Ketogenic Diet Research 2019
Ketogenic Diet Research 2019
TABLE OF CONTENTS
RANDOMIZED CONTROLLED TRIALS
• Diabetes
• Weight Loss
• Cancer
• Epilepsy
• Safety
• Autism
• Exercise
• Global Development Delay
• Metabolism
• Cardiovascular Risk
• Infantile Spasms
• Metabolism
META-ANALYSIS
• Weight Loss
• Epilepsy
SYSTEMATIC REVIEWS
• Weight Loss
• Epilepsy
• Infantile Spasms
• Cancer
• Autism
• Glut1 Deficiency
• Metabolism
• Acne
• Lennox-Gastaut syndrome
• Neurological Outcomes
RECOMMENDATIONS
Randomized Controlled Trials
DIABETES
• Study: “An Online Intervention Comparing a Very Low-Carbohydrate Ketogenic Diet and Lifestyle Recommendations Versus a Plate Method Diet in Overweight Individuals With Type 2 Diabetes: A Randomized Controlled Trial [Link]. Findings: Individuals with type II Diabetes improved glycemic control and lost more weight after being randomized to a very low-carbohydrate ketogenic diet and lifestyle online program rather than a conventional low-fat diabetes diet program.
• Study: “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.“ [Link]. Findings: The very low-calorie ketogenic diet intervention was the most effective in reducing body weight and improvement in glycemic control compared to a standard hypocaloric diet and was well tolerated in Type II Diabetes patients.
WEIGHT LOSS
• Study: “Obesity treatment by very low-calorie-ketogenic diet at two years: reduction in visceral fat and on the burden of disease.” [Link] Findings: Of those who completed the study, the analysis revealed that from the beginning (15 days) until the end of the observation, the weight reduction observed in the very-low-calorie-ketogenic diet was double that of the low-calorie diet.
• Study: “Comparison of a very low-calorie-ketogenic diet with a standard low-calorie diet in the treatment of obesity.” [Link] Findings: In a group of obese patients, the VLCK diet was significantly more effective than a standard Low-calorie diet. At one year follow-up in the group with a VLCK diet, most of the patients lost more than 10% of their initial weight. However, lean mass was well-preserved.
• Study: Very-low-calorie ketogenic diet with amino acid supplement versus very low restricted-calorie diet for preserving muscle mass during weight loss: a pilot double-blind study. [Link] Findings: The pilot study found that a VLCKD was highly effective in terms of body weight reduction without inducing lean body mass loss, thus preventing the risk of sarcopenia. Further, the results show that a low-carbohydrate diet, associated with a decreased caloric intake, is effective in weight loss.
• Study: “Effect of DHA supplementation in a very low-calorie ketogenic diet in the treatment of obesity: a randomized clinical trial.” [Link] Findings: Using a controlled, open design clinical trial, the patients of this study were randomized to receive either a very low-calorie ketogenic diet (VLCK) or an isocaloric VLCK diet without DHA (control group). The main finding of this study was that the very low-calorie ketogenic diet supplemented with DHA group improved inflammation-resolving eicosanoids compared with the isocaloric VLCK diet group, and was effective in inducing loss of body weight.
• Study: “Metabolic impact of a ketogenic diet compared to a hypocaloric diet in obese children and adolescents.” [Link] Findings: Children and adolescents on the hypocaloric diet were instructed to reduce their caloric intake by 500 calories daily while deriving 28%–33% and 50%–55% of these calories from fat and carbohydrates, respectively. Both groups had significant reductions in weight and fat mass, however, the ketogenic group had more pronounced improvements in weight loss and metabolic parameters than the hypocaloric diet. The authors conclude that the ketogenic may be a feasible and safe weight loss intervention for children.
• Study: “Effects of a very-low-calorie diet on body composition, metabolic state, and genes expression: a randomized double-blind placebo-controlled trial.” [Link] Findings: This is the first study that analyzes body composition, metabolic profile, inflammation, and oxidative stress genes expression after the administration of a very low carbohydrate ketogenic diet (VLCKD). Results of the study show the efficacy of a VLCKD with synthetic protein replacement for the reduction of cardiovascular risk, without the development of sarcopenia, or the activation of inflammatory and oxidative processes.
CANCER
• Study: “Impact of a ketogenic diet intervention during radiotherapy on body composition: II. Protocol of a randomized phase I study (KETOCOMP).” [Link] Findings: It can be expected that chemotherapy has an impact on body composition, due to its associated reduced energy intake, increased energy turnover, and inflammatory processes that often result in increases in skeletal muscle breakdown, among other things. Previous studies found that a ketogenic diet (KD) during the course of radiotherapy (RT) was feasible and led to a preservation or favorable changes of body composition. The study found that morning irradiation after an overnight fast with a ketogenic breakfast consisting of an medium-chain triglyceride (MCT) drink diminished the expected decrease of phase angle (PA), an indicator of cell wall integrity, during the course of radiotherapy treatment.
EPILEPSY
• Study: “Effects of a ketogenic diet on ADHD-like behavior in dogs with idiopathic epilepsy.” [Link] Findings: Epilepsy is a common chronic neurological disorder in dogs as well as in humans. External factors associated with diet and the dog’s lifestyle may also have an impact upon the seizure activity and behavior. The aims of this study were to describe the behavioral profile of dogs with idiopathic epilepsy (IE) while on a standardized non-ketogenic placebo diet to determine whether ADHD-like behaviors are present, and to examine the effect of a ketogenic medium chain triglyceride diet (MCTD) on the behavioral profile of dogs with idiopathic epilepsy. The study found that the use of the MCTD reduced one of these ADHD-related behaviors, chasing, and reduced stranger-related fear which suggests that the Ketogenic diet intervention may have anxiolytic properties.
• Study: “Ketogenic diet in the treatment of epilepsy in children under the age of 2 years: study protocol for a randomized controlled trial.” [Link] Background: Epilepsy is a condition whereby individuals are prone to recurrent epileptic seizures, a change in behavior or movement that is the direct result of changes in the electrical activity in the brain. Up to 65% of individuals with epilepsy will have seizures controlled with antiepileptic drugs (AEDs) or enter spontaneous remission in their lifetimes. However, 35% will continue to experience seizures despite treatment. First-line management of an individual presenting with epilepsy is antiepileptic medication. Although guidelines exist on which drug to use, management of epilepsy is still based on a ‘trial and error’ approach. When the type of epilepsy or seizure is unclear, it can be difficult to optimize treatment at the outset. Design: The protocol of an open-label RCT designed to evaluate the effectiveness of the KD in children with epilepsy under the age of 2 years who have failed two AEDs, compared to standard AED treatment.
• Study: “A randomized controlled trial of the ketogenic diet in refractory childhood epilepsy.” [Link] Findings: This trial provides class I evidence that the KD is an effective therapy in children and adolescents with refractory epilepsy compared with care as usual (CAU). Most often reported side effects are gastrointestinal symptoms, and authors noted that lipid profiles showed only a significant increase of total cholesterol at 6 weeks. Of significance, patients treated with the KD had a seizure reduction of at least 50% and a relevant reduction in seizure severity.
• Study: “Cognitive and behavioral impact of the ketogenic diet in children and adolescents with refractory epilepsy: A randomized controlled trial.” [Link] Findings: Epilepsy is a neurological disorder that is treated with antiepileptic drugs (AEDs) in the majority of the patients. However, AEDs are sometimes not efficacious. About one-third of patients suffer from intractable epilepsy Furthermore, patients often experience side effects that lead to discontinuation of the drugs. For these patients, alternative nonpharmacological treatment options are available, such as the ketogenic diet (KD). This RCT shows a positive cognitive and behavioral effect of the Ketogenic diet intervention in children and adolescents. With respect to mood, patients on the ketogenic diet showed higher levels of mood problems at baseline. However, levels of mood-disturbed behavior diminished, and at the 4-month follow up it was noted that there was an overall reduction in anxiety/tension/hostility in the patients randomized to the ketogenic diet, independently of seizure control. The study also found that the group had increased productivity, and cognitive test results also revealed a higher receptive vocabulary.
• Method: “Research into the (Cost-) effectiveness of the ketogenic diet among children and adolescents with intractable epilepsy: design of a randomized controlled trial.” [Link] • Study: “An economic evaluation of the ketogenic diet versus care as usual in children and adolescents with intractable epilepsy: An interim analysis.” [Link] Background: Epilepsy is a cost-intensive condition. In 2004, the total costs of epilepsy in Europe was €15.5 billion, with indirect costs being the single most dominant cost category (€8.6 billion.) In The Netherlands, the direct medical costs were €248 million in 2011, which is 0.3% of the health care budget. Although the majority of patients with epilepsy can be treated with antiepileptic drugs (AEDs), about 30% of patients have intractable epilepsy. Objectives: Cost-compare the ketogenic diet (KD) to care as usual (CAU) in children and adolescents with intractable epilepsy: an evaluation of economic and social perspectives in an RCT. Findings: Children with refractory epilepsy, randomized to the KD group had a significant reduction in seizures compared to children in the CAU group, 50%, and 18.2% respectively. However, costs per patient in the CAU group were €15,245 compared to €20,986 per patient in the KD group, resulting in an incremental cost-effectiveness ratio (ICER) of €18,044 per responder. However, no benefits in terms of quality-adjusted life years (QALYs) were found and, therefore, the authors determined that the cost per QALY increase was found to be high above any acceptable ceiling ratio. Of note: The authors concluded that the ketogenic diet is therefore not a cost-effective intervention when including the quality-adjusted life years. The authors further suggested that although the KD group had a significant reduction in seizures when compared to the care as usual group, the ketogenic diet lack of effectiveness in terms of quality of life suggests that the ketogenic diet may be an ineffective way of treating patients with epilepsy from an economic standpoint.
• Study: “Efficacy of the classic ketogenic and the modified Atkins diets in refractory childhood epilepsy. ” [Link] Background: The ketogenic diet (KD) is an established treatment for drug-resistant childhood epilepsy. However, the ketogenic diet may be too difficult to implement in pediatric patients because of its restrictive nature and has potential side effects. A more easily applied alternative dietary therapy has also been utilized for epilepsy patients. This study aimed to compare the two dietary approaches. Findings: This study evaluated the classic ketogenic diet, but found that it did not have a definite advantage in terms of efficacy. Instead, the Modified Atkins Diet had advantages with respect to better tolerability and fewer side effects. However, in the patient group aged <2 years, the benefits of the ketogenic diet were more pronounced than compared with those consuming a modified Atkins Diet.
• Study: “Risk of seizure recurrence after achieving initial seizure freedom on the ketogenic diet.” [Link] Background: In previous short-term outcome studies, 15–20% of patients with intractable epilepsy achieved seizure freedom, and one-third achieved >90% seizure reduction. The objective of this study, however, was to examine the likelihood of sustained seizure freedom in the long-term on the ketogenic diet. Findings: This study gives evidence to support the continued use of a ketogenic diet in patients with initial seizure freedom even after breakthrough seizures, as even the frequency of the breakthrough seizures were not a return to baseline frequency in the patients.
• Study: “A randomized trial of a medium-chain TAG diet as a treatment for dogs with idiopathic epilepsy.” [Link] Background: Despite antiepileptic drug treatment, like humans, approximately one-third of dogs with epilepsy continue experiencing seizures. A 6-month prospective, randomized, double-blinded, placebo-controlled cross-over dietary trial was designed to evaluate the efficacy and tolerability of a ketogenic medium-chain TAG diet (MCTD) in chronically antiepileptic drug-treated dogs with idiopathic epilepsy. Note: The medium-chain TAG diet consists of caprylic acid, capric acid, lauric acid, and medium-chain triglycerides. Study Participants: This study included twenty-one dogs of seventeen different breeds, including an American bulldog, two Beagles, two Border Collies, Boxer, Cavalier King Charles Spaniel, English Bull Terrier, English Springer Spaniel, German Shepherd, Golden Retriever, Lhasa Apso, Mastiff, Rhodesian Ridgeback, Saint Bernard, Siberian Husky, Slovakian Rough Haired Pointer, Welsh Springer Spaniel, and three crossbreeds. Findings: In conclusion, the data shows antiepileptic properties commonly associated with ketogenic diet, and provides evidence for the efficacy of an MCTD as used in this study as a therapeutic option for the treatment of intractable epilepsy in dogs.
• Study: “A pragmatic study on efficacy, tolerability and long-term acceptance of ketogenic diet therapy in 74 South Indian children with pharmacoresistant epilepsy.” [Link] Background: An international consensus was established in 2009 recommending the use of a ketogenic diet in children after two trials of antiepileptic drugs in cases of intractable epilepsy. Even though the efficacy of KD is fairly well established in the management of drug-resistant epilepsy in children, it is still being recommended to a few selected areas in the world. Many factors contribute to this scenario, including the lack of awareness among physicians and caregivers. However, another roadblock of the ketogenic diet as a treatment for intractable epilepsy is cultural acceptance and viability given local food preferences. Note: The typical South Indian diet is very rich in carbohydrates, especially rice. Severe restriction of rice makes the diet unpalatable, posing a threat to the adherence to a ketogenic diet for individuals with epilepsy, especially for long-term maintenance. Further, there is a lack of cultural acceptance for the treatment. Authors noted that a less restrictive alternative approach may improve acceptability and long-term adherence. However, in areas like Kerala, the significant amount of fish products consumed, and the use of coconut oil as a traditional cooking medium may have aided in cultural acceptability and success of the patients in this region. Results: The Ketogenic Diet may be a safe and effective option for children with intractable epilepsies, even while on a traditional carbohydrate-rich South Indian diet. However, this study clearly points out that the successful introduction of a ketogenic diet therapy in any population will need to consider the dietary preferences of the local culture to have a successful intervention.
• Study: “A randomized trial of classical and medium-chain triglyceride ketogenic diets in the treatment of childhood epilepsy.” [Link] Background: The ketogenic diet was first designed to induce a similar metabolic response as fasting, with the ketone bodies b-hydroxybutyrate and acetocetate becoming the primary energy source for the brain in the absence of adequate glucose supply. However, there are two main ways of implementing a ketogenic diet. First, the classical ketogenic diet is based on a ratio of fat to carbohydrate and protein, usually 3:1 or 4:1, with the fat provided by long-chain triglycerides. The classical ketogenic diet restricts both carbohydrates and protein. However, a modified ketogenic diet using MCT as an alternative fat source yield more ketones per kilocalorie of energy than long-chain triglycerides. Further, MCT is absorbed more efficiently, and its increased ketogenic potential means that less fat is needed in the MCT diet, allowing also allowing for more dietary carbohydrate and protein. Note: Most studies on the efficacy of the ketogenic diet have involved the classical ketogenic diet and not the MCT diet. Findings: This study reports the results of the first randomized trial comparing the classical and MCT versions of the ketogenic diet in the treatment of drug-resistant epilepsy, and found that the classical ketogenic diet does not show any advantages over the MCT diet in terms of efficacy. However, in terms of tolerability, there were increased reports of lethargy and vomiting, and constipation with the use of the classical ketogenic diet protocol.
• Study: “Vagus nerve stimulation in children with intractable epilepsy: a randomized controlled trial.” [Link] Background: Vagus nerve stimulation (VNS) is a neuromodulatory treatment that involves a surgical implantation of a pulse-generating device, and consists of recurring intermittent electrical stimulation of the vagus nerve. The aim of this study was to evaluate the effects of vagus nerve stimulation (VNS) in children with intractable epilepsy on seizure frequency and severity and in terms of tolerability and safety. Note: This study is the first randomized active controlled study on the effectiveness of VNS in children. Authors found no statistically significant difference in seizure frequency reduction and seizure severity when comparing high and low-stimulation groups. Adverse events during the vagus nerve stimulation study included voice alterations, coughing, and throat pain. The majority of side effects were transient and most of them were related to stimulus. Other reported behavioral changes include agitation, crying, and frequent startles. Findings: At the end of the randomized controlled blinded phase, seizure frequency reduction of 50% or more occurred in 16% of the high-output stimulation group and in 21% of the low-output stimulation group. There was no significant difference in the decrease in seizure severity between participants in the stimulation groups. VNS reduced seizure frequency by 50% or more in 26% of participants at the end of the add-on phase, and severity improved. The authors conclude that VNS is a safe and well-tolerated adjunct treatment of intractable epilepsy in children.
• Study: “Efficacy of 4:1 (classic) versus 2.5:1 ketogenic ratio diets in refractory epilepsy in young children: a randomized open-labeled study.” [Link] Background: The ketogenic ratio of lipids to non-lipids may play an important role in the efficacy and tolerability of ketogenic diets (KD). This study was the first of its kind to compare the efficacy and tolerability of 2.5:1 versus 4:1 lipid to non-lipid ratio ketogenic diet in children with intractable epilepsy. Findings: Researchers found comparable efficacy in reducing seizure frequency and severity, as well as comparable tolerability and biochemical profiles between both the diets. However, one notable exception was a trend (p = 0.06) towards higher cholesterol and HDL in the 2.5:1 group, not the 4:1 group.
SAFETY
• Study: “Efficacy and safety of very-low-calorie ketogenic diet: a double-blind randomized crossover study.“ [Link] Background: Calorie restriction is the most effective in quick weight loss, under medical control. Since the popularity of short-term very-low calorie ketogenic diet (VLCKD) is increasingly high among obese patients, it has become clinically important to understand the efficacy and safety of the diet. This study aimed to evaluate the safety of a low-calorie ketogenic diet with respect to weight loss. Findings: This study found that a very low calorie ketogenic diet was able to be used safely for a period of 3 weeks to significantly stimulate fat loss, and improve metabolism without the risk of increasing the possibility of cardiovascular, renal, and hepatic disease. However, this study was limited in the number of subjects and study period. Nevertheless, it does offer evidence regarding the safety and important clinical implications in the administration of a very-low-calorie ketogenic diet. Note: The 3 week VLCKD program did not induce any negative changes in the nutritional state of the global measurements observed. This included bone mineral content, which is important as previous mouse models suggested that there was evidence of bone mass density reduction.
AUTISM
• Study: “Ketogenic diet versus gluten free casein free diet in autistic children: a case-control study.” [Link] Background: The Ketogenic diet is gaining attention due to its proven effect on neurological conditions like epilepsy in children, and the gluten free casein free diet GFCF is a popular special diet used for ameliorating gastrointestinal manifestations of ASD such as bloating, diarrhea, and discomfort that may impact behavior in autistic children. This study aimed to evaluate a modified ketogenic diet vs the gluten-free casein-free diet in terms of efficacy in ameliorating symptoms and severity of ASD. Findings: All patients were given a neurological examination, Childhood Autism Rating Scale (CARS) rating, and Autism Treatment Evaluation Test (ATEC) scales assessment before and 6 months after starting the diet they were randomized for. In short, both the ketogenic diet and GFCF groups showed significant improvement in both ATEC and CARS scores in comparison to the control group. Thus, the authors concluded that a modified ketogenic diet and gluten free casein free diet may safely improve autistic symptoms and severity, and could be recommended for children with ASD.
EXERCISE
• Study: “The effects of a ketogenic diet on exercise metabolism and physical performance in off-road cyclists.”[Link] Findings: High-volume training on a ketogenic diet increases fat metabolism during exercise, reduces body mass and fat content, and decreases post-exercise muscle damage. These results suggest that long-term high-fat diets may be favorable for endurance athletes during preparatory seasons when high volume and low to moderate intensity training is most typical.
• Study: “Keto analogue and amino acid supplementation affect the ammonaemia response during exercise under ketogenic conditions.” [Link] Background: Ammonia is highly toxic to humans and can cross the blood-brain barrier, which can lead to decreased cerebral function, neuropsychiatric disorders, and even death in some cases. Ammonia-mediated excitotoxicity has also been implicated in damage to the central nervous system. Several studies have suggested that increased ammonaemia, or hyperammonaemia, also occurs during various types of exercise, and is related to both central and peripheral fatigue. Further, it has been found in previous studies that a low-carbohydrate diet increases the production of ammonia during exercise. As such, the study aimed to determine the effect of keto analogues and amino acids (KAAA) supplementation on ammonia production in subjects eating a low-carbohydrate diet who exercise. Findings: Exercise-induced hyperammonaemia can successfully be reduced through supplementation with either amino acids or combined keto analogues and amino acids (KAAA).
• Study: “Efficacy of ketogenic diet on body composition during resistance training in trained men: a randomized controlled trial.” [Link] Findings: 24 healthy men with more than 2 years of continuous experience in overload training participated in this randomized controlled study. The results found that the subjects who underwent resistance training during a ketogenic diet experienced a greater reduction in fat mass and visceral adipose tissue compared to their non-ketogenic diet counterparts. This indicates that a ketogenic diet may be an effective and safe alternative dietary approach to decrease fat mass and visceral adipose tissue without decreasing lean body mass. However, the authors suggest that the ketogenic diet may not be useful for increasing muscle mass during positive energy balance in men undergoing resistance training for 8 weeks.
GLOBAL DEVELOPMENT DELAY
• Study: “Prospective study of ketogenic diet in treatment of children with global developmental delay.” [Link] Background: Global Developmental Delay (GDD) is the general term used to describe a condition that occurs during the developmental period of a child between birth and 18 years, when the child does not reach developmental milestones in all or most areas at the expected times. GDD usually manifests in the child having lower intellectual functioning than what is perceived as normal. This study aims to examine the effect of the ketogenic diet on neurobehavioral, social, and emotional development in children with global developmental delay. Findings: The Ketogenic Diet can improve the neurobehavioral development and behavioral and emotional behaviors in children with GDD, and it has few adverse effects.
METABOLISM
• Study: “Effects of Twenty Days of the Ketogenic Diet on Metabolic and Respiratory Parameters in Healthy Subjects.“ [Link] Background: Despite the widespread use of the ketogenic diet, its effect on respiratory parameters is still not well investigated. One of the metabolic effects of the ketogenic diet is higher than the usual oxidation of fats, which reduces the respiratory exchange ratio (RER) values. Study authors theorized that the ketogenic diet decreases RER and metabolic CO2 production which may lead to decreased arterial carbon dioxide partial pressure (PETCO2), which may make the ketogenic diet a potential adjunctive therapy for managing patients with respiratory failure. This study aims to investigate the potential for weight loss and improved respiratory parameters in healthy subjects on a ketogenic diet vs a Mediterranean diet. Findings: The main findings of the study are that (1) the ketogenic diet significantly decreased the value of respiratory exchange ratio RER (2) the ketogenic diet significantly decreased carbon dioxide end-tidal partial pressure (PETCO2); (3) the ketogenic diet had no significant effect on resting energy expenditure, oxygen consumption, carbon dioxide production, or expired total ventilation; and (4) the ketogenic diet significantly decreased body mass and body fat mass. Thus, the authors concluded that the Ketogenic Diet may be beneficial for patients with increased carbon dioxide arterial partial pressure due to respiratory insufficiency or failure.
• Study: “The effect of the classical and medium-chain triglyceride ketogenic diet on vitamin and mineral levels.” [Link] Background: Nutritional deficiency can be a risk for individuals with chronic medical conditions such as intractable epilepsy as a result of the long-term use of antiepileptic medications such as valproate and Lamotrigine, or pre-existing difficulties feeding. This study aimed to examine the risk of nutritional deficiency in children on the restrictive ketogenic diet. This study aimed to examine plasma levels of vitamin A, E, zinc, selenium, and magnesium over the course of 12 months in children on the ketogenic diet and the medium chain triglyceride (MCT) diet. Study authors wanted to determine whether there were any significant changes in these indices in children on the classical ketogenic diet, the MCT diet, and children of a similar age. Findings: Mean plasma vitamin A decreased in the classical ketogenic diet group, but significantly increased in the MCT group. No significant change in plasma zinc was seen at 12 months, although mean plasma selenium and magnesium decreased. These findings are interesting, as high-fat foods tend to be high in vitamin A, and it unclear why plasma vitamin A decreased in children on the classical ketogenic diet, and increased in the MCT diet. Nevertheless, it is known that excessive vitamin A supplementation can cause hypervitaminosis, which is associated with adverse effects such as skeletal and intracranial abnormalities. Therefore, these findings suggest a potential need for the reformulation of vitamin supplements to meet the requirements of the two different dietary approaches.
CARDIOVASCULAR RISK
• Study: “Effects of n-3 polyunsaturated fatty acids (ω-3) supplementation on some cardiovascular risk factors with a ketogenic Mediterranean diet.” [Link] Background: the ketogenic diet (KD) has become a widely used nutritional approach for weight loss. Some of the ketogenic diet’s positive effects on metabolism and cardiovascular risk factors are similar to those seen after omega-3 polyunsaturated fatty acid supplementation. This study aimed to examine the effects of a ketogenic Mediterranean diet with phytoextracts combined with omega-3 supplementation on cardiovascular risk factors and inflammation. Findings: The results did suggest a positive synergistic effect of a Mediterranean ketogenic diet with phytoextracts on body composition, cardiovascular risk factors, and inflammatory markers. Supplementation with ω-3 fatty acids significantly improved the effects of a ketogenic diet on triacylglycerol, insulin, and adiponectin, and also decreased inflammatory mediators interleukin 1 beta (IL-1β), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α).
• Study: “Circulating proprotein convertase subtilisin kexin type 9 has a diurnal rhythm synchronous with cholesterol synthesis and is reduced by fasting in humans. ” [Link] Background: Genetic variants of proprotein convertase subtilisin kexin type 9 (PCSK9) influence plasma low-density lipoprotein (LDL) cholesterol in humans, accounting for both hypercholesterolemia and hypocholesterolemia and altered coronary risk. It is known that fasting plasma levels of PCSK9 correlate positively with LDL cholesterol levels in healthy and diabetic patients. This study aimed to examine the influence of hormonal, diurnal, and dietary changes from food deprivation or a ketogenic diet on the function of PCKS9. Findings: The study found that fasting strongly reduces circulating PCSK9 in healthy humans, occurring concomitantly with suppressed cholesterol synthesis. Despite these changes to circulating PCSK9, the study found that LDL cholesterol levels were not reduced. However, Growth Hormone which is known to be increased during fasting in humans, was found to reduce circulating PCSK9 in parallel to LDL cholesterol levels.
INFANTILE SPASMS
• Study: “Comparison of short- versus long-term ketogenic diet for intractable infantile spasms.” [Link] Background: While the ketogenic diet is accepted as a treatment for intractable epilepsy and infantile spasms, the ketogenic diet is not without adverse side effects. To minimize the adverse side effects, the study aimed to examine the different prognoses between a short-term 8-month ketogenic diet and a long-term, >2 year ketogenic diet in patients with refractory infantile spasms. Findings: Short-term 8 Month group: 37.5% experienced nausea/vomiting, diarrhea/constipation. 50% experienced hypertriglyceridemia. 31% experienced hypercholesterolemia. 31% experienced hepatitis. 0% experienced osteopenia. Long-term 2-year group: 41% experienced nausea/vomiting, diarrhea/constipation. 33% experienced hypertriglyceridemia. 29% experienced hypercholesterolemia. 25% experienced hepatitis. 20% experienced osteopenia. After successful discontinuation of the ketogenic diet, the prognoses were compared between the group that maintained the diet for 8 months and the group that maintained the diet for >24 months. There was no significant difference in the including relapse tendency, correlated EEG findings, and developmental outcome data between the two groups. However, serious complications such as osteopenia, ureteral stones, and growth failure significantly occurred only in the long-term trial group. In effect, the utility of the ketogenic diet for 8 months is justified, however, prolonged ketogenic diet treatment has similar outcomes and recurrence rate, but with more serious complications.
METABOLISM
• Study: “Acetone as a biomarker for ketosis buildup capability–a study in healthy individuals under combined high fat and starvation diets.” [Link] Background: Both fasting and high-fat diets have been used successfully in clinical settings to help individuals lose weight. These interventions are known to increase the level of ketones within the blood. However, much remains unknown about the effects of macronutrient manipulation on blood ketone levels. The purpose of this study was to see how macronutrient and energy manipulation would impact ketone levels, which rather than being measured directly, were measured by acetone, which has been validated as an accurate proxy measure of ketone levels within the body. Findings: The study found that when individuals consumed a diet with 79% or 90% fat, they had higher acetone levels than when consuming a diet consisting of 29% fat. The researchers were not able to discern a difference in acetone levels when individuals were on a diet with 79% fat or 90% fat. They suggest that diets with very high amounts of fat (such as 90%) may not be needed for clinical interventions. Note: However, it’s worth noting that due to the small sample size, the researchers may not have had enough statistical sensitivity to detect a difference between the high-fat diets with regards to their effects on acetone, and thus ketone levels.
• Study: “Glucose uptake by the brain on chronic high-protein weight-loss diets with either moderate or low amounts of carbohydrate.” [Link] Background: Previous dietary studies have shown that high-protein diets used in conjunction with low-carbohydrate diets lead to reduced hunger and food intake. However, little is known about the mechanisms behind this phenomenon. This study aimed to see whether any possible differences in hunger between a high-protein, low-carbohydrate diet (22 g/d) and a high-protein, medium-carbohydrate (182 g/d) could be attributed to glucose or ketone metabolism, especially in key areas of the brain involved in the regulation of hunger. Findings: Both groups experienced weight loss and the high-protein, the low-carbohydrate group experienced less hunger than the medium-carbohydrate group. However, despite a 9-fold difference in carbohydrate intake, the authors were unable to detect a difference between groups with regards to energy utilization by the brain in areas that were analyzed. This may also be due to the small sample size of the study, thus larger studies are needed.
Meta-Analyses
WEIGHT LOSS
• Very-low-carbohydrate ketogenic diet v. low-fat diet for long-term weight loss: a meta-analysis of randomized controlled trials. [Link]
• Do ketogenic diets really suppress appetite? A systematic review and meta-analysis. [Link]
EPILEPSY
• A systematic review of economic evaluations of treatments for patients with epilepsy. [Link]
• Anti-Tumor Effects of Ketogenic Diets in Mice: A Meta-Analysis. [Link]
• Ketosis proportionately spares glucose utilization in brain. [Link]
Systematic Reviews
WEIGHT LOSS
• Very-low-carbohydrate ketogenic diet v. low-fat diet for long-term weight loss: a meta-analysis of randomised controlled trials. [Link]
• Do ketogenic diets really suppress appetite? A systematic review and meta-analysis. [Link]
EPILEPSY
• The effectiveness of a ketogenic diet in children with refractory epilepsy: a systematic review. [Link]
• Safety and tolerability of the ketogenic diet used for the treatment of refractory childhood epilepsy: a systematic review of published prospective studies. [Link]
• Ketogenic diet and other dietary treatments for epilepsy I. [Link]
• The Anticonvulsant Effects of Ketogenic Diet on Epileptic Seizures and Potential Mechanisms. [Link]
• Ketogenic diet in the treatment of epilepsy in children under the age of 2 years: study protocol [Link] for a randomized controlled trial.
• Optimal clinical management of children receiving the ketogenic diet: recommendations of the International Ketogenic Diet Study Group. [Link]
• The ketogenic diet in childhood epilepsy: where are we now? [Link]
• Epilepsy: behavioral, psychological, and ketogenic diet treatments. [Link]
• A systematic review of economic evaluations of treatments for patients with epilepsy. [Link]
• Ketogenic diet for the treatment of epilepsy. [Link]
• The collective therapeutic potential of cerebral ketone metabolism in traumatic brain injury. [Link]
• Question 1: efficacy of the ketogenic diet in difficult childhood epilepsies. [Link]
• Harnessing the power of metabolism for seizure prevention: focus on dietary treatments. [Link]
• Dietary management of epilepsy. [Link]
• Progress in child epilepsy. [Link]
• Epilepsy update, part 2: nursing care and evidence-based treatment. [Link]
• Polyunsaturated fatty acids and epilepsy. [Link]
• Epilepsy progress in the dawn of the 21st century. [Link]
• The ketogenic diet–update on recent clinical trials. [Link]
INFANTILE SPASMS
• Efficacy of ketogenic diet for infantile spasms: A systematic review. [Link]
• Efficacy of Treatments for Infantile Spasms: A Systematic Review. [Link]
• Treatment of Infantile Spasms: Report of the Interdisciplinary Guideline Committee Coordinated by the German-Speaking Society for Neuropediatrics. [Link]
CANCER
• Roles of caloric restriction, ketogenic diet and intermittent fasting during initiation, progression and metastasis of cancer in animal models: a systematic review and meta-analysis. [Link]
• Systematic review: isocaloric ketogenic dietary regimes for cancer patients. [Link]
• Beneficial effects of ketogenic diets for cancer patients: a realist review with focus on evidence and confirmation. [Link]
• Role of ketogenic metabolic therapy in malignant glioma: A systematic review. [Link]
• Anti-Tumor Effects of Ketogenic Diets in Mice: A Meta-Analysis. [Link]
• Application of Bayesian evidence synthesis to modeling the effect of ketogenic therapy on survival of high-grade glioma patients. [Link]
AUTISM
• Are therapeutic diets an emerging additional choice in autism spectrum disorder management? [Link]
GLU1 DEFICIENCY
• GLUT1 deficiency syndrome into adulthood: a follow-up study. [Link]
• Glucose transporter protein type 1 (GLUT-1) deficiency syndrome. [Link]
METABOLISM
• Carnitine, nutritional supplementation and discontinuation of ketogenic diet therapies. [Link]
• Modulation of oxidative stress and mitochondrial function by the ketogenic diet. [Link]
ACNE
• Nutrition and acne: therapeutic potential of ketogenic diets. [Link]
LENNOX-GASTAUT SYNDROME
• Efficacy of the ketogenic diet in Lennox-Gastaut syndrome: a retrospective review of one institution’s experience and summary of the literature. [Link]
NEUROLOGICAL OUTCOMES
• Stroke outcome in the ketogenic state-a systematic review of the animal data. [Link]
• Ketosis proportionately spares glucose utilization in the brain. [Link]
• Ketogenic diet in pyruvate dehydrogenase complex deficiency: short- and long-term outcomes. [Link]
Recommendations
• Commentary on “Optimal clinical management of children receiving the ketogenic diet: recommendations of the International Ketogenic Diet Study Group”. [Link]
• The ketogenic diet: what do the recommendations mean? [Link]
• National consensus on the ketogenic diet. [Link]