The Medically Indicated Ketogenic Diet: Evidence for nutritional ketosis as part of clinical practice

Kevin Waggoner, Joelle M. Mendez-Hinds, Donna L. Herber*

Introduction: The ketogenic diet, a long history of clinical use and effectiveness

The ketogenic diet is characterized by a high fat content paired with moderate protein and very low carbohydrate intake [1].  Typically, a ketogenic ratio is used to describe the macronutrient profile of the diet by comparing grams of fat to the combined grams of protein plus carbohydrates.  Thus, ratios where the fat content is greater than one indicates a “ketogenic” diet. The diet is ketogenic in that the high fat consumption required trains the body to switch from using glucose and carbohydrates as the primary metabolic fuel source to using fatty acids and ketone bodies as fuel [2].  There are ensuing metabolic regulatory effects on blood glucose and blood insulin levels, where increasing amounts of serum ketones act to decrease circulating glucose, reduce the insulin response, and maintain homeostasis [3].  

The ketogenic diet allows the body to shift from carbohydrate-based metabolism to fat-based metabolism, thus stimulating hepatic ketogenesis, and entering nutritional ketosis [4].  Nutritional ketosis is a state where the blood levels of ketone bodies are significantly above baseline, typically >0.5 mmol/L. The ketone bodies, acetoacetate and beta-hydroxybutyrate, are energy substrates used by mitochondria to produce adenosine triphosphate (ATP), and can be used as alternative fuels to glucose by the brain, heart, and skeletal muscles [3].  

The ketogenic diet has been documented in the clinical literature as a therapeutic nutritional intervention for nearly 100 years [5].  What began as a thoughtful approach for children with refractory epilepsy has grown in use in populations living with obesity and/or type 2 diabetes.  This review is intended to summarize the large body of evidence for the medical use of the ketogenic diet.

Epilepsy: The hope to become seizure free, medication free

Fasting has been recognized as a potential treatment for seizures since ancient times, and dietary intervention that mimicked fasting was introduced in the 1920s [1].  For both children and adults with refractory epilepsy, dietary interventions which raise blood ketones (therapeutic nutritional ketosis) are efficacious and safe [6-10].  Patients that have failed to respond to three or more anti-epileptic drugs (about 30% of all patients) can see improvements in as little as two weeks with dietary intervention, though a three-month trial is recommended in order to assess effectiveness [11].  

Patients can expect to see a 40-50% chance of a 50% reduction in seizures with the ketogenic diet, though there are certain conditions that see as high as a 70% response rate (glucose transporter 1 deficiency syndrome (GLUT1DS), pyruvate dehydrogenase deficiency (PDCD), epilepsy with myoclonic-atonic seizures, infantile spasms, tuberous sclerosis complex, children with gastrostomy tubes, and Dravet syndrome) [11].  The diet is recommended as first line therapy for children with GLUT1D, PDCD, West Syndrome, and Doose Syndrome [12]. There are individual reports where children are able to discontinue all medications as seizures are completely controlled by the ketogenic diet alone [13]. Additionally, many pediatric patients who have been on the diet 2-3 years can discontinue the diet at the onset of puberty with no recurrence of seizures [11].  Some patients or their caregivers may choose to try dietary intervention even when seizures are well controlled by pharmacotherapy in an effort to reduce the amount of medication used – and resultant side effects – as well as the potential to improve cognitive function [14]. 

The classical ketogenic diet that is traditionally used with drug resistant seizures has a ratio of 4:1 or 3:1 of (grams of fat): (grams of protein plus grams of carbohydrate), making it an extremely restrictive diet [1].  Many patients discontinue the diet even when it effectively controls seizures if modifications cannot be made [10]. Several variants of the diet that are effective include the Modified Atkins Diet (MAD), medium chain triglyceride (MCT) diet, and low glycemic index therapy (LGIT) [7, 15-18]. These approaches have a lower ketogenic ratio (1.5:1 or 2:1) and/or add highly ketogenic fats (such as MCT) in order to improve diet adherence and add in additional protein or carbohydrate content.  The mechanism of action of ketosis for seizure control is poorly understood and many potential mechanisms may be at play [19-24].

Type 2 Diabetes: An intuitive, rational approach with tangible health and economic benefits

Carbohydrates are converted to the basic energy molecule glucose through normal digestion and metabolism, thus having the greatest impact on circulating blood glucose levels compared to fat and protein [25].  Prior to the development of medications for the treatment of diabetes, this disease was treated through dietary restriction of carbohydrates [26]. Even with the advent of injectable insulin, patients are counseled to calculate the amount of carbohydrates eaten and then administer the appropriate amount of insulin [27].  It is abundantly clear that the adverse physiological effects of both type 1 and type 2 diabetes revolve around the consumption of carbohydrates [28]. In particular, type 2 diabetes has been called by many a lifestyle disease, where susceptible individuals become diabetic through excess long-term consumption of carbohydrates, and resultant obesity, and also respond well to lifestyle modifications that reduce carbohydrate intake [29].

Single meal interventions in patients with type 2 diabetes demonstrate the power of macronutrient profiles to modify blood glucose levels and the resultant insulin response.  Replacing just breakfast and lunch with low carbohydrate meals led to significantly lower blood glucose and insulin compared to low fat meals [30]. Similarly, a high fat, high protein, low carbohydrate breakfast demonstrated greater reductions in fasting glucose, HbA1c and systolic blood pressure, reductions in medications, as well as less hunger, when compared to a high carbohydrate meal [31].

Very low carbohydrate dietary interventions lead to a metabolic state known as nutritional ketosis.  This is not biochemically the same as diabetic ketoacidosis (DKA) [32]. In DKA, the insulin/glucose axis is not intact, and when blood sugar levels rise without the compensatory insulin mechanisms, tissues cannot utilize glucose for fuel, leading the body to produce ketones.  During DKA, glucose is consistently over 300 mg/dL, ketones above 8 mmol/L, and blood pH below 7.3 [33]. In contrast, nutritional ketosis occurs with normal blood glucose levels, ketones between 0.5-4 mmol/L, and normal blood pH. The ketogenic diet has been demonstrated to be safe for type 2 diabetics, and may even be suitable for some type 1 diabetics with close monitoring [26, 34-37].  

In clinical protocols involving patients with type 2 diabetes, the ratio of fat:protein+carbohydrates is much less restrictive (1.5-2:1) than is the case of the classical ketogenic diet used with epilepsy (3-4:1), with a greater protein allowance.  The ketogenic diet has been shown to have greater beneficial effects on fasting blood glucose, HbA1c, circulating lipids, and cholesterol than low glycemic or low-fat approaches [26, 38-39]. One mechanism behind this may be related to a natural reduction in caloric intake (even though this is not part of the diet prescription), and the greater rate of adherence to the diet at 6 months [40].  Importantly, the lower the amount of dietary carbohydrate in the diet, the greater the benefits on health and weight [39]. Regarding type 2 diabetes and medication requirements, studies have shown that dietary carbohydrate restriction allowed for the majority of patients to lower or discontinue their diabetes medications, in addition to significantly decreasing hemoglobin A1c, body weight, and fasting triglyceride levels [35, 39]. The health benefits are routinely demonstrated when using a ketogenic diet, but economic benefits are realized as well with reductions and even elimination of reliance on medications in many patients [39].

Obesity: Improved dietary adherence, satiety, and long-term benefits

In-patient fasting protocols were common practice in the mid-20th century as a clinical solution to obesity.  Diets were soon developed in the 1960s that mimicked the state of ketosis, driving the body not towards fasting ketosis but rather towards nutritional ketosis.  Dietary intervention protocols targeting weight loss typically reduce calories below the 2000 kcal/day recommendation for healthy, normal weight individuals, but in most cases, the ketogenic diet is administered without intentionally restricting calories [39, 41].  Similar to the approach to the patient with type 2 diabetes, clinical protocols involving patients with obesity use a ketogenic ratio of fat:protein+carbohydrates at 1.5-2:1, with a greater protein allowance.  

The biochemistry underlying nutritional ketosis is complicated, but dietary intake of fat leads to the direct use of triglycerides for fuel by most tissues (except the brain) as well as hepatic ketogenesis to generate ketone bodies to fuel the brain [3].  As this fat utilization machinery starts to work harder than the enzymes and pathways relating to glycolysis (burning carbohydrates for fuel), stored body fat is also recruited as a fuel source [2]. Coupled with the typical reduction in calories seen with ketogenic diets, the body uses both dietary and stored fat for fuel in a way that is not possible when carbohydrates loads are high, as in a typical American diet.

The results from clinical trials studying ketogenic diets for weight loss are impressive and expansive, and can have long-term benefits [42-43].  Ketogenic diets (in comparison to low fat or Mediterranean style diets) show significantly greater initial reductions in weight, as well as better maintenance of weight loss [39, 44].  This very low carbohydrate approach (typically less than 30g per day) also reduces circulating triglyceride levels and improves high density lipoprotein levels (long term) [45]. The long-term safety of the ketogenic diet has been well documented [46-47].  National programs for promoting a healthy diet led to the characterization of fat as promoting heart disease, but the ketogenic diet has not been found to do so [48]. This may be due to a high intake of fat in the absence of a high intake of carbohydrates. 

In general, patients and clinicians report that a high fat, low carb dietary lifestyle is more satiating, with less reported hunger compared to low fat diets.  The satiety effects of ketone bodies have been well studied, as well as the role of fats and protein in promoting a sense of satiation [49]. Concurrently, when consuming a ketogenic diet, blood glucose levels, and the corresponding insulin response, do not fluctuate to the same extent as when consuming a high carbohydrate diet.  Therefore, the hunger cues and physiological effects of a “sugar crash” are not experienced. Importantly, a low-fat dietary intervention to promote weight loss purposefully reduces caloric intake by 500 kcal in order to achieve meaningful weight loss [41]. The ketogenic diet does not typically prescribe caloric restriction. However, investigators routinely report that patients will naturally reduce caloric intake when they are instructed to limit carbohydrate intake [40].  This may be due to the removal of high calorie, now restricted, foods, or due to the satiating effects of the diet. In any case, patients are not under the burden to restrict calories.

Other Disorders: Shifting whole body metabolism to improve patient nutrition

Acne, cancer, polycystic ovarian disease, neurodegenerative diseases and neuropsychiatric disorders are all the subject of numerous preclinical and clinical research programs for the utility of the ketogenic diet in boosting patient nutrition and their ability to fight disease [50].  There are currently 31 studies that are listed with looking at ketogenic dietary intervention for patients with cancer of a variety of types. The prototypical tumor type studied is glioma, as well as other brain tumors such as astrocytomas, given the blood brain barrier and difficulties in delivering traditional chemotherapy to the lesion site [51-53].  Ketones not only cross the blood brain barrier but also may be preferentially used by healthy cells, with tumors relying more on glucose metabolism [54-55]. The role of ketones in fueling the brain further comes into play when considering neurodegenerative diseases such as Alzheimer’s, Parkinson’s, Amyotrophic Lateral Sclerosis, migraine, autism, and head trauma [56-61]. When glucose utilization is disrupted at the level of neurons and glia, ketones can play an essential role in restoring normal cellular function.

Conclusion: Adherence, convenience, accessibility, palatability

The ketogenic diet, and resulting nutritional ketosis, is an important therapeutic tool for several medical indications including seizures, diabetes, and obesity.  While results are striking in the short and midterm, adherence beyond 6-12 months often proves difficult. Adherence to dietary interventions is directly related to the amount of social support and intervention provided by the program.  While high intervention programs lead to measurable nutritional ketosis, significant reductions in carbohydrate intake, and long-term health benefits, low intervention programs do not show the same success [39, 41]. Dietary interventions can include education, biomarker tracking, weekly calls or meetings with study coordinators, social group support meetings or online forums, recipes, food intake tracking tools, meal replacement formulations, and even study center provided whole food meals.  However, if these programs do not make the lifestyle convenient, accessible, and palatable, long term adherence will always be a challenge.


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