Is There Any Evidence Behind the Ketogenic Diet?

The very high fat, low carbohydrate ketogenic, or keto diet as it is commonly referred to, has been in existence for decades, and it appears to be making another come-back as a popular weight loss method, a way to improve mental clarity, and even a way to improve energy levels. While a diet that glorifies foods such as butter, bacon, and whipping cream is a dietitian’s worst nightmare, there is some interesting research to consider, and nutrition professionals should be aware of the potential applications for this diet.

History of the ketogenic diet
It is suspected that fasting and variations of a ketogenic diet (KD) were used to treat seizures as far back as 500 BC, but the first modern medical use of the diet occurred in the 1920s when doctors noticed that complete fasting, or a severe carbohydrate restriction, resulted in dramatic improvements in epileptic seizures, as well as improvements in behavior and cognitive effects. The KD was used for years in pediatric hospitals, until it fell out of favor with the advent of anti-epileptic drugs. It has recently regained attention because it works for many patients whose epilepsy does not respond to drug therapy. More recently, the KD has also been examined for its potential benefits for other neurological disorders ranging from migraine headaches to bipolar disorder, autism, brain cancer, Alzheimer’s, and Parkinson’s disease, and amyotrophic lateral sclerosis (ALS).

Variations of a KD have also been popularized by dieters because the severe restriction in calories and carbohydrates forces the body to burn stored fat as fuel, and dieters often notice rapid weight loss in the initial stages of a KD. The first phase of the Atkins Diet™, also known as the “induction” phase, is perhaps the most well-known commercialized keto diet. In the induction phase, carbohydrates are limited to 20 net grams (g) (total carbs minus fiber and sugar alcohols) supplemented by healthy fats from nuts and vegetable oils, proteins, and nonstarchy vegetables. The Atkins diet varies from a true KD, because the carbohydrates are gradually increased, so ketosis is not maintained long term, and the protein allowance is higher.

Mechanism of action
A keto diet is different than what many dieters term a “low-carb diet.” On a KD, carbohydrates are severely restricted, usually to less than 50 g/day, and any glycogen stored in the liver is quickly depleted. In the absence of glucose, the preferred fuel, the body shifts into a metabolic state known as ketosis. During ketosis, dietary or stored fatty acids are tapped as an alternate source of fuel, and in the process, ketones are produced by the liver. The ketone bodies are converted to acetyl-CoA, which enters the citric acid cycle to produce energy. Fatty acids yield significantly more energy in the form of adenosine triphosphate (ATP) than glucose. After several days on a KD, ketones can provide as much as 70% of the brain’s energy as a replacement for glucose. 

Typical ketogenic diets contain approximately 80% of daily energy from fat, with enough protein to meet individual needs; usually about 15% of daily energy. Carbohydrate intake is maintained at approximately 5% of daily energy, or 20-50 g/day. Adherence to the KD can be confirmed by the presence of urinary ketones. Although ketones are acidic, it is unlikely that dietary ketosis would result in ketoacidosis, the serious condition associated with type 1 diabetes. Ketoacidosis results when insulin levels are dangerously low and ketones accumulate in much higher levels than is possible in dietary ketosis. Ketoacidosis can lead to coma or even death. A KD should not be undertaken by those with type 1 diabetes, without medical clearance and close monitoring and medical follow-up because of the high risk of hypoglycemia and other metabolic complications.

Research on its uses

• Weight loss: Anecdotal reports from dieters suggest that adhering to a KD for weight loss is often easier than following a lower-fat, or overall calorie-restricted diet, because satiety levels are improved on a higher fat keto diet, and physical energy levels are increased, despite a reduction in calories. In a study that examined the effects of a KD on appetite and the appetite-stimulating hormone ghrelin, researchers determined that ghrelin levels and appetite were indeed reduced when subjects were ketotic. (Sumithran, et al, 2013)

In terms of actual weight loss, the KD also appears to be beneficial, at least in the somewhat short-term period of one year. In a review and meta-analysis of 13 studies and almost 1,600 overweight or obese subjects, scientists found a significant reduction in body weight among individuals who followed a KD, compared to those who followed a low-fat diet for 12 months or more. (Bueno, et al, 2013) Whether the weight loss would continue for a longer term is unclear.

• Diabetes and cardiovascular risk factors: Dietitians may be surprised to learn that such an extreme and seemingly unhealthy diet has been shown, in some studies, to improve glycemic control and reduce risk factors associated with cardiovascular disease, including blood pressure, cholesterol, triglyceride levels, and A1C—although there may be some tradeoffs. Most of the benefit to lipids from a KD results from improvement in triglycerides and an increase in high-density lipoprotein (HDL) cholesterol. Along with these benefits, however, many studies also show an increase in low-density lipoprotein (LDL) cholesterol from a KD. 

Researchers who conducted a randomized controlled trial examined weight loss and metabolic marker changes in subjects on a low carbohydrate KD (approximately 5% of energy from carbohydrate), and a low carbohydrate non KD (approximately 40% of energy from carbohydrate). They determined that both diets resulted in weight loss and improved insulin sensitivity. However, they noted an increase in LDL cholesterol and some inflammatory markers, as well as more feelings of fatigue in subjects who followed the KD. (Johnston et al, 2006)

In a review of dietary treatments for diabetes, researchers compared the effects of a low carbohydrate diet (20-60 g/day), a low-glycemic index diet, a Mediterranean diet, and a high-protein diet using various metabolic measures in subjects with diabetes. A meta-analysis showed that the low-carbohydrate diet resulted in significant improvement in weight, A1C levels, and HDL cholesterol. However, similar improvements were seen with all diets; the low-carbohydrate diet pattern was not necessarily any more effective than the other diet patterns overall (Ajala, et al, 2013).

• Epilepsy and neurological diseases: Although the mechanism of action is still not understood, the evidence points to benefit from the KD on the treatment of epilepsy, especially for children who may be more susceptible to its effects on the brain. Numerous studies have shown a reduction in the number of seizures in most subjects who follow the KD. In addition, studies have reported that many epilepsy patients are able to resume a regular diet after 2 years on a KD, with no subsequent increase in seizures.

The KD appears to protect and even increase the number of mitochondria (the organelles that produce energy) in the brain; this may be one reason for the diet’s neurological benefits. An increased energy reserve might allow neurons in the brain to better fight off disease stressors that would otherwise damage or kill them. Because of the diet’s neuroprotective effects, it is currently being studied as a treatment in several neurological diseases, such as autism, migraine headache, and depression, but there is no significant research available at this time. There is however, some early research on use of the diet in Alzheimer’s and Parkinson’s disease, and ALS.

Some Alzheimer’s patients treated with a KD have experienced a reduction in Alzheimer’s-related seizures, as well as improved cognitive function. Promising results have also been noted in animal studies, but it is unclear if the results could be similar in humans. Findings from preliminary studies on Parkinson’s disease and ALS suggest that a KD may protect dopaminergic and motor neurons from degeneration and help to preserve movement and motor function. Although studies have primarily been conducted on mice or very small groups of human subjects, scientists are hopeful that a KD may eventually prove to be a beneficial addition to treatment for these and other neurological diseases. (Rho & Stafstrom, 2012)

• Cancer: Because cancer cells rely on glucose for energy production, it has long been suggested that a KD may help to slow the growth of cancerous tumors. Several trials are currently underway to examine the effects of a KD along with traditional cancer treatment on breast, lung, pancreatic, head and neck, and brain cancers. Results of several studies on recurrent glioblastoma (a type of brain tumor) have been promising, with subjects experiencing tumor regression.

Nutritional consequences of the keto-diet
The biggest drawback to the KD is that it is extremely restrictive and difficult to adhere to long term. In addition, because of its many dietary limitations, micronutrient deficiency is likely a concern with long-term use. A study on nutrient composition of a very strict 4:1 KD (the ratio of fat to carbohydrate and protein combined) determined that the diet met only 3 of the 28 daily recommended intakes (DRIs) for young children. The least restrictive 1:1 KD still met only 12 of 28 DRIs. (Zupec‐Kania & Zupanc, 2008)

Another important long-term consequence of the diet is the possible negative impact on lipid levels, especially if saturated fats are used as a fat source. Short-term side effects are also common, and include gastrointestinal problems, especially vomiting, reflux, and constipation, dehydration, lethargy, and headache. These symptoms generally resolve within several days to a week on the diet. 

Dietitians should be aware that most of the evidence suggests the use of the KD may be helpful for individuals with epilepsy who do not respond to medication, or possibly for those with other neurological conditions as listed. It may have limited benefits for weight loss or glycemic control, but in most cases, it should not be considered a long-term dietary strategy. 

Individuals who are interested in attempting the diet should be advised that it is not considered a substitute for traditional medical treatment, but it may be helpful as a complementary therapy. Those who follow a KD long term should be monitored medically to ensure that no complications arise. Finally, it is essential that they work closely with a registered dietitian nutritionist (RDN) to ensure that the diet is individualized and any supplements are provided to meet nutritional needs, especially in the case of children, where growth is an important consideration.

References and recommended reading

Ajala O, English P, Pinkney J. Systematic review and meta-analysis of different dietary approaches to the management of type 2 diabetes. Am J Clin Nutr. 2013;97(3):505-16. doi:10.3945/ajcn.112.042457.

Atkins RC. Dr. Atkins’ New Diet Revolution. Lanham, MD: The Rowman and Littlefield Publishing Group, Inc.; 2002.

Branco AF, Ferreira A, Simões RF, et al. Ketogenic diets: from cancer to mitochondrial diseases and beyond. Eur J Clin Invest. 2016;46(3):285-98. doi:10.1111/eci.12591.

Bueno NB, de Melo IS, de Oliveira SL, da Rocha Ataide T. Very-low-carbohydrate ketogenic diet v. low-fat diet for long-term weight loss: a meta-analysis of randomised controlled trials. Br J Nutr. 2013;110(7):1178-87. doi:10.1017/S0007114513000548.

Dashti HM, Mathew TC, Hussein T, et al. Long-term effects of a ketogenic diet in obese patients. Exp Clin Cardiol. 2004;9(3):200–205. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2716748/. Accessed September 29, 2016.

Johnston CS, Tjonn SL, Swan PD, White A, Hutchins H, Sears B. Ketogenic low-carbohydrate diets have no metabolic advantage over nonketogenic low-carbohydrate diets1–3. Am J Clin Nutr. 2006;83(5):1055-61. https://www.ncbi.nlm.nih.gov/pubmed/16685046. Accessed September 29, 2016.

Paoli A, Rubini A, Volek JS, Grimaldi KA. Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets. Eur J Clin Nutr. 2013;67:789–796. doi:10.1038/ejcn.2013.116.

Schachter SC, Kossoff E, Sirven J. Ketogenic diet. Epilepsy Foundation website. http://www.epilepsy.com/learn/treating-seizures-and-epilepsy/dietary-therapies/ketogenic-diet. Published August 2013. Accessed September 7, 2016.

Stafstrom CE, Rho JM. The ketogenic diet as a treatment paradigm for diverse neurological disorders. Front Pharmacol. 2012;3:59. doi:10.3389/fphar.2012.00059.

Sumithran P, Prendergast LA, Delbridge E, Purcell K, Shulkes A, Kriketos A, Proietto J. Ketosis and appetite-mediating nutrients and hormones after weight loss. Eur J Clin Nutr. 2013;67(7):759-64. doi:10.1038/ejcn.2013.90.

Wheless JW. History of the ketogenic diet. Epilepsia. 2008;49(Suppl 8):3-5. doi:10.1111/j.1528-1167.2008.01821.x.

Zupec‐Kania B, Zupanc ML. Long‐term management of the ketogenic diet: Seizure monitoring, nutrition, and supplementation. Epilepsia. 2008;49(Suppl 8):23-6. doi:10.1111/j.1528-1167.2008.01827.x.