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Argumentative Essay: Ketogenic Diet

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Primary implements, adverse effects, counterclaim, in response to the counterclaim, in conclusion.

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StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

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Ketogenic diet.

Wajeed Masood ; Pavan Annamaraju ; Mahammed Z. Khan Suheb ; Kalyan R. Uppaluri .

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Last Update: June 16, 2023 .

• Continuing Education Activity

Despite continuous advances in the medical world, obesity remains a significant worldwide health hazard, contributing to adult mortality rates as high as 2.8 million per year. Obesity is closely linked to numerous chronic diseases, including diabetes, hypertension, and heart disease, often resulting from an unhealthy lifestyle and poor dietary habits. The implementation of appropriately tailored diet regimens for weight reduction can help mitigate the obesity epidemic to some extent. One diet regimen that has shown efficacy in rapid weight loss is the very low-carbohydrate and high-fat ketogenic diet. This activity aims to review the evaluation and considerations for the ketogenic diet while highlighting the role of the interprofessional team in educating patients about the associated risks and benefits of this dietary approach.

• Differentiate between the ketogenic diet and other dietary approaches, considering their specific mechanisms, macronutrient composition, and potential benefits and risks.
• Screen patients for potential contraindications or conditions that may require modifications or close monitoring when implementing the ketogenic diet.
• Assess and monitor patients' progress, including weight loss, metabolic markers, and potential adverse effects associated with the ketogenic diet.
• Collaborate with registered dietitians and other healthcare professionals to provide comprehensive support and education to patients on the ketogenic diet.
• Introduction

Despite continuous advances in the medical world, obesity remains a major worldwide health hazard, contributing to adult mortality as high as 2.8 million per year. [1] This pervasive issue is closely linked to the development of chronic diseases, including diabetes, hypertension, and heart disease, all predominantly associated with an unhealthy lifestyle and poor dietary habits. However, implementing appropriately tailored diet regimens for weight reduction can potentially mitigate the obesity epidemic to some extent. Among these regimens, the very low-carbohydrate and high-fat ketogenic diet has emerged as a highly effective approach for rapid weight loss. [1] [2] [3]

The ketogenic or keto diet is a dietary approach characterized by high-fat and low-carbohydrate intake, aiming to facilitate weight loss, enhance mental clarity, and boost energy levels. [4] By significantly reducing carbohydrate consumption and increasing fat and protein intake, this diet induces a metabolic state called ketosis, where the body utilizes fat as its primary fuel source instead of carbohydrates. The primary goal of the ketogenic diet is to decrease overall body fat and improve metabolic health. Recent research indicates potential benefits in reducing the risk of certain diseases, including type 2 diabetes, hyperlipidemia, heart disease, and cancer. [4]

A ketogenic diet primarily consists of high fat intake, moderate protein consumption, and low carbohydrate intake. The macronutrient distribution typically ranges from approximately 55% to 60% fat, 30% to 35% protein, and 5% to 10% carbohydrates. For instance, in a 2000 kcal per day diet, the carbohydrate allowance would amount to approximately 20 to 50 grams daily. [5]

History and Origin

Russell Wilder first used the ketogenic diet to treat epilepsy in 1921. [5] He also coined the term "ketogenic diet." Through his observations, Wilder noticed the diet reduced the frequency and intensity of seizures in a subset of his patients who followed this dietary approach. For almost a decade, the ketogenic diet was viewed as a therapeutic option for pediatric epilepsy, but its prominence diminished with the advent of antiepileptic drugs.

The diet was popularized in the 1970s and has since been widely studied as a potential treatment for various conditions. [5]  In recent years, the ketogenic diet has experienced a resurgence, particularly as a weight loss intervention, proving its efficacy in the short term. [6]

Physiology and Biochemistry

Carbohydrates typically serve as the main source of energy production in the body's tissues. However, when carbohydrate intake is restricted to less than 50 grams daily, insulin secretion decreases significantly, leading the body into a catabolic state. As a result, glycogen stores are depleted, triggering a series of metabolic changes. Two prominent metabolic processes come into play when carbohydrates are limited in body tissues: gluconeogenesis and ketogenesis. [7] [8]

Gluconeogenesis is the process by which the body produces glucose internally, primarily in the liver, using substrates such as pyruvate, lactic acid, glycerol, and specific amino acids classified as glucogenic. [9] [10] [9] When glucose availability drops, the endogenous breakdown of glucose cannot provide sufficient energy, ie, adenosine triphosphate (ATP). The metabolic pathway switches to ketogenesis to provide an alternate energy source in the form of ketone bodies. Ketone bodies replace glucose as a primary source of energy.

During ketogenesis, insulin secretion is low due to feedback from blood glucose levels, leading to a decrease in the stimulation of fat and glucose storage. Other hormonal changes may contribute to the increased fat breakdown resulting in fatty acids. Fatty acids are metabolized to acetoacetate, later converted to beta-hydroxybutyrate and acetone. These primary ketone bodies (ie, acetoacetate, beta-hydroxybutyrate, and acetone) accumulate in the body as the ketogenic diet is sustained and serve as an alternative energy source for the body. This metabolic state is referred to as "nutritional ketosis." As long as the body is deprived of carbohydrates, the metabolism remains ketotic. Nutritional ketosis is generally considered safe since it involves the production of ketone bodies in moderate concentrations without significantly impacting blood pH. Nutritional ketosis differs from ketoacidosis, a severe and life-threatening condition characterized by excessively high levels of ketone bodies, leading to acidosis in the blood. [9]

Ketone bodies synthesized within the body can be effectively utilized as an energy source by vital organs such as the heart, muscle tissue, and kidneys. [11] Ketone bodies can also cross the blood-brain barrier to provide an alternative energy source for the brain. RBCs and the liver do not utilize ketones due to a lack of mitochondria and enzyme diaphorase.

Ketone body production depends on several factors, such as resting basal metabolic rate (BMR), body mass index (BMI), and body fat percentage. Ketone bodies, often referred to as a "super fuel," produce a greater amount of ATP than glucose. When comparing energy production, 100 grams of acetoacetate generates 9,400 grams of ATP, 100 grams of beta-hydroxybutyrate yields 10,500 grams of ATP, while 100 grams of glucose produces only 8,700 grams of ATP. Ketone bodies enable the body to maintain efficient fuel production even when experiencing a caloric deficit. Additionally, ketone bodies can reduce free radical damage and enhance the body's antioxidant capacity. [11] [12]

Four types of ketogenic diets are categorized based on the percentage of macronutrients they contain, allowing for increased compliance with the regimens. These include the classic long-chain triglyceride (LCT) ketogenic diet, medium-chain triglyceride (MCT) ketogenic diet, modified Atkins diet (MAD), and low glycemic index treatment.

• Issues of Concern

Adverse Effects

The ketogenic diet's short-term effects (up to 2 years) are well-reported and established. However, the long-term health implications are unknown due to limited literature. [13] [14] [15]

The ketogenic diet may present some common and generally mild short-term adverse effects, known as the "keto flu." These symptoms can include nausea, vomiting, headache, fatigue, dizziness, insomnia, reduced exercise tolerance, and constipation. These symptoms resolve in a few days to weeks. Ensuring adequate fluid and electrolyte intake can help counter some of these symptoms. Long-term adverse effects include hepatic steatosis, hypoproteinemia, hypocitraturia, hypercalciuria, kidney stones, and vitamin and mineral deficiencies. [16] [5] [16]

• Nutrient deficiencies: Keto diets are very restrictive and can lead to inadequate intake of essential vitamins, minerals, and phytochemicals. [4]
• Digestive issues: High-fat, low-fiber diets can cause digestive problems, such as constipation, diarrhea, and bloating.
• Kidney stones: A high-fat, low-carbohydrate diet can increase the risk of developing kidney stones.
• Heart disease: A ketogenic diet can increase the risk of heart disease due to its high saturated fat content and lack of fiber. [4]
• Muscle loss: Rapid weight loss on a ketogenic diet can lead to muscle loss, negatively impacting athletic performance.
• Cognitive decline: The effects of low-carbohydrate diets on brain metabolism can potentially lead to cognitive decline. [17] [18]

Cautions and Contraindications

Patients with diabetes taking insulin or oral hypoglycemic agents may experience severe hypoglycemia if their medications are not appropriately adjusted before initiating a ketogenic diet. The ketogenic diet is contraindicated in individuals with pancreatitis, liver failure, disorders of fat metabolism, primary carnitine deficiency, carnitine palmitoyltransferase deficiency, carnitine translocase deficiency, porphyrias, or pyruvate kinase deficiency. Additionally, individuals following a ketogenic diet may rarely experience a false positive breath alcohol test due to the conversion of acetone to isopropanol by hepatic alcohol dehydrogenase, resulting in an inaccurate reading.

• Clinical Significance

Recent epidemiological studies have challenged the popular belief that high-fat diets directly cause obesity and diseases like coronary heart disease, diabetes, and cancer. These studies have not observed a conclusive causal relationship between dietary fat intake and these conditions. Additionally, research on animals fed high-fat diets has not demonstrated a direct link to obesity. On the contrary, very low-carbohydrate and high-fat diets, such as the ketogenic diet, have shown benefits for weight loss.

Evidence Behind the Ketogenic Diet

Regarding overall caloric intake, carbohydrates comprise around 55% of the typical American diet, ranging from 200 to 350 grams daily. [19]  Until recently, the significant potential of refined carbohydrates to cause detrimental effects was largely overlooked. However, emerging research has highlighted the negative impact of consuming excessive amounts of sugar-laden foods. Studies have shown that a higher intake of sugar-laden foods is associated with a 44% increased prevalence of metabolic syndrome and obesity and a 26% higher risk of developing diabetes. [19]

A comprehensive study conducted in 2012 examining cardiometabolic deaths in the United States revealed that approximately 45.4% of these deaths, including those attributed to heart disease, stroke, and type 2 diabetes, were associated with suboptimal intakes of 10 specific dietary factors. Among the nutritional factors examined, the study found that the highest estimated mortality was associated with high sodium intake, accounting for 9.5% of cardiometabolic deaths. This was followed by nuts and seeds (8.5%), high intake of processed meats (8.2%), low intake of omega-3 fats (7.8%), low intake of vegetables 7.6%), low intake of fruits (7.5%), and high intake of artificially sweetened beverages (7.4%). [20] The lowest estimated mortality was associated with consuming low polyunsaturated fats (2.3%) and unprocessed red meats (0.4%). In addition to the direct harm caused by excessive consumption of low-quality carbohydrates, another concern is that such consumption can crowd out healthier food options from the diet. When individuals consume an excess of low-quality carbohydrates, there may be limited space in their diet for more nutritious foods like nuts, unprocessed grains, fruits, and vegetables. [20]

1) Diabetes 

A recently published randomized crossover trial comparing the effects of ketogenic and Mediterranean diets revealed that patients who adhered to a well-formulated ketogenic diet experienced improved glucose control and reduced body weight. [21]  Although the blood sugar levels were reduced, the decrease in HbA1c levels was modest, with a reduction of less than 20%. Additionally, study participants had difficulty adhering to the strict dietary regimen. [21]  These findings have led to debates, as some argue that any restriction on carbohydrate intake would inevitably lead to a reduction in blood sugar and HbA1c levels.

2) Heart disease 

Research suggests that a ketogenic diet can reduce the risk of heart disease. A systematic review published in the American Journal of Clinical Nutrition in 2019 found that a ketogenic diet can lower markers of inflammation, which is associated with a decreased risk of heart disease. Furthermore, a study published in Circulation in 2020 demonstrated that a low-carbohydrate, high-fat ketogenic diet could reduce low-density lipoprotein (LDL) cholesterol levels, a significant risk factor for heart disease. These findings indicate that a ketogenic diet may effectively reduce the risk of heart disease.

3) Obesity 

Over the past century, the prevalence of obesity has increased, leading to the emergence of various diet programs. Among them, the ketogenic diet has shown significant benefits compared to other diets. A meta-analysis of 11 studies found that the low-carbohydrate diet group experienced considerable weight reductions compared to the low-fat diet group. Individuals assigned to a very low-carbohydrate ketogenic diet (VLCKD) experienced decreases in body weight, triglycerides, and diastolic blood pressure, as well as increases in HDL-C and LDL-C. Moreover, the VLCKD resulted in more significant long-term weight loss compared to a low-fat diet, suggesting it is a potential alternative option for obesity management. [22]  Similarly, a meta-analysis of randomized controlled trials (RCTs) revealed that the ketogenic diet is particularly effective in improving metabolic parameters related to glycemic control, weight management, and lipid control in obese individuals, particularly those with preexisting diabetes. Compared to low-fat diets, the ketogenic diet demonstrated superior outcomes in terms of glycemic control, weight loss, and lipid markers. [23]  The ketogenic diet also showed positive effects on insulin resistance and lipid markers, suggesting it can improve metabolic markers independent of weight loss.

4) Nonalcoholic fatty liver disease 

Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent disease characterized by hepatic adiposity, which can lead to liver damage, fibrosis, and inflammation. Weight loss is recommended as part of the general clinical management of NAFLD. However, it has been reported that low-carbohydrate diets, particularly those high in fat, may exacerbate hepatic steatosis due to their impact on cholesterol levels and liver function. [24] The ketogenic diet induces a shift in the gut microbiome, resulting in increased folate production and reduced inflammation and oxidative stress. Furthermore, the ketogenic diet promotes a sense of satiety and induces epigenetic modifications that play a role in the pathogenesis of NAFLD and allows the expression of antiinflammatory markers at the genetic level. [24]  

5) Polycystic ovarian syndrome (PCOS)  

PCOS is related to increased insulin resistance, hyperinsulinemia, T2DM, dyslipidemia, and hyperandrogenism. The mechanism by which a ketogenic diet helps PCOS is unclear. However, many theories postulate lowering insulin resistance helps with improving androgen levels. A crossover study compared the effects of a standard diet and a low-carbohydrate diet on PCOS and showed that the low-carbohydrate diet decreased glycemia, fasting serum insulin, and testosterone and increased insulin sensitivity. [25]

6) Neurodegenerative disorders 

• Alzheimer disease: A ketogenic diet regulates brain metabolism, mitochondrial homeostasis, and inflammation in Alzheimer disease by increasing mitochondrial function and reducing oxidative stress. [26]
• Parkinson disease: A pilot RCT compared the effect of a low-fat diet versus the ketogenic diet in Parkinson's disease. The study had 47 patients, and both groups showed a decrease in the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS). However, the group on the ketogenic diet showed a more significant reduction than the low-fat diet group. Also, the ketogenic group showed more significant improvements in nonmotor symptoms. [27]
• Epilepsy: The ketogenic diet, described initially as a successful treatment for epilepsy, has regained attention through numerous studies showcasing its effectiveness in patients with drug-resistant epilepsy and certain pediatric epilepsy syndromes. [28]

7) Cancer 

The therapeutic impact of the ketogenic diet on tumors, such as neuroblastoma, acute myeloid leukemia, and glioblastoma, is attributed to its ability to downregulate GPR109A expression, activate mTORC1, and reduce glucose uptake at the tumor site. This results in suppressed tumor growth, improved survival rates, and enhanced efficacy of chemotherapy.

A recent systemic review and meta-analysis of RCTs comparing the long-term effects (more than 1 year) of dietary interventions on weight loss revealed a lack of substantial evidence supporting the recommendation of low-fat diets. [29] Low-carbohydrate diets were found to be more effective in achieving significant weight loss compared to low-fat interventions. Additionally, a carbohydrate-restricted diet was found to maintain better an individual's basal metabolic rate (BMR), suggesting that the quality of calories consumed can impact the number of calories burned. In comparison to a very low-carb diet, a low-fat diet resulted in a decrease of more than 400 kcal per day in BMR. [29]

A well-formulated ketogenic diet not only restricts carbohydrates but also moderates protein intake to less than 1 gram per pound of body weight, with the option to increase to 1.5 grams per pound for individuals engaged in heavy exercise involving weight training. This limitation on protein intake aims to prevent endogenous glucose production through gluconeogenesis. However, there are no specific restrictions on fat or overall daily calorie intake.

Individuals on a ketogenic diet typically experience rapid weight loss, often up to 10 pounds in 2 weeks or less. This initial weight loss is attributed to the diet's diuretic effect; the loss of water weight is followed by fat loss. Interestingly, the ketogenic diet tends to preserve lean body muscle mass. As nutritional ketosis is sustained, hunger decreases, and the overall reduction in caloric intake further aids in weight loss.

• Other Issues

Long-term compliance with a ketogenic diet can be challenging, as is the case with any lifestyle change. While the ketogenic diet has shown superior results in inducing rapid and sustained weight loss in individuals with obesity for up to two years, understanding its clinical impacts, safety, tolerability, efficacy, treatment duration, and long-term prognosis after discontinuation of the diet requires further investigation.

The duration of following a ketogenic diet can range from a minimum of 2 to 3 weeks up to 6 to 12 months. Close monitoring of renal functions while on a ketogenic diet is imperative, and the transition from a ketogenic diet to a standard diet should be gradual and well-controlled.

• Enhancing Healthcare Team Outcomes

To counter the obesity epidemic, some healthcare practitioners recommend the ketogenic diet. However, practitioners should use evidence-based medicine when recommending this diet for individualized patient care. 

Overweight individuals with metabolic syndrome, insulin resistance, and type 2 diabetes will likely experience improvements in clinical markers of disease risk by adopting a well-formulated, very low-carbohydrate diet. This diet can enhance glucose control through reduced glucose intake and improved insulin sensitivity. In addition to weight reduction, particularly in abdominal obesity and insulin resistance, low-carb diets may also help improve blood pressure, blood glucose regulation, triglyceride levels, and HDL cholesterol levels. However, it's important to note that LDL cholesterol levels may increase when following this diet.

Numerous studies have highlighted the potential therapeutic benefits of the ketogenic diet in various neurological disorders, including epilepsy, dementia, amyotrophic lateral sclerosis (ALS), and traumatic brain injury, and acne, cancers, and metabolic disorders. [5]

The lack of long-term studies and the complexity of the mechanism make it premature to generally recommend the ketogenic diet for preventing type 2 diabetes or cardiovascular disease. However, it can be considered for primary weight loss.

While the ketogenic diet may help one lose weight in the short term, this weight loss is not sustained over the long run. In addition, countless studies show that the diet is associated with many complications that often lead to emergency room visits and admissions for dehydration, electrolyte disturbances, and hypoglycemia. [30] [31] [32]

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Disclosure: Wajeed Masood declares no relevant financial relationships with ineligible companies.

Disclosure: Pavan Annamaraju declares no relevant financial relationships with ineligible companies.

Disclosure: Mahammed Khan Suheb declares no relevant financial relationships with ineligible companies.

Disclosure: Kalyan Uppaluri declares no relevant financial relationships with ineligible companies.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

• Cite this Page Masood W, Annamaraju P, Khan Suheb MZ, et al. Ketogenic Diet. [Updated 2023 Jun 16]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

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• An isoproteic cocoa butter-based ketogenic diet fails to improve glucose homeostasis and promote weight loss in obese mice. [Am J Physiol Endocrinol Metab....] An isoproteic cocoa butter-based ketogenic diet fails to improve glucose homeostasis and promote weight loss in obese mice. Greenwell AA, Saed CT, Tabatabaei Dakhili SA, Ho KL, Gopal K, Chan JSF, Kaczmar OO, Dyer SA, Eaton F, Lopaschuk GD, et al. Am J Physiol Endocrinol Metab. 2022 Jul 1; 323(1):E8-E20. Epub 2022 May 16.
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A Review of Ketogenic Diet and Lifestyle

Erin mcgaugh , md, brandon barthel , md.

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The ketogenic diet has become increasing popular in recent years. With 25.4 million unique searches, the keto diet was the most Googled diet in the United States in 2020. 1 With increased consumer interest, the “keto” food industry has grown rapidly, and as a result, the global ketogenic diet market was valued at $9.57 billion in 2019. 2 The ketogenic diet has been discussed in popular culture by celebrities, health magazines, and documentaries. The popularity of this diet, and diets in general may be explained by the obesity epidemic in the United States and Missouri.

Introduction

As of 2018, the prevalence of obesity in this country is 42%. 3 In Missouri, two-thirds of the adult population is overweight or obese. 4 Patients trying to lose weight often turn to popular diets, and in the past few years, the ketogenic diet has been a trendy option. With the increased interest in this diet, researchers are working to understand the impact of this pattern of eating on patients’ health. There is evidence of benefit, especially regarding weight loss, but there are also risks and concerns. The goal of this review is to offer clarity to physicians counseling patients on the ketogenic diet with the latest literature about benefits and risks.

History of the Ketogenic Diet

In 1911, the first modern use of starvation for the treatment of epilepsy was noted. Two physicians in Paris reported that seizures were less severe in period of starvation. 5 While this was the origin for the ketogenic diet, it wasn’t until 1921 that any physician tried to generate ketosis. Dr. Rollin Woodyatt noted that under conditions of starvation, acetone, and beta-hydroxybutyric acid appear. 5 Woodyatt also uncovered that acetone and beta-hydroxybutyric acid were observed if patients ate a low carbohydrate diet. Around the same time, Dr. Russell Wilder theorized that ketonemia could be produced for therapeutic benefit, but with a low carb diet rather than starvation. 5 He developed the term “ketogenic diet.” The ketogenic diet become very popular in the treatment of childhood epilepsy. 5 As better epilepsy medications were developed throughout the twentieth century, the ketogenic diet lost prominence as an epilepsy treatment.

In the 1970s, nutritional ketosis was introduced as an idea for weight loss by Dr. Robert Atkins. In his book published in 1972, he describes how reducing carbohydrates “creates a unique chemical situation in the body…ketones are excreted, and hunger disappears.” 6 Although the Atkins diet was one of the first, many other low carb diets have been popularized since the 1970s, from the South Beach Diet to variations of the Paleo and Mediterranean diets. While the details of low-carbohydrate diets may have changed, they have remained a mainstream option for weight loss. Over the past few decades, many studies have sought to quantify the efficacy of low carb diets in terms of weight loss as well as evaluate the potential for amelioration of chronic disease. As research has investigated the mechanisms behind ketosis and weight loss, the ketogenic diet has become the de facto low carb diet of choice in the media and public dialogue. 1

What is the Ketogenic Diet?

The mainstay of the ketogenic diet is that dietary carbohydrates are kept very low, with varying levels of protein and fat. The classic ketogenic diet is defined as a diet with one gram protein per kilogram of body weight, 10–15g carbohydrates per day, and the remaining calories from fat. 7 The goal of the diet is to induce ketosis. Ketosis is thought to alter metabolic pathways to induce weight loss and potentially improve other health outcomes, such as a reduction of hyperglycemia and improvement in lipid profiles.

What is Ketosis?

Under ordinary circumstances, the body primarily relies on carbohydrates for energy production. Insulin functions to extract and store energy derived from glucose. When the body has reduced carbohydrates available, insulin secretion is reduced. Initially, stored glucose in the form of glycogen is available for fuel, but after three to four days, this is depleted. Stored fat then becomes the most readily available fuel, and its breakdown into free fatty acids provides the raw materials for ketone production in the liver. Ketone production is primarily seen in times of starvation and prolonged exercise, but is also a function of adherence to a very-low carbohydrate diet. Importantly, in physiological ketosis, there is no change in blood pH versus pathological ketosis where there is a lowering of blood pH.

Ketogenic Diet Weight Loss Mechanisms

There is evidence that the ketogenic diet is an effective weight loss therapy. However, the exact mechanisms behind this weight loss remain unclear. For example, in a review of thermodynamic principles of weight loss, Feinman and Fine explain that low-carbohydrate diets have decreased insulin fluxes causing an increased rate of lipolysis. 8 In other words, insulin inhibits lipolysis, and decreased insulin in low-carb diets causes increased fat breakdown. 8 This theory is demonstrated in a study that follows 15 subjects for 12 weeks. The first six weeks they ate a low-carbohydrate diet and the next six weeks a low-fat diet. Blood results after the low-carbohydrate diet displayed decreased circulating triacylglycerol levels versus the low-fat diet. 9 This reiterates the idea that low-carb diets increase fat breakdown. 9

Another proposed weight loss mechanism is with decreased carbohydrate intake, the body will have to undergo increased amounts of gluconeogenesis to provide glucose to the brain. 10 Gluconeogenesis is an expensive metabolic process. 10 Theoretically, restricting carbohydrates depletes glucose stores, and increases gluconeogenesis. 10 Another mechanism of weight loss is theorized to be direct appetite suppression. In a study with 17 men, subjects were given a high protein diet with two weeks of high-carb and two weeks of moderate-carb intake. During the low-carb, ketogenic diet phase, the participants reported significantly decreased hunger, leading the authors to hypothesize that ketosis itself may suppress hunger. 11 While these mechanisms provide insight into how the ketogenic diet promotes decreased appetite and fat loss, it is important to note that evidence shows weight loss from the ketogenic diet can be partially attributed to water loss. In another study, 20 obese subjects were followed for four months on a ketogenic diet. Utilizing body composition assessments, investigators noted a substantial reduction in weight due to free water loss early in the study. 12 It is important to look at length of duration in ketogenic diet studies as early, dramatic weight loss may be due to diuresis.

With these mechanisms in mind, numerous studies have evaluated the keto diet’s weight loss efficacy. There are many examples of randomized controlled trials where significant weight loss is achieved. For example, a meta-analysis by Mansoor et al. looked at mean weight loss in 11 randomized controlled trials for six months with a total of 1,369 participants. In the trials analyzed, participants were randomized into low carbohydrate versus low-fat diet plans. This study found that compared to low-fat diets, low-carbohydrate diets participants lost 2.17 kg more than the low-fat diets (95% CI −3.36, −0.99). 13 However, the duration of some included studies was only six months. When looking at studies with a longer duration, the weight loss is less superior. For example, in a meta-analysis by Bueno et al., they analyzed 13 randomized controlled trials with a total of 1,415 subjects that were followed for at least 12 months. Again, the very-low-carbohydrate ketogenic diet was compared to a low-fat diet. After twelve months, subjects adhering to the ketogenic diet had lost 0.91 kg compared to the low-fat diet arm (95% CI −1.65, −0.17). 14 While this was a significant result, the weight loss is less than what is seen in the shorter trials.

An interesting perspective is seen in a retrospective analysis of 89 subjects who were followed for 12 months. Subjects followed a diet plan which cycled between shorter periods of a ketogenic Mediterranean diet followed by longer periods of a traditional Mediterranean diet. For a majority (88.25%) of subjects there was substantial weight loss 100.7 ± 16.54 to 84.59 ± 9.71 kg. 15 This study gives a good example of a weight loss regimen that patients may find more feasible. It combines benefits of the ketogenic diet’s short-term effects, with a maintenance diet that is less restrictive.

Ketogenic Diet and Diabetes Mellitus

Before the advent of insulin, diet was a mainstay in type 1 diabetes treatment. Famously Dr. Frederick Allen used a low-carbohydrate starvation diet to treat diabetes. 16 However, the use of such diets decreased with the discovery of insulin. More recently, there has been significant interest in the use of ketogenic diets to treat type 2 diabetes in conjunction with obesity. There are several proposed mechanisms that support the use of ketogenic diets to improve hyperglycemia. Most importantly, decreased circulating glucose and increased insulin sensitivity. 17

Testing this hypothesis, investigators have looked to see if the ketogenic diet can help improve hyperglycemia. One small, shorter study recruited 28 participants to follow for 16 weeks. In this study all 28 subjects that were enrolled received ketogenic diet counseling with a goal of less than 20 grams of carbohydrates per day. At the end of the 16 weeks, 21 participants had completed the trial. The mean fasting glucose decreased by 16.6% from 9.08 ± 4.09 mmol/L at baseline to 7.57 ± 2.63 mmol/L at week 16 (p = 0.04). 18 The hemoglobin A1c decreased from 7.5 ± 1.4% at baseline to 6.3 ± 1.0% at week 16 (p < 0.001). 18 These results were encouraging, but with short duration and small sample size.

In a two-year, open label, non-randomized, controlled study, 349 participants received either standard care or were educated to follow a ketogenic diet. 19 At the end of two years, those who had followed diets to stimulate ketosis had a 0.9% decrease in HbA1c versus a 0.4% increase in the standard of care arm. In addition, those following the ketogenic diet decreased their use of diabetic medications by 81%, while medication use increased in standard of care patients. 19 Another similar trial looking at glycemic control outcomes after two years showed no significant difference in HbA1c levels between the low-fat and low-carbohydrate groups. 20 These studies show than in the shorter term, there seem to be clinically significant improvements in glycemia control outcomes. However, in the longer term, while there are examples of improved HbA1c and medication use, there is less extreme improvement.

A very recent meta-analysis by Goldenberg et al. evaluated the efficacy of low-carb and very-low-carb diets in type 2 diabetes that seemed to support the idea that while significant benefit in weight loss, glycemic control, and insulin sensitivity were seen in the short term, the benefits seemed to wane after 12 months. 21 Participants in some trials seemed to struggle with adherence to the very-low-carb diet, suggesting that loss of efficacy in longer studies may be related to difficulty in maintaining such a restrictive eating pattern over a long period of time. 21

It is important to understand the impact of the ketogenic diet in patients with type 1 diabetes. Although it has not been studied extensively, there have been trials showing positive outcomes. One small trial with ten participants were randomized into a carbohydrate restricting arm versus a standard carbohydrate counting arm. They were followed for 12 weeks. At the end of 12 weeks, the carbohydrate restricted arm had significant reductions in HbA1c (8.9 to 8.2%, p<0.05) and a significant decrease in daily insulin use (64.4 to 44.2 units per day p<0.05). 22

A critical point to mention is the hypoglycemic risk of the ketogenic diet in the type 1 diabetes population. In an observational study with 11 participants, subjects were followed on a ketogenic diet for three years. A main finding of this study was that participants had 6.3 episodes of hypoglycemia per week compared to on to two episodes a week, noted in previous literature. 23 Of similar concern, there are case studies indicating that the ketogenic diet in people with type 1 diabetes can precipitate ketoacidosis. 24 Thus, significant caution would need to be observed in patients with type 1 diabetes who wish to follow a ketogenic diet.

Ketogenic Diet and Cardiovascular Disease

A common concern physicians have with the ketogenic diet is its effect on blood lipids and lipoproteins, and more broadly, its effect on cardiovascular disease risk factors. Despite the frequent concern that the ketogenic diet increases LDL-cholesterol, a recent comprehensive review of evidence by the National Lipid Association Task Force, showed variable responses of LDL-cholesterol. 25

The meta-analysis by Mansoor et al. evaluated cardiovascular risk factors in addition to weight loss as noted above. They evaluated 11 randomized controlled trials with 1,369 participants placed into ketogenic versus low-fat diet arms. They found that the ketogenic diet participants, after six months, had decreased blood triglycerides (−0.26 mmol/l; 95% CI −0.37, −0.15), but an increase in both HDL-cholesterol (0.14 mmol/l; 95% CI 0.09, 0.19) and LDL-cholesterol (0.16 mmol/l; 95% CI 0.003, 0.33). 13

In another meta-analysis, the authors reviewed eight randomized controlled trials lasting six months with 1,633 participants in a ketogenic versus low-fat randomization. In this analysis, they found no significant difference in LDL-cholesterol levels between groups (0.07 mmol/L; 95% confidence interval [CI], 0.02–0.13; P <0.009] 26 . HDL-cholesterol and plasma triglycerides at six and 12 months increased and decreased, respectively (0.08 mmol/L; 95% CI, 0.06–0.11; P<1×10−5 and −0.13 mmol/L; 95% CI, −0.19 to −0.08; P<1×10−5). 26

Further analysis suggests that the variation in diet composition may have a significant effect on the lipid changes seen. The increase in LDL-cholesterol seen in some of the randomized controlled studies may be due to the increased intake of saturated fats when carbohydrates are lowered. One meta-analysis centered on randomized controlled trials analyzed long-term effects of low-fat versus high-fat diets. The meta-analysis included 32 studies with 8,862 participants that were followed for a minimum of 12 months. Results showed a decrease in total cholesterol (−4.55 mg/dL; 95% CI −8.03 to −1.07; p=.01) and LDL-cholesterol (−3.11 mg/dL; 95% CI −4.51 to −1.71; p<0.0001) were more prominent in the low-fat arm. 27 Further analysis showed that lower total and LDL-cholesterol were associated with lower saturated fat intake, and increased monounsaturated fat was related to high HDL-cholesterol and lower saturated fat intake. 27

In summary, there are enough randomized controlled studies showing increased LDL-cholesterol in the ketogenic diet for it to be a consideration in certain patient populations. However, when looking at meta-analyses, the LDL-cholesterol response is variable. Diet composition likely plays an important role in the lipid changes seen in patients adhering to a ketogenic diet, so a high-quality diet with adequate intake of fruits and vegetables and low intake of saturated fats would be preferred. Ketogenic diets have been shown to repeatedly decrease triglycerides and increase HDL-cholesterol levels.

Ketogenic Diet in Pregnancy

There is evidence that women who become pregnant on low-carbohydrate diets have increased risk of birth defects. The National Birth Defects Prevention Study retrospectively looked at mothers with infants with stillbirths, anencephaly, or spina bifida (1,740) versus mothers with infants without defects (9,545). They found that women with restricted carbohydrate intake, defined as less than the fifth percentile among the control group were 30% more likely to have infants with neural tube defects (Odds ratio of 1.30, 95% (1.02, 1.67) p<.01) as well as decreased folic acid levels. 28 Women who plan to become pregnant should be advised to avoid restrictive low-carbohydrate diets. Adequate folate supplementation should be stressed if they choose to continue with a low-carb diet.

Although ketogenic diets are popular and patients show great interest, their use must be approached with caution. There is data showing impressive short-term weight loss, but most analyses suggest that long-term, their efficacy is comparable to other hypocaloric diets. At least part of this effect may be due to difficulty with long-term adherence to such a restrictive eating pattern. In addition, some of the weight lost during the acute period of following a ketogenic diet may be related to water loss, rather than true fat loss. Thus, the impressive short-term weight loss numbers may appear inflated. For patients with type 2 diabetes, it is likely that any weight loss achieved with the ketogenic diet could lower A1c and help reduce the medication burden. Care must be taken to taper diabetes medications appropriately to reduce the risk of hypoglycemia.

Lastly, long-term safety and health have yet to be proven, especially with regard to lipid profile alterations and cardiovascular impact. Studies generally show improvement in HDL and triglycerides, but LDL response is variable. This may be due to significant variability in the content of the diet of each specific person. Those interested in the keto diet should be encouraged to limit saturated fat and ensure adequate consumption of fruits and vegetables in order to maintain micronutrient and fiber intake.

Erin McGaugh, MD, is a graduate of University of Missouri–Kansas City School of Medicine (UMKC SOM). Brandon Barthel, MD, (above), is Assistant Professor of Medicine in Internal Medicine and Endocrinology, Truman Medical Center at UMKC SOM, Kansas City, Missouri.

None reported.

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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

Affiliations.

• 1 School of Journalism and Communication, Wuhan Sports University, Wuhan 430079, China.
• 2 Reproductive Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
• 3 Tianjiu Research and Development Center for Exercise Nutrition and Foods, Hubei Key Laboratory of Exercise Training and Monitoring, College of Health Science, Wuhan Sports University, Wuhan 430079, China.
• 4 School of Economics and Management, Wuhan Sports University, Wuhan 430079, China.
• PMID: 36012064
• PMCID: PMC9408028
• DOI: 10.3390/ijerph191610429

A ketogenic diet, characterized by low calories with high levels of fat, adequate levels of protein, and low levels of carbohydrates, has beneficial effects on body weight control in overweight patients. In the present study, a meta-analysis was conducted to investigate the role of a ketogenic diet in body weight control and glycemic management in overweight patients with type 2 diabetes mellitus (T2DM). In summary, we systematically reviewed articles from the Embase, PubMed, Web of Science and Cochrane Library databases and obtained eight randomized controlled trials for meta-analysis. The results show that a ketogenic diet had significantly beneficial effects on the loss of body weight (SMD, -5.63, p = 0.008), the reduction of waist circumference (SMD, -2.32, p = 0.04), lowering glycated hemoglobin (SMD, -0.38, p = 0.0008) and triglycerides (SMD, -0.36, p = 0.0001), and increasing high-density lipoproteins (SMD, 0.28, p = 0.003). Overall, these results suggest that a ketogenic diet may be an effective dietary intervention for body weight and glycemic control, as well as improved lipid profiles in overweight patients with T2DM. Hence, a ketogenic diet can be recommended for the therapeutic intervention of overweight patients with T2DM.

Keywords: body weight control; glycated hemoglobin; glycemic management; high-density lipoprotein; therapeutic intervention; very low-carbohydrate diet.

Publication types

• Meta-Analysis
• Systematic Review
• Research Support, Non-U.S. Gov't
• Blood Glucose / analysis
• Body Weight
• Diabetes Mellitus, Type 2* / therapy
• Diet, Ketogenic*
• Glycemic Control
• Triglycerides
• Weight Loss
• Blood Glucose

Grants and funding