SCIENCE  |  NUTRITION

Ketogenic Diet

A ketogenic diet (KD) is a high-fat, low-carbohydrate diet that shifts the body’s metabolism towards fat utilization, producing ketone bodies as a primary energy source instead of glucose. Typically, this diet consists of around 70-80% fat, 10-20% protein, and 5-10% carbohydrates. The reduction in carbohydrate intake forces the body into a metabolic state called ketosis, where fat is burned for energy, leading to potential benefits in weight loss, glycemic control, and cognitive performance.

Recent studies have explored the effects of ketogenic diets (KDs) on various health aspects, particularly lipid profiles and diabetes management. A meta-analysis of RCTs indicated that KDs significantly increased total cholesterol (TC), LDL-C, and apolipoprotein B levels in normal-weight adults, while also increasing HDL-C and apolipoprotein A levels (Nutr Rev. 2023 Oct 10;81(11):1393-1401). In diabetes management, KDs have shown benefits such as reducing HbA1c and triglycerides in pre-diabetes or type 2 diabetes patients, although the advantage over other strategies is limited (Diabetes Obes Metab. 2022 Dec;24(12):2431-2442). Another study found that low carbohydrate diets effectively reduced HbA1c levels and improved glycemic and cardiometabolic parameters (Nutrients. 2022 Oct 19;14(20):4391).

Combining KDs with exercise improved cardiorespiratory fitness and cardiometabolic risk factors in obese individuals but led to greater muscle mass loss compared to standard dietary advice (Nutrients. 2020 Feb 14;12(2):482). Regarding blood pressure, a meta-analysis of 23 RCTs found no significant impact of KDs on systolic or diastolic blood pressure (Nutr Metab Cardiovasc Dis. 2024 Apr;34(4):823-837). In contrast, a study on military personnel found that a two-week KD improved cognitive performance, mood, and reduced subjective sleepiness during extended wakefulness compared to a carbohydrate-based diet (J Sleep Res. 2023 Aug;32(4)

In longevity studies, a ketogenic diet significantly increased median lifespan and survival in mice, with aged mice showing preserved physiological function and regulated mTORC1 signaling (Cell Metab. 2017 Sep 5;26(3):539-546.e5). Another study found that a cyclic KD reduced midlife mortality, improved memory performance, and modestly improved healthspan measures in aging mice (Cell Metab. 2017 Sep 5;26(3):547-557.e8).

PUBLICATIONS

  1. Effect of ketogenic diet on blood pressure: A GRADE-Assessed systematic review and meta-analysis of randomized controlled trials.
          • Nutr Metab Cardiovasc Dis. 2024 Apr;34(4):823-837.
          • Design: Systematic review and meta-analysis of 23 randomized controlled trials with 1664 participants.
          • Summary: Ketogenic diets (KDs) did not exert any significant impacts on systolic or diastolic blood pressure. Further research is needed to examine the proportion of fat intake needed to induce favorable clinical impacts.
  2. The effect of a 2 week ketogenic diet, versus a carbohydrate-based diet, on cognitive performance, mood and subjective sleepiness during 36 h of extended wakefulness in military personnel: An exploratory study.
          • J Sleep Res. 2023 Aug;32(4):e13832.
          • Design: Randomized cross-over trial with seven male military personnel comparing a 2-week ketogenic diet and a carbohydrate-based diet, followed by 36 hours of extended wakefulness.
          • Summary: The ketogenic diet improved cognitive performance, mood, and reduced subjective sleepiness during extended wakefulness compared to a carbohydrate-based diet. Participants on the KD showed higher D-β-hydroxybutyrate and lower glucose levels, with significant improvements in vigilance, memory, and fatigue.
  3. Effects of very low-carbohydrate ketogenic diets on lipid profiles in normal-weight (body mass index < 25 kg/m2) adults: a meta-analysis.
          • Nutr Rev. 2023 Oct 10;81(11):1393-1401.
          • Design: Meta-analysis of randomized controlled trials evaluating lipid profiles in normal-weight adults.
          • Summary: Ketogenic diets significantly increased total cholesterol (TC), LDL-C, and apoB levels but also increased HDL-C and apoA. Triglyceride levels were not significantly different between KDs and control diets. Normal-weight individuals should consider the risk of hypercholesterolemia when consuming a KD.
  4. Overall, plant-based, or animal-based low carbohydrate diets and all-cause and cause-specific mortality: A systematic review and dose-response meta-analysis of prospective cohort studies.
          • Ageing Res Rev. 2023 Sep;90:101997.
          • Design: Systematic review and dose-response meta-analysis of prospective cohort studies with 421,022 participants.
          • Summary: Plant-based low carbohydrate diets were associated with a reduced risk of all-cause mortality, whereas animal-based low carbohydrate diets were linked to a higher risk of cancer mortality. Moderate carbohydrate content diets were associated with the lowest risk of all-cause and cardiovascular disease (CVD) mortality.
  5. Very low carbohydrate (ketogenic) diets in type 2 diabetes: A systematic review and meta-analysis of randomized controlled trials.
          • Diabetes Obes Metab. 2022 Dec;24(12):2431-2442.
          • Design: Systematic review and meta-analysis of randomized controlled trials with 606 participants.
          • Summary: Very low carbohydrate/ketogenic diets (VLC/KDs) may cause reductions in HbA1c and triglycerides in those with pre-diabetes or type 2 diabetes (T2D), but evidence of an advantage over other strategies is limited.
  6. Comparison of the Effectiveness of Low Carbohydrate Versus Low Fat Diets, in Type 2 Diabetes: Systematic Review and Meta-Analysis of Randomized Controlled Trials.
          • Nutrients. 2022 Oct 19;14(20):4391.
          • Design: Systematic review and meta-analysis of randomized controlled trials with 1391 participants.
          • Summary: Low carbohydrate diets significantly reduced HbA1c levels and improved other glycaemic and cardiometabolic parameters in the short-to-intermediate term. However, a low carbohydrate diet appears to be equally effective as a low-fat diet in terms of control of cardiometabolic markers and the risk of adverse events in obese patients with type 2 diabetes.
  7. Effects of the Ketogenic Diet on Muscle Hypertrophy in Resistance-Trained Men and Women: A Systematic Review and Meta-Analysis.
          • Int J Environ Res Public Health. 2022 Oct 3;19(19):12629.
          • Design: Systematic review and meta-analysis of five studies involving 111 athletes or resistance-trained participants.
          • Summary: No significant differences were found in fat-free mass variables between ketogenic diet and control diet groups. More research is needed with similar diet and control interventions.
  8. The Effects of Concurrent Training Combined with Low-Carbohydrate High-Fat Ketogenic Diet on Body Composition and Aerobic Performance: A Systematic Review and Meta-Analysis.
          • Int J Environ Res Public Health. 2022 Sep 14;19(18):11542.
          • Design: Systematic review and meta-analysis of eight studies with 170 participants.
          • Summary: Concurrent training combined with a low-carbohydrate high-fat ketogenic diet did not significantly impact lean mass, body fat percentage, body mass, VO2max, or aerobic performance in trained participants.
  9. Effect of a ketogenic diet versus Mediterranean diet on glycated hemoglobin in individuals with prediabetes and type 2 diabetes mellitus: The interventional Keto-Med randomized crossover trial.
          • Am J Clin Nutr. 2022 Sep 2;116(3):640-652.
          • Design: Randomized crossover trial with 40 participants following ketogenic and Mediterranean-plus diets for 12 weeks each.
          • Summary: HbA1c values did not differ significantly between the diets, but both improved from baseline. The ketogenic diet reduced triglycerides more but increased LDL cholesterol and had lower nutrient intakes compared to the Mediterranean diet, which was more sustainable.
  10. Effects of very low-carbohydrate ketogenic diet on lipid metabolism in patients with type II diabetes mellitus: a meta-analysis.
          • Nutr Hosp. 2022 Aug 25;39(4):916-923.
          • Design: Meta-analysis of randomized controlled trials up to September 2021.
          • Summary: Very low-carbohydrate ketogenic diets did not significantly affect total cholesterol, HDL, or LDL levels but did reduce triglyceride levels in type 2 diabetes patients, particularly in the short term.
  11. Ketogenic Diet Benefits to Weight Loss, Glycemic Control, and Lipid Profiles in Overweight Patients with Type 2 Diabetes Mellitus: A Meta-Analysis of Randomized Controlled Trails.
          • Int J Environ Res Public Health. 2022 Aug 22;19(16):10429.
          • Design: Meta-analysis of eight randomized controlled trials.
          • Summary: Ketogenic diets significantly improved body weight, waist circumference, glycated hemoglobin, triglycerides, and HDL levels in overweight type 2 diabetes patients, indicating its effectiveness for glycemic and lipid control.
  12. Dose-dependent effect of carbohydrate restriction for type 2 diabetes management: a systematic review and dose-response meta-analysis of randomized controlled trials.
          • Am J Clin Nutr. 2022 Jul 6;116(1):40-56.
          • Design: Systematic review and dose-response meta-analysis of 50 trials with 4291 patients.
          • Summary: Carbohydrate restriction led to significant reductions in HbA1c, fasting plasma glucose, body weight, total cholesterol, LDL cholesterol, triglycerides, and systolic blood pressure, showing linear and dose-dependent effects for most outcomes.
  13. A Comparative Study Evaluating the Effectiveness Between Ketogenic and Low-Carbohydrate Diets on Glycemic and Weight Control in Patients With Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis.
          • Cureus. 2022 May 31;14(5):e25528.
          • Design: Systematic review and meta-analysis of 15 studies from 2000 to 2022.
          • Summary: The ketogenic diet was more effective in reducing glycated hemoglobin and body weight compared to low-carbohydrate diets, but the potential cardiovascular risks need to be considered for patients with type 2 diabetes.
  14. The Effect of a Ketogenic Low-Carbohydrate, High-Fat Diet on Aerobic Capacity and Exercise Performance in Endurance Athletes: A Systematic Review and Meta-Analysis.
          • Nutrients. 2021 Aug 23;13(8):2896.
          • Design: Systematic review and meta-analysis of 10 studies on the effects of a K-LCHF diet on endurance athletes.
          • Summary: The meta-analysis found no significant effect of the K-LCHF diet on VO2max, time to exhaustion, HRmax, or RPE, but did observe a significant effect on substrate oxidation response to respiratory exchange rate. High-quality interventions are needed to further explore these effects.
  15. A Ketogenic Low-Carbohydrate High-Fat Diet Increases LDL Cholesterol in Healthy, Young, Normal-Weight Women: A Randomized Controlled Feeding Trial.
          • Nutrients. 2021 Mar 2;13(3):814.
          • Design: Randomized controlled feeding trial with crossover design, involving 24 healthy, young, normal-weight women assigned to a 4-week ketogenic LCHF diet followed by a 4-week control diet or the reverse sequence.
          • Summary: The ketogenic LCHF diet increased LDL cholesterol, ApoB, and both small, dense and large, buoyant LDL cholesterol in all participants, suggesting a deleterious blood lipid profile. This raises concerns about the diet’s impact on cardiovascular health in this demographic.
  16. Influences of Ketogenic Diet on Body Fat Percentage, Respiratory Exchange Rate, and Total Cholesterol in Athletes: A Systematic Review and Meta-Analysis.
          • Int J Environ Res Public Health. 2021 Mar 12;18(6):2912.
          • Design: Meta-analysis of 8 studies on the effects of ketogenic diets in professional athletes.
          • Summary: The ketogenic diet reduced body fat percentages and respiratory exchange rates, and increased total cholesterol levels in athletes. Other parameters like BMI, cardiorespiratory fitness, heart rate, HDL cholesterol, glucose level, and insulin level were unaffected.
  17. 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.
          • Nutrients. 2020 Jul 6;12(7):2005.
          • Design: Meta-analysis of 14 randomized controlled trials on ketogenic diets for metabolic control in overweight or obese patients.
          • Summary: Ketogenic diets were more effective in improving metabolic parameters, including glycemic, weight, and lipid controls in overweight or obese patients, especially those with preexisting diabetes, compared to low-fat diets.
  18. Effects of a Ketogenic Diet on Muscle Fatigue in Healthy, Young, Normal-Weight Women: A Randomized Controlled Feeding Trial.
          • Nutrients. 2020 Mar 30;12(4):955.
          • Design: Randomized controlled feeding trial with crossover design, involving 24 healthy, young, normal-weight women assigned to a 4-week ketogenic LCHF diet followed by a 4-week control diet or the reverse sequence.
          • Summary: The ketogenic LCHF diet had no effect on grip strength or time to fatigue during handgrip tests, but significantly decreased cycling time to fatigue and increased perceived exertion. Participants also reported increased muscle fatigue during daily activities, suggesting an unfavorable impact of the diet on muscle fatigue and exertion.
  19. The Effect of an 8 Week Prescribed Exercise and Low-Carbohydrate Diet on Cardiorespiratory Fitness, Body Composition and Cardiometabolic Risk Factors in Obese Individuals: A Randomised Controlled Trial.
          • Nutrients. 2020 Feb 14;12(2):482.
          • Design: Randomized controlled trial with 33 participants in the experimental group (EX-LC) and 31 in the control group (EX-CO), involving an 8-week intervention with a low-carbohydrate diet and supervised exercise.
          • Summary: The combination of a low-carbohydrate diet and prescribed exercise improved cardiorespiratory fitness and cardiometabolic risk factors but led to greater muscle mass loss compared to standard dietary advice and similar exercise training. Achieving a ketogenic state was associated with significant reductions in body fat and C-reactive protein (CRP).
  20. High Rates of Fat Oxidation Induced by a Low-Carbohydrate, High-Fat Diet, Do Not Impair 5-km Running Performance in Competitive Recreational Athletes.
          • J Sports Sci Med. 2019 Nov 19;18(4):738-750. eCollection 2019 Dec.
          • Design: Randomized counterbalanced crossover design with seven male athletes who completed VO2max tests and 5K time trials on high-carbohydrate low-fat (HCLF) and low-carbohydrate high-fat (LCHF) diets.
          • Summary: The study found no significant difference in exercise performance between the HCLF and LCHF diets in 5K time trials after initial adaptation. High rates of fat oxidation on the LCHF diet did not impair running performance compared to the HCLF diet.
  21. A network meta-analysis on the comparative efficacy of different dietary approaches on glycaemic control in patients with type 2 diabetes mellitus.
          • Eur J Epidemiol. 2018 Feb;33(2):157-170.
          • Design: Network meta-analysis of 56 trials comparing 9 dietary approaches for type 2 diabetes patients.
          • Summary: Low-carbohydrate and Mediterranean diets were ranked as the best dietary approaches for reducing HbA1c and fasting glucose levels, with the Mediterranean diet being the most effective for improving glycemic control in type 2 diabetes patients.
  22. Twelve-month outcomes of a randomized trial of a moderate-carbohydrate versus very low-carbohydrate diet in overweight adults with type 2 diabetes mellitus or prediabetes.
          • Nutr Diabetes. 2017 Dec 21;7(12):304.
          • Design: Randomized trial of 34 adults assigned to a very low-carbohydrate ketogenic diet (LCK) or a moderate-carbohydrate, calorie-restricted, low-fat (MCCR) diet for 12 months.
          • Summary: Participants in the LCK group had greater reductions in HbA1c levels, lost more weight, and reduced more diabetes-related medications compared to the MCCR group, indicating the benefits of an LCK diet for individuals with type 2 diabetes or prediabetes.
  23. Ketogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice.
          • Cell Metab. 2017 Sep 5;26(3):547-557.e8.
          • Design: Study on C57BL/6 male mice fed a cyclic ketogenic diet (KD) to observe effects on longevity and healthspan.
          • Summary: The cyclic KD reduced midlife mortality, improved memory performance, and modestly improved healthspan measures in aging mice, suggesting the potential benefits of a ketogenic diet for aging.
  24. A Ketogenic Diet Extends Longevity and Healthspan in Adult Mice.
          • Cell Metab. 2017 Sep 5;26(3):539-546.e5.
          • Design: Study on C57BL/6 mice assigned to a ketogenic, low-carbohydrate, or control diet to assess longevity and healthspan.
          • Summary: The ketogenic diet significantly increased median lifespan and survival compared to controls. In aged mice, only those on the ketogenic diet displayed preservation of physiological function, increased protein acetylation levels, and regulated mTORC1 signaling.
  25. Systematic review and meta-analysis of dietary carbohydrate restriction in patients with type 2 diabetes.
          • BMJ Open Diabetes Res Care. 2017 Feb 23;5(1):e000354.
          • Design: Meta-analysis of 10 randomized trials comparing low to moderate carbohydrate diets with high carbohydrate diets in type 2 diabetes patients.
          • Summary: Low to moderate carbohydrate diets were more effective in lowering HbA1c in the first year compared to high carbohydrate diets. The greater the carbohydrate restriction, the greater the glucose-lowering effect.
  26. Comparison of low- and high-carbohydrate diets for type 2 diabetes management: a randomized trial.
          • Am J Clin Nutr. 2015 Oct;102(4):780-90.
          • Design: Randomized controlled trial of 115 obese adults with type 2 diabetes assigned to a low-carbohydrate or high-carbohydrate diet for 52 weeks.
          • Summary: Both diets led to substantial weight loss and reduced HbA1c and fasting glucose. The low-carbohydrate diet achieved greater improvements in lipid profile, blood glucose stability, and reductions in diabetes medication requirements.
  27. Systematic review and meta-analysis of different dietary approaches to the management of type 2 diabetes.
          • Am J Clin Nutr. 2013 Mar;97(3):505-16.
          • Design: Systematic review and meta-analysis of 20 randomized controlled trials on various diets for type 2 diabetes management.
          • Summary: Low-carbohydrate, low-GI, Mediterranean, and high-protein diets all led to greater improvements in glycemic control compared to control diets. The Mediterranean diet showed the largest effect size for reducing HbA1c.
  28. 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(Suppl 7):S44-54.
          • Design: Meta-analysis of 23 randomized controlled trials comparing low-carbohydrate and low-fat diets on metabolic risk factors.
          • Summary: Both diets improved metabolic risk factors, but low-carbohydrate diets led to greater increases in HDL cholesterol and greater decreases in triglycerides compared to low-fat diets.
  29. Ketogenic low-carbohydrate diets have no metabolic advantage over nonketogenic low-carbohydrate diets.
          • Am J Clin Nutr. 2006 May;83(5):1055-61.
          • Design: Randomized controlled trial of 20 adults assigned to ketogenic low-carbohydrate (KLC) or nonketogenic low-carbohydrate (NLC) diets for 6 weeks.
          • Summary: Both diets were equally effective in reducing body weight and insulin resistance, but the KLC diet was associated with adverse metabolic and emotional effects, indicating no metabolic advantage over the NLC diet.
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