels of β-HB, promotes histone acetylation of the Sirt7 promoter, and activates Sirt7 transcription. This in turn inhibits the transcription of mitochondrial ribosome-encoding genes and mitochondrial biogenesis, leading to cardiomyocyte apoptosis and cardiac fibrosis. 264 This study highlighted the unknown detrimental effects of the KD.

In atrial fibrillation which is the most common arrhythmia encountered in clinical practice, the concentration of β-HB in heart tissues is significantly higher. 265 The potential detrimental effects of β-HB have also been confirmed in clinical studies. A retrospective study assessed the relationship between serum β-HB and prognosis in 405 stable hemodialysis patients. Increased serum β-HB levels are independently associated with cardiovascular events and all-cause death. In addition, increased circulating β-HB is independently associated with major adverse cardiovascular events. 266 Twenty patients on the ketogenic diet at one institution were investigated in another research. Prolonged QT interval was found in three patients (15%). There was a significant correlation between prolonged QT interval and both low serum bicarbonate and high beta-hydroxybutyrate. In addition, three patients had evidence of cardiac chamber enlargement. One patient with severe dilated cardiomyopathy and prolonged QT interval normalized when the diet was discontinued. 267 Taken together, these findings suggest that KD consumption or β-HB accumulation may increase the risks of cardiovascular disease, suggesting that long-term consumption of a KD should be carefully considered in cardiovascular disease.

By digesting animal protein and other components of animal products—red meat—symbiotic bacteria in the gut produce metabolites that have been linked to insulin resistance and cancer formation. One such molecule, trimethylamine N-oxide (TMAO), has recently gained a lot of attention as a possible and a closely linked risk factor for gut microbiota and cardiovascular and kidney disease. Trimethylamine is produced by gastrointestinal bacteria after they metabolize dietary choline and carnitine. Trimethylamine is then absorbed and oxidized to TMAO under the action of flavin-monooxygenases (FMOs), mainly FMO3. 268 KD changes the pattern of energy metabolism and makes more use of fat and ketone bodies through a very-low-carbohydrate and high-fat diet. The researchers compared the ketogenic diet in mice with the obesity-inducing high-fat diet and found that the ketogenic diet, while apparently healthier, significantly reduced glucose tolerance. The liver of the mice became less responsive to insulin and became insulin resistant. 269 In people with hepatic insulin resistance, low hepatic insulin activity increases FMO3 expression, further enhancing TMAO levels. Hepatic insulin resistance, often associated with hepatic steatosis, may lead to increased cardiovascular risk and an increased risk of type 2 diabete, and these increased risks are also associated with elevated TMAO (Fig. 6 ).

Improvements and mechanisms of the functions of the KD exert on cardiac diseases. The KD increases levels of β-HB, promotes histone acetylation of the Sirt7 promoter and activates Sirt7 transcription in cardiac fibrosis and increases the availability of non-glucose substrates in cMPC1 −/− hearts

Function in other inflammation diseases

Inflammatory bowel disease.

A recent study found that the KD can alleviate colitis in a dextran sulfate sodium mouse model compared with a low-carbohydrate diet and normal diet. 20 A 16-week KD intervention before colitis induction in mice was found to increase the abundance of Akkermansia and Roseburia and simultaneously alter the gut metabolites. Upon DSS treatment, the KD-fed mice had decreased weight loss and disease activity index scores with reduced inflammatory cell infiltration in the intestinal epithelium. The KD was found to exert an anti-inflammation effect via reducing the production of RORγt + CD3 − group 3 innate lymphoid cells as well as the related inflammatory cytokines including IL-17α, IL-18, IL-22, and CCL-4. The KD-fed mice remained to have overabundant Akkermansia in feces. Importantly, transplantation of the feces of KD-fed mice to germ-free mice retained the above effects, highlighting the KD-modulated gut microbiota have a profound role in alleviating colitis.

Irritable bowel syndrome

A study also showed that KD contributes to beneficial effects in a rat model of irritable bowel syndrome via reducing the stress on gut mitochondrial biogenesis. 270 Feeding with KD was found to be able to reduce intestinal inflammation, improve cellular redox status and restore mitochondrial function in the model. Such effects might be exerted due to the upregulation of the PPAR-γ/PGC-1α axis (Table 2 ).

The covid-19 pandemic is now a global threat. Especially, severe covid-19 with cytokine storm syndrome is desperately lethal and a main cause of mortality. The KD has been proposed as an adjunct therapy for covid-19 patients due to its contribution to the reduction of critical risk factors such as obesity, type 2 diabetes and hypertension, anti-inflammation, and metabolism modulation. 21 , 271 It is proposed that switching lipid metabolism, which can be achieved by a ketogenic diet rich in MCTs or by intermittent fasting, may disfavor viral replication and infection and inhibit cytokine storm. 272 Importantly, it is also believed that the induction of ketosis may help to prevent the cytokine storm. 273 , 274 A recent retrospective analysis of 34 covid-19 patients receiving an eucaloric KD in comparison to 68 who received a eucaloric standard diet showed that the former might have a lower risk in motility and ICU admission. 275 Thus, the KD could be a theoretical preventive and supportive care option for patients with covid-19. But clinical evidence are needed.

Adverse effects and challenges

Short-term adverse effects, such as fatigue, irritability, headache, nausea, dehydration, hypoglycemia, diarrhea, metabolic acidosis, and refusal to eat, are commonly seen during the first few weeks of the KD as responses to diet-induced metabolic shift and are usually predictable and preventable. 276 , 277 Long-term adverse effects of KD include elevated cardiovascular risks with poor cholesterol profiles and nephrolithiasis, likely due to the metabolic effects of the KD, such as uric acidemia, hypocitraturia, hypercalciuria, aciduria, growth retardation, decreased bone mineral density, anemia, and neuropathy, 276 , 277 and are usually monitored during follow-up. Furthermore, there are adverse effects that can span the duration of KD therapy, which frequently include gastrointestinal disturbances, including constipation, abdominal pain, emesis, and gastroesophageal reflux disease. 277 Due to the lack of sufficient clinical evidence of the long-term safety of the KD, the use of KD in chronic diseases remains debatable. 276

Moreover, due to the lack of sufficient clinical evidence demonstrating the efficacy and safety of KD, there still are debates on using KD in several diseases, 276 including diabetes, cardiovascular disease, and Alzheimer’s disease. As type 1 diabetes is often associated with metabolic irregularities, hyperketonemia and ketosis may increase the risk of complications. 278 Risks of KD in certain diseases are also demonstrated in animal models. In spontaneously hypertensive rats, the KD increases hypertension, 279 , 280 impairs endothelium-dependent relaxation in mesenteric arteries, 280 causes renal damage 279 and aggravates interstitial fibrosis and inflammatory responses in the heart. 281 In the rat, The KD exacerbated disorders of glucose and lipid metabolisms and activated the renin-angiotensin-aldosterone system, 279 and the ketone body might reduce eNOS expression via NF-κB singling pathway in vein endothelial cells, 280 which could collectively contribute to hypertension and endothelial dysfunction. Meanwhile, KD reduced renal autophagy to cause damage and the β-hydroxybutyrate was found to promote TGF-β-induced fibrosis in cardiac fibroblasts. 281 The KD can be detrimental to cognitive behavior. In an Alzheimer’s disease rat model, KD worsened cognitive performance likely because it exacerbated gut dysbiosis. 282 Consistently, a very recent study showed that the KD and hypoxia-altered gut microbiota increased intestinal IFN-γ-producing Th1 cells and consequently impaired cognitive behavior in mice. 86 Also, in an animal model of early Parkinson’s disease, long-term KD seemed to be insufficient for the neuroprotective effect. 283

Furthermore, the KD is a multidisciplinary therapy that requires the involvement of experienced caregivers, such as doctors, nurses, and dietitians, in addition to the patients. 284 Thus, successful implementation of the KD requires well-organized and consistently functioning cooperation between caregivers and patients, and clinical settings that support this cooperation. Moreover, as a patient-centered therapy, treatment adherence remains a major challenge of the KD. 277 , 284 Ineffectiveness, adverse effects, diet restrictiveness, and unpalatable taste may decrease the patient’s motivation and lead to the discontinuation and consequent failure of the treatment.

Future directions

Dietary interventions for the treatment and prevention of diseases are now widely acknowledged and have increasingly gained importance. Diet planning may not only serve as a medical approach for the treatment of diseases but can also provide a way to maintain health in the general population. The KD, as a potential therapeutic approach for various diseases, still faces challenges with regard to broad clinical application. Future studies are needed to provide high-quality clinical evidence on the efficacy and safety of the KD in diseases other than epilepsy; to further modify the diet to decrease the adverse effects and increase tolerability; and to comprehensively understand the mechanisms that may, in turn, guide disease- or patient-customized application and even a KD-derived drug design.

The KD exhibits broad therapeutic potential in many diseases other than epilepsy; however, the clinical implementation of the KD is not well established yet. High-quality RCTs must be conducted to confirm the safety and efficacy of the KD. In addition, based on clinical research, it is important to identify the syndromes and conditions that can benefit from the KD-based therapies, contraindications for use, KD variants with good effectiveness and tolerability, and factors and biomarkers that can predict KD-related outcomes, which may collectively guide the clinical utilization of the KD in different diseases.

Despite the adverse effects described, the KD usually does not have long-term tolerability, which not just introduces barriers to compliance by caregivers and patients but also compromises the clinical efficacy of the therapy. Although several KD variants are available to increase adherence, additional modifications are still needed and should be specifically designed for distinct diseases to increase both efficacy and tolerability, while facilitating dynamic adjustment to minimize the short- and long-term adverse effects.

The mechanisms of action of the KD, especially at the cellular and molecular levels, in different types of diseases, are poorly understood. As a metabolic therapy, the KD may function via a combination of multiple and complex mechanisms involving metabolic, cellular, and molecular responses. Recent studies have shown that the gut microbiota plays an important role in these processes. Given that the composition of the gut microbiota varies in specific diseases, the possibility of disease-specific mechanisms of KD that are mediated through a functional axis that originates with gut microbes is worth exploring regarding the beneficial effects and side effects of the KD. Therefore, further in-depth investigations into the intrinsic therapeutic mechanisms of the KD in different diseases are needed, as it will not only provide insights into disease pathogenesis from new perspectives, but also lead to the identification of key intermediate biochemical pathways, molecules, and/or other factors, such as gut microbes, that govern the KD treatment-related effects, and these can be utilized as promising targets for drug design or the development of novel customized interventional strategies to mirror the effects of KD.

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These authors contributed equally: Huiyuan Zhu, Dexi Bi, Youhua Zhang, Cheng Kong

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Department of Pathology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China

Huiyuan Zhu, Dexi Bi, Youhua Zhang & Qing Wei

Research Institute of Intestinal Diseases, Tongji University School of Medicine, Shanghai, China

Cheng Kong, Jiahao Du, Xiawei Wu & Huanlong Qin

Department of Gastrointestinal Surgery, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China

Cheng Kong & Huanlong Qin

Shanghai Clinical College, Anhui Medical University, Hefei, China

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Zhu, H., Bi, D., Zhang, Y. et al. Ketogenic diet for human diseases: the underlying mechanisms and potential for clinical implementations. Sig Transduct Target Ther 7 , 11 (2022). https://doi.org/10.1038/s41392-021-00831-w

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The ketogenic diet: Pros and cons

Affiliations.

• 1 Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, AB, Canada; Department of Medicine, University of Alberta, Edmonton, AB, Canada; Division of Cardiology, University of Alberta, Edmonton, AB, Canada.
• 2 Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, AB, Canada; Department of Medicine, University of Alberta, Edmonton, AB, Canada; Division of Cardiology, University of Alberta, Edmonton, AB, Canada. Electronic address: [email protected].
• PMID: 31805451
• DOI: 10.1016/j.atherosclerosis.2019.11.021

Diets have been at the center of animated debates for decades and many claims have been made in one direction or the other by supporters of opposite camps, often with limited evidence. At times emphasis has been put on a single new aspect that the previous diets had overlooked and the new one was to embrace in order to improve weight loss and well-being. Unfortunately, very few randomized clinical trials involving diets have addressed the combined question of weight loss and cardiovascular outcomes. The recently introduced ketogenic diet requires a rigorous limitation of carbohydrates while allowing a liberal ingestion of fats (including saturated fats) and has generated a flurry of interest with many taking the pro position and as many taking the cons position. The ketogenic diet causes a rapid and sensible weight loss along with favourable biomarker changes, such as a reduction in serum hemoglobin A1c in patients with diabetes mellitus type 2. However, it also causes a substantial rise in low density lipoprotein cholesterol levels and many physicians are therefore hesitant to endorse it. In view of the popular uptake of the keto diet even among subjects not in need of weight loss, there is some preoccupation with the potential long-term consequences of a wide embrace of this diet by large segments of the population. On the contrary, numerous lines of evidence show that plant-based diets are associated with reduction in oncological and cardiovascular diseases and a prolonged life span. The debate reproduced in this article took place during a continuous medical education program between two cardiologists with largely differing views on the matter of effectiveness, sustainability, and safety of the ketogenic diet compared to alternative options.

Copyright © 2019 Elsevier B.V. All rights reserved.

Publication types

• Diet, Ketogenic* / adverse effects
• Diet, Reducing* / adverse effects

Key takeaways

• Potential risks
• Common mistakes
• Intermittent fasting
• Getting started

A keto diet for beginners

Evidence based

• What is keto?
• Foods to eat
• Foods to avoid
• Keto macros
• Printable leaflet

On a keto diet, you cut way back on carbohydrates, also known as carbs, in order to burn fat for fuel.

In this beginner’s guide, you’ll learn all you need to know about ketogenic diets, including how to get started to achieve the best results safely and effectively.

Learn more about keto and…

1. What is a keto diet?

• Video course
• Science>
• For doctors>

In this guide, you’ll learn how to eat a keto diet. Our visual guides, recipes, meal plans, and simple two-week Get Started program are everything you need to succeed on keto.

The keto video course

You can quickly learn more about the keto diet in this video course.

Precautions before starting a keto diet

There are controversies and myths about a keto diet, but for most people, it appears to be very safe. However, two groups often require medical supervision:

• Do you take medication for high blood pressure? More >
• Do you take medication for diabetes , such as insulin? More >

Some people should avoid keto altogether:

• Do you breastfeed? More >

For more details about the pros and cons in different situations, check out our full guide: Is a keto diet right for you?

Disclaimer: While the ketogenic diet has many proven benefits, it’s still controversial. The main potential danger regards medications, e.g. for diabetes, where doses may need to be adapted (see above). Discuss any changes in medication and relevant lifestyle changes with your doctor. Full disclaimer >

This guide is written for adults with health issues, including obesity, that could benefit from a ketogenic diet.

Related content

2. What to eat on a keto diet?

Visual guides.

Here are typical foods to enjoy on a ketogenic diet. The numbers are net carbs per 100 grams (3.5 ounces) of food.

The fewer carbs you eat, the more effective the diet appears to be for reaching ketosis, losing weight, or improving type 2 diabetes.

Counting carbs can be helpful at first. But if you stick to our recommended foods and recipes you can stay keto even without counting.

• Red meat, such as beef, pork and lamb: 0 grams
• Poultry, such as chicken and turkey: 0 grams
• Fish of all types, including salmon, tuna, sole, trout, and halibut: 0 grams
• Natural fats, such as butter and olive oil: 0 grams
• Cheese: 1 gram
• Eggs: 1 gram
• Above-ground vegetables, including leafy greens, broccoli, cauliflower, tomatoes, and eggplant: 1 to 5 grams

Planning keto

With the right strategy, creating keto meals is easy.

One way is to start by picking a protein source, such as meat, fish, seafood, eggs, or tofu. Then, to complete your meal, choose two low carb vegetables and add a healthy source of fat.

What to drink

A splash of milk or cream in your coffee or tea is OK, but beware that the carbs can add up if you drink multiple cups in a day (and definitely avoid caffe lattes!). The occasional glass of wine is fine, too — but steer clear of sweet alcoholic drinks.

Carb counts per glass or cup of beverage

• Water: 0 grams
• Coffee and tea: 0 grams
• Dry red or white wine: 2 grams per 5 ounces/150 ml

Check out our full guides to keto drinks and keto alcohol .

Try to avoid

Foods to stay away from include:

• Bread, tortillas, muffins, bagels, pancakes
• Pasta and rice
• Cakes, cookies, and other baked goods
• Sugar and anything made with sugar
• Most fruits and fruit juice 7

Also, avoid or limit highly processed foods and instead fill your diet with our recommended keto-friendly food options.

Keto macros: Carbs, protein, & fat

When following a keto diet, the idea is to eat very few carbs, a moderate amount of protein, and just as much fat as you need to feel satisfied, rather than stuffed.

Carbohydrates Limit carbs to 20 or fewer grams of net carbs per day, or 5 to 10% of calories. Although it’s possible that you may not need to be this strict, eating fewer than 20 grams of net carbs every day virtually guarantees that you’ll be in nutritional ketosis. Learn more >

Protein Eat enough protein to meet your needs. Most people need at least 70 grams per day, or 20 to 35% of calories from protein. Learn more >

Keto diet recipes

Weight loss without hunger

Science shows keto and low carb diets are often effective for losing weight. 9

In fact, more than 35 high-quality scientific studies show that, when compared to other diets, low carb and keto diets lead to greater weight loss.

Why do keto diets work so well for losing weight? As discussed earlier, being in ketosis lowers insulin levels, which can help you access your body fat stores more easily. 10

Another reason may be that keto diets help people naturally eat less, as a result of feeling more satisfied. 11 Read more It’s possible that following a low carb diet might help you burn more calories — although this hasn’t been widely studied. 12

Also, very low carb diets may potentially have a weight loss edge over diets with more modest carb reduction. 13

More than 300 people have shared their stories of losing weight — and achieving other health improvements — by following a keto lifestyle.

Check out our full guides to learn more about keto and weight loss:

• How to lose weight
• Why low carb can help you lose weight
• How to lose weight with a low carb diet
• Top 10 weight-loss tips for women 40+

Control or reverse type 2 diabetes 14

Keto and low carb diets can provide powerful blood sugar control for people with type 2 diabetes. 15 Why? Because carbohydrates raise blood sugar much more than either protein or fat. 16 To lower blood sugar — and potentially reverse type 2 diabetes — eat fewer carbs. It can be that simple.

Improve metabolic health & blood pressure

Ketogenic diets may play a strong role in improving several markers of metabolic health, including blood pressure, blood sugar, HDL cholesterol, and triglyceride levels. 19 20

Learn more about insulin resistance in our guides:

• What you need to know about insulin resistance
• How to treat insulin resistance

Control type 1 diabetes

People with type 1 diabetes need to take insulin injections no matter what type of diet they eat. However, low carb diets often improve blood sugar control and reduce the risk of hypoglycemia (dangerously low-blood sugar). 22

Improve fatty liver disease

In non-alcoholic fatty liver disease (NAFLD), too much fat is stored in the liver. Recent research suggests a keto or low carb diet may help reduce or even reverse NAFLD. Read more What causes NAFLD? Excess fat can build up in the liver for a number of reasons, including eating more calories than needed. 23

Other potential benefits

Although there’s less high-quality research about the benefits of a keto diet for other conditions, emerging evidence suggests that it might be helpful for some people — and for many, it’s certainly worth trying.

• Polycystic ovary syndrome (PCOS)
• Irritable bowel syndrome (IBS)
• Mental health
• Physical endurance

4. Potential risks of a keto diet

However, these side effects are rare and we suspect they may vary with the variety of foods eaten.

However, individuals with diabetes or insulin resistance often respond to low carb eating with improved lipid markers overall, as discussed earlier.

If your LDL increases after starting a keto or low carb diet, please read our guides on LDL hyper-responders , the potential dangers of LDL cholesterol , and how to lower LDL cholesterol.

5. How to get into ketosis

Ketosis is a metabolic state in which your body uses fat and ketones rather than glucose (sugar) as its main fuel source.

How can you get into ketosis quickly and stay there? Here are three things to know:

• Eat less than 20 grams of net carbs per day. Cutting way back on carbs can help you get into ketosis rapidly, often within a few days.
• Avoid eating too often. If you’re not hungry, don’t eat. Intermittent fasting or even just eliminating snacks can help you get into ketosis faster.
• Measure ketones. Testing for ketones in your blood, breath, or urine can confirm that you are indeed in ketosis. Each of these methods comes with pros and cons. For a detailed comparison, see our full guide to the best way to test ketones.

6. Common mistakes

Going overboard with fat

Eating too many nuts and dairy products

Fear of too much protein

Chasing higher ketone levels

7. Intermittent fasting & keto

Some people on a keto diet choose to also practice intermittent fasting to speed up weight loss or when trying to reverse type 2 diabetes.

Intermittent fasting involves cycling between periods of fasting and eating. When eating a keto diet, many people feel hungry less often. And since we advise eating only when you are hungry, this means that you might naturally begin to eat fewer meals a day — or you may deliberately plan fewer meals to match your reduced appetite. For some people, this could mean eating two meals a day (often skipping breakfast). For others, this could mean eating once a day, which is often referred to as OMAD, meaning “one meal a day.”

8. The keto flu & side effects

Once you’ve been on a keto diet for a few weeks or more, you will likely feel great and have lots of energy. However, the first few days to weeks can be tough, as your body switches from burning mostly glucose to burning mostly fat for fuel.

When your body makes this shift, you may experience what’s commonly known as the “keto flu.” It happens as a result of changes to your body’s balance of fluid and minerals when you begin eating very few carbs.

Symptoms of keto flu include:

• Irritability
• Lack of motivation
• Difficulty focusing (“brain fog”)
• Muscle cramps
• Less energy for intense exercise

Fortunately, you can minimize these symptoms before they start by replenishing fluids and salt. Good strategies include drinking a cup or two of salty broth or being liberal with the salt shaker.

Also, remember that these symptoms are temporary. As your body adapts to its new way of getting energy — from fat instead of sugar — symptoms should quickly subside.

Learn more in our complete guide: The keto flu, other side effects, and how to cure them .

9. Keto FAQ

Here are a few of the more commonly asked questions about keto:

Is keto safe?

Learn more about ketosis and ketoacidosis .

Keto diets aren’t harmful to your heart, kidneys, or bones either.

How much weight can I expect to lose on keto?

Most people lose about 2 to 4 pounds (1 to 2 kilos) during the first week. Some people lose even more.

Keep in mind that a good portion of this is water weight, though. After the first couple of weeks, weight loss often slows down quite a bit. While a lot of people continue losing about 1 pound (0.5 kilo) of weight a week, many others lose more or less than this. Learn more For instance, younger men tend to drop weight quickly and steadily. By contrast, women over 40 often lose weight more gradually and may go for a few weeks without losing any weight at all.

Weight loss typically slows down as you approach your goal weight. If your weight loss hasn’t budged for several weeks or months, check out our Top 10 tips to break a weight loss stall .

And remember that a “normal” body weight varies depending on the individual. This is based on your genes, health history, and other factors you have little control over.

How will I know whether I’m in ketosis?

• Dry mouth or a metallic taste in the mouth
• Increased thirst and more frequent urination
• “Keto breath” or “fruity breath,” which may be more apparent to others
• Initial fatigue, followed by an increase in energy
• Decreased appetite and food intake (one of the more welcome side effects!)

However, the only objective way to verify that you’re in ketosis is by checking your ketone levels.

What is the difference between keto and low carb?

At Diet Doctor, we define keto and low carb diets by the following:

Keto : Less than 20 grams of net carbs per day Moderate low carb : Between 20 and 50 grams of net carbs per day Liberal low carb : Between 50 and 100 grams of net carbs per day

More questions and answers:

Should I aim for high ketone levels to speed up weight loss? >

Can I eat a keto diet as a vegetarian or vegan? >

How long can someone be on a keto diet? >

Check out our full keto FAQ page >

10. How to start a keto diet now

Before starting a keto diet, check with your healthcare provider if you take:

• medications for diabetes
• medications for high blood pressure

In general, you should discuss any significant diet or lifestyle changes with your doctor.

If you are breastfeeding, a keto diet may not be right for you at this time. You can still limit unnecessary carbs without eating a strict keto diet. Learn more >

Here’s our leaflet with basic keto advice. Print it out, put it on your fridge — or give it to your curious friends!

More on getting started

1. Clean out your fridge, freezer, and pantry. Toss or give away the sugary and starchy foods. You can use our kitchen clean-out list to help you make sure your kitchen is keto-friendly when you start your diet.

If you share a house with someone not joining you on keto, discuss getting rid of the foods that are most likely to tempt you and storing the rest in an out-of-the-way spot.

2. Create a simple plan for the week. A simple plan for keto meals will help keep you on track. If you are not handy in the kitchen, plan for meals that are easy to put together from basic ingredients. Meals should always include a protein source. Add a vegetable or two, plus butter, olive oil, or cheese, and you’re all set.

Or, if you are comfortable in the kitchen, try our weekly meal plans. They make getting started even easier for you. Check out our free 30-day keto meal plan. You’ll get keto recipes for breakfast, lunch, and dinner for two weeks.

3. With your plan in hand, shop and restock. Focusing on keto-friendly foods you love, restock your fridge, freezer, and pantry. You can use this shopping list of low carb foods to guide you.

But you don’t need to buy everything at once. Choose foods you currently enjoy. You might add in some items you’ve been avoiding because you’ve been counting calories or restricting fat. You may be happy to know that bacon, cheese, and many kinds of nuts are keto-friendly.

The following steps are optional, but might help you find motivation and support as you get started:

4. Take “before” pictures and measurements. This gives you a baseline, from which to track your progress. You may be amazed at how quickly things improve.

5. Sign up for our newsletter. Join DD plus, and become a part of our members-only Facebook group. You’ll get resources to help you stay on track and meet others who are starting their keto journey.

A ketogenic diet for beginners - the evidence

This guide is written by Dr. Andreas Eenfeldt, MD , Dr. Bret Scher, MD and was last updated on November 29, 2022. It was medically reviewed by Dr. Michael Tamber, MD on February 15, 2022.

The guide contains scientific references. You can find these in the notes throughout the text, and click the links to read the peer-reviewed scientific papers. When appropriate we include a grading of the strength of the evidence, with a link to our policy on this. Our evidence-based guides are updated at least once per year to reflect and reference the latest science on the topic.

All our evidence-based health guides are written or reviewed by medical doctors who are experts on the topic. To stay unbiased we show no ads, sell no physical products, and take no money from the industry. We're fully funded by the people, via an optional membership. Most information at Diet Doctor is free forever.

Read more about our policies and work with evidence-based guides , nutritional controversies , our editorial team , and our medical review board .

Should you find any inaccuracy in this guide, please email [email protected] .

Most studies have shown that low carb diets are equivalent to or better than low fat diets for weight loss. These three meta-analyses of randomized trials found that low carb was superior to low fat:

Nutrients 2020: Impact of a ketogenic diet on metabolic parameters in patients with obesity or overweight and with or without type 2 diabetes: a meta-analysis of randomized controlled trials [strong evidence]

PLoS One 2015: Dietary intervention for overweight and obese adults: Comparison of low carbohydrate and low fat diets. A meta-analysis [strong evidence] Learn more

The British Journal of Nutrition 2016: Effects of low carbohydrate diets v. low fat diets on body weight and cardiovascular risk factors: a meta-analysis of randomised controlled trials [strong evidence] Learn more ↩

Obesity Reviews 2015: Do ketogenic diets really suppress appetite? A systematic review and meta-analysis [strong evidence]

European Journal of Clinical Nutrition 2013: Ketosis and appetite-mediating nutrients and hormones after weight loss [non-controlled study; weak evidence]

Nutrients 2020: Impact of a ketogenic diet on metabolic parameters in patients with obesity or overweight and with or without type 2 diabetes: A meta-analysis of randomized controlled trials [strong evidence] Diabetes Research and Clinical Practice 2018: Effect of dietary carbohydrate restriction on glycemic control in adults with diabetes: A systematic review and meta-analysis [strong evidence] ↩

Journal of the American College of Nutrition 2013: Improvements in glucose metabolism and insulin sensitivity with a low carbohydrate diet in obese patients with type 2 diabetes [uncontrolled study; weak evidence]

JCI Insight 2019: Dietary Carbohydrate Restriction Improves Metabolic Syndrome Independent of Weight Loss [randomized trial; moderate evidence]

But the following study reported no difference in weight loss between the low fat and low carb groups, and there was also no difference in weight loss when taking insulin resistance status into account. Therefore, it is still unclear how much lowering insulin contributes to weight loss.

Obesity 2015: Weight loss on low fat vs. low carb diets by insulin resistance status among overweight adults & adults with obesity: A randomized pilot trial [moderate evidence] ↩

Nutrients 2019: Non-energy-restricted low carbohydrate diet combined with exercise intervention improved cardiometabolic health in overweight Chinese females [moderate evidence]

Annals of Internal Medicine 2014: Effects of low carbohydrate and low fat diets; a randomized trial [moderate evidence]

Annals of Internal Medicine 2005: Effect of a low carbohydrate diet on appetite, blood glucose levels, and insulin resistance in obese patients with type 2 diabetes [non-randomized trial; weak evidence] ↩

Although low-sugar berries — such as blackberries, raspberries, and strawberries — are ok in small to moderate amounts. ↩

Current Diabetes Reports 2021: Efficacy of ketogenic diets on type 2 diabetes: a systematic review [strong evidence]

The British Journal of Nutrition 2013: Very-low-carbohydrate ketogenic diet v. low fat diet for long-term weight loss: a meta-analysis of randomised controlled trials [strong evidence]

Diabetes Research and Clinical Practice 2018: Effect of dietary carbohydrate restriction on glycemic control in adults with diabetes: A systematic review and meta-analysis [strong evidence] ↩

Several meta-analyses of randomized controlled trials (RCTs), considered the highest level of scientific evidence, conclude that low carb diets can be more effective than low fat diets for losing weight:

Nutrients 2020: The effect of low fat and low carbohydrate diets on weight loss and lipid levels: a systematic review and meta-analysis [strong evidence]

The British Journal of Nutrition 2016: Effects of low carbohydrate diets v. low fat diets on body weight and cardiovascular risk factors: a meta-analysis of randomised controlled trials [strong evidence] Learn more

Journal of Medical Internet Research 2017: An online intervention comparing a very low carbohydrate ketogenic diet and lifestyle recommendations versus a plate method diet in overweight individuals with type 2 diabetes: a randomized controlled trial [randomized trial; moderate evidence]

Diabetes & Metabolic Syndrome 2017: Induced and controlled dietary ketosis as a regulator of obesity and metabolic syndrome pathologies [randomized trial; moderate evidence]

Nutrients 2020: The effects of a low calorie ketogenic diet on glycaemic control variables in hyperinsulinemic overweight/obese females [non-controlled study; weak evidence] ↩

For example, in a small study, 10 overweight adults who followed a non-calorie-restricted, very low carb diet ended up reducing their usual intake by 1,000 calories, on average — even though they were allowed to eat all the fat and protein they wanted:

Annals of Internal Medicine 2005: Effect of a low carbohydrate diet on appetite, blood glucose levels, and insulin resistance in obese patients with type 2 diabetes [non-randomized trial; weak evidence]

Obesity Reviews 2015: Do ketogenic diets really suppress appetite? A systematic review and meta-analysis [strong evidence] ↩

This finding has been referred to as the “metabolic advantage” of low carb. In two studies, people who had previously lost weight were found to burn between 200 to nearly 500 more calories per day on a low carb maintenance diet compared to a higher carb maintenance diet:

Journal of the American Medical Association 2012: Effects of dietary composition during weight loss maintenance: a controlled feeding study [randomized trial; moderate evidence]

British Medical Journal 2018: Effects of a low carbohydrate diet on energy expenditure during weight loss maintenance: randomized trial [randomized trial; moderate evidence] ↩

This is mainly based on the consistent experience of low carb clinicians, and stories from people trying different levels of carb restriction [weak evidence] .

Additionally, one meta-analysis of RCTs found that very low carb diets limited to 50 grams of carbohydrates per day resulted in greater fat loss than low carb diets that provided about 40% of calories from carbs:

Obesity Reviews 2016: Impact of low‐carbohydrate diet on body composition: meta‐analysis of randomized controlled studies [strong evidence for fat mass loss on very low carb diets in particular] ↩

Some disagree with the use of the word “reverse” when it comes to type 2 diabetes. The concern is that it implies the disease is completely gone, never to return. At Diet Doctor, we use the term “reverse” to indicate that blood sugar levels are no longer in the diabetic range without the use of medications. However, we acknowledge that high glucose levels will likely recur if a patient goes back to their prior high carb eating habits. Therefore, “reverse” does not imply a forever cure. ↩

Meta-analyses of RCTs have shown that low carb diets consistently outperform other diets for blood sugar control:

International Journal of Endocrinology 2021: Comparing the efficacy and safety of low carbohydrate diets with low fat diets for type 2 diabetes mellitus patients: a systematic review and meta-analysis of randomized clinical trials [strong evidence]

Diabetes Research and Clinical Practice 2018: Effect of dietary carbohydrate restriction on glycemic control in adults with diabetes: A systematic review and meta-analysis [strong evidence]

The American Journal of Clinical Nutrition 2018: Effects of low carbohydrate- compared with low fat diet interventions on metabolic control in people with type 2 diabetes: a systematic review including GRADE assessments [strong evidence]

BMJ Open Diabetes Research and Care 2017: Systematic review and meta-analysis of dietary carbohydrate restriction in patients with type 2 diabetes [strong evidence]

Diabetes, Obesity & Metabolism 2019: An evidence‐based approach to developing low‐carbohydrate diets for type 2 diabetes management: a systematic review of interventions and methods [strong evidence] ↩

Diabetes Care 2004: Dietary carbohydrate (amount and type) in the prevention and management of diabetes [overview article; ungraded] ↩

In a 2019 position statement, the American Diabetes Association stated: “Reducing overall carbohydrate intake for individuals with diabetes has demonstrated the most evidence for improving glycemia and may be applied in a variety of eating patterns that meet individual needs and preferences:”

Diabetes Care 2019: Nutrition therapy for adults with diabetes or prediabetes: a consensus report [report; ungraded] ↩

This has been demonstrated in several clinical trials:

Cureus 2020: Effects of the ketogenic diet on glycemic control in diabetic patients: Meta-analysis of clinical trials [strong evidence]

European Journal of Clinical Nutrition 2017: The interpretation and effect of a low carbohydrate diet in the management of type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials [strong evidence]

Nutrition and Metabolism 2008: The effect of a low carbohydrate, ketogenic diet versus a low-glycemic index diet on glycemic control in type 2 diabetes mellitus [randomized trial; moderate evidence]

Frontiers in Endocrinology 2019: Long-term effects of a novel continuous remote care intervention including nutritional ketosis for the management of type 2 diabetes: A 2-year non-randomized clinical trial [non-randomized study; weak evidence] ↩

In reviews of RCTs of low carb and low fat diets, metabolic health markers improved the most in those who ate very low carbohydrate or ketogenic diets:

Nutrition Reviews 2019: Effects of carbohydrate-restricted diets on low-density lipoprotein cholesterol levels in overweight and obese adults: a systematic review and meta-analysis [strong evidence]

British Journal of Nutrition 2013: Very low carbohydrate ketogenic diet v. low fat diet for long-term weight loss: a meta-analysis of randomised controlled trials [strong evidence] ↩

The metabolic syndrome consists of hypertension, abdominal obesity, low HDL (below 40 mg/dl in men or 50 mg/dl in women), triglycerides above 150 mg/dL, and elevated fasting glucose. ↩

In one trial, all 22 participants had such impressive results after eating a ketogenic diet for 12 weeks that they no longer met the criteria for metabolic syndrome:

Journal of Medicinal Food 2011: A pilot study of the Spanish Ketogenic Mediterranean Diet: an effective therapy for the metabolic syndrome [non-randomized trial; weak evidence]

Lipids 2009: Carbohydrate restriction has a more favorable impact on the metabolic syndrome than a low fat diet [randomized trial; moderate evidence]

Experimental & Clinical Cardiology 2004: Long-term effects of a ketogenic diet in obese patients [non-randomized trial; weak evidence] ↩

There is still a shortage of high-quality studies, but what exists is promising, sometimes showing remarkable improvements.

Diabetes, Obesity and Metabolism 2019: Low versus high carbohydrate diet in type 1 diabetes: A 12-week randomized open-label crossover study [randomized trial; moderate evidence]

PLOS ONE 2018: Low-carbohydrate diets for type 1 diabetes mellitus: A systematic review [weak evidence, downgraded due to lack of high-quality studies]

Pediatrics 2018: Management of type 1 diabetes with a very low–carbohydrate diet [online survey, very weak evidence for an exceptionally strong positive effect]

Asia Pacific Journal of Clinical Nutrition 2016: A randomised trial of the feasibility of a low carbohydrate diet vs standard carbohydrate counting in adults with type 1 diabetes taking body weight into account [moderate evidence for a positive effect, though a very small study]

Stories of people trying low carb for type 1 diabetes ↩

Medicine 2016: Nonalcoholic fatty liver disease is associated with excessive calorie intake rather than a distinctive dietary pattern [case-control study; very weak evidence]

Journal of Investigative Medicine 2017: Influence of dietary macronutrients on liver fat accumulation and metabolism [overview article; ungraded] ↩

The American Journal of Clinical Nutrition 2012: Effect of short-term carbohydrate overfeeding and long-term weight loss on liver fat in overweight humans [non-controlled study; weak evidence]

The American Journal of Clinical Nutrition 2012: Sucrose-sweetened beverages increase fat storage in the liver, muscle, and visceral fat depot: A 6-mo randomized intervention study [randomized trial; moderate evidence] ↩

Nutrients 2017: Nonalcoholic fatty liver disease and insulin resistance: New insights and potential new treatments [overview article; ungraded] ↩

Journal of Hepatology Reports 2021: Treatment of NAFLD with intermittent calorie restriction or low carb high fat diet – a randomized controlled trial [moderate evidence]

Frontiers in Endocrinology 2020: Efficacy of a 2-month very low calorie ketogenic diet (VLCKD) compared to a standard low calorie diet in reducing visceral and liver fat accumulation in patients with obesity [randomized controlled trial; moderate evidence]

Asia Pacific Journal of Clinical Nutrition 2020: Impact of a low carbohydrate and high fiber diet on nonalcoholic fatty liver disease [randomized controlled trial; moderate evidence]

Hepatology Research 2018: Comparison of efficacy of low carbohydrate and low fat diet education programs in non-alcoholic fatty liver disease: A randomized controlled study [randomized trial; moderate evidence]

Proceedings of the National Academy of Sciences of the United States of America 2020: Effect of a ketogenic diet on hepatic steatosis and hepatic mitochondrial metabolism in nonalcoholic fatty liver disease [non-controlled study; weak evidence] ↩

The Journal of Nutrition 2020: The ketogenic diet: evidence for optimism but high-quality research needed [overview article; ungraded] ↩

JAMA Internal Medicine 2019: The ketogenic diet for obesity and diabetes: enthusiasm outpaces evidence [overview article; ungraded] ↩

Current Developments in Nutrition 2021 Elevated LDL-Cholesterol with a Carbohydrate-Restricted Diet: Evidence for a Lean Mass Hyper-Responder Phenotype [observational study with self-reported data, very weak evidence]

British Journal of Nutrition 2016: Effects of low carbohydrate diets v. low fat diets on body weight and cardiovascular risk factors: a meta-analysis of randomised controlled trials [strong evidence]

Cardiovascular Diabetology 2018: Cardiovascular disease risk factor responses to a type 2 diabetes care model including nutritional ketosis induced by sustained carbohydrate restriction at 1 year: an open label, non-randomized, controlled study. [non-randomized trial; weak evidence]

Sports (Basel) 2018: The three-month effects of a ketogenic diet on body composition, blood parameters, and performance metrics in CrossFit trainees: a pilot study [non-randomized trial; weak evidence]

British Journal of Nutrition 2016: Effects of low carbohydrate diets v. low fat diets on body weight and cardiovascular risk factors: a meta-analysis of randomised controlled trials [strong evidence] ↩

Diabetes 2004: Effect of a high protein, low carbohydrate diet on blood glucose control in people with type 2 diabetes [randomized trial; moderate evidence]

American Jopurnal of Clinical Nutrition 2003: An increase in dietary protein improves the blood glucose response in persons with type 2 diabetes [randomized trial; moderate evidence] ↩

These include enzyme deficiencies, which interfere with the body’s ability to make and use ketones or to properly digest fats:

Department of Neurology 2012: Chapter 45 – Ketogenic diet [textbook chapter; ungraded] ↩

Nutrition Bulletin 2011: Ketosis, ketoacidosis and very-low-calorie diets: Putting the record straight [overview article; ungraded] ↩

This answer is based on clinical experience of low carb practitioners and was unanimously agreed upon by our low carb expert panel. You can learn more about our panel here [weak evidence] . ↩

Nutritional ketosis is defined as having a beta-hydroxybutyrate level of 0.5 to 3.0 mmol/L in the blood. Learn more: What is optimal ketosis? ↩

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Keto diet works best in small doses, yale researchers find.

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A ketogenic diet — which provides 99% of calories from fat and protein and only 1% from carbohydrates — produces health benefits in the short term, but negative effects after about a week, Yale researchers found in a study of mice.

The results offer early indications that the keto diet could, over limited time periods, improve human health by lowering diabetes risk and inflammation. They also represent an important first step toward possible clinical trials in humans.

The keto diet has become increasingly popular as celebrities, including Gwyneth Paltrow, Lebron James, and Kim Kardashian, have touted it as a weight-loss regimen.

In the Yale study, published in the Jan. 20 issue of Nature Metabolism , researchers found that the positive and negative effects of the diet both relate to immune cells called gamma delta T-cells, tissue-protective cells that lower diabetes risk and inflammation.

A keto diet tricks the body into burning fat, said lead author Vishwa Deep Dixit of the Yale School of Medicine. When the body’s glucose level is reduced due to the diet’s low carbohydrate content, the body acts as if it is in a starvation state — although it is not — and begins burning fats instead of carbohydrates. This process in turn yields chemicals called ketone bodies as an alternative source of fuel. When the body burns ketone bodies, tissue-protective gamma delta T-cells expand throughout the body.

This reduces diabetes risk and inflammation, and improves the body’s metabolism, said Dixit, the Waldemar Von Zedtwitz Professor of Comparative Medicine and of Immunobiology. After a week on the keto diet, he said, mice show a reduction in blood sugar levels and inflammation.

But when the body is in this “starving-not-starving” mode, fat storage is also happening simultaneously with fat breakdown, the researchers found. When mice continue to eat the high-fat, low-carb diet beyond one week, Dixit said, they consume more fat than they can burn, and develop diabetes and obesity.

“ They lose the protective gamma delta T-cells in the fat,” he said.

Long-term clinical studies in humans are still necessary to validate the anecdotal claims of keto’s health benefits.

“ Before such a diet can be prescribed, a large clinical trial in controlled conditions is necessary to understand the mechanism behind metabolic and immunological benefits or any potential harm to individuals who are overweight and pre-diabetic,” Dixit said.

There are good reasons to pursue further study: According to the Centers for Disease Control, approximately 84 million American adults — or more than one out of three — have prediabetes (increased blood sugar levels), putting them at higher risk of developing type 2 diabetes, heart disease, and stroke. More than 90% of people with this condition don’t know they have it.

“ Obesity and type 2 diabetes are lifestyle diseases,” Dixit said. “Diet allows people a way to be in control.”

With the latest findings, researchers now better understand the mechanisms at work in bodies sustained on the keto diet, and why the diet may bring health benefits over limited time periods.

“ Our findings highlight the interplay between metabolism and the immune system, and how it coordinates maintenance of healthy tissue function,” said Emily Goldberg, the postdoctoral fellow in comparative medicine who discovered that the keto diet expands gamma-delta T cells in mice.

If the ideal length of the diet for health benefits in humans is a subject for later studies, Dixit said, discovering that keto is better in small doses is good news, he said: “Who wants to be on a diet forever?”

The research was funded in part by grants from the National Institutes of Health.

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In 1921, a distinguished physician at the Mayo Clinic suggested trying what he called a ketogenic diet, a high-fat diet designed to be so carbohydrate-deficient it could effectively mimic the fasting state. Oddly, the success of ketogenic diets against pediatric epilepsy seems to get conflated by keto diet proponents into suggesting it is beneficial for everyone.

By eschewing carbohydrates, you force your body to burn fat. And indeed, the amount of fat you burn shoots up when you eat a keto diet. At the same time, however, the fat you take in shoots up when you eat a keto diet. What happens to our overall body-fat balance? Body fat loss slows upon switching to the ketogenic diet.

Just looking at the scale, the ketogenic diet seems like a success, but what happens inside bodies tells a different story. On the keto diet, rates of body fat loss may slow by more than half, so most of what is lost is water. The reason less fat is burned on a ketogenic diet is presumably the same reason people who start fasting may start burning less fat: Without carbohydrates, the preferred fuel, our bodies start burning more of our own protein .

Inadequate intake of 17 micronutrients has been documented in those on ketogenic diets. Children have gotten scurvy, and some have even died from deficiency of the mineral selenium , which can cause sudden cardiac death. Bone fractures disproportionately plague children on ketogenic diets, along with growth stunting and kidney stones , and constipation is a frequently cited side effect. Keto diets have also been shown to reduce the richness and diversity of our gut flora , and all of that saturated fat can have a profound impact on the heart: A meta-analysis of four cohort studies following the diets, diseases, and deaths of more than a quarter million people found that those who eat lower-carb diets suffer a significantly higher risk of all-cause mortality, meaning they live, on average, significantly shorter lives.

For substantiation of any statements of fact from the peer-reviewed medical literature, please see the associated videos below.

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The Truth About Keto Diet Pills: Do They Really Work?

Keto diet pills claim they can help you sustain ketosis, but do they really?

This article is based on reporting that features expert sources.

Keto Diet Pills: Do They Really Work?

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Chances are you’ve heard about – or possibly even tried – the keto diet, a low-carb, high-fat approach to weight loss that is widely popular but not the easiest or most sustainable diet to follow.

The keto diet eliminates nearly all carbohydrates and relies on calories from fat for fuel, a process called ketosis. However, getting into and staying in ketosis can be tricky because you need a specific amount of macronutrients: 90% fat, 6% protein and 4% carbs, traditionally. (A modified keto diet clocks in at around 82% fat, 12% protein and 6% carbs.)

Given how challenging the keto diet can be, it’s no surprise that manufacturers have created keto supplements claiming to help you boost energy, burn fat and lose weight fast .

For those looking to shed pounds, it’s hard not to be intrigued by these claims. But it raises the question: Do keto supplements actually work, or is it simply clever marketing?

What Are Keto Diet Pills?

While the human body naturally produces ketones when it breaks down fat for fuel, keto supplements claim to increase ketone levels, help you achieve ketosis faster and, ultimately, lose weight.

Keto supplements typically contain two active ingredients:

• Ketone beta-hydroxybutyrate (BHB) , a compound that the liver produces from fats. These small molecules circulate in the bloodstream and are used up by the body’s tissue for energy.
• Medium-chain triglycerides (MCTs) , a type of fat found in coconut and palm oil that can be used as a source of energy for the body in ketosis.

“In theory, taking extra ketones in the diet may help the body lose weight by using ketones for energy and, therefore, burn fat,” explains Erin Holley, a registered dietitian at the Ohio State University Wexner Medical Center in Columbus. “The claim is that you can take these keto diet pills and not have to follow a low-carb diet .”

Such supplements are also marketed to help ameliorate the so-called “keto flu,” an unofficial term that refers to a group of flu-like symptoms that can develop within about a week of switching to a keto diet .

Symptoms include:

• Brain fog .
• Irritability.
• Constipation .
• Sleep changes.

However, there’s no evidence to support that keto pills can help prevent keto flu. While the exact causes of the keto flu are unclear, symptoms typically resolve within a few days as your body adjusts.

Types of Keto Diet Supplements

The three most common types of keto diet supplements are:

Many keto pills contain BHB salts or BHB esters and are promoted as a natural weight loss supplement .

Keto powders

Similar to keto pills, keto powders contain some form of BHB. Many keto powder supplements may also include electrolytes to help people stay hydrated and remain in ketosis.

Keto gummies

One of the newer keto supplements on the market, keto gummies are deceiving because many don’t actually contain any ketones. Instead, they are often made with apple cider vinegar , which companies say boosts metabolism and, therefore, promotes weight loss . However, there’s not enough scientific evidence to support this claim.

Some keto gummies may also contain MCT oil , and most are sweetened with a non-nutritive sweetening agent, such as stevia . Most also contain gelatin, which gives them their signature chewy-candy texture.

Keto Supplement Warnings

It’s important to note that the Food and Drug Administration does not approve dietary supplements , including vitamins, minerals, herbs and keto products, so there’s a chance that what's in the bottle is not actually what's on the label, and bottle contents may even contain heavy metals and other contaminants.

If you decide to purchase keto supplements, make sure to check for products that have been tested and certified by third-party organizations, such as the National Sanitation Foundation, ConsumerLab.com and U.S. Pharmacopeia.

“These companies will test to make sure that what’s on the label is actually inside the bottle because a lot of times with supplements, it might not even contain what it claims to contain,” says Diana Guevara, a registered dietitian nutritionist with UTHealth Houston School of Public Health.

Keep in mind, however, that while third-party tests can check for ingredients, they do not check for efficacy.

You should also be cautious of potentially misleading recommendations, adds Dr. Neal H. Patel, a family medicine physician with Providence St. Joseph Hospital in Orange County, California.

“Most people will scour Amazon to see which (supplement) has the highest stars and ratings, but be wary because sometimes the ones that are with the highest stars may be rated high because they are cheaper,” he points out.

Do Keto Pills Work?

There’s not enough research on the efficacy of keto supplements to support the claim that taking keto pills, powders or gummies will help you achieve ketosis.

“We just don’t know whether (these supplements) will work,” Guevara says. “They’re very expensive, and there’s a chance for them to be contaminated, so for me, it’s a lose-lose-lose all around.”

One small 2021 study , for instance, found that people with obesity who followed a low-calorie ketogenic diet and took 24 grams of a BHB salt supplement per day for six weeks experienced enhanced ketosis. However, having higher levels of ketones in the blood didn’t seem to boost these participants' weight loss when compared to other groups, such as those following only the keto diet without the supplement.

Other research, such as this 2020 study , suggests that taking exogenous ketones can help boost concentrations of ketones in the blood quickly. Whether they have an appreciable effect on weight loss, however, is still murky, and more robust studies with strong evidence are lacking.

“It’s still unclear as to whether exogenous ketones will produce the same type of ketosis effects as diet,” confirms Gaby Vaca-Flores, a registered dietitian and education manager at HUM Nutrition in Los Angeles.

One of the reasons why supplementation may not be all that effective is because the body seeks to maintain an even level of ketones to prevent a potentially toxic buildup of these chemicals in the bloodstream. When the body senses that ketone levels are high, the liver stops making its own and will try to flush out excess ketones in your urine , a process called ketonuria.

“Supplements are often expensive (urine) because, at best, you’ll just pee it out,” Guevara says. “At worst, it could be harmful for your liver because it does have to process everything you’re taking.”

Ultimately, the jury is still out on whether or not these supplements work. But one thing is for certain: Experts do not recommend keto pills – or any diet pill , for that matter.

"(While they're) probably safe to use for most people, I certainly don’t recommend diet pills for anyone,” Holley says.

Beware of Scams and Overly Expensive Keto Pills

In addition to health concerns, there’s a risk of scams with some keto products, namely supplements being pushed heavily on social media. In July 2020, AARP reported that two women in their 80s had been scammed out of more than $200 each when they purchased keto diet pills. AARP also warned that the number of reported scams is on the rise.

The FDA encourages consumers to be cautious of any supplements being pushed via email or pop-up ads, as these points of contact are more likely to lead to a scam product. Also, keep an eye out for certain words and phrases in any marketing text, such as “quick fix,” “guaranteed results” and “scientific breakthrough.” They’re usually a red flag of false advertising.

What’s more, because dietary supplement products are not regulated by the FDA, it can be difficult to know whether you’re getting what you pay for. If you're intent on purchasing a keto supplement, do your homework and ask the company to provide its research or evidence that the supplement does what the company is saying it does. A reputable manufacturer should be able to provide information about how its product has been tested and what it contains.

Is the Keto Diet Worth It?

If you’re considering the keto diet, Guevara encourages you to ask yourself why you’re doing it and if it’s really worth it.

“ Very restrictive diets are hard to follow, and they’re not sustainable,” she says. “With the keto diet specifically, when we look at it for weight loss, most of that weight you’re losing quickly at the beginning is water weight . You’re not losing fat. It’s very exciting to see that number drop, but it’s not going to be metabolically better for you.”

Patel says he isn’t a fan of the keto diet, but he notes that instituting a water-only fast “for at least 24 hours and longer” would be one way to get into ketosis faster without spending money on supplements.

“Obviously, you would want to consult with your doctor if you decide to do a prolonged fast based on your overall health and medications you take,” he adds.

Overall, there are few shortcuts to healthy and sustainable weight loss , and using a supplement to speed up the process could lead you to lose more money than weight.

“Truly, these are a waste of your money,” Holley emphasizes. “Do not fall for this gimmick. If you’re thinking about purchasing these, please speak with your doctor or a dietitian first.”

Worst Foods for Gut Health

The U.S. News Health team delivers accurate information about health, nutrition and fitness, as well as in-depth medical condition guides. All of our stories rely on multiple, independent sources and experts in the field, such as medical doctors and licensed nutritionists. To learn more about how we keep our content accurate and trustworthy, read our  editorial guidelines .

Guevara is a registered dietitian nutritionist with UTHealth Houston School of Public Health.

Holley is a registered dietitian with the Ohio State University Wexner Medical Center in Columbus.

Patel is a family medicine physician with Providence St. Joseph Hospital in Orange County, California.

Vaca-Flores is a registered dietitian and education manager at HUM Nutrition in Los Angeles.

Tags: diets , diet and nutrition , weight loss , supplements

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Component of keto diet plus immunotherapy may reduce prostate cancer

by Deanna Csomo Ferrell, University of Notre Dame

Adding a pre-ketone supplement—a component of a high-fat, low-carb ketogenic diet—to a type of cancer therapy in a laboratory setting was highly effective for treating prostate cancer, researchers from the University of Notre Dame found.

Recently published online in the journal Cancer Research , the study from Xin Lu, the John M. and Mary Jo Boler Collegiate Associate Professor in the Department of Biological Sciences, and collaborators tackled a problem oncologists have battled: Prostate cancer is resistant to a type of immunotherapy called immune checkpoint blockade (ICB) therapy. ICB therapy blocks certain proteins from binding with other proteins and paves the way for our body's fighter cells, T cells, to kill the cancer.

"Prostate cancer is the most common cancer for American men, and immunotherapy has been really influential in some other cancers, like melanoma or lung cancer , but it hasn't been working almost at all for prostate cancer," said Lu, who is affiliated with the Boler-Parseghian Center for Rare and Neglected Diseases. Adding a dietary supplement might overcome this resistance, the lead author in the study, Sean Murphy, suggested.

Murphy, a '24 alumnus who was a doctoral student in Lu's lab, had been following a keto diet himself. Knowing that cancer cells feed off of sugar, he decided that depriving mouse models of carbohydrates—a key component of the keto diet—might prevent cancer growth.

He divided the models into different groups: immunotherapy alone, ketogenic diet alone, a pre-ketone supplement alone, the ketogenic diet with the immunotherapy, the supplement with the immunotherapy, and the control. While the immunotherapy alone had almost no effect on the tumors (just like what happens to most patients with prostate cancer), both the ketogenic diet with the immunotherapy and the pre-ketone supplement with the immunotherapy reduced the cancer and extended the lives of the mouse models.

The supplement with the immunotherapy worked best.

"It turned out this combination worked really well," Lu said. "It made the tumor become very sensitive to the immunotherapy, with 23 percent of the mice cured—they were tumor-free; in the rest, the tumors were shrinking really dramatically."

The evidence points to the possibility that a supplement providing ketones, which are what is produced in the body when people eat a keto diet, might prevent the prostate cancer cells from being resistant to immunotherapy. This may lead to future clinical studies that examine how ketogenic diets or keto supplements could enhance cancer therapy.

While keto diets allow for minimal carbohydrates, the success of this study is not about the lack of carbohydrates, Murphy and Lu stressed. It is about the presence of the ketone body, a substance produced by the liver and used as an energy source when glucose is not available. The ketones disrupt the cycle of the cancer cells, allowing the T cells to do their job to destroy them.

The discovery was also exciting on a molecular level, Lu said. Any type of dietary study can suffer from the potential issue of causation: Are the results from the diet or other changes made because of the diet? But Lu and his collaborators confirmed their results using single-cell RNA sequencing, which examines the gene expression of single cells within the tumor.

"We found that this combination of the supplement and the immunotherapy reprogrammed the whole immune profile of the tumors and recruited many T cells into the tumors to kill prostate cancer cells," Lu said.

The successful therapy also reduced the number of a type of immune cell called neutrophils. Once in the tumor microenvironment , neutrophils' natural properties become greatly distorted, and they become largely responsible for inhibiting T cell activities and allowing more tumor progression. Dysregulation of neutrophils is also associated with many other diseases.

"With the main ketone body depleting neutrophils, it opens the door for investigating the effects of the keto diet and the ketone supplement on diseases ranging from inflammatory bowel disease to arthritis," Murphy said.

"What's exciting is that we're getting closer to the mechanism, backed up by genetic models and what we're seeing in the tumors themselves, of why this works," he said.

Co-authors include Sharif Rahmy, Dailin Gan, Guoqiang Liu, Yini Zhu, Maxim Manyak, Loan Duong, Jianping He, James H. Schofield, Zachary T. Schafer, Jun Li and Xuemin Lu, all from the University of Notre Dame.

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• Research article
• Open access
• Published: 25 May 2023

Effects of ketogenic diet on health outcomes: an umbrella review of meta-analyses of randomized clinical trials

• Chanthawat Patikorn 1 , 2 ,
• Pantakarn Saidoung 1 ,
• Tuan Pham 3 ,
• Pochamana Phisalprapa 4 ,
• Yeong Yeh Lee 5 ,
• Krista A. Varady 6 ,
• Sajesh K. Veettil 1 &
• Nathorn Chaiyakunapruk 1 , 7  

BMC Medicine volume  21 , Article number:  196 ( 2023 ) Cite this article

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Systematic reviews and meta-analyses of randomized clinical trials (RCTs) have reported the benefits of ketogenic diets (KD) in various participants such as patients with epilepsy and adults with overweight or obesity . Nevertheless, there has been little synthesis of the strength and quality of this evidence in aggregate.

To grade the evidence from published meta-analyses of RCTs that assessed the association of KD, ketogenic low-carbohydrate high-fat diet (K-LCHF), and very low-calorie KD (VLCKD) with health outcomes, PubMed, EMBASE, Epistemonikos, and Cochrane database of systematic reviews were searched up to February 15, 2023. Meta-analyses of RCTs of KD were included. Meta-analyses were re-performed using a random-effects model. The quality of evidence per association provided in meta-analyses was rated by the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) criteria as high, moderate, low, and very low.

We included 17 meta-analyses comprising 68 RCTs (median [interquartile range, IQR] sample size of 42 [20–104] participants and follow-up period of 13 [8–36] weeks) and 115 unique associations. There were 51 statistically significant associations (44%) of which four associations were supported by high-quality evidence (reduced triglyceride ( n  = 2), seizure frequency ( n  = 1) and increased low-density lipoprotein cholesterol (LDL-C) ( n  = 1)) and four associations supported by moderate-quality evidence (decrease in body weight, respiratory exchange ratio (RER), hemoglobin A 1c , and increased total cholesterol). The remaining associations were supported by very low (26 associations) to low (17 associations) quality evidence. In overweight or obese adults, VLCKD was significantly associated with improvement in anthropometric and cardiometabolic outcomes without worsening muscle mass, LDL-C, and total cholesterol. K-LCHF was associated with reduced body weight and body fat percentage, but also reduced muscle mass in healthy participants.

Conclusions

This umbrella review found beneficial associations of KD supported by moderate to high-quality evidence on seizure and several cardiometabolic parameters. However, KD was associated with a clinically meaningful increase in LDL-C. Clinical trials with long-term follow-up are warranted to investigate whether the short-term effects of KD will translate to beneficial effects on clinical outcomes such as cardiovascular events and mortality.

Peer Review reports

Ketogenic diets (KD) have received substantial attention from the public primarily due to their ability to produce rapid weight loss in the short run [ 1 , 2 ]. The KD eating pattern severely restricts carbohydrate intake to less than 50 g/day while increasing protein and fat intake [ 3 , 4 , 5 , 6 ]. Carbohydrate deprivation leads to an increase in circulating ketone bodies by breaking down fatty acids and ketogenic amino acids. Ketones are an alternative energy source from carbohydrates that alter physiological adaptations. These adaptions have been shown to produce weight loss with beneficial health effects by improving glycemic and lipid profiles [ 7 , 8 ]. KD has also been recommended as a nonpharmacological treatment for medication-refractory epilepsy in children and adults [ 8 , 9 ]. Evidence suggests that KD has reduced seizure frequency in patients with medication-refractory epilepsy, and even allowing some patients to reach complete and sustained remission. 11 However, the exact anticonvulsive mechanism of KD remains unclear [ 10 , 11 ].

Several systematic reviews and meta-analyses of randomized clinical trials (RCTs) have reported on the use of KD in patients with obesity or type 2 diabetes mellitus (T2DM) to control weight and improve cardiometabolic parameters [ 1 , 12 , 13 , 14 , 15 ], in patients with refractory epilepsy to reduce seizure frequency [ 16 ], and in athletes to control weight and improve performance [ 17 ]. To date, there has been little synthesis of the strength and quality of this evidence in aggregate. This umbrella review therefore aims to systematically identify relevant meta-analyses of RCTs of KD, summarize their findings, and assess the strength of evidence of the effects of KD on health outcomes.

The protocol of this study was registered with PROSPERO (CRD42022334717). We reported following the 2020 Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) (Additional file 1 ) [ 18 ]. Difference from the original review protocol is described with rationale in Additional file 2 : Table S1.

Search strategy and eligibility criteria

We searched PubMed, EMBASE, Epistemonikos, and the Cochrane database of systematic reviews (CDSR) from the database inception to February 15, 2023 (Additional file 2 : Table S2). No language restriction was applied. Study selection was independently performed in EndNote by two reviewers (C.P. and PS). After removing duplicates, the identified articles' titles and abstracts were screened for relevance. Full-text articles of the potentially eligible articles were retrieved and selected against the eligibility criteria. Any discrepancies were resolved by discussion with the third reviewer (SKV).

We included studies that met the following eligibility criteria: systematic reviews and meta-analyses of RCTs investigating the effects of any type of KD on any health outcomes in participants with or without any medical conditions compared with any comparators. When more than 1 meta-analysis was available for the same research question, we selected the meta-analysis with the largest data set [ 19 , 20 , 21 ]. Articles without full-text and meta-analyses that provided insufficient or inadequate data for quantitative synthesis were excluded.

Data extraction and quality assessment

Two reviewers (CP and PS) independently performed data extraction and quality assessment (Additional file 2 : Method S1). Discrepancies were resolved with consensus by discussing with the third reviewer (SKV). We used AMSTAR- 2 -A Measurement Tool to Assess Systematic Reviews- to grade the quality of meta-analyses as high, moderate, low, or critically low by assessing the following elements, research question, a priori protocol, search, study selection, data extraction, quality assessment, data analysis, interpretation, heterogeneity, publication bias, source of funding, conflict of interest [ 22 ].

Data synthesis

For each association, we extracted effect sizes (mean difference [MD], the standardized mean difference [SMD], and risk ratio [RR]) of individual studies included in each meta-analysis and performed the meta-analyses to calculate the pooled effect sizes and 95% CIs using a random-effects model under DerSimonian and Laird [ 23 ], or the Hartung-Knapp- Sidik-Jonkman approach for meta-analyses with less than five studies [ 24 ].  p  < 0.05 was considered statistically significant in 2-sided tests. Heterogeneity was evaluated using the I 2 statistic. The evidence for small-study effects was assessed by the Egger regression asymmetry test [ 25 ]. Statistical analyses were conducted using Stata version 16.0 (StataCorp). We presented effect sizes of statistically significant associations with the known or estimated minimally clinically important difference (MCID) thresholds for health outcomes [ 14 , 26 , 27 , 28 , 29 , 30 ].

We assessed the quality of evidence per association by applying the GRADE criteria (Grading of Recommendations, Assessment, Development, and Evaluations) in five domains, including (1) risk of bias in the individual studies, (2) inconsistency, (3) indirectness, (4) imprecision, and (5) publication bias [ 31 ]. We graded the strength of evidence (high, moderate, low, and very low) using GRADEpro version 3.6.1 (McMaster University).

Sensitivity analyses

Sensitivity analyses were performed by excluding small-size studies (< 25 th percentile) [ 32 ] and excluding primary studies having a high risk of bias rated by the Cochrane’s risk of bias 2 tool (RoB 2) for RCTs from the identified associations [ 19 , 20 , 21 , 33 ].

Seventeen meta-analyses were included (Fig.  1 and Additional file 2 : Table S3) [ 1 , 2 , 15 , 16 , 17 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ]. These meta-analyses comprised 68 unique RCTs with a median (interquartile range, IQR) sample size per RCT of 42 (20–104) participants and a median (IQR) follow-up period of 13 (8–36) weeks. The quality of meta-analyses assessed using AMSTAR-2 found that none were rated as high confidence, 2 (12%) as moderate confidence, 2 (12%) as low confidence, and 13 (76.0%) as critically low confidence (Table 1 and Additional file 2 : Table S4).

Study selection flow of meta-analyses. Abbreviation: CDSR, Cochrane database of systematic review

Types of KD identified in this umbrella review were categorized as (1) KD, which limits carbohydrate intake to < 50 g/day or < 10% of the total energy intake (TEI) [ 35 ], (2) ketogenic low-carbohydrate, high-fat diet (K-LCHF), which limits carbohydrate intake to < 50 g/day or < 10% of TEI with high amount of fat intake (60–80% of TEI) [ 38 , 46 ], (3) very low-calorie KD (VLCKD), which limits carbohydrate intake to < 30–50 g/day or 13–25% of TEI with TEI < 700–800 kcal/day, and (4) modified Atkins diet (MAD), which generally limits carbohydrate intake to < 10 g/day while encouraging high-fat foods [ 15 , 47 ]. Meta-analyses of long-chain triglyceride KD, medium-chain triglyceride KD, and low glycemic index treatment were not identified.

Description and summary of associations

We identified 115 unique associations of KD with health outcomes (Additional file 2 : Table S5). The median (IQR) number of studies per association was 3 [ 4 , 5 , 6 ], and the median (IQR) sample size was 244 (127–430) participants. Outcomes were associated with KD types, including 40 (35%) KD, 18 (16%) K-LCHF, 13 (11%) VLCKD, 25 (22%) KD or K-LCHF, 5 (4%) KD or VLCKD, 1 (1%) KD or MAD, and 13 (11%) KD, K-LCHF, or VLCKD.

The associations involved 40 (35%) anthropometric measures (i.e., body weight, body mass index [BMI] [calculated as weight in kilograms divided by height in meters squared], waist circumference, muscle mass, fat mass, body fat percentage, and visceral adipose tissue), 37 (32%) lipid profile outcomes (i.e., triglyceride, total cholesterol, high-density lipoprotein cholesterol [HDL-C], and low-density lipoprotein cholesterol [LDL-C]), 22 (19%) glycemic profile outcomes (i.e., hemoglobin A 1c [HbA 1c ], fasting plasma glucose, fasting insulin, and homeostatic model assessment of insulin resistance [HOMA-IR]), 6 (5%) exercise performance (i.e., maximal heart rate, respiratory exchange ratio [RER], maximal oxygen consumption (VO 2 max), 5 (4%) blood pressure outcomes (i.e., systolic blood pressure [SBP], diastolic blood pressure [DBP], and heart rate), 1 (1%) outcome associated with seizure frequency reduction ≥ 50% from baseline, and 3 other outcomes (i.e., serum creatinine, C-peptide, and C-reactive protein). In addition, there is 1 association (1%) of adverse events.

Participants in the identified associations included 68 (59%) associations in adults with overweight or obesity with or without T2DM or dyslipidemia, 15 (13%) athletes or resistance-trained adults, 12 (10%) adults with T2DM, 11 (10%) healthy participants ≥ 16 years old, 8 (7%) cancer patients, and 1 (1%) in children and adolescents with epilepsy.

Using GRADE, 115 associations were supported by very low strength of evidence ( n  = 66, 57%), with the remaining being low ( n  = 36, 31%), moderate ( n  = 9, 8%), and high quality of evidence ( n  = 4, 3%) (Additional file 2 : Table S5). Almost half, or 44% (51 associations), were statistically significant based on a random-effects model, of which 51% (26 associations) were supported by a very low level of evidence, followed by low (17 associations [33%]), moderate (4 associations [8%]), and high (4 associations [8%]) levels of evidence. Overall beneficial outcomes associated with KD were BMI [ 37 , 42 ], body weight [ 1 , 2 , 35 , 36 , 37 , 41 ], waist circumference [ 37 , 42 ], fat mass [ 37 , 42 ], body fat percentage [ 38 , 40 ], visceral adipose tissue [ 37 ], triglyceride [ 1 , 2 , 36 , 42 ], HDL-C [ 1 , 2 , 42 ], HbA 1c  [ 2 , 34 , 35 ],  HOMA-IR [ 2 , 42 ], DBP [ 1 ], seizure frequency reduction ≥ 50% from baseline [ 16 ], and respiratory exchange ratio [ 17 , 39 ]. Adverse outcomes associated with KD were reduced muscle mass [ 37 , 38 ], and increased LDL-C [ 2 , 35 ], and total cholesterol [ 2 , 17 ]. In terms of safety, one association showed no significant increase in adverse events (e.g., constipation, abdominal pain, and nausea) with KD [ 44 ].

Eight out of 13 associations supported by moderate to high-quality evidence were statistically significant (Table 2 ). There were 4 statistically significant associations supported by high-quality evidence, including the following: (1) KD or MAD for 3–16 months was associated with a higher proportion of children and adolescents with refractory epilepsy achieving seizure frequency reduction ≥ 50% from baseline compared with regular diet (RR, 5.11; 95% CI, 3.18 to 8.21) [ 16 ], (2) KD for 3 months was associated with reduced triglyceride in adults with T2DM compared with regular diet (MD, -18.36 mg/dL; 95% CI, -24.24 to -12.49, MCID threshold 7.96 mg/dL) [ 14 , 35 ], (3) KD for 12 months was associated with reduced triglyceride in adults with T2DM compared with regular diet (MD, -24.10 mg/dL; 95% CI, -33.93 to -14.27, MCID threshold 7.96 mg/dL) [ 14 , 35 ], and (4) KD for 12 months was associated with increased LDL-C in adults with T2DM compared with regular diet (MD, 6.35 mg/dL; 95% CI, 2.02 to 10.69, MCID threshold 3.87 mg/dL) [ 14 , 35 ]. In addition, there were 4 statistically significant associations supported by moderate-quality evidence: (1) KD for 3 months was associated with reduced HbA 1c in adults with T2DM compared with regular diet (MD, -0.61%; 95% CI, -0.82 to -0.40, MCID threshold 0.5%) [ 14 , 35 ], (2) VLCKD for 4–6 weeks was associated with reduced body weight in T2DM adults with overweight or obesity compared with a low-fat diet or regular diet (MD, -9.33 kg; 95% CI, -15.45 to -3.22, MCID threshold 4.40 kg) [ 14 , 15 ], (3) K-LCHF for 4–6 weeks was associated with reduced respiratory exchange ratio in athletes compared with a high-carbohydrate diet (SMD, -2.66; 95% CI, -3.77 to -1.54) [ 39 ], and (4) K-LCHF for 11–24 weeks was associated with increased total cholesterol in athletes compared with regular diet (MD, 1.32 mg/dL; 95% CI, 0.64 to 1.99) [ 14 , 17 ].

Types of KD showed different effects on health outcomes with changes more than the MCID thresholds in different populations (Fig.  2 ). KD or MAD for 3–16 months was associated with a 5-times higher proportion of children and adolescents with refractory epilepsy achieving seizure frequency reduction ≥ 50% from baseline compared with a regular diet (RR, 5.11; 95% CI, 3.18 to 8.21) [ 16 ]. In healthy participants, K-LCHF for 3–12 weeks could reduce body weight by 3.68 kg (95% CI, -4.45 to -2.90) but also significantly reduced muscle mass by 1.27 kg (95% CI, -1.83 to -0.70, MCID threshold 1.10 kg) [ 14 , 26 , 38 ]. In adults with T2DM, KD for 3–12 months was found to have significant associations with changes more than the MCID thresholds, including reduction of triglyceride and HbA 1c ; however, KD for 12 months led to a clinically meaningful increase in LDL-C by 6.35 mg/dL (95% CI, 2.02 to 10.69, MCID threshold 3.87 mg/dL) [ 14 , 35 ]. In adults with overweight or obesity and/or metabolic syndrome, VLCKD for 4–6 weeks demonstrated a clinically meaningful weight loss of 9.33 kg (95% CI, -15.45 to -3.22, MCID threshold 4.40 kg) [ 14 , 15 ]. VLCKD for 3–96 weeks led to a clinically meaningful improvement in BMI, body weight, waist circumference, triglyceride, fat mass, and insulin resistance, while preserving muscle mass [ 42 ].

Associations of Types of Ketogenic Diet with Health Outcomes. Abbreviations: BMI, body mass index, DBP, diastolic blood pressure; GRADE, Grading of Recommendations, Assessment, Development, and Evaluations; HbA 1c , hemoglobin A 1c ; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, homeostatic model of insulin resistance; LDL-C, low-density lipoprotein cholesterol; SBP, systolic blood pressure; TEI, total energy intake

Excluding RCTs with small sizes in 7 associations found that the strength of evidence of one association was downgraded to very low quality, i.e., KD for 12 months, and the increase of LDL-C in adults with T2DM compared with a control diet. Another association was downgraded to low quality, i.e., KD for 12 months and the reduction of triglyceride in adults with T2DM compared with the control diet (Additional file 2 : Table S6). The remaining associations retained the same rank.

This umbrella review was performed to systematically assess the potential associations of KD and health outcomes by summarizing the evidence from meta-analyses of RCTs. Sensitivity analyses were performed to provide additional evidence from high-quality RCTs, which further increased the reliability of results. We identified 115 associations of KD with a wide range of outcomes. Most associations were rated as low and very low evidence according to the GRADE criteria because of serious imprecision and large heterogeneity in findings, and indirectness due to a mix of different interventions and comparators.

Our findings showed that KD or MAD resulted in better seizure control in children and adolescents with medication-refractory epilepsy (approximately a third of cases) for up to 16 months [ 10 , 11 , 16 ]. Anti-epileptic mechanisms of KD remain unknown but are likely multifactorial. Enhanced mitochondrial metabolism and an increase in ketone bodies or reduction in glucose across the blood–brain barrier resulted in synaptic stabilization [ 48 , 49 , 50 ]. Other mechanisms include an increase in gamma-aminobutyric acid (GABA) [ 51 ], more beneficial gut microbiome [ 52 ], less pro-inflammatory markers [ 53 ], and epigenetic modifications (e.g. beta-hydroxybutyrate [beta-OHB]) [ 54 ].

In adults, KD was associated with improved anthropometric measures, cardiometabolic parameters, and exercise performance. Our findings, however, demonstrated differences in the level of associations with type of KD. On the one hand, VLCKD is very effective in producing weight loss while preserving muscle mass in adults with overweight or obesity, with specific benefits on anthropometric and cardiometabolic parameters [ 15 , 42 ]. On the other hand, a significant portion of the weight loss seen in K-LCHF was due to muscle mass loss [ 17 , 38 ]. Overall KD was negatively associated with reduced muscle mass and increased LDL-C and total cholesterol.

Our findings demonstrated that KD could induce a rapid weight loss in the initial phase of 6 months, after which time further weight loss was hardly achieved [ 35 ]. Furthermore, weight loss induced by KD is relatively modest and appears comparable to other dietary interventions that are effective for short-term weight loss, e.g., intermittent fastingand Mediterranean diet [ 55 , 56 , 57 ].

KD is one of the dietary interventions employed by individuals to achieve rapid weight loss, which usually comes with reduced muscle mass [ 58 ]. However, KD has been hypothesized to preserve muscle mass following weight loss based on several mechanisms, including the protective effect of ketones and its precursors on muscle tissue [ 59 , 60 , 61 ], and increased growth hormone secretion stimulated by low blood glucose to increase muscle protein synthesis [ 58 , 62 , 63 ].

With regards to KD effects on lipid profiles, our results demonstrate an effective reduction in serum triglyceride levels with 3 months of lowered dietary carbohydrate intake, with even further reduction by month 12 [ 35 ]. Triglyceride levels are consistently shown to decrease after KD. Acute ketosis (beta-OHB ≈ 3 mM) due to ketone supplementation also shows decreases in triglycerides, indicating a potential effect of ketones on triglycerides independent of weight loss. One possible mechanism is the decreased very low-density lipoprotein content in the plasma due to low insulin levels. Due to a lack of insulin, lipolysis increases in fat cells [ 2 , 13 , 15 ]. Of note, the converse has also been observed as a phenomenon known as carbohydrate-induced hypertriglyceridemia, whereby higher dietary carbohydrate intake leads to higher serum triglycerides levels, potentially mediated by changes in triglyceride clearance and hepatic de novo lipogenesis rates [ 64 ]. Though our aggregate results also confirm an increase in LDL-C and total cholesterol with KD and K-LCHF, respectively, it is important to note that an increase in either of these levels does not necessarily signify a potentially deleterious cardiovascular end-point. This qualification derives from the fact that LDL particles are widely heterogeneous in composition and size, with small dense LDL particles being significantly more atherogenic than larger LDL particles [ 65 ]. Our observed aggregate effect of KD on cholesterol levels does not account for the difference in LDL particle size, nor does it distinguish the sources of dietary fat, which can also be a significant effector of LDL particle size distribution and metabolism [ 66 ].

Most RCTs of KD were conducted in patients with a limited group of participants, such as those with overweight, obesity, metabolic syndrome, cancer, and refractory epilepsy. In addition, most outcomes measured were limited to only surrogate outcomes. Thus, more clinical trials with a broader scope in populations and outcomes associated with KD would expand the role of KD in a clinical setting. For example, participant selection could be expanded from previous trials to include elderly patients, nonalcoholic fatty live disease (NAFLD) patients, and polycystic ovarian syndrome patients. Outcomes of interest of could be expanded to include (1) clinical outcomes such as cardiovascular events and liver outcomes, (2) short- and long-term safety outcomes such as adverse events (e.g., gastrointestinal, neurological, hepatic, and renal), eating disorder syndrome, sleep parameters, lipid profiles, and thyroid function and (3) other outcomes such as adherence and quality of life. More importantly, long-term studies are needed to investigate the sustainability of the clinical benefits of KD.

Our findings are useful to support the generation of evidence-based recommendations for clinicians contemplating use of KD in their patients, as well as for the general population. We further emphasize the importance of consultation with healthcare professionals before utilizing KD and any other dietary interventions. We demonstrated the benefits of KD on various outcomes in the short term. However, these improvements may prove difficult to sustain in the long term because of challenges in adherence. As for any diet interventions to achieve sustainable weight loss, factors of success include adherence, negative energy balance, and high-quality foods. Thus, communication and education with KD practitioners are important to ensure their adherence to the diet. Some individuals might benefit from switching from KD to other dietary interventions to maintain long-term weight loss.

Limitations

This umbrella review has several limitations. Firstly, we focused on published meta-analyses which confined us from assessing the associations of KD on outcomes and populations that were not included in existing meta-analyses. Secondly, most of the included meta-analyses were rated with AMSTAR-2 as critically low confidence, mainly due to a lack of study exclusion reasons, unexplained study heterogeneity, and unassessed publication bias. However, these domains unlikely affected our findings. Thirdly, we could not perform a dose–response analysis to understand the effects of different levels of carbohydrate intake on health outcomes because of insufficient details of carbohydrate intake reported in the meta-analyses. Fourthly, most RCTs of KD were limited to a relatively small number of participants with a short-term follow-up period, which limited our assessment of sustained beneficial effects after stopping KD. Lastly, due to decreased adherence, carbohydrate intake most likely increased across the course of the trials. For example, subjects in the KD arm of the A TO Z Weight Loss Study [ 67 ], started with a carbohydrate intake < 10 g/day but ended at 12 months with a carbohydrate intake accounting for 34% of TEI. In the DIRECT trial, subjects in the KD group started with carbohydrate intake of 20 g/day and ended at 12 months with 40% of TEI from carbohydrate intake [ 68 ]. Thus, we cannot be certain how the precise degree of ketosis contributed to the beneficial effects noted.

Beneficial associations of practicing KD were supported by moderate- to high-quality evidence, including weight loss, lower triglyceride levels, decreased HbA 1c , RER, and decreased seizure frequency. However, KD was associated with a clinically meaningful increase in LDL-C. Clinical trials with long-term follow-up are warranted to investigate whether these short-term effects of KD will translate to beneficial effects on more long-term clinical outcomes such as cardiovascular events and mortality.

Availability of data and materials

All data generated or analysed during this study are included in this published article and its supplementary information files.

Abbreviations

Beta-hydroxybutyrate

Body mass index

Diastolic blood pressure

Gamma-aminobutyric acid

High-density lipoprotein cholesterol

Hemoglobin A 1c

Homeostatic model assessment of insulin resistance

Ketogenic low-carbohydrate high-fat diet

Ketogenic diets

Low-density lipoprotein cholesterol

Modified Atkins diet

Minimally clinically important difference

Nonalcoholic fatty liver disease

Randomized clinical trials

Respiratory exchange ratio

Systolic blood pressure

Type 2 diabetes mellitus

Total energy intake

Very low-calorie ketogenic diet

Maximal oxygen consumption

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Acknowledgements

The authors would like to acknowledge Thunchanok Ingkaprasert and Wachiravit Youngjanin for their editorial assistance.

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Chanthawat Patikorn, Pantakarn Saidoung, Sajesh K. Veettil & Nathorn Chaiyakunapruk

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CP, PS, SKV, and NC conceived and designed the study protocol. CP, PS, and SKV performed a literature review and data analysis. CP, PS, TP, PP, YYL, KAV, SKV, and NC interpreted the study findings. CP and PS were major contributors to writing the manuscript. All authors read and approved the final manuscript.

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Method S1. Data extraction. Table S1. Difference from original review protocol. Table S2. Search strategy. Table S3. Excluded studies with reasons.  Table S4. Quality assessment. Table S5. Summary of associations. Table S6. Sensitivity analyses. 

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Patikorn, C., Saidoung, P., Pham, T. et al. Effects of ketogenic diet on health outcomes: an umbrella review of meta-analyses of randomized clinical trials. BMC Med 21 , 196 (2023). https://doi.org/10.1186/s12916-023-02874-y

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DOI : https://doi.org/10.1186/s12916-023-02874-y

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Component of keto diet plus immunotherapy may reduce prostate cancer

Published: April 26, 2024

Author: Deanna Csomo Ferrell

Adding a pre-ketone supplement — a component of a high-fat, low-carb ketogenic diet — to a type of cancer therapy in a laboratory setting was highly effective for treating prostate cancer, researchers from the University of Notre Dame found.

Recently published online in the journal Cancer Research, the  study from Xin Lu , the John M. and Mary Jo Boler Collegiate Associate Professor in the Department of Biological Sciences, and collaborators tackled a problem oncologists have battled: Prostate cancer is resistant to a type of immunotherapy called immune checkpoint blockade (ICB) therapy. ICB therapy blocks certain proteins from binding with other proteins and paves the way for our body’s fighter cells, T cells, to kill the cancer.

“Prostate cancer is the most common cancer for American men, and immunotherapy has been really influential in some other cancers, like melanoma or lung cancer, but it hasn’t been working almost at all for prostate cancer,” said Lu, who is affiliated with the Boler-Parseghian Center for Rare and Neglected Diseases. Adding a dietary supplement might overcome this resistance, the lead author in the study, Sean Murphy, suggested.

Murphy, a ’24 alumnus who was a doctoral student in Lu’s lab, had been following a keto diet himself. Knowing that cancer cells feed off of sugar, he decided that depriving mouse models of carbohydrates — a key component of the keto diet — might prevent cancer growth.

He divided the models into different groups: immunotherapy alone, ketogenic diet alone, a pre-ketone supplement alone, the ketogenic diet with the immunotherapy, the supplement with the immunotherapy, and the control. While the immunotherapy alone had almost no effect on the tumors (just like what happens to most patients with prostate cancer), both the ketogenic diet with the immunotherapy and the pre-ketone supplement with the immunotherapy reduced the cancer and extended the lives of the mouse models.

The supplement with the immunotherapy worked best.

“It turned out this combination worked really well,” Lu said. “It made the tumor become very sensitive to the immunotherapy, with 23 percent of the mice cured — they were tumor-free; in the rest, the tumors were shrinking really dramatically.”

The evidence points to the possibility that a supplement providing ketones, which are what is produced in the body when people eat a keto diet, might prevent the prostate cancer cells from being resistant to immunotherapy. This may lead to future clinical studies that examine how ketogenic diets or keto supplements could enhance cancer therapy.

While keto diets allow for minimal carbohydrates, the success of this study is not about the lack of carbohydrates, Murphy and Lu stressed. It is about the presence of the ketone body, a substance produced by the liver and used as an energy source when glucose is not available. The ketones disrupt the cycle of the cancer cells, allowing the T cells to do their job to destroy them.

The discovery was also exciting on a molecular level, Lu said. Any type of dietary study can suffer from the potential issue of causation: Are the results from the diet or other changes made because of the diet? But Lu and his collaborators confirmed their results using single-cell RNA sequencing, which examines the gene expression of single cells within the tumor.

“We found that this combination of the supplement and the immunotherapy reprogrammed the whole immune profile of the tumors and recruited many T cells into the tumors to kill prostate cancer cells,” Lu said.

The successful therapy also reduced the number of a type of immune cell called neutrophils. Once in the tumor microenvironment, neutrophils’ natural properties become greatly distorted, and they become largely responsible for inhibiting T cell activities and allowing more tumor progression. Dysregulation of neutrophils is also associated with many other diseases.

“With the main ketone body depleting neutrophils, it opens the door for investigating the effects of the keto diet and the ketone supplement on diseases ranging from inflammatory bowel disease to arthritis,” Murphy said.

“What’s exciting is that we’re getting closer to the mechanism, backed up by genetic models and what we’re seeing in the tumors themselves, of why this works,” he said.

Co-authors include Sharif Rahmy, Dailin Gan, Guoqiang Liu, Yini Zhu, Maxim Manyak, Loan Duong, Jianping He, James H. Schofield, Zachary T. Schafer, Jun Li and Xuemin Lu, all from the University of Notre Dame.

The research was supported by a grant from the American Institute for Cancer Research, funding from the National Institutes of Health and a core facility grant from Indiana Clinical and Translational Sciences Institute. Other support included the Department of Defense and the Boler Family Foundation at the University of Notre Dame. A provisional patent application has been filed based on this study by the IDEA Center at Notre Dame.

Contact: Jessica Sieff , associate director of media relations, 574-631-3933, [email protected]

Originally published by Deanna Csomo Ferrell at news.nd.edu on April 26, 2024 .

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Why Does the Keto Diet Cause a Skin Rash?

Keto rash, or prurigo pigmentosa , is a rare inflammatory skin problem. Also called Nagashima disease, the keto rash causes an itchy rash with vesicles (fluid-filled blisters). It often appears on your neck and trunk. The blisters change and crust into darker-pigmented spots that form a netlike pattern.

The keto rash is often linked to the ketogenic (keto) diet or health conditions that produce ketosis . In this state, your body uses stored fat rather than glucose for energy. The ketogenic diet is a low-carbohydrate, high-fat eating plan. It is most often recommended to treat people with epilepsy that is hard to control.

Treatments for the keto rash include home cures like increasing carbohydrate intake and making up for vitamin deficiencies. Antibiotics and other drugs are often useful when these treatments don't work.

This article explains all you need to know about the keto rash, its causes, treatments, and ways to prevent it.

Maskot / Getty Images

What Does the Keto Rash Look Like?

The appearance of a keto rash can vary based on your skin tone and texture. Most case reports are in people in Asia and the Middle East, with some reports in White or Hispanic people. Descriptions of the rash in people of darker skin tones are lacking.

The condition includes the following characteristics:

• Inflamed, itchy, red papules (small, well-defined skin bumps) or vesicles
• Symmetrical distribution of spots on your trunk and neck
• Occasional appearance of spots on your face, scalp, and suprapubic region (lower abdomen and groin)
• Rare involvement of mucous membranes , hair, and nails
• Formation of a netlike pattern of dark spots as the inflammatory phase of the rash ends and the bumps scale and crust

While a keto rash can affect anyone, it is most common among people of Asian descent. It affects women twice as often as men, though it may be due to a higher prevalence of dieting behaviors among women than men.

A keto rash typically occurs 31 days after starting a keto diet. For most people, the rash subsides about 18 days after ending the keto diet.

A Note on Gender and Sex Terminology

Verywell Health acknowledges that  sex and gender  are related concepts, but they are not the same. To reflect our sources accurately, this article uses terms like “female,” “male,” “woman,” and “man” as the sources use them.

What Causes a Keto Rash?

The exact cause of a keto rash is not known. The rash is named as a result of its link to the ketogenic diet.

A ketogenic diet involves limiting protein and carbohydrates, so most of your energy is produced from fat. The lack of carbohydrates in the diet triggers a state of ketosis, in which your body derives energy from the breakdown of fat. Ketosis can also be triggered by fasting , insulin-dependent diabetes, or bariatric surgery .

There is growing evidence that the connection between the keto rash and ketogenesis may involve the  gut microbiome  (the microorganisms in your digestive tract ). An imbalance in the gut microbiome triggered by ketogenesis may impact a person's immune response, leading to a keto rash.

In addition to ketosis, the following potential triggers for the condition have been identified:

• Friction from clothing
• Chromium in acupuncture needles
• Atopic dermatitis  (eczema)
• Anorexia nervosa  (eating disorder)
• Rapid weight loss
• Sjögren’s syndrome  (an autoimmune disease that affects moisture-producing glands and tissues)
• Helicobacter pylori  ( H. pylori ) infection (bacterial infection)

A Word From Verywell

It's always best to let your provider know if you plan to start the ketogenic diet since it can cause adverse health effects for some people. Also, let your provider know if you are experiencing keto rash symptoms in order to get proper treatment and eliminate other more serious causes of the rash.

How to Treat the Keto Rash

The best way to treat a keto rash varies by individual. Contact a healthcare provider regarding the onset of a keto rash or any rash that persists and worsens. Some of the following strategies may provide relief or even resolve symptoms.

Reintroduce Carbohydrates

You may be able to treat a keto rash by reintroducing carbohydrates without returning to average carbohydrate intake levels. This may help you maintain the benefits of a keto diet without the side effect of a keto rash.

Research indicates that modifying carbohydrate intake with guidance from a registered dietitian nutritionist (RDN) trained in ketogenic therapies can help achieve lower prescribed carbohydrate levels. There is evidence that maintaining these defined carbohydrate levels can reduce the keto rash without sacrificing ketogenesis.

Correct Nutrient Deficiencies

Removing entire food groups from your diet can lead to nutrient deficiencies. Research indicates that certain nutrient deficiencies manifest as skin disorders.

Consuming a low-carbohydrate diet like the keto diet increases the risk of nutritional deficiencies due to a lack of nutrients from vegetables, fruits, whole grains, and legumes. As a result, low-carb diets are often insufficient in the following nutrients:

Eliminate Food Allergens

Following a keto diet involves increasing your intake of fats to meet the high-fat requirement. Unfortunately, keto-friendly foods such as eggs, dairy, fish, and nuts, which meet this criteria, are among the most common food allergens .

If you have a specific food allergy, consuming the allergen can trigger or worsen a rash. It is important to have the allergy diagnosed and then avoid the specific food allergen.

According to the American College of Allergy, Asthma, and Immunology, the following eight types of foods account for 90% of all adverse food reactions:

• Milk and dairy

Depending on your level of sensitivity, a food allergy can trigger life-threatening effects. Get immediate medical help if you have any of the following signs of a food allergy:

• Vomiting and/or stomach cramps
• Shortness of breath
• Repetitive cough
• Shock or circulatory collapse (interruption of blood circulation)
• Tight, hoarse throat; trouble swallowing
• Swollen tongue , affecting your ability to breathe or talk
• Pale or blue skin color
• Dizziness or feeling faint
• Anaphylaxis (a life-threatening reaction that can impair breathing and send your body into shock; possibly with multiple allergic symptoms)

Incorporate Anti-Inflammatory Supplements

There is some evidence that certain nutritional supplements may help reduce inflammation in the treatment of atopic dermatitis (eczema). While the research is inconclusive and warrants further investigation, symptom improvement of skin disorders has been linked to the following nutrients:

• Evening primrose oil
• Prebiotics and probiotics

Take Care of Your Skin

To care for skin affected by a keto rash, follow these general guidelines to protect the affected area and relieve symptoms of inflammation and itching:

• Avoid scrubbing your skin when bathing or scratching to relieve itching.
• Use fragrance-free and dye-free gentle cleansers.
• Discontinue the use of cosmetic lotions or ointments.
• When bathing, use warm (not hot) water and avoid scrubbing with a washcloth or loofah.
• Pat dry, don't rub your skin after bathing.
• Allow the affected area to remain exposed to the air whenever possible.
• Add colloidal oatmeal to a lukewarm bath to relieve itching.
• Try the following topical treatments: moisturizers, calamine lotion , hydrocortisone cream (1%)

Discuss Medications With a Healthcare Provider

Depending on your symptoms and the extent of your rash, your healthcare provider may recommend medications to treat your keto rash.

Research indicates that oral and/or topical prescription medications can resolve a keto rash within 18 days when combined with discontinuation of the ketogenic diet. A commonly used treatment is oral doxycycline , ranging from 100 to 200 milligrams daily for two weeks to two months.

Your healthcare provider can determine the best medication for your condition, which may include the following:

• Oral minocycline
• Topical steroids
• Topical antibiotics
• Oral antihistamines
• Oral prednisolone
• Topical antifungals

How to Prevent a Keto Rash

Any drastic dietary change can trigger side effects. Reducing your carbohydrate intake to a very low level very quickly is likely to increase your risk of developing a keto rash.

While there is no definitive way to prevent a keto rash since its cause is unknown, you may be able to reduce your risk of having the condition by taking the following measures:

• Consult a healthcare provider before starting a ketogenic diet to develop a plan of action that involves a safe, slow transition into a new eating plan.
• Don't ignore any rash symptoms, no matter how minor. Try increasing your carbohydrate intake at the first sign of a rash to prevent symptoms from becoming worse. If the ketogenic diet has been prescribed for epilepsy, discuss the rash and any recommended dietary changes to relieve it with a healthcare provider.
• Consult a healthcare provider to discuss the types of vitamins and minerals needed to balance a keto diet to avoid deficiencies.
• Stay hydrated by drinking as much water as possible and limiting caffeinated beverages.

The keto rash is a blister-like rash often linked to the keto diet or other causes of ketosis. Ketosis is the state in which your body uses fat rather than glucose for fuel.

The keto diet is mainly used to treat drug-resistant epilepsy. However, it has also been used for weight loss and diabetes management.

Your risk of having a keto rash or other symptoms may increase as your body adjusts to a keto diet. While it may have healthful uses, the keto diet is a very strict eating plan. It is best started with the oversight of a healthcare provider.

Contact your healthcare provider if you are following a keto diet and notice any signs of a skin rash or other irritation. While a rash can be linked to the keto diet, it can also be a sign of health conditions that require treatment.

American Osteopathic College of Dermatology (AOCD). Purigo pigmentosa .

D'Andrea Meira I, Romão TT, Pires do Prado HJ, Krüger LT, Pires MEP, da Conceição PO.  Ketogenic diet and epilepsy: what we know so far .  Front Neurosci . 2019;13:5. doi:10.3389/fnins.2019.00005

Xiao A, Kopelman H, Shitabata P, Nami N. Ketogenic diet-induced prurigo pigmentosa (the “keto rash”): a case report and literature review .  J Clin Aesthet Dermatol . 2021;14(12 Suppl 1):S29-S32.

Wong M, Lee E, Wu Y, Lee R.  Treatment of prurigo pigmentosa with diet modification: a medical case study .  Hawaii J Med Public Health . 2018;77(5):114-117.

Wong CY, Chu DH. Cutaneous signs of nutritional disorders .  Int J Womens Dermatol . 2021;7(5Part A):647-652. doi:10.1016/j.ijwd.2021.09.003

Crosby L, Davis B, Joshi S, et al. Ketogenic diets and chronic disease: weighing the benefits against the risks.   Front Nutr . 2021;8:702802. doi:10.3389/fnut.2021.702802

Harvard T.H. Chan School of Public Health. The nutrition source: diet review: ketogenic diet for weight loss .

American College of Allergy, Asthma, and Immunology. Food allergy .

Mohajeri S and Newman SA. Review of evidence for dietary influences on atopic dermatitis . Skin Therapy Letter . 2014:19(4).

Schlichte MJ, Vandersall A, Katta R. Diet and eczema: a review of dietary supplements for the treatment of atopic dermatitis .  Dermatol Pract Concept . 2016;6(3):23-29. doi:10.5826/dpc.0603a06

Penn Medicine. Rash .

Mercy. Nine things to know before kick starting a keto diet .

By Anna Giorgi Giorgi is a freelance writer with more than 25 years of experience writing health and wellness-related content.

Keto Research

Welcome to Keto Research.  

Research into ketogenic diets is scattered around the internet and often difficult to interpret. The purpose of this site is to accumulate the research in the forms of videos and research papers and make them available to the public. The videos are largely taken from presentations made by experts in the fields of nutrition, diabetes, and heart disease.  The research papers represent some of the most up-to-date findings on ketogenic diet and its impact on health.

Stephen O'Brien

FEATURED VIDEO

STARTING KETO? ADVICE FROM EXPERTS

Information from ruled.me .

What are ketones?

Beginner's guide.

A little more science.

If you are starting keto, you may benefit from the information at ruled.me .

THE SCIENCE

Dr. Stephen Phinney - Part I

Dr.. Stephen Phinney - Part II

Dr. Jason Fung

Dr. Paul Mason

PERSONAL STORIES

One Doctor's Experience

One Person's Experience

20 Years Experience

Why eat keto.

LDL AND CHOLESTEROL

Evaluating LDL

Interpreting LDL Scores

Making Sense of LDL

Understanding LDL

HOW DID FAT GET A BAD NAME?

The Big Fat Surprise

How It Happened

Dietary Guidelines

Vegan Keto for a day

Vegan Keto Experience

Vegan Keto Nutrition

My take: The ketogenic and vegan diets are both restrictive. When combining the two, the resulting set of allowed foods in quite small. In my opinion, a keto-vegan diet is so severely restrictive that it would be difficult to maintain long term. It will also be difficult to get all the vital nutrients your body needs.

VEG ETARIAN KETO

Guide to vegetarian keto

Vegetarian keto recipies

Low Carb Veggie Recipies

Veggie Keto

My take: Expanding the veggie portion of a ketogenic diet makes a lot of sense. But, there are certain nutrients (esp. vitamin B12 and EPA) that can be difficult to get from non-animal sources. My opinion is that eggs should be a part of any ketogenic diet.

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Effects of ketogenic diet on health outcomes: an umbrella review of meta-analyses of randomized clinical trials

Chanthawat patikorn.

1 Department of Pharmacotherapy, College of Pharmacy, University of Utah, 30 2000 E, Salt Lake City, Utah 84112 USA

2 Department of Social and Administrative Pharmacy, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand

Pantakarn Saidoung

3 Division of Gastroenterology, Hepatology & Nutrition, Department of Internal Medicine, University of Utah, Salt Lake City, Utah USA

Pochamana Phisalprapa

4 Division of Ambulatory Medicine, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand

Yeong Yeh Lee

5 School of Medical Sciences, Universiti Sains Malaysia, Kota Bharu, Malaysia

Krista A. Varady

6 Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois USA

Sajesh K. Veettil

Nathorn chaiyakunapruk.

7 IDEAS Center, Veterans Affairs Salt Lake City Healthcare System, Salt Lake City, Utah USA

Associated Data

All data generated or analysed during this study are included in this published article and its supplementary information files.

Systematic reviews and meta-analyses of randomized clinical trials (RCTs) have reported the benefits of ketogenic diets (KD) in various participants such as patients with epilepsy and adults with overweight or obesity . Nevertheless, there has been little synthesis of the strength and quality of this evidence in aggregate.

To grade the evidence from published meta-analyses of RCTs that assessed the association of KD, ketogenic low-carbohydrate high-fat diet (K-LCHF), and very low-calorie KD (VLCKD) with health outcomes, PubMed, EMBASE, Epistemonikos, and Cochrane database of systematic reviews were searched up to February 15, 2023. Meta-analyses of RCTs of KD were included. Meta-analyses were re-performed using a random-effects model. The quality of evidence per association provided in meta-analyses was rated by the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) criteria as high, moderate, low, and very low.

We included 17 meta-analyses comprising 68 RCTs (median [interquartile range, IQR] sample size of 42 [20–104] participants and follow-up period of 13 [8–36] weeks) and 115 unique associations. There were 51 statistically significant associations (44%) of which four associations were supported by high-quality evidence (reduced triglyceride ( n  = 2), seizure frequency ( n  = 1) and increased low-density lipoprotein cholesterol (LDL-C) ( n  = 1)) and four associations supported by moderate-quality evidence (decrease in body weight, respiratory exchange ratio (RER), hemoglobin A 1c , and increased total cholesterol). The remaining associations were supported by very low (26 associations) to low (17 associations) quality evidence. In overweight or obese adults, VLCKD was significantly associated with improvement in anthropometric and cardiometabolic outcomes without worsening muscle mass, LDL-C, and total cholesterol. K-LCHF was associated with reduced body weight and body fat percentage, but also reduced muscle mass in healthy participants.

Conclusions

This umbrella review found beneficial associations of KD supported by moderate to high-quality evidence on seizure and several cardiometabolic parameters. However, KD was associated with a clinically meaningful increase in LDL-C. Clinical trials with long-term follow-up are warranted to investigate whether the short-term effects of KD will translate to beneficial effects on clinical outcomes such as cardiovascular events and mortality.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12916-023-02874-y.

Ketogenic diets (KD) have received substantial attention from the public primarily due to their ability to produce rapid weight loss in the short run [ 1 , 2 ]. The KD eating pattern severely restricts carbohydrate intake to less than 50 g/day while increasing protein and fat intake [ 3 – 6 ]. Carbohydrate deprivation leads to an increase in circulating ketone bodies by breaking down fatty acids and ketogenic amino acids. Ketones are an alternative energy source from carbohydrates that alter physiological adaptations. These adaptions have been shown to produce weight loss with beneficial health effects by improving glycemic and lipid profiles [ 7 , 8 ]. KD has also been recommended as a nonpharmacological treatment for medication-refractory epilepsy in children and adults [ 8 , 9 ]. Evidence suggests that KD has reduced seizure frequency in patients with medication-refractory epilepsy, and even allowing some patients to reach complete and sustained remission. 11 However, the exact anticonvulsive mechanism of KD remains unclear [ 10 , 11 ].

Several systematic reviews and meta-analyses of randomized clinical trials (RCTs) have reported on the use of KD in patients with obesity or type 2 diabetes mellitus (T2DM) to control weight and improve cardiometabolic parameters [ 1 , 12 – 15 ], in patients with refractory epilepsy to reduce seizure frequency [ 16 ], and in athletes to control weight and improve performance [ 17 ]. To date, there has been little synthesis of the strength and quality of this evidence in aggregate. This umbrella review therefore aims to systematically identify relevant meta-analyses of RCTs of KD, summarize their findings, and assess the strength of evidence of the effects of KD on health outcomes.

The protocol of this study was registered with PROSPERO (CRD42022334717). We reported following the 2020 Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) (Additional file 1 ) [ 18 ]. Difference from the original review protocol is described with rationale in Additional file 2 : Table S1.

Search strategy and eligibility criteria

We searched PubMed, EMBASE, Epistemonikos, and the Cochrane database of systematic reviews (CDSR) from the database inception to February 15, 2023 (Additional file 2 : Table S2). No language restriction was applied. Study selection was independently performed in EndNote by two reviewers (C.P. and PS). After removing duplicates, the identified articles' titles and abstracts were screened for relevance. Full-text articles of the potentially eligible articles were retrieved and selected against the eligibility criteria. Any discrepancies were resolved by discussion with the third reviewer (SKV).

We included studies that met the following eligibility criteria: systematic reviews and meta-analyses of RCTs investigating the effects of any type of KD on any health outcomes in participants with or without any medical conditions compared with any comparators. When more than 1 meta-analysis was available for the same research question, we selected the meta-analysis with the largest data set [ 19 – 21 ]. Articles without full-text and meta-analyses that provided insufficient or inadequate data for quantitative synthesis were excluded.

Data extraction and quality assessment

Two reviewers (CP and PS) independently performed data extraction and quality assessment (Additional file 2 : Method S1). Discrepancies were resolved with consensus by discussing with the third reviewer (SKV). We used AMSTAR- 2 -A Measurement Tool to Assess Systematic Reviews- to grade the quality of meta-analyses as high, moderate, low, or critically low by assessing the following elements, research question, a priori protocol, search, study selection, data extraction, quality assessment, data analysis, interpretation, heterogeneity, publication bias, source of funding, conflict of interest [ 22 ].

Data synthesis

For each association, we extracted effect sizes (mean difference [MD], the standardized mean difference [SMD], and risk ratio [RR]) of individual studies included in each meta-analysis and performed the meta-analyses to calculate the pooled effect sizes and 95% CIs using a random-effects model under DerSimonian and Laird [ 23 ], or the Hartung-Knapp- Sidik-Jonkman approach for meta-analyses with less than five studies [ 24 ].  p  < 0.05 was considered statistically significant in 2-sided tests. Heterogeneity was evaluated using the I 2 statistic. The evidence for small-study effects was assessed by the Egger regression asymmetry test [ 25 ]. Statistical analyses were conducted using Stata version 16.0 (StataCorp). We presented effect sizes of statistically significant associations with the known or estimated minimally clinically important difference (MCID) thresholds for health outcomes [ 14 , 26 – 30 ].

We assessed the quality of evidence per association by applying the GRADE criteria (Grading of Recommendations, Assessment, Development, and Evaluations) in five domains, including (1) risk of bias in the individual studies, (2) inconsistency, (3) indirectness, (4) imprecision, and (5) publication bias [ 31 ]. We graded the strength of evidence (high, moderate, low, and very low) using GRADEpro version 3.6.1 (McMaster University).

Sensitivity analyses

Sensitivity analyses were performed by excluding small-size studies (< 25 th percentile) [ 32 ] and excluding primary studies having a high risk of bias rated by the Cochrane’s risk of bias 2 tool (RoB 2) for RCTs from the identified associations [ 19 – 21 , 33 ].

Seventeen meta-analyses were included (Fig.  1 and Additional file 2 : Table S3) [ 1 , 2 , 15 – 17 , 34 – 45 ]. These meta-analyses comprised 68 unique RCTs with a median (interquartile range, IQR) sample size per RCT of 42 (20–104) participants and a median (IQR) follow-up period of 13 (8–36) weeks. The quality of meta-analyses assessed using AMSTAR-2 found that none were rated as high confidence, 2 (12%) as moderate confidence, 2 (12%) as low confidence, and 13 (76.0%) as critically low confidence (Table ​ (Table1 1 and Additional file 2 : Table S4).

Study selection flow of meta-analyses. Abbreviation: CDSR, Cochrane database of systematic review

Characteristics of meta-analyses of randomized clinical trials studying ketogenic diet

Abbreviations : AMSTAR-2 A Measurement Tool to Assess Systematic Reviews, BMI body mass index, CRP C-reactive protein, DBP diastolic blood pressure, FPG fasting plasma glucose, HbA 1c hemoglobin A 1c , HCD high carbohydrate diet, HDL-C high-density lipoprotein cholesterol, HOMA-IR homeostatic model of insulin resistance, K-LCHF ketogenic low-carbohydrate high-fat diet, KD ketogenic diet, LCD low-calorie diet, LDL-C low-density lipoprotein cholesterol, LFD low-fat diet, MAD modified Atkins diet, RD regular diet, SBP systolic blood pressure, T2DM type 2 diabetic mellitus, TC total cholesterol, TG triglyceride, VLCKD very low-calorie ketogenic diet, VO 2 max maximum oxygen consumption, VO 2 peak peak oxygen consumption

Types of KD identified in this umbrella review were categorized as (1) KD, which limits carbohydrate intake to < 50 g/day or < 10% of the total energy intake (TEI) [ 35 ], (2) ketogenic low-carbohydrate, high-fat diet (K-LCHF), which limits carbohydrate intake to < 50 g/day or < 10% of TEI with high amount of fat intake (60–80% of TEI) [ 38 , 46 ], (3) very low-calorie KD (VLCKD), which limits carbohydrate intake to < 30–50 g/day or 13–25% of TEI with TEI < 700–800 kcal/day, and (4) modified Atkins diet (MAD), which generally limits carbohydrate intake to < 10 g/day while encouraging high-fat foods [ 15 , 47 ]. Meta-analyses of long-chain triglyceride KD, medium-chain triglyceride KD, and low glycemic index treatment were not identified.

Description and summary of associations

We identified 115 unique associations of KD with health outcomes (Additional file 2 : Table S5). The median (IQR) number of studies per association was 3 [ 4 – 6 ], and the median (IQR) sample size was 244 (127–430) participants. Outcomes were associated with KD types, including 40 (35%) KD, 18 (16%) K-LCHF, 13 (11%) VLCKD, 25 (22%) KD or K-LCHF, 5 (4%) KD or VLCKD, 1 (1%) KD or MAD, and 13 (11%) KD, K-LCHF, or VLCKD.

The associations involved 40 (35%) anthropometric measures (i.e., body weight, body mass index [BMI] [calculated as weight in kilograms divided by height in meters squared], waist circumference, muscle mass, fat mass, body fat percentage, and visceral adipose tissue), 37 (32%) lipid profile outcomes (i.e., triglyceride, total cholesterol, high-density lipoprotein cholesterol [HDL-C], and low-density lipoprotein cholesterol [LDL-C]), 22 (19%) glycemic profile outcomes (i.e., hemoglobin A 1c [HbA 1c ], fasting plasma glucose, fasting insulin, and homeostatic model assessment of insulin resistance [HOMA-IR]), 6 (5%) exercise performance (i.e., maximal heart rate, respiratory exchange ratio [RER], maximal oxygen consumption (VO 2 max), 5 (4%) blood pressure outcomes (i.e., systolic blood pressure [SBP], diastolic blood pressure [DBP], and heart rate), 1 (1%) outcome associated with seizure frequency reduction ≥ 50% from baseline, and 3 other outcomes (i.e., serum creatinine, C-peptide, and C-reactive protein). In addition, there is 1 association (1%) of adverse events.

Participants in the identified associations included 68 (59%) associations in adults with overweight or obesity with or without T2DM or dyslipidemia, 15 (13%) athletes or resistance-trained adults, 12 (10%) adults with T2DM, 11 (10%) healthy participants ≥ 16 years old, 8 (7%) cancer patients, and 1 (1%) in children and adolescents with epilepsy.

Using GRADE, 115 associations were supported by very low strength of evidence ( n  = 66, 57%), with the remaining being low ( n  = 36, 31%), moderate ( n  = 9, 8%), and high quality of evidence ( n  = 4, 3%) (Additional file 2 : Table S5). Almost half, or 44% (51 associations), were statistically significant based on a random-effects model, of which 51% (26 associations) were supported by a very low level of evidence, followed by low (17 associations [33%]), moderate (4 associations [8%]), and high (4 associations [8%]) levels of evidence. Overall beneficial outcomes associated with KD were BMI [ 37 , 42 ], body weight [ 1 , 2 , 35 – 37 , 41 ], waist circumference [ 37 , 42 ], fat mass [ 37 , 42 ], body fat percentage [ 38 , 40 ], visceral adipose tissue [ 37 ], triglyceride [ 1 , 2 , 36 , 42 ], HDL-C [ 1 , 2 , 42 ], HbA 1c  [ 2 , 34 , 35 ],  HOMA-IR [ 2 , 42 ], DBP [ 1 ], seizure frequency reduction ≥ 50% from baseline [ 16 ], and respiratory exchange ratio [ 17 , 39 ]. Adverse outcomes associated with KD were reduced muscle mass [ 37 , 38 ], and increased LDL-C [ 2 , 35 ], and total cholesterol [ 2 , 17 ]. In terms of safety, one association showed no significant increase in adverse events (e.g., constipation, abdominal pain, and nausea) with KD [ 44 ].

Eight out of 13 associations supported by moderate to high-quality evidence were statistically significant (Table ​ (Table2). 2 ). There were 4 statistically significant associations supported by high-quality evidence, including the following: (1) KD or MAD for 3–16 months was associated with a higher proportion of children and adolescents with refractory epilepsy achieving seizure frequency reduction ≥ 50% from baseline compared with regular diet (RR, 5.11; 95% CI, 3.18 to 8.21) [ 16 ], (2) KD for 3 months was associated with reduced triglyceride in adults with T2DM compared with regular diet (MD, -18.36 mg/dL; 95% CI, -24.24 to -12.49, MCID threshold 7.96 mg/dL) [ 14 , 35 ], (3) KD for 12 months was associated with reduced triglyceride in adults with T2DM compared with regular diet (MD, -24.10 mg/dL; 95% CI, -33.93 to -14.27, MCID threshold 7.96 mg/dL) [ 14 , 35 ], and (4) KD for 12 months was associated with increased LDL-C in adults with T2DM compared with regular diet (MD, 6.35 mg/dL; 95% CI, 2.02 to 10.69, MCID threshold 3.87 mg/dL) [ 14 , 35 ]. In addition, there were 4 statistically significant associations supported by moderate-quality evidence: (1) KD for 3 months was associated with reduced HbA 1c in adults with T2DM compared with regular diet (MD, -0.61%; 95% CI, -0.82 to -0.40, MCID threshold 0.5%) [ 14 , 35 ], (2) VLCKD for 4–6 weeks was associated with reduced body weight in T2DM adults with overweight or obesity compared with a low-fat diet or regular diet (MD, -9.33 kg; 95% CI, -15.45 to -3.22, MCID threshold 4.40 kg) [ 14 , 15 ], (3) K-LCHF for 4–6 weeks was associated with reduced respiratory exchange ratio in athletes compared with a high-carbohydrate diet (SMD, -2.66; 95% CI, -3.77 to -1.54) [ 39 ], and (4) K-LCHF for 11–24 weeks was associated with increased total cholesterol in athletes compared with regular diet (MD, 1.32 mg/dL; 95% CI, 0.64 to 1.99) [ 14 , 17 ].

Summary of significant associations of ketogenic diet with health outcomes supported by moderate to high quality of evidence

Abbreviations : GRADE Grading of Recommendations, Assessment, Development, and Evaluations, HbA 1c hemoglobin A 1c , HCD high carbohydrate diet, K-LCHF ketogenic low-carbohydrate high-fat diet, KD ketogenic diet, LCD low-calorie diet, LDL-C low-density lipoprotein cholesterol, LFD low-fat diet, MAD modified Atkins diet, MD mean difference, MCID minimally clinically important difference, N/A not applicable, RD regular diet, RR risk ratio, SMD standardized mean difference, T2DM type 2 diabetes mellitus, VLCKD very low-calorie ketogenic diet

Types of KD showed different effects on health outcomes with changes more than the MCID thresholds in different populations (Fig.  2 ). KD or MAD for 3–16 months was associated with a 5-times higher proportion of children and adolescents with refractory epilepsy achieving seizure frequency reduction ≥ 50% from baseline compared with a regular diet (RR, 5.11; 95% CI, 3.18 to 8.21) [ 16 ]. In healthy participants, K-LCHF for 3–12 weeks could reduce body weight by 3.68 kg (95% CI, -4.45 to -2.90) but also significantly reduced muscle mass by 1.27 kg (95% CI, -1.83 to -0.70, MCID threshold 1.10 kg) [ 14 , 26 , 38 ]. In adults with T2DM, KD for 3–12 months was found to have significant associations with changes more than the MCID thresholds, including reduction of triglyceride and HbA 1c ; however, KD for 12 months led to a clinically meaningful increase in LDL-C by 6.35 mg/dL (95% CI, 2.02 to 10.69, MCID threshold 3.87 mg/dL) [ 14 , 35 ]. In adults with overweight or obesity and/or metabolic syndrome, VLCKD for 4–6 weeks demonstrated a clinically meaningful weight loss of 9.33 kg (95% CI, -15.45 to -3.22, MCID threshold 4.40 kg) [ 14 , 15 ]. VLCKD for 3–96 weeks led to a clinically meaningful improvement in BMI, body weight, waist circumference, triglyceride, fat mass, and insulin resistance, while preserving muscle mass [ 42 ].

Associations of Types of Ketogenic Diet with Health Outcomes. Abbreviations: BMI, body mass index, DBP, diastolic blood pressure; GRADE, Grading of Recommendations, Assessment, Development, and Evaluations; HbA 1c , hemoglobin A 1c ; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, homeostatic model of insulin resistance; LDL-C, low-density lipoprotein cholesterol; SBP, systolic blood pressure; TEI, total energy intake

Excluding RCTs with small sizes in 7 associations found that the strength of evidence of one association was downgraded to very low quality, i.e., KD for 12 months, and the increase of LDL-C in adults with T2DM compared with a control diet. Another association was downgraded to low quality, i.e., KD for 12 months and the reduction of triglyceride in adults with T2DM compared with the control diet (Additional file 2 : Table S6). The remaining associations retained the same rank.

This umbrella review was performed to systematically assess the potential associations of KD and health outcomes by summarizing the evidence from meta-analyses of RCTs. Sensitivity analyses were performed to provide additional evidence from high-quality RCTs, which further increased the reliability of results. We identified 115 associations of KD with a wide range of outcomes. Most associations were rated as low and very low evidence according to the GRADE criteria because of serious imprecision and large heterogeneity in findings, and indirectness due to a mix of different interventions and comparators.

Our findings showed that KD or MAD resulted in better seizure control in children and adolescents with medication-refractory epilepsy (approximately a third of cases) for up to 16 months [ 10 , 11 , 16 ]. Anti-epileptic mechanisms of KD remain unknown but are likely multifactorial. Enhanced mitochondrial metabolism and an increase in ketone bodies or reduction in glucose across the blood–brain barrier resulted in synaptic stabilization [ 48 – 50 ]. Other mechanisms include an increase in gamma-aminobutyric acid (GABA) [ 51 ], more beneficial gut microbiome [ 52 ], less pro-inflammatory markers [ 53 ], and epigenetic modifications (e.g. beta-hydroxybutyrate [beta-OHB]) [ 54 ].

In adults, KD was associated with improved anthropometric measures, cardiometabolic parameters, and exercise performance. Our findings, however, demonstrated differences in the level of associations with type of KD. On the one hand, VLCKD is very effective in producing weight loss while preserving muscle mass in adults with overweight or obesity, with specific benefits on anthropometric and cardiometabolic parameters [ 15 , 42 ]. On the other hand, a significant portion of the weight loss seen in K-LCHF was due to muscle mass loss [ 17 , 38 ]. Overall KD was negatively associated with reduced muscle mass and increased LDL-C and total cholesterol.

Our findings demonstrated that KD could induce a rapid weight loss in the initial phase of 6 months, after which time further weight loss was hardly achieved [ 35 ]. Furthermore, weight loss induced by KD is relatively modest and appears comparable to other dietary interventions that are effective for short-term weight loss, e.g., intermittent fastingand Mediterranean diet [ 55 – 57 ].

KD is one of the dietary interventions employed by individuals to achieve rapid weight loss, which usually comes with reduced muscle mass [ 58 ]. However, KD has been hypothesized to preserve muscle mass following weight loss based on several mechanisms, including the protective effect of ketones and its precursors on muscle tissue [ 59 – 61 ], and increased growth hormone secretion stimulated by low blood glucose to increase muscle protein synthesis [ 58 , 62 , 63 ].

With regards to KD effects on lipid profiles, our results demonstrate an effective reduction in serum triglyceride levels with 3 months of lowered dietary carbohydrate intake, with even further reduction by month 12 [ 35 ]. Triglyceride levels are consistently shown to decrease after KD. Acute ketosis (beta-OHB ≈ 3 mM) due to ketone supplementation also shows decreases in triglycerides, indicating a potential effect of ketones on triglycerides independent of weight loss. One possible mechanism is the decreased very low-density lipoprotein content in the plasma due to low insulin levels. Due to a lack of insulin, lipolysis increases in fat cells [ 2 , 13 , 15 ]. Of note, the converse has also been observed as a phenomenon known as carbohydrate-induced hypertriglyceridemia, whereby higher dietary carbohydrate intake leads to higher serum triglycerides levels, potentially mediated by changes in triglyceride clearance and hepatic de novo lipogenesis rates [ 64 ]. Though our aggregate results also confirm an increase in LDL-C and total cholesterol with KD and K-LCHF, respectively, it is important to note that an increase in either of these levels does not necessarily signify a potentially deleterious cardiovascular end-point. This qualification derives from the fact that LDL particles are widely heterogeneous in composition and size, with small dense LDL particles being significantly more atherogenic than larger LDL particles [ 65 ]. Our observed aggregate effect of KD on cholesterol levels does not account for the difference in LDL particle size, nor does it distinguish the sources of dietary fat, which can also be a significant effector of LDL particle size distribution and metabolism [ 66 ].

Most RCTs of KD were conducted in patients with a limited group of participants, such as those with overweight, obesity, metabolic syndrome, cancer, and refractory epilepsy. In addition, most outcomes measured were limited to only surrogate outcomes. Thus, more clinical trials with a broader scope in populations and outcomes associated with KD would expand the role of KD in a clinical setting. For example, participant selection could be expanded from previous trials to include elderly patients, nonalcoholic fatty live disease (NAFLD) patients, and polycystic ovarian syndrome patients. Outcomes of interest of could be expanded to include (1) clinical outcomes such as cardiovascular events and liver outcomes, (2) short- and long-term safety outcomes such as adverse events (e.g., gastrointestinal, neurological, hepatic, and renal), eating disorder syndrome, sleep parameters, lipid profiles, and thyroid function and (3) other outcomes such as adherence and quality of life. More importantly, long-term studies are needed to investigate the sustainability of the clinical benefits of KD.

Our findings are useful to support the generation of evidence-based recommendations for clinicians contemplating use of KD in their patients, as well as for the general population. We further emphasize the importance of consultation with healthcare professionals before utilizing KD and any other dietary interventions. We demonstrated the benefits of KD on various outcomes in the short term. However, these improvements may prove difficult to sustain in the long term because of challenges in adherence. As for any diet interventions to achieve sustainable weight loss, factors of success include adherence, negative energy balance, and high-quality foods. Thus, communication and education with KD practitioners are important to ensure their adherence to the diet. Some individuals might benefit from switching from KD to other dietary interventions to maintain long-term weight loss.

Limitations

This umbrella review has several limitations. Firstly, we focused on published meta-analyses which confined us from assessing the associations of KD on outcomes and populations that were not included in existing meta-analyses. Secondly, most of the included meta-analyses were rated with AMSTAR-2 as critically low confidence, mainly due to a lack of study exclusion reasons, unexplained study heterogeneity, and unassessed publication bias. However, these domains unlikely affected our findings. Thirdly, we could not perform a dose–response analysis to understand the effects of different levels of carbohydrate intake on health outcomes because of insufficient details of carbohydrate intake reported in the meta-analyses. Fourthly, most RCTs of KD were limited to a relatively small number of participants with a short-term follow-up period, which limited our assessment of sustained beneficial effects after stopping KD. Lastly, due to decreased adherence, carbohydrate intake most likely increased across the course of the trials. For example, subjects in the KD arm of the A TO Z Weight Loss Study [ 67 ], started with a carbohydrate intake < 10 g/day but ended at 12 months with a carbohydrate intake accounting for 34% of TEI. In the DIRECT trial, subjects in the KD group started with carbohydrate intake of 20 g/day and ended at 12 months with 40% of TEI from carbohydrate intake [ 68 ]. Thus, we cannot be certain how the precise degree of ketosis contributed to the beneficial effects noted.

Beneficial associations of practicing KD were supported by moderate- to high-quality evidence, including weight loss, lower triglyceride levels, decreased HbA 1c , RER, and decreased seizure frequency. However, KD was associated with a clinically meaningful increase in LDL-C. Clinical trials with long-term follow-up are warranted to investigate whether these short-term effects of KD will translate to beneficial effects on more long-term clinical outcomes such as cardiovascular events and mortality.

Acknowledgements

The authors would like to acknowledge Thunchanok Ingkaprasert and Wachiravit Youngjanin for their editorial assistance.

Abbreviations

Authors’ contributions.

CP, PS, SKV, and NC conceived and designed the study protocol. CP, PS, and SKV performed a literature review and data analysis. CP, PS, TP, PP, YYL, KAV, SKV, and NC interpreted the study findings. CP and PS were major contributors to writing the manuscript. All authors read and approved the final manuscript.

No funding was obtained for the conduct of this study.

Availability of data and materials

Declarations.

Not applicable.

The authors declare that they have no competing interests.

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April 27, 2024

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