Ketogenic Diets for Cardiometabolic Outcomes: What Is the Evidence?

While the ketogenic diet (keto diet) 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).^1-6

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, β-hydroxybutyrate (βHB) 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 keto diet and the popularity of diets promoting ketosis (i.e., Atkins diet), a growing body of research has been published recently regarding the keto diet’s effect on cardiometabolic measures.

Clinical Trials Using the Keto Diet

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.^9-11 These trials generally show comparatively better weight loss after six months following a keto diet compared to a low-fat diet, though the weight loss after 12 months is often not statistically different.

When evaluating cardiometabolic biomarkers, keto diets 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 keto diet, 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 βHB 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.

Exogenous Ketones

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 keto diet.^17-20 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 keto diet.

In 2017, one of the first human trials to examine the metabolic effects of exogenous ketones was conducted using 15 healthy volunteers.²¹ In this crossover trial, subjects were randomly assigned to ingest βHB as a ketone ester or a ketone salt at two different doses (12 g or 24 g) to determine changes in blood levels of βHB 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.²² 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 Keto Diets

For short-term use, the keto diet 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 keto diets 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 keto diet 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

Keto Diet Conclusion

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, when introducing the keto diet 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).

Thomas G. Guilliams, PhD (Tom) earned his doctorate in molecular immunology from the Medical College of Wisconsin in Milwaukee. For the past two decades, he has spent his time investigating the mechanisms and actions of lifestyle and nutrient-based therapies, and is an expert in the therapeutic uses of dietary supplements. Tom serves as an adjunct assistant professor at the University of Wisconsin School of Pharmacy and was the VP of Science for Ortho Molecular Products for 24 years (he now serves them as a consultant). Since 2014 he has been writing a series of teaching manuals (Road Maps) that outline and evaluate the evidence for the principles and protocols that are fundamental to the functional and integrative medical community.  He is the founder and director of the Point Institute, an independent research and publishing organization that facilitates the distribution of his many publications. A frequent guest-speaker, Dr. Guilliams provides training to a variety of health care disciplines in the use of lifestyle and natural medicines. He lives in the woods outside of Stevens Point, Wisconsin with his wife and children.

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