While the ketogenic diet (KetoDiet) may have had its roots as a treatment modality for epilepsy as far back as the 1920s, variations of this diet are now mostly popular for their metabolic outcomes (e.g., weight loss, improved glycemic control, etc.) or for cognitive support/neurological conditions (e.g., Alzheimer’s disease, malignant glioma, migraine headache, and other neurologic disorders).1,2,3,4,5,6 The original ketogenic diet was composed of 80-90% fat, with protein (8-15%) and carbohydrates (2-5%) making up the remainder of calories. By limiting the intake of carbohydrates, the body is shifted into a state of “ketosis,” where it derives most of its energy from ketones which are generated from fat (i.e., acetoacetate, ?-hydroxybutyrate, and acetone). Ketosis stimulates gluconeogenesis to offset the lack of dietary carbohydrates, causing a metabolic shift towards the burning of fats (lipolysis), which results in lower serum glucose and insulin levels. Because of the change in metabolism induced by the KetoDiet, and the popularity of diets promoting ketosis (i.e., Atkins Diet), a growing body of research has been published recently regarding the KetoDiet’s effect on cardiometabolic measures.
Clinical Trials Using the KetoDiet
Many clinical trials have been performed to investigate the effects of ketogenic-specific diets on weight loss and cardiometabolic biomarkers (though most still achieve this by reducing carbohydrate intake).7,8 In the past decade, there have been at least three systematic reviews and meta-analyses conducted to analyze the overall findings of these trials, mostly designed to compare the effects of a ketogenic diet against conventional low-fat hypocaloric diets.9,10,11 These trials generally show comparatively better weight loss after six months following a KetoDiet compared to a low-fat diet, though the weight loss after 12 months is often not statistically different. When evaluating cardiometabolic biomarkers, KetoDiets generally result in statistically lower TG levels and higher HDL-C levels, though they are often also associated with increased LDL-C levels. Variations in ketogenic diet composition (such as a modified Atkins Diet, classic ketogenic diet, MCT diet, etc.) and inter-individual responses may affect lipid profiles. Some studies have shown favorable shifts in LDL particle numbers (a change from pattern B to pattern A)12,13 whereas others have not.14,15
Since the most recent meta-analysis of ketogenic diets (2013), a few notable trials have emerged. In 2014, a moderate carbohydrate diet was compared to a very-low-carbohydrate diet to determine the effects on HbA1c, lipids, insulin resistance, and weight.16 Subjects included in the trial (N = 34) had type 2 diabetes (HbA1c >6.5%) or prediabetes (HbA1c above 6%) and a BMI of 25 or above. Subjects attended 13, two-hour classes devoted to diet instructions and lifestyle interventions, including sleep, exercise, and behavioral modification strategies. Participants were randomized to receive either a medium carbohydrate, low-fat, calorie-restricted, carbohydrate counting diet (MCCR) consistent with the American Diabetes Association recommendations, or a very low calorie, high-fat, ad libitum ketogenic (LCK) diet for three months. The MCCR diet was structured to derive 45-50% of calories from carbohydrates (roughly 165 g/day), while subjects consumed similar protein levels and less fat than they had before entering the study. Calorie restriction specified for the MCCR group was to consume 500 fewer kcal/day than their calculated maintenance needs as derived from the Institute of Medicine. For the KetoDiet, subjects were instructed to follow a very-low-carbohydrate diet, gradually reducing carbohydrate intake to 20-50 grams/day, with the goal of achieving ketosis (as measured by blood levels of beta-hydroxybutyrate between 0.5 and 3 mM twice per week using a home test kit).
At the end of the trial, the LCK group had reductions in HbA1c levels by 0.6%, whereas no changes were observed in the MCCR group (the difference between groups was significant; P = 0.04). Forty-four percent of the LCK group was able to discontinue one or more diabetic medications versus only 11% in the MCCR group (P = 0.03). The LCK group lost 5.5 kg (or 11 lbs.), whereas the MCCR group lost 2.6 kg (or 5.72 lbs.) Interestingly, no statistically significant changes occurred for fasting glucose, insulin, HOMA-IR, blood pressure, or lipids. Carbohydrate cravings were statistically lower in both groups, with a greater change occurring in the LCK group (-0.6; P < 0.01) versus (-0.03; P < 0.05) in the MCCR.
While the process of reducing carbohydrates has a direct effect on circulating glucose and the need for insulin, the formation of ketones is also considered to be important for mediating the unique outcomes of the KetoDiet17,18,19,20 In fact, several recent studies have shown that the consumption of exogenous ketones can produce effects similar to those obtained from the dietary induction of ketones using the KetoDiet. In 2017, one of the first human trials to examine the metabolic effects of exogenous ketones was conducted using 15 healthy volunteers. In this crossover trial, subjects were randomly assigned to ingest ?-hydroxybutyrate (?HB) as a ketone ester or a ketone salt at two different doses (12 g or 24 g) to determine changes in blood levels of ?HB and various glucose and lipid parameters over a four-hour period. Ingestion of both drinks resulted in significant decreases in mean plasma free-fatty acids, triglycerides, and glucose after one hour (all P < 0.05). Also, in 2018, researchers analyzed the effects of ketone monoesters consumed prior to an oral glucose tolerance test (OGTT) in 20 healthy subjects. In this cross-over trial, subjects were randomized to receive either a monoester supplement (482 mg/kg body mass) or placebo 30 minutes prior to an OGTT. Results showed that compared to placebo, monoester supplementation decreased the glucose AUC by 16% (P = 0.001), non-esterified fatty acid AUC levels by 44% (P < 0.001), and C-peptide incremental AUC (P= 0.005). Although these studies using exogenous ketones are interesting, it is currently unknown how achieving a state of ketosis via dietary manipulation compares to the state of ketosis induced via supplementation of exogenous ketones, and how the individual’s background diet may affect their results using exogenous ketone supplements.
Safety of KetoDiets
For short-term use, the KetoDiet appears safe in subjects with obesity and type 2 diabetes.23 Importantly, nutritional ketosis is safe and is not related to the life-threatening effects seen in ketoacidosis.24 Some adverse side-effects that are reported with the use of KetoDiets include hypercholesterolemia, mineral deficiencies, acidosis, constipation (due to lack of fiber), and excessive weight loss.26 Rare side-effects that have occurred in children may include cardiomyopathy and prolonged QT syndrome.25 If side-effects are to occur, it is most common to see them revealed during the first few weeks of starting a ketogenic diet. Most of the trials have indicated that once the body becomes adapted to the diet over the course of months, the incidence of side-effects becomes similar to any other diet. The KetoDiet should not be applied in those with a pyruvate carboxylase deficiency, beta-oxidation defects, primary carnitine deficiency, porphyrias, and gastroesophageal reflux disease.26 Additional sodium intake for those beginning a ketogenic diet may be necessary to avoid hyponatremia, as it is established that low-carbohydrate diets (initially) increase water and sodium loss.27 Soup-broths or electrolyte supplements can be easily obtained for this purpose. Patients currently taking diuretic medications may need to have their medications temporarily withdrawn or halved due to potentiation effects when applying a ketogenic diet.28
The use of very-low carbohydrate diets that induce ketosis may be helpful for promoting weight loss in obese, insulin resistant, and type 2 diabetic subjects. However, it should not be considered an ideal long-term dietary pattern. Also, introducing the KetoDiet in the context of the Mediterranean Diet pattern, subjects are more likely to avoid poor protein sources (i.e. processed meats) while increasing their intake of low-carbohydrate vegetables and phytonutrients. These choices are likely to improve long-term weight loss, adherence to dietary changes, and limit negative changes in lipid profiles. Clinicians should be aware that intense carbohydrate restriction that induces hypoglycemia will often be accompanied by changes in mood, increased stress (and cortisol levels), and insomnia in many individuals. These symptoms can be modulated by altering the timing of the intake of carbohydrates (shifting intake toward evening).
1 Wilder RM. The effects of ketonemia on the course of epilepsy. Mayo Clin Bull. 1921;2:307–308.
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3 Watson, John. Romanowski Anya. Ketogenic Diet: Which Patients Benefit? Medscape.com.
https://www.medscape.com/viewarticle/894041. Published on March 20th, 2018. Accessed on April 2nd, 2018.
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8 Yancy WS Jr, Foy M, Chalecki AM, et al. A low-carbohydrate, ketogenic diet to treat type 2 diabetes. Nutr Metab (Lond). 2005 Dec 1;2:34.
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11 Nordmann AJ, Nordmann A, Briel M, et al. Effects of low-carbohydrate vs low-fat diets on weight loss and cardiovascular risk factors: a meta-analysis of randomized controlled trials. Arch Intern Med. 2006 Feb 13;166(3):285-93.
12 Volek JS, Phinney SD, Forsythe CE, et al. Carbohydrate restriction has a more favorable impact on the metabolic syndrome than a low-fat diet. Lipids. 2009 Apr;44(4):297-309.
13 Volek JS, Sharman MJ, Forsythe CE. Modification of lipoproteins by very low-carbohydrate diets. J Nutr. 2005 Jun;135(6):1339-42.
14 McDonald TJW, Ratchford EV, Henry-Barron BJ, et al. Impact of the modified Atkins diet on cardiovascular health in adults with epilepsy. Epilepsy Behav. 2018 Feb;79:82-86.
15 Azevedo de Lima P, Baldini Prudêncio M, Murakami DK, et al. Effect of classic ketogenic diet treatment on lipoprotein subfractions in children and adolescents with refractory epilepsy. Nutrition. 2017 Jan;33:271-277.
16 Saslow LR, Kim S, Daubenmier JJ, et al. A randomized pilot trial of a moderate carbohydrate diet compared to a very low carbohydrate diet in overweight or obese individuals with type 2 diabetes mellitus or prediabetes. PLoS One. 2014 Apr 9;9(4):e91027.
17 Veech RL, Chance B, Kashiwaya Y, et al. Ketone bodies, potential therapeutic uses. IUBMB Life. 2001 Apr;51(4):241-7.
18 Courchesne-Loyer A, Croteau E, Castellano CA, et al. Inverse relationship between brain glucose and ketone metabolism in adults during short-term moderate dietary ketosis: A dual tracer quantitative positron emission tomography study. J Cereb Blood Flow Metab. 2017 Jul;37(7):2485-2493.
19 Bough KJ, Wetherington J, Hassel B, et al. Mitochondrial biogenesis in the anticonvulsant mechanism of the ketogenic diet. Ann Neurol. 2006 Aug;60(2):223-35.
20 Manninen AH. Very-low-carbohydrate diets and preservation of muscle mass. Nutr Metab (Lond). 2006 Jan 31;3:9.
21 Stubbs BJ, Cox PJ, Evans RD, et al. On the Metabolism of Exogenous Ketones in Humans. Front Physiol. 2017 Oct 30;8:848.
22 Myette-Côté É, Neudorf H, Rafiei H, et al. Prior ingestion of exogenous ketone monoester attenuates the glycaemic response to an oral glucose tolerance test in healthy young individuals. J Physiol. 2018 Feb 15.
23 Goday A, Bellido D, Sajoux , et al. Short-term safety, tolerability and efficacy of a very low-calorie-ketogenic diet interventional weight loss program versus hypocaloric diet in patients with type 2 diabetes mellitus. Nutr Diabetes. 2016 Sep 19;6(9):e230.
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28 Yancy WS Jr, Foy M, Chalecki AM, et al. A low-carbohydrate, ketogenic diet to treat type 2 diabetes. Nutr Metab (Lond). 2005 Dec 1;2:34.
About Thomas G. Guilliams, PhD
Dr. Guilliams earned his doctorate from the Medical College of Wisconsin (Milwaukee) where he studied molecular immunology in the Microbiology Department. Since 1996, he has spent his time studying the mechanisms and actions of natural-based therapies and is an expert in the therapeutic uses of nutritional supplements. As the Vice President of Scientific Affairs for Ortho Molecular Products, he has developed a wide array of products and programs which allow clinicians to use nutritional supplements and lifestyle interventions as safe, evidence-based and effective tools for a variety of patients. Tom teaches at the University of Wisconsin-School of Pharmacy, where he holds an appointment as a Clinical Instructor; at the University of Minnesota School of Pharmacy and is a faculty member of the Fellowship in Anti-aging Regenerative and Functional Medicine. He lives outside of Stevens Point, Wisconsin with his wife and children.