research articles on keto diet

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The Potential Health Benefits of the Ketogenic Diet: A Narrative Review

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Considering the lack of a comprehensive, multi-faceted overview of the ketogenic diet (KD) in relation to health issues, we compiled the evidence related to the use of the ketogenic diet in relation to its impact on the microbiome, the epigenome, diabetes, weight loss, cardiovascular health, and cancer. The KD diet could potentially increase genetic diversity of the microbiome and increase the ratio of Bacteroidetes to Firmicutes . The epigenome might be positively affected by the KD since it creates a signaling molecule known as β-hydroxybutyrate (BHB). KD has helped patients with diabetes reduce their HbA1c and reduce the need for insulin. There is evidence to suggest that a KD can help with weight loss, visceral adiposity, and appetite control. The evidence also suggests that eating a high-fat diet improves lipid profiles by lowering low-density lipoprotein (LDL), increasing high-density lipoprotein (HDL), and lowering triglycerides (TG). Due to the Warburg effect, the KD is used as an adjuvant treatment to starve cancer cells, making them more vulnerable to chemotherapy and radiation. The potential positive impacts of a KD on each of these areas warrant further analysis, improved studies, and well-designed randomized controlled trials to further illuminate the therapeutic possibilities provided by this dietary intervention.

1. Introduction

Ketogenic diets have started to increase in popularity as doctors and researchers investigate the potential benefits. Nutritional ketosis, the aspirational endpoint of ketogenic diets, is achieved by restricting carbohydrate intake, moderating protein consumption, and increasing the number of calories obtained from fat [ 1 ]. Theoretically, this restriction of carbohydrates causes the body to switch from glucose metabolism as a primary means of energy production. This results in the use of ketone bodies from fat metabolism, a metabolic state where the body prefers to utilize fat as its primary fuel source. Recent studies utilizing Low-carbohydrate, High-fat (LCHF) diets, such as the ketogenic diet, show promise in helping patients lose weight, reverse the signs of metabolic syndrome, reduce, or eliminate insulin requirements for type II diabetics [ 2 ], reduce inflammation, improve epigenetic profiles, alter the microbiome, improve lipid profiles, supplement cancer treatments, and potentially increase longevity [ 3 ] and brain function.

The number of Americans suffering from obesity, diabetes, and metabolic syndrome is on the rise. The markers of metabolic syndrome include an increase in abdominal adiposity, insulin resistance, elevated triglycerides, and hypertension [ 4 , 5 ]. All of these negative health markers increase the risk of cardiovascular disease, diabetes, stroke, and Alzheimer’s disease. According to WebMD, there are currently 27 million people with Type 2 diabetes and 86 million with pre-diabetes. In addition, the Centers of Disease Control and Prevention (CDC) also estimates that almost 40% of adults and around 20% of American children are obese [ 6 , 7 ]. Many researchers believe these diseases are a result of carbohydrate intolerance and insulin resistance. Thus, a diet that reduces the exposure to carbohydrates, including whole grains, might become a more logical recommendation for improving health [ 8 ]. In line with this, two dietary regimens, the standard ketogenic diet, and the therapeutic ketogenic diet ( Figure 1 ), which restrict carbohydrate consumption to varying degrees are being studied for their health impacts. The therapeutic ketogenic diet, which severely restricts both carbohydrates and protein, is typically used in the treatment of epilepsy and cancer. However, the Dietary Guidelines for Americans suggests that between 45 and 65% of caloric intake should come from carbohydrates ( Figure 1 ). If a person consumed 2000 calories per day that would equate to an average of 225–325 g of carbohydrates each day [ 9 ].

A comparison between the macronutrient breakdown of the standard American diet, therapeutic ketogenic diet, and the typical ketogenic diet. The therapeutic ketogenic diet is typically used in epilepsy and cancer treatments.

One emerging diet that is becoming mainstream is a low-carb/high-fat diet. However, there is a difference between a low-carb and a low-carb ketogenic diet (LCKD). Ketosis is normally achieved through either fasting or carbohydrate restriction. It is important to clarify that a low-carb diet typically refers to a diet with an intake of 50 to 150 g of carbohydrate per day. However, although this is a lower amount of carbohydrates than the standard American diet, it is not low enough to enter nutritional ketosis. Only when a patient restricts carbohydrates to less than 50 g/day will the body be incapable of fueling the body by glucose and will switch to burning fat [ 10 ]. The ketogenic diet is a reversal of the current food pyramid supported by the dietary guidelines. Thus, instead of a diet rich in carbohydrates, it is high in fat ( Figure 2 ). The resulting carbohydrate restriction lowers blood glucose levels, and the subsequent insulin changes will instruct the body to change from a state of storing fat to a state of fat oxidation [ 10 ]. Once fats are utilized as the primary fuel source in the liver, the production of ketone bodies begins, a process known as ketogenesis. During ketosis, three major ketone bodies are formed and utilized by the body for energy: acetone, acetoacetate, and β-hydroxybutyrate [ 11 ]. All cells that contain mitochondria can meet their energy demands with ketone bodies, including the brain and muscle. In addition, research suggests that β-hydroxybutyrate acts as a signal molecule and may play a role in suppressing appetite [ 12 ].

A visual comparison of the recommended dietary food pyramid, including major macromolecule components, to the ketogenic diet food pyramid.

However, there is some heterogeneity in the available data. Thus, the aim of this review is to highlight the role the ketogenic diet has in altering the microbiome, epigenetics, weight loss, diabetes, cardiovascular disease, and cancer as summarized below ( Figure 3 ).

The potential therapeutic impacts of the ketogenic diet on the microbiome, epigenome, diabetes, weight loss and cardiovascular disease.

2. The Effect of the Ketogenic Diet on the Microbiome

The microbiome consists of trillions of microscopic organisms in the human gastrointestinal tract. It comprises over 8000 different types of bacteria, viruses, and fungi living in a complex ecosystem [ 13 ]. Recent research suggests that the genetic make-up of a microbiome can be affected by lifestyle factors which include but are not limited to sleep, exercise, antibiotic use, and even diet. These bacteria can alter our response to different food sources because they differ in their ability to harvest energy from food, affecting the postprandial glucose response (PPGR) [ 13 ]. Since the controlling of glucose levels in the blood seems to reduce the risk of metabolic disease, diabetes, and obesity, this might be an innovative way to help reduce disease risk. A study conducted at the Weizmann Institute demonstrated that a mathematical algorithm could be used to determine an individual’s microbiome profile and predict their glycemic response to different types of foods [ 14 ]. Thus, the patients were able to change from stable blood glucose to unstable levels by simply eating the foods that the program predicted as good or bad based on their microbiome. Their initial results were confirmed by a repeat study at the Mayo Clinic with a different population [ 13 ]. It is important to note that the composition of the microbiome, which is believed to have a fundamental role in human health, is shaped predominantly by environmental factors. According to a study conducted by Rothschild et al. [ 15 ], the average heritability of the gut microbiome taxa is only 1.9%, while over 20% of variability was associated with diet and lifestyle.

Thus, research into the complex interactions that exist between diet, the microbiome, and host metabolic rates have increased. A study exploring the benefits of prebiotic foods, such as inulin and oligosaccharides, observed an increase in the number of Bifidobacteria in the colon and the presence of other critical butyrate-producing bacteria [ 16 ]. Another study determined that the diversity of the gut microbiota was influenced more by a Westernized diet than by the body mass index of the subjects [ 17 ]. The patients who followed the Westernized diet showed an increase in Firmicutes and a decrease in Bacteroidetes in their microbiome, which are negative changes. A review article also reported positive changes in the gut microbiome and overall health in energy-restrictive diets or diets rich in fiber and vegetables [ 18 ]. Thus, people eating processed and bland food had reduced diversity of their microbiota, while people eating a diet rich in fruit and vegetables had increased diversity in their gut microbiota [ 19 ]. Moreover, gut biomes that lacked genetic diversity were related to overall adiposity, insulin resistance, dyslipidemia, and an inflammatory phenotype [ 20 ].

Discovering how the gut microbiota and diet interact and how this interaction is connected to overall health, is critical. It is important to determine whether new dietary changes, such as a ketogenic diet, will positively or negatively affect overall microbiome diversity and species make-up. Some research has found that whole grains play an important role in the development of a healthy microbiome and are necessary for good health [ 21 ]. Thus, a person consuming a ketogenic diet might not consume enough whole grains to maintain a healthy microbiome [ 12 ]. According to Adam-Perrot et al. [ 12 ] low-carb diets are at greater risk of being nutritionally inadequate by lacking in fiber, necessary vitamins, minerals, and iron. This idea is based on analysis of popular diets and food surveys conducted to determine nutrient intake while consuming varying levels of carbohydrates [ 22 ]. Thus, it is even more critical that people on a LCKD choose desirable low carbohydrate foods that are rich in fiber. In addition, a ketogenic diet should maintain moderate protein intake of around 1.5 g/day per kg of respective body weight [ 23 ]. If people consume red meat and organ meats, then they should be able to obtain adequate amounts of iron as well. Additionally, the consumption of small amounts of leafy greens, nuts, berries, and resistant starchy vegetables, all of which are optional ketogenic foods, could potentially maintain healthy gut microbiota [ 23 ].

Currently, scientists do not have any data on the long-term effects of the ketogenic diet on the gut microbiome. Based on various studies, many predict that the diet will positively affect the microbiome by increasing the Bacteroidetes and Bifidobacteria species associated with improved health and decreasing microbial species known to increase health risks. In fact, a study found that the disrupted gut microbiota of epileptic infants was improved with a one-week ketogenic diet, which managed to increase their Bacteroides amount by ~24% [ 24 ]. Another 6-month study on children with refractory epilepsy found a significant decrease in Firmicutes and an increase in Bacteroides although the overall diversity decreased [ 25 ].

Studies have shown that a low ratio of Firmicutes to Bacteroidetes is an indicator of a healthy microbiome [ 26 ]. A few studies found that obese patients were more likely to have a higher Firmicutes to Bacteroidetes ratio [ 26 , 27 , 28 ] and higher levels of short chain fatty acids (SCFAs) in their stool [ 5 ]. However, another study found that obese patients showed an increase in Bacteroidetes , while Firmicutes remained the same [ 29 ]. Therefore, it appears that reducing obesity with the KD may result in positive changes in the microbiome. A study by Basciani et al. [ 30 ] recently analyzed the changes in the gut microbiota in obese, insulin-resistant patients who followed isocaloric ketogenic diets which varied in their source of proteins. The very low-calorie ketogenic diets (VLCKDs) contained either whey, vegetable, or animal proteins. The data indicated all groups had a decrease in relative abundance of Firmicutes and an increase in Bacteroidetes after 45 days. However, the positive changes were less pronounced in the group that consumed animal protein sources.

Recently, a few short-term studies tested the impact of the KD on patient microbiomes. A study by Nagpal et al. [ 31 ] analyzed the effect of a modified Mediterranean Ketogenic Diet (MMKD) vs. the American Heart Association Diet (AHAD) on the microbiome of patients with normal cognition or mild cognitive impairment. They found that the MMKD did not show significant changes in the Firmicutes or Bacteroides phyla at 6 weeks. However, they did see a decrease in the family Bifidobacteriaceae and an increase in family Verrucomicrobiaceae , which was considered a positive change. Furthermore, the beneficial SCFA, butyrate, increased in the MMKD. The presence of butyrate has been known to increase gut health [ 31 ].

3. The Effect of the Ketogenic Diet on the Epigenome

Epigenetics refers specifically to changes “on top” of the genome that can modify and alter levels of gene expression. These epigenetic markers are heritable, yet recent research suggests that some changes can be reversed or occur through environmental changes [ 20 ]. The modifications of the genome involve DNA methylation, changes to chromatin structure, histone modification, and noncoding RNAs. Most notable are histone modifications. For example, the N-terminal of histone tails can be acetylated, methylated, phosphorylated, ubiquitinated, or SUMOylated. Histone deacetylases (HDACs) are enzymes that can remove acetyl groups and condense the chromatin. Similarly, sirtuins (SIRTs) are also capable of deacetylating histones. Histone lysine methylation can either activate or repress a gene’s activity based on the exact location and number of methyl groups added to the histone tail [ 32 ]. Research has found that most epigenetic modification occur during early embryogenesis, but the genome can acquire changes later in life. Some of the later epigenetic modifications are caused or modified because of diet [ 32 ].

Some ketogenic food sources that positively regulate epigenetic activity are cruciferous vegetables, dietary fiber, foods rich in long-chain fatty acids, and berries, such as raspberries [ 20 ]. The benefits of some of these food sources have a multitude of positive effects. For instance, black raspberries not only positively affect methylation patterns in the WNT-signaling pathway, but they also profoundly impact the microbiome make-up (increased Lactobacillus , Bacteroidaceae , and anti-inflammatory bacterial species), and increased production of butyrate by fermentation in the gut [ 20 ]. Thus, it appears that diets rich in certain foods can positively modify genes that increase overall cell health.

The benefits of the ketogenic diet might also go beyond treating existing disease, and instead help prevent chronic and degenerative disease [ 23 ]. A literature review by Miller et al. [ 23 ] argued that a state of nutritional ketosis will positively affect mitochondrial function and enhance resistance to oxidative stress and noted that the ketones directly up-regulate bioenergetic proteins that influence antioxidant defenses [ 23 ]. According to Boison [ 33 ], “Ketone bodies, such as β-hydroxybutyrate (BHB), and their derivatives have received the most attention as mediators of the anti-seizure, neuroprotective, and anti-inflammatory effects of KD therapy” [ 34 , 35 , 36 ]. The ketogenic diet’s mechanism of action might be due to increased levels of adenosine [ 37 , 38 ], which blocks DNA methylation and, thus, exerts an epigenetic change. A study in epileptic rats subjected to the KD therapy found ameliorated DNA methylation mediated changes in gene expression by increasing adenosine [ 39 ], which blocks DNA methylation [ 40 ]. It is also being studied for its role in the aging process since it is linked to the positive regulation of epigenetic modifications, such as nuclear lamin architecture [ 41 ], reduced telomere length [ 42 , 43 ], DNA methylation, and chromatin structure [ 44 ].

The effect of the ketogenic diet on brain health appears to be well supported and is due specifically to the production of BHB [ 23 ]. They found that BHB is more than a fuel molecule; it plays important roles in cell signaling. The signaling functions of BHB link the effects of environmental factors on epigenetic regulation and cellular processes since it is an endogenous class 1 HDAC inhibitor [ 45 ]. Thus, a ketogenic diet has been linked to increased global histone acetylation, with a specific increase in the expression of protective genes, such as Foxo3a [ 46 ].

Evidence also suggests that BHB can have a direct epigenetic effect via a novel histone modification known as β-hydroxybutyrlation of H3K9, which results in improved gene regulation in the hypothalamus and improved overall aging [ 47 ]. Furthermore, the energy carrier molecule, nicotinamide adenine dinucleotide (NAD) is important in oxidative respiration. In its oxidative state (NAD+), NAD also acts as a cofactor for sirtuin enzymes and poly-ADP-ribose polymerase (PARP). Sirtuins and PARP play roles in gene expression, DNA damage repair, and fatty acid metabolism [ 46 ]. The energy available to a cell is measured by the NAD+/NADH ratio, which is modified by the utilization of glucose versus BHB as a fuel source [ 48 ]. During a ketogenic state, more NAD is found in the oxidative state which allows sirtuins and PARP to be more active. Additionally, catabolism of BHB into acetyl-CoA, another energy carrier molecule, raises acetyl-CoA levels. It has been found that the production of two moles of acetyl-CoA using BHB as the precursor reduces only one mole of NAD+ to NADH. However, four moles of NAD+ are produced by glucose metabolism. Thus, the ketogenic diet creates excess NAD+ for the cell and has a positive impact on the redox state of the cell [ 48 ]. This might have positive impacts on the activity of NAD+ dependent enzymes, such as sirtuins. Newman et al. [ 49 ] found that increased acetyl-CoA favors both enzymatic and nonenzymatic protein acetylation, specifically in the mitochondria, which improves overall mitochondrial function.

BHB produced by a ketogenic diet may also increase the efficiency of ATP production in the mitochondria and reduce the number of free radicals. As a result of the positive impacts of BHB, one study found that BHB precursor molecules improved cognition and disease progression in an Alzheimer’s mouse model [ 50 ]. Additionally, the presence of BHB showed improvement in a case study of a patient with Alzheimer’s disease [ 51 ]. The presence of D-β-hydroxybutyrate protect neurons from oxidative damage by reducing the cytosolic NAD+/NADPH ratio, resulting in an increase in the antioxidant agent known as reduced glutathione [ 52 ]. BHB also inhibits NF-kB, which is known to regulate the expression of multiple pro-inflammatory genes. This results in a diminished pro-inflammatory response [ 52 ]. Similarly, the BHB precursor, 1,3 butanediol, also modulates the expression of the inflammasome via histone β-hydroxybutyrlation. Thus, it reduces the expression of caspase-1, IL-1B, and IL-18 [ 53 ], which are inflammation markers. A study in C. elegans found that BHB alone could extend their life span [ 3 ]. Thus, the endogenous effects of BHB produced by a ketogenic diet might enhance health and increase longevity.

4. The Effect of the Ketogenic Diet on Weight Loss

According to recent Harvard models, 50% of the children today are likely to be obese by the age of 35 years [ 9 ]. As scientists try to determine the most effective strategies to combat the obesity epidemic, many studies have emerged that compare the health outcomes of different diets. A recent meta-analysis of seven random-controlled trials using diazoxide or octreotide for suppressing insulin secretion in obese patients found that it led to reduced body weight, fat mass, while maintaining lean mass [ 54 ]. However, the cost of artificially reducing insulin levels was an increase in blood glucose levels. While these studies seem promising as an indicator of biomarkers that can stimulate weight loss, it seems more logical to help patients achieve lower insulin levels via changes to their diet. The reduction of carbohydrate intake naturally reduces blood glucose levels, thus reducing insulin as a result. Many studies have now demonstrated that the ketogenic diet reduces both blood glucose and insulin levels [ 55 , 56 , 57 ]

A study conducted by Fumagalli et al. [ 58 ] analyzed the genetic profiles of patients and looked at the impacts on metabolism. They specifically looked at human CHC22 clathrin, which plays a central role in intracellular traffic of insulin-responsive glucose transporter 4 (GLUT4). The GLUT4 pathway is the dominant mechanism used by humans to remove glucose from the circulating blood after a meal. They found two major gene variants, one which is more frequent in farming populations than in hunter-gatherers. Hunter-gatherers have the gene that allows GLUT4 to be sequestered more effectively and thus have an inherent increased risk of insulin resistance. It is hypothesized that as humans became farmers and increased glucose in the diet, it was beneficial for the blood sugar to be lowered more easily with the newer form of CHC22. Thus, people with different forms of CHC22 are likely to differ in their ability to clear blood sugar after a meal. The people with the form that allows blood sugar levels to remain elevated could eventually lead to diabetes in the face of a high-carbohydrate load in the diet. This new finding might explain why some patients are successful on a high-carbohydrate low-fat diet, while others prefer to maintain weight with a low-carbohydrate, high-fat diet [ 58 ].

The importance of dietary adherence is of great concern for the success of any diet study. The study conducted by Shai et al. [ 59 ] that was able to control for the feeding of at least one meal a day (cafeteria meal), might better reveal the true effects of a sustained ketogenic diet. The Shai study [ 59 ] compared a low-fat, restricted-calorie diet (LFD), a Mediterranean, restricted-calorie diet (MD), and a low-carbohydrate, non-restricted calorie diet (LC) on 322 moderately obese subjects over a period of two years. The dietary adherence was >85% at the end of two years. This study instructed the LC group to be ketogenic for the first 2 months (<20 g/day) and gradually increase to 120 g/day of carbohydrates. The results found that the greatest weight loss occurred in the low-carb group and both the LC and MD were more effective than the LFD. Although, the weight loss during the first 3 months in the LC group was significantly greater than either of the other two groups, as carbohydrates were added back into their diet, their weight rebounded back to a level close to the MD group. Shai et al. [ 59 ] found that one of the benefits of the LC group was the similar calorie deficit achieved even though it was not a calorie-restricted diet. The researchers propose that a LC diet may be the optimal choice for individuals that cannot follow a calorie restricted diet since these subjects will be permitted to eat until satiated but will still most likely end up lowering their total caloric intake.

A similar long-term (56 week) ketogenic study was conducted on 66 obese people with a BMI >30 [ 60 ]. All patients were instructed to eat <20 g of carbohydrates in the form of green vegetables and salads for 12 weeks and then they could increase the carbohydrates to 40 g/day for the remainder of the study. The weight and body mass index of all patients decreased significantly. More interestingly, the patients were advised to maintain a state of nutritional ketosis and they were able to show continued decreases in both BW and BMI throughout the study. Consequently, this study did not show the plateau and gradual increases seen in the Shai study [ 59 ] which allowed the reintroduction of carbohydrates after the initial weight loss period. A similar study by Samaha et al. [ 61 ] also found that patients lost significantly more weight on a 30 g/carbohydrate per day diet for six months compared to a LFD. Another possible benefit from the ketogenic diet is that there is a measurable biomarker that signifies dietary adherence, which is β-hydroxybutyrate (BHB). When an individual is in ketosis, the body will begin ketone production and the level of BHB in the blood will be over 0.5 mmol. Studies that include this measurement can therefore confirm dietary adherence and determine the true effects of the diet on health outcomes, like weight loss. Mohorko et al. [ 57 ] conducted a 12-week ketogenic diet study on obese patients who were calorie restricted (1200–1500 kcal) for the first two weeks and then were instructed to eat ad-libitum for hunger for the remaining weeks while eating the macronutrient composition necessary to remain in a state of nutritional ketosis. BHB was measured throughout the study and patients maintained levels above 0.5 mmol throughout the 12 weeks. Patients showed significant weight loss in both the men and women groups (average of (-)18 kg for men and (-)11 kg for women). Interestingly, as the diet progressed, the patients Fat Mass (FM) became the largest component of weight loss and it significantly correlated with BHB. Another valuable outcome in this study was the reduction of the hunger hormone, leptin, as well as a slight increase in energy expenditure, even while weight decreased throughout all 12 weeks. Another long-term study was done by Hallberg et al. [ 2 ] which followed diabetic patients on a ketogenic diet for one year. At the beginning of this study, 92% of the patients in the ketogenic group were obese. These patients were instructed to eat less than 30 g of total carbohydrates per day and the goal was to maintain BHB blood levels of 0.5–3.0 mmol/L. These patients had an average of 12% decrease in body weight, with some patients achieving as high as ~40% change. The patients who were in the standard care diet group (American Diabetic Association recommended diet) did not see any significant change in body weight [ 2 ].

A short-term, 4-week ketogenic diet (KD) on 20 obese Chinese females had profound outcomes [ 62 ]. In this study, compliance to the diet was measured with urinary ketone strips. These participants were given a monitored 4-week normal diet which was followed up with a 4-week KD with the same daily caloric intake but a drastic reduction in carbohydrates to <10% of calories. The effect was a significant decrease in body weight, body mass index, waist circumference, hip circumference, body fat %, and decreased fasting leptin levels. Similar positive outcomes were seen in other KD diet studies [ 56 , 63 , 64 ]. Similarly, a recent meta-analysis concluded that very low-calorie ketogenic diets are a very effective strategy for treating obesity [ 65 ]. An 8-week study conducted by Goss et al. [ 66 ] compared the very low carbohydrate diet (VLCD) (<10% carbohydrates) to a low-fat diet in older obese adults with BMI between 30 and 40. This study precisely measured fat loss with DXA and MRI measurements. Both groups exhibited decrease in total fat, but the VLCD experienced ~3 fold greater decrease in visceral adipose tissue and a significant decrease in intermuscular adipose tissue with a 5-fold greater reduction in total body fat mass.

Another long-term study monitored weight loss as well as changes in visceral fat mass using DEXA. The study by Moreno et al. [ 67 ] compared a very low-calorie ketogenic diet (VLCK) to a low-calorie (LC) diet as a treatment for obesity over two years. Participants in the active stage consumed 600–800 kcal/day and <50 g of carbohydrates per day until they were 80% of target weight loss goals (stage 1). Urinary ketone strips were used during stage 1 to confirm a state of ketosis. Then they used a standard low-calorie diet (10% below total metabolic expenditure) during stage 2 until they achieved another 20% weight loss, followed by long-term maintenance of weight loss in stage 3. The comparison control group used the low-calorie diet throughout the study to achieve weight loss. The weight loss in kilograms in the VLCK diet was double that of the LC diet throughout most of the study and remained significant. The amount of visceral fat loss in the VLCK diet group was 3X greater than the control group while preserving lean body and skeletal bone mass. The main side effects recorded in the VLCK were fatigue, headache, constipation, and nausea. However, none of these side effects were severe enough to cause the patients to drop out of the study and most subsided within the first month [ 67 ].

A meta-analysis conducted by Bueno et al. [ 68 ] compared randomized controlled trials of very low carb ketogenic diets (VLCKD) with low fat diets for 1 year. This study found a significant difference in decreased body weight for the VLCKD group. Another study compared a KD (<30 g carbohydrates/day) with two control groups (standard American diet (SAD) without exercise and SAD with 3-5 days of exercise for 30 minutes) over ten weeks [ 69 ]. The KD outperformed the other control groups in all variables tested, with 5 out of 7 being statistically significant. The patients showed significant decreases in body mass index (BMI), body fat mass (BFM), and weight while their resting metabolic rate (RMR) increased. The RMR in the experimental group produced a positive, sizeable change with a magnitude of slope that was more than 10X the two control SAD groups. These results reveal that diet plays a more significant role in outcomes than exercise [ 69 ].

The ability to control hunger is also a key component to weight loss success. Castro et al. [ 70 ] evaluated patients from the very low-calorie ketogenic diet (VLCK) study and found a negative correlation between BHB levels and the urge to eat and feelings of hunger during the phase of maximum ketosis, even though there was no significant change in ghrelin hormone. This result is supported by other large investigations in overweight and obese adults which also found that low-carbohydrate diets were more effective in controlling hunger than low-fat diets [ 71 , 72 ]. A 2-week study conducted by Choi et al. [ 73 ] compared varying nutrition drinks on weight loss in obese adults. There were three groups: 4:1 fat to protein and carbohydrate ratio, 1.7:1 ratio with increased protein, and a balanced nutrition drink with similar carbohydrates to recommended dietary advice. All groups decreased body weight and body fat mass, but only the 1.7:1 KD-group maintained protein mass. Furthermore, only the KD groups improved blood lipid levels with appetite reduction. Since this was a nutritional drink feeding study, all the groups had similar caloric reduction; thus, results were due to macronutrient composition. In addition, levels of ketosis were strongly related to positive differences in food cravings, alcohol cravings, physical activity, sleep patterns, and sexual activity [ 73 ]. This outcome might also be supported by a recent finding that postprandial glycemic dips were the best predictor of appetite and energy intake following a meal and large glycemic dips are usually associated with high carbohydrate consumption [ 74 ]. Furthermore, a study showed that high carbohydrate meals had a greater impact on brain reward and homeostatic activity in ways that could impede weight loss maintenance [ 75 ]. Interestingly, the increased brain activity findings were partially associated with higher insulin levels, too. Thus, the ability of the KD to reduce hunger, lower glycemic fluctuations, and reduce influences on areas of the brain associated with addiction are all positive signs that a ketogenic diet should be considered as a treatment option for obesity.

One of the major concerns for rapid weight loss is the lowering of the resting metabolic rate (RMR). This bodily change can lead to weight regain, which is known as adaptive thermogenesis. Thus, it is typical for hunger to increase and energy expenditure to decrease during weight loss, which is a hindrance to long-term weight loss maintenance. Gomez-Arbelaez et al. [ 76 ] tested this outcome in subjects on the very low-calorie ketogenic (VLCK) diet study and followed them for 2 years. In this study, twenty obese patients lost 20.2 kg of body weight after four months and sustained this weight loss without the expected reduction in RMR. Authors of the study hypothesize that RMR did not drop because the subjects maintained their lean body mass. DEXA scans revealed that although they lost ~20 kg of fat mass, they only lost 1 kg of muscle mass. This conclusion was also supported by normal renal activity and positive nitrogen balance while subjects maintained their fat loss upon follow-up [ 76 ].

A study by Hall et al. [ 77 ] hypothesized that the development of obesity is “a consequence of the insulin-driven shift in fat partitioning toward storage and away from oxidation resulting from an increased proportion of dietary carbohydrates.” To test this hypothesis, they tested seventeen obese men in metabolic wards with a four-week high-carbohydrate diet followed by a four week, isocaloric ketogenic diet. The results showed that a state of ketosis increased energy expenditure (~100 kcal/d), most likely due to beta oxidation and the partitioning of fuel towards ATP production rather than fat storage [ 77 ]. However, this level of energy expenditure change due to a ketogenic diet is not as high as measured in another study. In the study by Ebbeling et al. [ 78 ], it was noted that short-term feeding studies do not consider the body’s process of fat adaptation, which takes at least 2–3 weeks, if not longer. Thus, the Framingham study by Ebbeling et al. [ 78 ] conducted a randomized trial on 164 patients where they lost weight and were then placed on varying diets of carbohydrate content for twenty weeks to measure changes in energy expenditure. The difference in total energy expenditure was 209–278 kcal/d or around 60 kcal/d increase for every 10% decrease in the carbohydrate percentage of total energy intake. This study concluded that dietary quality could affect energy expenditure independently of body weight. In accordance, Mobbs et al. [ 79 ] has suggested that ketogenic diets “reverse obesity by preventing the inhibitory effects of lipids on glycolysis, thus maintaining relatively elevated post-prandial thermogenesis.” Further studies will need to be conducted to evaluate and confirm the exact mechanisms of action.

More recent studies on the KD are analyzing the outcomes of the diet in conjunction with other comorbidities related to obesity. A small study was conducted by Carmen et al. [ 80 ] that followed three obese participants on a 10% carbohydrate KD for 6–7 months that exhibitied comorbid binge eating and food addiction symptoms. No adverse effects were found, and participants had reductions in binge eating episodes and food addiction symptoms. All three lost 10–24% BW and maintained treatment outcomes 9–17 months after initiating the diet and continued adherence to the diet [ 80 ]. Another study looked at the outcomes for male and female severely obese patients who also suffered from non-alcoholic fatty liver syndrome (NAFLD) [ 81 ]. They used a very low-calorie ketogenic diet of <50 g of carbohydrates and <800 kcal/day. Both males and females showed significant losses in body weight. However, males lost significantly more weight and had greater reductions in waist circumference. The patients also improved their biomarker for NAFLD, which was a reduction in gamma-glutamyl transferase [ 81 ]. To determine if the ketogenic diet negatively affects kidney function, Bruci et al. [ 82 ] conducted a 3-month very low-calorie ketogenic diet (VLCKD) study for weight loss in obese patients with and without mild kidney failure. All patients were advised to consume <20 g carbohydrates and 500–800 calories per day. The average mean weight loss from initial weight was nearly 20%, participants had significant reduction in fat mass, and 27.7% of the patients with mild kidney failure acquired normalized glomerular filtrate rate. It was, therefore, concluded that a KD not only leads to weight loss but also improvement in kidney function.

Please refer to Table S1 in the Supplementary Materials for a comparison of studies evaluating the KD in relation to weight loss outcomes.

5. The Effect of the Ketogenic Diet on Diabetes

According to the latest CDC report, an estimated 30 million people have diabetes and around 84 million have pre-diabetes. That statistic predicts that ~45% of Americans are either diabetic or pre-diabetic. Diabetes is a major health concern that is accompanied by a long list of secondary complications and diabetics are at increased risk of microvascular pathology of the retina, renal glomerulus, peripheral neuropathy, and atherosclerotic disease affecting arteries [ 83 ]. Many of these diabetic complications have been linked to elevated levels of glucose over long periods of time, which is measured as hemoglobin A1c (HbA1c) [ 83 ].

Type 2 diabetes is caused by hyperinsulinemia and insulin levels are directly affected by carbohydrate consumption. Protein intake can cause slight increases in blood glucose and subsequent insulin secretion, but fat consumption has no major effect on either [ 84 ]. If hyperinsulinemia is directly affected by nutrient intake, then it could be argued that these blood markers could be controlled by the conscious control of food choices. Of further note, the American Diabetes Association (ADA) recommends a goal of an HbA1c less than 7%, and the American College of Endocrinology sets a target level of 6.5%, even though few patients ever obtain that goal. Thus, Brownlee et al. [ 83 ] argued that patients should increase efforts to minimize glycemic variability since it can reduce risks of diabetic complications, independent of HbA1c. The DiRECT study by Lean et al. [ 85 ] found that weight loss alone could result in almost 46% of patients achieving diabetes remission at 12 months. Yet, this does not address the issue of diabetic patients who are not overweight. Thus, many scientists are now examining the potential benefits related to diabetes and improved blood markers that can result from eating a ketogenic diet. Although no professional organization in endocrinology or diabetology has focused on the rational use of ketogenic diet for either diabetes or obesity conditions, Kalra et al. [ 86 ] argues nutrition should be considered as an integral part of metabolic management of diabetes, and the ketogenic diet should at least be offered as a treatment option.

Interestingly, the use of a diet low in carbohydrates for the treatment of diabetes is not a new or novel idea. In fact, prior to the invention of insulin, diet was the main intervention used by diabetic patients. The physicians, Dr. Elliot Joslin and Dr. Frederick Allen, were both recommending their patients in the 1920s to eat foods without carbohydrate content, and it highly resembled the current ketogenic recommendations [ 87 ]. According to Feinman et al. [ 88 ] the number one goal of both type 1 and type 2 diabetics should be glycemic control. It is argued that carbohydrate restriction can benefit diabetic patient blood markers even in the absence of weight loss [ 88 ]. This is important since many diabetics are not overweight yet still need to manage their blood glucose levels. The benefits of carbohydrate restriction in type 1 diabetics reduces the error in determining insulin amount to match the increased blood glucose since dramatic spikes are less likely [ 88 ].

A recent study compared the use of a low-calorie (LC) diet vs. a very low-carbohydrate ketogenic diet (VLCKD) on health outcomes for type 2 diabetics. The VLCKD group approached normal blood sugar level in just 24 weeks unlike the LC group [ 87 ]. The VLCKD group reduced insulin doses by half, on average, and sulfonylurea doses were halved or discontinued. The HbA1c levels dropped significantly in the VLCKD to 6.2% vs. 7.5% in the LC group. Thus, the VLCKD group managed to reach both the ADA and American College of Endocrinology target level for HbA1c. According to Hussain et al. [ 87 ] the VLCKD was not found to have an adverse effect on glucose metabolism, insulin resistance, or cause chronic dehydration. However, they did caution that diabetic patients should only attempt this nutritional therapy while being closely monitored by a physician to reduce the risk of hypoglycemia since drugs will need to be quickly reduced to match changes in blood markers elicited by the diet [ 87 ]. A study by Webster et al. [ 89 ] found that type 2 diabetic patients who self-selected to follow a KD reduced their mean HbA1c from 7.5% to 5.9% at the 15-month follow-up. As a result, their HbA1c levels reached the normal range (which is under 6.0%), and they had achieved partial or full type 2 diabetes remission.

A study conducted by Westman et al. [ 8 ] compared the effects of a low-carbohydrate ketogenic diet (LCKD) versus a low-glycemic index diet (LGID) on glycemic control in type 2 diabetic patients which was measured by hemoglobin A1C (HbA1c). They enrolled forty nine patients and randomly assigned them to the different diets. Both groups followed group meetings, nutritional advice, and an exercise recommendation. Both interventions showed improvements in hemoglobin A1c, fasting glucose, fasting insulin, and weight loss. However, the LCKD had greater improvements, including a reduction or elimination of diabetes medications in 95% of patients vs. 62% in the LGID group [ 8 ]. As mentioned previously, the study by Dashti et al. [ 60 ] compared the health outcomes of a ketogenic diet on obese diabetics with high blood glucose levels to non-diabetic obese patients over 56 weeks. This study concluded that all markers, such as body weight, body mass index, blood glucose, total cholesterol, LDL, triglycerides, and urea all showed a significant decrease in both groups throughout the study, with more positive outcomes seen in the diabetic group [ 60 ]. The kidney tests also showed normal function. This study demonstrated that the diet is safe to use for longer periods of time in obese diabetic subjects.

A year-long randomized study compared the effects of a very low-carbohydrate ketogenic diet (LCK) versus a moderate-carbohydrate, calorie-restricted, low-fat diet (MCCR) in pre-diabetic or type 2 diabetic patients [ 90 ]. The results showed that the LCK exhibited greater improvements in their HbA1c, weight loss, and medication use than those assigned to the MCCR diet [ 90 ]. Another randomized controlled study by the same researcher compared the LCK against the diet program based on the online American Diabetes Associations’ “Create Your Plate” diet. The purpose of this study was twofold. The researcher had already seen the benefits of the LCK in a previous study that had personalized intervention. They wanted to see if an online program could be just as successful at helping overweight individuals with type 2 diabetes. The results indicated that the online ketogenic program was more successful in helping patients manage their diabetes by reducing their HbA1c, lowering triglycerides, increasing weight loss, and retention rates were higher than in the control group [ 91 ]. In addition, a previous study has discovered that a carbohydrate restricted diet was more successful than a low-fat diet in improving diabetic markers for metabolic syndrome in forty subjects with atherogenic dyslipidemia [ 92 ].

A recent study recently conducted at Indiana University was one of the first long-term studies that required use of routine blood tests to determine the patients’ state of nutritional ketosis while maintaining a KD diet. Patients were highly compliant, and experienced improved diabetic conditions [ 2 ]. The diet intervention also reversed the diabetic status of some patients, whose HbA1cs became normal. The 2-year follow-up to this study revealed that 74% of KD group remained enrolled [ 93 ]. This group had a significant improvement in HbA1c, fasting glucose, and fasting insulin while the usual care group had no changes from baseline. The mean dose of prescribed insulin decreased by 81% and the diabetes reversal increased to 53.5%. Diabetes remission was 17.6% and diabetes complete remission was 6.7% [ 93 ]. The long-term success in diabetes treatment for this digitally monitored continuous care intervention group is evidence of the feasibility and adherence of the KD in type 2 diabetes treatment [ 2 , 93 ].

Additionally, the study by Shai et al. [ 59 ] showed that patients were able to reduce their fasting blood glucose on a low carbohydrate or a Mediterranean diet, while the low-fat group saw the opposite effect. The patients in the low carbohydrate group were also able to significantly decrease their HbA1c [ 59 ]. Another meta-analysis that compared very low-carbohydrate ketogenic diets (VLCKDs) to low-fat diets (LFDs) found that the VLCKD showed greater improvements in fasting glucose, insulin analysis, HbA1c, and C-reactive protein [ 68 ]. Additionally, a recent meta-analysis of low-carbohydrate or very-low carbohydrate diets found that patients adhering to the diet for 6 months can have diabetes remission without severe complications [ 94 ]. Several recent studies on the KD show positive improvements in glycemic profiles [ 56 , 66 , 82 , 89 , 95 ].

Currently, the ADA recommends that type 1 diabetics eat a low-fat diet rich in whole grain carbohydrates. One study showed the low-fat diet has not been found to improve HbA1c in all patients, regardless of diabetes state [ 96 ]. It looked at the HbA1c outcomes for type 1 diabetics (T1D) who were advised to reduce carbohydrate intake (<75 g of carbs/day) to reduce the need for insulin. The patients in this study had a 50% adherence rate, and those who strictly adhered to the diet reduced their HbA1c by 1.8%. Another randomized trial [ 97 ] determined the feasibility of a LC diet (<75 g/day) versus standard carb counting in adults with T1D. Of the ten people in the 12-week study, the LC group exhibited significant decreases in HbA1c, decreased daily insulin use, and reduction in body weight. All of the outcomes in the carb counting group were unchanged. Thus, these T1D patients had positive outcomes without meeting the KD threshold of <50 g/day while consuming significantly less carbohydrates than the typical diet.

Interestingly, some type 1 diabetes patients have taken it upon themselves to treat and control their diabetes with the very low–carbohydrate diet (VLCD), against the advice of current medical professionals. Lennerz et al. [ 98 ] evaluated the results of this choice by recruiting type 1 diabetics who self-selected to follow a VLCD (<30 g/day). They found these patients on a social media site and then asked for permission to contact physicians and confirm health outcomes. Shockingly, 97% of the patients were able to achieve the ADA glycemic targets for HbA1c with an average of 5.6% and a mean daily insulin dosage of 0.40 U/kg per day. Participants in this group reported increased levels of overall health, increased satisfaction with diabetes management, and decreased number of adverse events. These results are unprecedented in type 1 diabetic patients. If these outcomes are confirmed in clinical trials, the chronic health issues associated with type 1 diabetes could be prevented or significantly reduced by diet alone. Almost one-fourth of these patients did not discuss their VLCD with their care providers, which means they were making these changes without the support of their physicians. Even in an intensively treated group in the Diabetes Control and Complication Trial, the best HbA1c achieved was 7.2%, but that was coupled with increased rates of hypoglycemia [ 98 ].

Although there are only a few randomized controlled trials evaluating the effects of the KD on diabetes, there are some recent case studies and qualitative studies that shed some light on the issue [ 55 , 64 , 99 , 100 ]. The positive outcomes in these studies might reflect the motivation of these patients who opted or volunteered to ensue KD diets. A paper by Walton et al. [ 64 ] presented 11 case studies on women with T2D that volunteered to eat a KD with <30 g of carbohydrate per day. Their HbA1c was > 6.5% and dropped to 5.6% with diabetes reversal. Another case study by Lichtash et al. [ 99 ] involved a women patient with T2D and normal weight. After failed glycemic control with standard care, she voluntarily began a KD with intermittent fasting. Her HbA1c dropped from 9.3% to 5.8% after 14 months while maintaining her weight. Similarly, Wong et al. [ 100 ] examined type 1 and type 2 diabetics who opted to do a KD for >3 months. Participants reported better glycemic control, decreased medicine use, weight loss, and satiety. Most of these patients expressed the KD as a normal way of eating and plan to continue for the rest of their lives. A similar T2D cohort was recruited [ 55 ] for a retrospective study on 49 patients who followed KD for > 3 months and compared their outcomes to 75 patients who followed usual care (UC). 100% of the KD cohort either discontinued or reduced insulin dosage while only 23% of UC did. The KD cohort had a greater reduction in fasting plasma glucose, weight loss, as well as a superior reduction in HbA1c compared to UC. Thus, it seems that those patients who opt to follow the diet are having positive outcomes.

Please refer to Table S2 in the Supplementary Materials for a comparison of studies evaluating the KD in relation to diabetic outcomes.

6. The Effect of the Ketogenic Diet on Lipidology and Cardiovascular Risk

Cardiovascular disease (CVD) and its risk factors are a major health issue in industrialized nations. Moreover, large epidemiological studies are starting to show that CVD is becoming a larger problem in developing or low-income countries as well [ 101 ]. There has been a long-standing viewpoint that a diet high in saturated fat is unhealthy and will eventually lead to cardiovascular disease. Many hypothesized that a diet rich in saturated fat will increase LDL, and thus more fat in the blood leads to fat deposits in the vessels, resulting in increased risk of cardiovascular disease [ 102 ]. This idea was fortified by Ancel Keys in his 7-country study and eventually led to the diet-heart hypothesis [ 102 ]. Moreover, the United States accepted the idea proposed by Keys and adopted the low-fat diet (LFD) as the optimal diet to fight the increasing levels of CVD in the U.S. Additionally, the mainstream view for decades was that high total cholesterol also leads to atherosclerosis and cardiovascular disease [ 103 ]. As a result, the prescription of the LFD that consisted of ~60% energy from carbohydrates became the standard of care for physicians starting in the 1980s [ 98 ]. According to the 2015 Dietary Guidelines for Americans, people are still recommended to consume a diet that limits saturated fat intake to less than 10%, with some organizations placing even stricter limitations and advising around 7% [ 104 ]. However, randomized controlled trials have started to question the validity that saturated fat intake and a single blood marker, LDL, can accurately predict risk. Many scientists now argue for the need to analyze specifically how different types of macronutrients that replace saturated fat in the diet are impacting risk [ 105 ]. It is also important to consider the data regarding LDL as the single biomarker chosen to monitor and determine cardiovascular risk [ 105 ].

New research is also starting to question that mindset set forth by Ancel Keys, and many scientists have argued that the global dietary recommendations should be revisited and updated [ 106 ]. For example, a recent analysis of the literature done by Ravnskov et al. [ 103 ] compiled all the data on PubMed from initial to 2015 on over 68,000 patients. Ravnskov et al. [ 103 ] argued that that if the main goal of prevention of disease is prolonging life, then all-cause mortality should be the measurement used for determining health outcomes. Interestingly, they found that 30% of patients showed no association between LDL and all-cause mortality, while 70% showed a statistically significant inverse relationship. Contradicting the diet-heart hypothesis, they also found that the 4-year mortality among patients with the highest levels of LDL were almost 36% lower than those patients with the lowest LDL levels. Furthermore, the patients placed on statins had higher rates of mortality risk than those with the highest LDL. The results of these studies question the standardized method of using total cholesterol and LDL as the biomarkers of coronary heart disease.

Thus, if total cholesterol and LDL are not true indicators of cardiovascular risk, then one must ask what other blood markers could serve as better indicators of coronary heart disease. In a review by Feinman et al. [ 88 ] they argue that the best indicators of CVD risk are ApoB [ 107 ], the ratio of TC/HDL, increased levels of small dense LDL particles (sdLDL) [ 108 , 109 ], and the ratio of ApoB to ApoA1 [ 88 ]. If these markers are, in fact, a better indicator of disease risk, then understanding the effect of diet on these other biomarkers is of great importance. One study by Krauss et al. [ 110 ] compared patients who consumed diets of varying carbohydrate intake (54%, 39% or 26%) with the amount of saturated fat varying between 7% or 15%. This study showed that a high saturated fat intake, combined with carbohydrate restriction (26%) did raise total LDL. However, the higher total LDL levels were due to an increase in the larger sized LDL particles, which are less atherogenic than the sdLDL, and the patients saw a subsequent lowering of the sdLDL particles [ 9 , 110 ].

A large prospective study called the European and Prospective Investigation into Cancer and Nutrition Study (EPIC) also found that diets high in glycemic load (GL) and glycemic index (GI) were associated with a greater risk in Cardiovascular Heart Disease (CHD) [ 111 ]. Glycemic index is a measurement of the ability of carbohydrates to increase blood glucose levels. The glycemic load is the product of the GI of a particular food and its available carbohydrate. This study included around 520,000 men and women between the ages of 35 and 70 over a period of 8 years [ 111 ]. The study found a greater risk of CHD with higher sugar consumption. Their findings supported other observational studies that suggest that replacing saturated fat with sugar or refined carbohydrates might increase cardiovascular risk, rather than lower it [ 112 , 113 ]. Additionally, the very large PURE study recently showed that a diet higher in saturated fat did increase LDL, but also increased HDL, lowered triglycerides (TG), lowered the TC/HDL ratio, and lowered the ApoB/ApoA1 ratio [ 106 ]. They also found that the diets high in carbohydrate intake had the complete opposite effect on these atherogenic biomarkers. The benefit of the PURE study is that it revealed the risk associated with varying macronutrient composition in diets from over 5 continents in 18 countries, regardless of cultural food trends. Thus, it was a global look at the effect of dietary patterns on health regardless of background and ethnicity. The PURE study concluded their findings do not support the current recommendations to limit total fat intake to 30% of energy and saturated fat to less than 10%, and the recommended amount of <7% saturated fat might even be harmful. Instead, they argue that individuals who eat a diet high in carbohydrates might benefit by replacing some of those carbs with fat [ 106 ]. According to the PURE study, the ApoB to ApoA1 ratio was the strongest lipid predictor of myocardial infarction and ischemic stroke. Since this biomarker has been found to increase with carbohydrate intake, they concluded that this factor could provide the mechanistic explanation for higher risks seen in people with the highest carbohydrate intake [ 106 ]. This idea was supported by a recent article on Medscape, which argued that the predictive power of the ApoB to ApoA1 ratio was superior to other biomarkers to assess CV risk [ 114 ]. It also mentioned adding other lipid parameters to the ApoB/ApoA1 ratio did not improve the predictive power.

A study done by Lu et al. [ 115 ] compared the ability of either the ApoB/ApoA1 ratio or LDL to predict coronary heart disease (CHD) in normal and overweight patients. They found every quartile increase in the ApoB/ApoA1 ratio showed an increase in CHD prevalence. Meanwhile, the increases in LDL quartiles did not predict the highest percentages of CHD [ 115 ]. The ratio had an even stronger predictive capability in the overweight subjects. Furthermore, other studies have also supported the findings of the PURE study. One study conducted on postmenopausal women found an inverse relationship between dietary saturated fat intake and atherogenic disease progression [ 116 ]. Another study previously mentioned even found a positive association between plasma phospholipids and CHD mortality [ 117 ]. According to another study conducted by Dreon et al. [ 108 ], a decrease in saturated fat intake did lower total LDL, but it appeared to only reduce the amount of the large, buoyant LDL particles. They argue that more emphasis on CVD risk should be placed on high levels of triglycerides (TG), decreased concentration of HDL, and increased amounts of sdLDL particles. If these biomarkers are potentially more effective predictors of coronary heart disease, then the analysis of a diet’s effect on these lipid markers is of great importance [ 109 ].

Only a few studies have looked at the health impact of very high fat consumption (VLCKD) on overall health (which could include analysis of weight maintenance, lipid profiles, and inflammation markers [ 69 ]. To accurately determine the effect of a KD on cardiovascular risk markers, it is important to only look at studies that restricted carbohydrates below 50 g/day to ensure the patients would be in a state of nutritional ketosis. One study compared a KD to the standard American diet (SAD) and the SAD plus exercise. Not only did the KD outperform the other groups in multiple health outcomes, but it also showed a much more significant decline in triglycerides [ 69 ]. Another study compared a LC diet group (<30 g/day) to a LF diet in obese patients after 6 months [ 61 ]. Once again, the LC group had a drastic decrease in TG, while no significant difference was seen in total cholesterol (TC), HDL or LDL. This led investigators to conclude that the LC diet did not have adverse effects on serum lipid levels.

The impact of the prescribed low-fat diet versus diets higher in fat on cardiovascular lipids levels are beginning to emerge. One 2-year diet study compared the effect of a low-fat diet (LFD), low carbohydrate diet (LC), and a Mediterranean diet (MD) on lipid profiles of overweight patients [ 59 ]. The LC group had a significant decrease in triglycerides and the total cholesterol/HDL ratio decreased the most in the LC group. Their ratio decreased by 20% compared to a 12% decrease in the LF group [ 59 ]. The beneficial biomarker, HDL, increased in all groups, while the LDL changes were similar in all groups, which has also been noted in other studies [ 118 ]. A metabolic ward study of shorter duration conducted by Hall et al. [ 77 ] also found that triglycerides decreased in the reduced carbohydrate group. However, they saw the LDL levels increase in the LC group. Meanwhile, the Choi et al. [ 73 ] study mentioned earlier did not find an increase in LDL. It was conducted on obese patients with tightly controlled nutrition drinks, which had similar calorie reduction. Only the KD groups improved blood lipid profiles while reducing appetite. The KD groups saw a decrease in triglycerides and LDL, and no significant change in HDL [ 73 ].

Another 6-month study compared a low-calorie KD to a low-calorie diet in obese patients; some were diabetic. They found that both the diabetic and non-diabetic patients in the KD group showed the best lipid outcomes [ 87 ]. They found a significant decrease in triglycerides, a decrease in total cholesterol, a decrease in LDL, and an increase in HDL. A study conducted by Walton et al. [ 64 ] followed 11 women with type 2 diabetes for 90 days on a KD. The women in this study had increased HDL, a significant decrease in TG, and a significant decrease in the TG: HDL ratio, although LDL levels were not significantly changed. Another cardiovascular benefit was the lowering of the patient’s systolic and diastolic blood pressure. When evaluating type 1 diabetic patients who self-selected to be on a LCD, they found that these patients showed a decrease in TG, while having increases in HDL, TC, and LDL [ 98 ]. The researchers hypothesized that the total LDL elevation on the KD, if associated with a low TG, may reflect an increase in the large, buoyant lipoprotein particles which are considered a lower risk subtype. When the KD was followed for one year in type 2 diabetics and adherence was confirmed with BHB, it was noted that TG decreased by 24%, HDL increased 18%, LDL increased 10%, while ApoB was unchanged [ 2 ]. Although these lipid changes are considered favorable, the increase in LDL seen in some groups is still an area of concern. One analysis suggested that the risk from a slight increase in LDL might be offset by emphasizing the consumption of unsaturated fatty acids rather than saturated fatty acids [ 9 ].

The DIETFITS study also concluded that the increase in saturated fat intake may improve overall lipid profiles if they are adhering to a high-quality, whole-food based, low carbohydrate diet [ 104 ]. One major area of concern would be whether the KD would have these same beneficial changes in patients with dyslipidemia. A 56-week study tested the effect of the KD on obese patients with and without high cholesterol levels [ 119 ]. It is important to note that these patients were instructed to include 5 tablespoons of olive oil into the diet, which is a form of unsaturated fatty acids. Throughout the experiment, the patients saw continuous improvements in their lipid markers. Not only did both groups have decreased LDL, decreased TG, and increased HDL levels, but the patients with high cholesterol levels also ended the study with blood profiles that were more like normal subjects.

A more recently published case study on a young man who used a Mediterranean KD diet for treating his IBS had some interesting findings [ 120 ]. The doctors looked at more detailed lipid subfractions to determine the lipid outcomes of cardiovascular risk, which was unique. First, the authors mention that a typical lipid profile analysis would suggest the diet was having adverse effects on the patient. His total cholesterol changed from 160 to 450 mg/dL, even though a portion of that was due to increased HDL levels. Many argue that HDL-P is a superior predictive measure of good cardiovascular health. The HLD-P in this patient increased from 5699 nmol/L to 12,080 nmol/L. The current association between LDL-C and cardiovascular risk is driven by atherogenic small dense and/or oxidized LDL. It is believed that these two components can penetrate the endothelium of blood vessels and contribute to plaque formation [ 121 , 122 ]. Yet, large LDL are not associated with cardiovascular risk and may provide a protective effect. This patient saw an increase of LDL from 90 to 321 mg/dL. The LDL subfraction revealed that almost the entire increase in his LDL-C was caused by an increase in large LDL, while his small and medium LDL decreased by almost 10%. Thus, these authors argued that the typical analysis of lipid profiles from patients on ketogenic diets may not accurately reveal risk unless more detailed lipid subfraction tests are conducted.

Please refer to Table S3 in the Supplementary Materials for a comparison of studies evaluating the KD in relation to lipidology outcomes.

7. The Effect of the Ketogenic Diet on Cancer

Cancer currently remains the second leading cause of death (~22%) in the United States and is second only to heart disease [ 123 ]. Typically, cancer occurs in adults because of multiple mutations in numerous genes, genes that usually regulate cell growth and proliferation [ 124 , 125 , 126 ]. Today it is the accepted model that as many as six mutations need to occur to produce cancer (usually to oncogenes and tumor suppressor genes). Oncogenes are genes that regulate cellular pathways that can increase cellular growth, while tumor suppressor genes regulate pathways that inhibit abnormal cell growth. As the mutated cell population expands, it accrues the necessary changes to ignore growth control signals, avoid apoptosis, escape immune surveillance, and creates an environment to thrive (using mechanisms like angiogenesis and tolerance for anoxic environments) and eventually the capability to metastasize [ 124 ]. These mutations can result from many causes, such as DNA replication errors, failed DNA repair mechanisms, mutagen exposures, or increased reactive oxygen species [ 127 ].

Consequently, preventative mechanisms that could lower cancer incidence would be related to reducing these external causes or activating internal pathways to reduce cellular error. Additionally, epidemiologic evidence linking obesity to elevated cancer incidence found that 14% and 20% of all cancer deaths in men and women, respectively, are due to being overweight and obese [ 128 ]. As a result, the Annual Report to the Nation on Cancer emphasized the increasing contribution of obesity on cancer incidence [ 129 ]. One mechanism believed to contribute to obesity’s role in cancer is the increase in adipocytes in the body, which can increase circulating levels of insulin and Insulin Growth Factor 1 (IGF1) hormones. These hormones bind receptors in many cell types and activate P13K/AKT signaling pathways that increase cell survival and upregulate transcription factors that promote cell proliferation [ 130 ]. Both hormones also increase glucose uptake into cells, resulting in increased energy molecules being available for cell growth. Insulin is an anabolic hormone that promotes glucose uptake into cells, reduces the release of fatty acids from adipocytes, prevents ketone production in the liver, and stimulates fat and glycogen storage [ 131 ]. Additionally, many recent publications support the idea that prolonged, increased levels of serum insulin is likely to promote cancer growth [ 132 , 133 , 134 ].

The alterations in the metabolism of cancer cells were first described by Warburg et al. in 1927 [ 135 ] It was discovered that cancer cells acquire mutations in critical genes that change the way cancer cells acquire energy. First, cancer cells use glycolysis for ATP production and reduce their dependency on the oxidative cellular respiration in the mitochondria. This results in the cancer cells gaining only 2 ATP per glucose molecule instead of the average 36 ATP from typical cellular respiration processes, resulting in an enormous demand for glucose. Secondly, it allows the cancers cells to rapidly divide even in the absence of oxygen, since glycolysis is an anaerobic process that occurs in the cytosol. Currently, altered metabolism has been described as a primary signature of cancer [ 125 , 136 , 137 ]. Since this discovery, the use of metabolic therapies for dealing with cancer have been overshadowed by discoveries in the genetics and molecular signatures of cancer [ 138 ].

Therefore, it seems reasonable to hypothesize that diet could have profound effects on reducing cancer risk, especially if that diet is known to decrease body weight, lower insulin levels, and target the metabolic weaknesses of cancer cells. Some researchers hypothesize that the ketogenic diet might reduce cancer risk because it capitalizes on the reduced expression of ketolytic enzymes in cancer cells [ 48 ]. The diet would starve the cancer cells by reducing their ability to utilize glucose, while normal cells can adapt and begin utilizing ketone bodies for their energy demands. Another potential benefit could be the decrease in insulin that results from being in nutritional ketosis, which would reduce insulin-like growth factors that support cancer proliferation [ 48 ]. Especially given the fact that 20% of all cancer cases in North America can be attributed to obesity and 38% of all attributable cancer cases are linked to the increase in BMI since 1982 [ 139 ]. There have also been numerous studies that have linked cancer risk to hyperinsulinemia [ 140 , 141 , 142 , 143 , 144 ]. It is suggested that insulin resistance leads to hyperinsulinemia, and insulin has both pro-mitotic and antiapoptotic activity that may assist in tumor progression. Thus, any diet that can reduce obesity and lower insulin levels, such as the ketogenic diet, might reduce cancer risk.

Support for a KD as a mono-therapeutic approach for treating cancer is demonstrated in many mouse models. However, due to the heterogeneity of these studies (types of cancers, KD protocol, length of study, etc.), we discuss them separately. Poff et al. [ 145 ] tested a KD on systematic metastatic cancer in mice. They found that KD alone significantly decreased blood glucose levels, reduced tumor growth, and improved mean survival time by 56.7%. A similar study looked at the effect of the KD on mice with gastric tumor cells. Both tumor growth and mean survival time were improved [ 146 ]. In one study, Allen et al. [ 147 ] found that a KD reduced tumor growth in lung cancer xenografts.

In another study, they tested the use of a calorie-restricted KD on the growth and vascularity of malignant mouse astrocytoma (CT-2A) and human malignant glioma (U87-MG). When compared to an unrestricted high carbohydrate standard diet, they found that tumor growth decreased by 65% for CT-2A and 35% for U87-MG tumors [ 148 ]. They also found that signs of angiogenesis were reduced in the calorie restricted KD group. It is important to note that the mice in this study were fed KetoCal, a new nutritionally balanced high fat/low carbohydrate ketogenic diet for children with epilepsy. This finding suggests that the use of KetoCal should be considered not only for epilepsy, but as an alternative therapeutic option for malignant brain cancer. Another study found that a KetoCal KD diet also increased mean survival time and slowed tumor growth in mice with brain cancer [ 149 ]. Additionally, one study on mice by Morsher et al. [ 150 ] compared a KD and SD on neuroblastoma, with or without calorie restriction. It was found that the best results were in the calorie restricted KD group, with reduced tumor growth and survival time.

Meanwhile, a few studies have tried to compare the effect of a KD (with varying levels of carbohydrate amounts) on prostate cancer, with differing results. Caso et al. [ 151 ] studied mice that were either randomized into a standard Western diet, non-carbohydrate KD (NCKD) with 0% carbs, 10% carbohydrate KD, or 20% carbohydrate KD. The group with the slowest tumor growth was the 20% carbohydrate KD, while the WD had the most rapid growth. However, they did not find a significant improvement in survival among any of the carbohydrate restricted groups when compared to the WD. This result is different than a similar study done by Masko et al. [ 152 ], which compared a NCKD, 10% carbohydrate, and 20% carbohydrate diet in mice with prostate cancer. They concluded that none of these diet groups differed greatly in their tumor size throughout most of the study, and the diet did not affect survival. However, another study conducted on mice with prostate cancer compared a WD with a NCKD and found that the NCKD was significantly associated with lower tumor volumes at the end of the 53-day experiment [ 153 ]. Regardless of the varying results, a meta-analysis done by Klement et al. [ 154 ] analyzed a total of 29 animal studies and found that the majority (72%) found evidence of reduced tumor growth because of KDs.

The data of the effect of KD in human patients is limited mostly to case studies and cohort studies. A meta-analysis of 24 human studies, found that 42% found that the KD can reduce tumor growth [ 154 ]. In addition, it has been found that most human studies had positive impacts [ 154 , 155 ], with many other studies found it stabilized disease [ 154 , 155 ] and one study found a pro-tumorigenic effect of the KD [ 154 , 155 ]. However, another review of 14 studies of the use of KD in cancer found mixed results [ 154 ]. It was found that people responded differently to the diet, with some cancers being reduced, some neutral in effect, and some cancers getting progressively worse. This finding could be related to a recent publication by Chang et al. [ 156 ] that tested relative expression of several key enzymes in ketolytic and glycolytic metabolism in human anaplastic glioma and glioblastoma. They found genetically heterogeneous tumors with varying expressions of key enzymes. However, they found most cells had an enzyme profile with decreased levels of mitochondrial ketolytic enzymes and increased expression of glycolytic enzymes, suggesting that human brain tumors are more dependent on glucose and have defects in ketone metabolism.

The prognosis of patients with gliomas is extremely poor, with an average survival duration of 1.5 years [ 138 ]. Due to the poor outcomes with brain cancer, many studies using KD have been aimed at helping brain cancer patients. A small study by van der Louw et al. [ 157 ] followed three patients with recurrent diffuse intrinsic pontine glioma (DIPG). Although all three patients succumbed to the disease, it was determined that the use of KD is safe and feasible, but its effect on survival was not clear. Another 12-week randomized, controlled study also found that the use of KD in women with ovarian and endometrial cancer had favorable effects on physical function, perceived energy, and diminished food cravings for starchy and fast-food fats [ 158 ].

One of the most intriguing studies was a case study of a 38-year-old man with glioblastoma multiforme was treated with standard of care (SOC) along with a calorie-restricted ketogenic metabolic therapy, hyperbaric oxygen therapy, and other metabolic therapies [ 159 ]. The patient remains in excellent health with no neurological issues after 24 months of treatment. Thus, it seems that the ketogenic diet might be best utilized as an adjuvant therapy and should be started when the disease is first diagnosed. Recently the KEATING study [ 160 ] used either the modified ketogenic diet (MKD) or the medium chain triglyceride ketogenic diet (MCTKD) as an adjuvant therapy for glioblastoma. The Global Health Status (GHS) increased for patients in MKD cohort and decreased for the MCTKD patients. They had a low retainment with only 3 of 12 patients completing the 12-month intervention. The three patients who did complete the study chose to continue doing the KD. The researchers of the KEATING study suggested that the KD intervention should be reduced to six weeks and only be utilized during the time of chemo and radiation therapy.

Yet, another study by Panhans et al. [ 161 ] had greater compliance. This study recruited patients with a diversity of CNS malignancies (GBM, astrocytoma, and oligodendroglioma). These patients were asked to do a more standard KD of 3:1 for 120 days and aimed to keep carbohydrates under 20 g/day. One cohort was provided KD meals by Epigenix Foundation for the first 30 days, while the others were given only meal plans. Adherence to the diet was confirmed with ketone and glucose levels measured with Precision Xtra meters. The six patients with the highest ketones were alive at the end of the study. The two patients with the lowest ketones succumbed to their disease. Five patients were able to maintain 100% adherence for the duration of the study. Overall, patients’ symptoms improved, which included higher energy levels, increased physical activity, increased cognitive function, decreased appetite, and reduced seizure. It is important to note that one patient had increased seizures. The researchers stated that the KD was well tolerated and discussed its feasibility for future experiments. This cancer clinic also stated that as interest in the KD grows, they now openly discuss the risks and potential benefits on a regular basis with patients and emphasize the lack of robust clinical evidence.

The ketogenic diet is also now being tested as an adjuvant therapy for other cancers as well. For example, Clinicaltrials.gov currently lists over 100 trials looking at the ketogenic diet and 12 of those were related to CNS malignancies [ 161 ]. Therefore, data is starting to emerge on the impacts of KD on other cancer types. For instance, a study compared the typical diet with 55% of calories from carbohydrate (CHO) against a KD with around 6% from CHO in breast cancer patients in a 6-week trial [ 162 ]. The KD group’s global quality of life was higher at the 6-week mark and no adverse effects were seen in either group. Interestingly, the KD group lowered caloric intake without any restrictions, which may have been due to the satiating effects of fat. The KD diet was found to have no adverse effects on thyroid hormones, electrolytes, LDH, urea, or albumin. Yet, the KD diet was found to have potential beneficial effects, such as significantly reduced levels of lactate and ALP. Decreased lactate levels might slow metastases by reducing the acidity of the tumor microenvironment while reducing its ability to use it as a substrate for increasing biomass. Furthermore, it is believed that increased levels of ALP in breast cancer is a negative prognostic marker.

Another 12-week study in ovarian and endometrial cancer patients found an adherence level of 57–80% [ 163 ]. The focus of this study was to determine if the diet negatively affected lipid profiles since that is a current concern of many doctors and may restrict their decision on whether to suggest the KD diet for their cancer patients. They compared the KD versus the American Cancer Society (ACS) high-fiber, low fat diet. No changes were seen in lipid profiles to TC, TG, HDL-C, LDL-C, TC:HDL-C ratio or TG:HDL-C ratio after adjusting for baseline levels and weight loss. Another recent study looked at the effects of the diet on the body composition of KD patients while receiving radiation therapy. Klement et al. [ 164 ] compared a nonKD vs a KD with supplemental essential amino acids (KETOCOMP study). The KD had significantly associated with loss of 0.5 kg of fat mass and 0.4 kg of body weight per week, while showing no change in fat free mass or skeletal muscle mass. Thus, KD with ample amino acid intake could improve body composition during radiotherapy. Finally, a recent study conducted by Hagihara et al. [ 165 ] analyzed the effects of a 3-month KD as an adjuvant therapy for patients with advanced cancers of many types. They found that the diet was well tolerated, did not have any major negative outcomes, and improved life expectancy. Researchers were also able to stratify survival outcomes with three factors: albumin, blood sugar, and CRP levels. Thus, it was argued that stable adherence and highly reproducible results should be in favor of using the ketogenic diet as a standard for therapeutic treatment during chemotherapy with advanced cancer diagnoses.

Please refer to Table S4 in the Supplementary Materials for a comparison of studies evaluating the KD in relation to cancer outcomes.

8. Discussion

A well-formulated ketogenic diet can provide low carbohydrate intake, while providing adequate fiber sources such as seeds, nuts, coconut, avocado, spinach, broccoli, cauliflower, and berries. Together, all these rich pre-biotic foods would lead to an increase in Bacteroides and Bifidobacterium and a subsequent decrease in Firmicutes. With disease rates increasing rapidly in the United States and other modern nations, it is increasingly important that we determine the safety, efficacy, and potential life-saving benefits of alternative diets. What might be discovered is that patients should be given individualized diets based on the species comprising their microbiome. This might enable patients to eat certain foods that maximize their ability to remain in a state of nutritional ketosis and optimize their overall health outcomes. The regular monitoring of the microbiome might be necessary to continually moderate and change dietary needs for diversity. It might also be determined that fecal microbiota transplants might be necessary to fully alter and change the microbiome at the onset of a new diet which could then be further modified and enhanced through diet. Regardless, much more research is needed in this area to determine the effect of the ketogenic diet on the microbiome.

Even though the ketogenic diet shows promise in helping patients lose weight, obesity is more than excess adipose tissue being stored on the body. It has been linked to many other metabolic issues, such as diabetes, cardiovascular disease, neurological disorders, and cancer. The ability to improve glycemic control in diabetics is critical for long-term health especially since some would argue that the biggest indicator of cardiovascular disease risk was HbA1c [ 88 ]. Surprisingly, the United Kingdom Prospective Diabetes Study (UKPDS) examined 5102 newly diagnosed type 2 diabetics and found that patients showed a 14% decrease in myocardial infarction for every 1% reduction in their HbA1c [ 166 , 167 , 168 ]. The ability to have tight glycemic control is even more challenging in type 1 diabetics since they are unable to make insulin and must inject it in response to glucose spikes induced by diet. Thus, their greatest challenge is controlling postprandial glycemia [ 98 ]. Some scientists argue that reducing carbohydrate intake is the easiest way for a type 1 diabetic to control their blood sugar levels since it will reduce the error in determining the insulin amount needed to match their increased blood glucose levels [ 88 ]. However, the benefits from the low carbohydrate diet might also improve other health markers in diabetics, such as abdominal fat and health-related quality of life factors as shown in other studies [ 169 , 170 ]. Type 2 diabetics have also improved or eliminated their diabetic state through diet, specifically a diet that restricts carbohydrate consumption. Type 2 diabetes results in insulin resistant cells and this has been linked to other complications and atherosclerotic processes such as inflammation, decreased size of LDL particles, and endothelial dysfunction [ 171 ]. Thus, the benefits of a healthy, low carbohydrate diet on diabetes might also improve the markers for cardiovascular disease as well.

Although the debate about diet and heart health continues, many new studies are revealing that the picture is much more complicated than the diet-heart hypothesis suggested. The need for more randomized, controlled studies of long-term duration are necessary to determine the true effect of dietary macronutrients on cardiovascular risks. It appears from preliminary studies that a ketogenic diet might have favorable outcomes on CVD, but some still view the idea with great skepticism. In medicine, randomized controlled trials are considered the gold standard and many physicians feel that there is not enough of these studies to consider changing their medical advice. It is interesting that while current scientists are unwilling to consider these dietary recommendations due to the lack of long-term evidence, the entire United States adopted the current dietary guidelines based mainly on an epidemiological study done by Ancel Keys [ 102 ]. Additionally, when the available randomized controlled studies and prospective cohort studies of that time were analyzed, they did not support the recommendation of dietary fat and coronary heart disease [ 172 , 173 ]. Regardless, the necessity in discovering a healthy diet for most people is an important endeavor, especially since we are currently seeing an epidemic of diabetes and obesity, both of which are linked to cardiovascular disease risk.

The potential of the ketogenic diet to aid in cancer treatment is still up for debate. However, the positive results seen in mice warrant that this metabolic therapy should be evaluated further. From the studies presented, it appears that in mice and humans, the diet seems to be most beneficial when used as an adjuvant with other therapies and when administered as soon as possible. It might also be critical to genetically analyze each tumor and determine its metabolic profile to determine if it is exhibiting the Warburg effect. If so, then the KD diet might be a useful addition to the treatment protocol. In summary, a ketogenic diet may have positive impacts on the pathogenesis of cancer, although the determination of its use as a monotherapy or adjuvant therapy in humans need further study.

In conclusion, it is becoming more and more apparent that a “systems biology” approach to human health might be the way of the future. Future studies might need to consider numerous factors such as lifestyle, dietary intake, genotype, gut microbiome composition, and genome-wide information on the epigenome to create a successful plan for maximizing good health. According to Gerhauser et al. [ 20 ], “this ambitious goal can only be reached in large interdisciplinary research projects, combining expertise of food technologists, nutritionists, food chemists, molecular biologists, epigeneticists, clinicians, nutritional epidemiologists, bioinformaticians, and statisticians to achieve an integrated view of the influence of diet on human health.” Others argue that a diagnosis of high-risk epigenetic states may lead to a better understanding of the links between nutrition, the epigenome, and cancer risk [ 32 ]. If these markers can be identified and better understood, then new interventions can be created. New research suggests that long-term dietary choices affect diversity and gene expression of the gut microbiome. One such path might be the use of the ketogenic diet to increase beneficial metabolites which can have positive impacts on the genome. Additionally, a recent study analyzed the genetic variants for personalized management of ketogenic diets [ 174 ] and it suggested that certain genetic and dynamic markers of KD response may help identify individuals that will benefit the most from a KD diet. Thus, the use of the ketogenic diet might have a multitude of therapeutic effects, including but not limited to, helping with weight loss, improving lipid markers for cardiovascular health, healing a disrupted microbiome, improving epigenetic markers, reversing diabetes, or reducing the need for medication, and improving responses to cancer treatments. However, if a high fat/low carbohydrate KD diet seems too restrictive, then the use of personalized nutritional advice using microbiome sequencing might be the way of the future for stabilizing many of these diseases and improving metabolic health.

Acknowledgments

We thank Rozanne Wille and Charles Larssen for critical reading of the manuscript. This work is supported by the Office of Research & Creative Activity and the Department of Biology, Western Kentucky University.

Supplementary Materials

The following are available online at https://www.mdpi.com/article/10.3390/nu13051654/s1 , Table S1: Main studies reporting the effects of low-carbohydrate diets, including ketogenic diets, on weight loss, Table S2: Main studies reporting the effects of low-carbohydrate diets, including ketogenic diets, on diabetes health markers, Table S3: Main studies reporting the effects of low-carbohydrate diets, including ketogenic diets, on lipidology health markers, Table S4: Main studies reporting the effects of low-carbohydrate diets, including ketogenic diets, on cancer.

Author Contributions

Both authors contributed to conceptualization, writing, and editing of this review. Both authors have read and agreed to the published version of the manuscript.

No funding was utilized in writing this review.

Institutional Review Board Statement

Informed consent statement, data availability statement, conflicts of interest.

The authors declare no conflict of interest.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

• Research article
• Open access
• Published: 25 May 2023

Effects of ketogenic diet on health outcomes: an umbrella review of meta-analyses of randomized clinical trials

• Chanthawat Patikorn 1 , 2 ,
• Pantakarn Saidoung 1 ,
• Tuan Pham 3 ,
• Pochamana Phisalprapa 4 ,
• Yeong Yeh Lee 5 ,
• Krista A. Varady 6 ,
• Sajesh K. Veettil 1 &
• Nathorn Chaiyakunapruk 1 , 7  

BMC Medicine volume  21 , Article number:  196 ( 2023 ) Cite this article

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Systematic reviews and meta-analyses of randomized clinical trials (RCTs) have reported the benefits of ketogenic diets (KD) in various participants such as patients with epilepsy and adults with overweight or obesity . Nevertheless, there has been little synthesis of the strength and quality of this evidence in aggregate.

To grade the evidence from published meta-analyses of RCTs that assessed the association of KD, ketogenic low-carbohydrate high-fat diet (K-LCHF), and very low-calorie KD (VLCKD) with health outcomes, PubMed, EMBASE, Epistemonikos, and Cochrane database of systematic reviews were searched up to February 15, 2023. Meta-analyses of RCTs of KD were included. Meta-analyses were re-performed using a random-effects model. The quality of evidence per association provided in meta-analyses was rated by the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) criteria as high, moderate, low, and very low.

We included 17 meta-analyses comprising 68 RCTs (median [interquartile range, IQR] sample size of 42 [20–104] participants and follow-up period of 13 [8–36] weeks) and 115 unique associations. There were 51 statistically significant associations (44%) of which four associations were supported by high-quality evidence (reduced triglyceride ( n  = 2), seizure frequency ( n  = 1) and increased low-density lipoprotein cholesterol (LDL-C) ( n  = 1)) and four associations supported by moderate-quality evidence (decrease in body weight, respiratory exchange ratio (RER), hemoglobin A 1c , and increased total cholesterol). The remaining associations were supported by very low (26 associations) to low (17 associations) quality evidence. In overweight or obese adults, VLCKD was significantly associated with improvement in anthropometric and cardiometabolic outcomes without worsening muscle mass, LDL-C, and total cholesterol. K-LCHF was associated with reduced body weight and body fat percentage, but also reduced muscle mass in healthy participants.

Conclusions

This umbrella review found beneficial associations of KD supported by moderate to high-quality evidence on seizure and several cardiometabolic parameters. However, KD was associated with a clinically meaningful increase in LDL-C. Clinical trials with long-term follow-up are warranted to investigate whether the short-term effects of KD will translate to beneficial effects on clinical outcomes such as cardiovascular events and mortality.

Peer Review reports

Ketogenic diets (KD) have received substantial attention from the public primarily due to their ability to produce rapid weight loss in the short run [ 1 , 2 ]. The KD eating pattern severely restricts carbohydrate intake to less than 50 g/day while increasing protein and fat intake [ 3 , 4 , 5 , 6 ]. Carbohydrate deprivation leads to an increase in circulating ketone bodies by breaking down fatty acids and ketogenic amino acids. Ketones are an alternative energy source from carbohydrates that alter physiological adaptations. These adaptions have been shown to produce weight loss with beneficial health effects by improving glycemic and lipid profiles [ 7 , 8 ]. KD has also been recommended as a nonpharmacological treatment for medication-refractory epilepsy in children and adults [ 8 , 9 ]. Evidence suggests that KD has reduced seizure frequency in patients with medication-refractory epilepsy, and even allowing some patients to reach complete and sustained remission. 11 However, the exact anticonvulsive mechanism of KD remains unclear [ 10 , 11 ].

Several systematic reviews and meta-analyses of randomized clinical trials (RCTs) have reported on the use of KD in patients with obesity or type 2 diabetes mellitus (T2DM) to control weight and improve cardiometabolic parameters [ 1 , 12 , 13 , 14 , 15 ], in patients with refractory epilepsy to reduce seizure frequency [ 16 ], and in athletes to control weight and improve performance [ 17 ]. To date, there has been little synthesis of the strength and quality of this evidence in aggregate. This umbrella review therefore aims to systematically identify relevant meta-analyses of RCTs of KD, summarize their findings, and assess the strength of evidence of the effects of KD on health outcomes.

The protocol of this study was registered with PROSPERO (CRD42022334717). We reported following the 2020 Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) (Additional file 1 ) [ 18 ]. Difference from the original review protocol is described with rationale in Additional file 2 : Table S1.

Search strategy and eligibility criteria

We searched PubMed, EMBASE, Epistemonikos, and the Cochrane database of systematic reviews (CDSR) from the database inception to February 15, 2023 (Additional file 2 : Table S2). No language restriction was applied. Study selection was independently performed in EndNote by two reviewers (C.P. and PS). After removing duplicates, the identified articles' titles and abstracts were screened for relevance. Full-text articles of the potentially eligible articles were retrieved and selected against the eligibility criteria. Any discrepancies were resolved by discussion with the third reviewer (SKV).

We included studies that met the following eligibility criteria: systematic reviews and meta-analyses of RCTs investigating the effects of any type of KD on any health outcomes in participants with or without any medical conditions compared with any comparators. When more than 1 meta-analysis was available for the same research question, we selected the meta-analysis with the largest data set [ 19 , 20 , 21 ]. Articles without full-text and meta-analyses that provided insufficient or inadequate data for quantitative synthesis were excluded.

Data extraction and quality assessment

Two reviewers (CP and PS) independently performed data extraction and quality assessment (Additional file 2 : Method S1). Discrepancies were resolved with consensus by discussing with the third reviewer (SKV). We used AMSTAR- 2 -A Measurement Tool to Assess Systematic Reviews- to grade the quality of meta-analyses as high, moderate, low, or critically low by assessing the following elements, research question, a priori protocol, search, study selection, data extraction, quality assessment, data analysis, interpretation, heterogeneity, publication bias, source of funding, conflict of interest [ 22 ].

Data synthesis

For each association, we extracted effect sizes (mean difference [MD], the standardized mean difference [SMD], and risk ratio [RR]) of individual studies included in each meta-analysis and performed the meta-analyses to calculate the pooled effect sizes and 95% CIs using a random-effects model under DerSimonian and Laird [ 23 ], or the Hartung-Knapp- Sidik-Jonkman approach for meta-analyses with less than five studies [ 24 ].  p  < 0.05 was considered statistically significant in 2-sided tests. Heterogeneity was evaluated using the I 2 statistic. The evidence for small-study effects was assessed by the Egger regression asymmetry test [ 25 ]. Statistical analyses were conducted using Stata version 16.0 (StataCorp). We presented effect sizes of statistically significant associations with the known or estimated minimally clinically important difference (MCID) thresholds for health outcomes [ 14 , 26 , 27 , 28 , 29 , 30 ].

We assessed the quality of evidence per association by applying the GRADE criteria (Grading of Recommendations, Assessment, Development, and Evaluations) in five domains, including (1) risk of bias in the individual studies, (2) inconsistency, (3) indirectness, (4) imprecision, and (5) publication bias [ 31 ]. We graded the strength of evidence (high, moderate, low, and very low) using GRADEpro version 3.6.1 (McMaster University).

Sensitivity analyses

Sensitivity analyses were performed by excluding small-size studies (< 25 th percentile) [ 32 ] and excluding primary studies having a high risk of bias rated by the Cochrane’s risk of bias 2 tool (RoB 2) for RCTs from the identified associations [ 19 , 20 , 21 , 33 ].

Seventeen meta-analyses were included (Fig.  1 and Additional file 2 : Table S3) [ 1 , 2 , 15 , 16 , 17 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ]. These meta-analyses comprised 68 unique RCTs with a median (interquartile range, IQR) sample size per RCT of 42 (20–104) participants and a median (IQR) follow-up period of 13 (8–36) weeks. The quality of meta-analyses assessed using AMSTAR-2 found that none were rated as high confidence, 2 (12%) as moderate confidence, 2 (12%) as low confidence, and 13 (76.0%) as critically low confidence (Table 1 and Additional file 2 : Table S4).

Study selection flow of meta-analyses. Abbreviation: CDSR, Cochrane database of systematic review

Types of KD identified in this umbrella review were categorized as (1) KD, which limits carbohydrate intake to < 50 g/day or < 10% of the total energy intake (TEI) [ 35 ], (2) ketogenic low-carbohydrate, high-fat diet (K-LCHF), which limits carbohydrate intake to < 50 g/day or < 10% of TEI with high amount of fat intake (60–80% of TEI) [ 38 , 46 ], (3) very low-calorie KD (VLCKD), which limits carbohydrate intake to < 30–50 g/day or 13–25% of TEI with TEI < 700–800 kcal/day, and (4) modified Atkins diet (MAD), which generally limits carbohydrate intake to < 10 g/day while encouraging high-fat foods [ 15 , 47 ]. Meta-analyses of long-chain triglyceride KD, medium-chain triglyceride KD, and low glycemic index treatment were not identified.

Description and summary of associations

We identified 115 unique associations of KD with health outcomes (Additional file 2 : Table S5). The median (IQR) number of studies per association was 3 [ 4 , 5 , 6 ], and the median (IQR) sample size was 244 (127–430) participants. Outcomes were associated with KD types, including 40 (35%) KD, 18 (16%) K-LCHF, 13 (11%) VLCKD, 25 (22%) KD or K-LCHF, 5 (4%) KD or VLCKD, 1 (1%) KD or MAD, and 13 (11%) KD, K-LCHF, or VLCKD.

The associations involved 40 (35%) anthropometric measures (i.e., body weight, body mass index [BMI] [calculated as weight in kilograms divided by height in meters squared], waist circumference, muscle mass, fat mass, body fat percentage, and visceral adipose tissue), 37 (32%) lipid profile outcomes (i.e., triglyceride, total cholesterol, high-density lipoprotein cholesterol [HDL-C], and low-density lipoprotein cholesterol [LDL-C]), 22 (19%) glycemic profile outcomes (i.e., hemoglobin A 1c [HbA 1c ], fasting plasma glucose, fasting insulin, and homeostatic model assessment of insulin resistance [HOMA-IR]), 6 (5%) exercise performance (i.e., maximal heart rate, respiratory exchange ratio [RER], maximal oxygen consumption (VO 2 max), 5 (4%) blood pressure outcomes (i.e., systolic blood pressure [SBP], diastolic blood pressure [DBP], and heart rate), 1 (1%) outcome associated with seizure frequency reduction ≥ 50% from baseline, and 3 other outcomes (i.e., serum creatinine, C-peptide, and C-reactive protein). In addition, there is 1 association (1%) of adverse events.

Participants in the identified associations included 68 (59%) associations in adults with overweight or obesity with or without T2DM or dyslipidemia, 15 (13%) athletes or resistance-trained adults, 12 (10%) adults with T2DM, 11 (10%) healthy participants ≥ 16 years old, 8 (7%) cancer patients, and 1 (1%) in children and adolescents with epilepsy.

Using GRADE, 115 associations were supported by very low strength of evidence ( n  = 66, 57%), with the remaining being low ( n  = 36, 31%), moderate ( n  = 9, 8%), and high quality of evidence ( n  = 4, 3%) (Additional file 2 : Table S5). Almost half, or 44% (51 associations), were statistically significant based on a random-effects model, of which 51% (26 associations) were supported by a very low level of evidence, followed by low (17 associations [33%]), moderate (4 associations [8%]), and high (4 associations [8%]) levels of evidence. Overall beneficial outcomes associated with KD were BMI [ 37 , 42 ], body weight [ 1 , 2 , 35 , 36 , 37 , 41 ], waist circumference [ 37 , 42 ], fat mass [ 37 , 42 ], body fat percentage [ 38 , 40 ], visceral adipose tissue [ 37 ], triglyceride [ 1 , 2 , 36 , 42 ], HDL-C [ 1 , 2 , 42 ], HbA 1c  [ 2 , 34 , 35 ],  HOMA-IR [ 2 , 42 ], DBP [ 1 ], seizure frequency reduction ≥ 50% from baseline [ 16 ], and respiratory exchange ratio [ 17 , 39 ]. Adverse outcomes associated with KD were reduced muscle mass [ 37 , 38 ], and increased LDL-C [ 2 , 35 ], and total cholesterol [ 2 , 17 ]. In terms of safety, one association showed no significant increase in adverse events (e.g., constipation, abdominal pain, and nausea) with KD [ 44 ].

Eight out of 13 associations supported by moderate to high-quality evidence were statistically significant (Table 2 ). There were 4 statistically significant associations supported by high-quality evidence, including the following: (1) KD or MAD for 3–16 months was associated with a higher proportion of children and adolescents with refractory epilepsy achieving seizure frequency reduction ≥ 50% from baseline compared with regular diet (RR, 5.11; 95% CI, 3.18 to 8.21) [ 16 ], (2) KD for 3 months was associated with reduced triglyceride in adults with T2DM compared with regular diet (MD, -18.36 mg/dL; 95% CI, -24.24 to -12.49, MCID threshold 7.96 mg/dL) [ 14 , 35 ], (3) KD for 12 months was associated with reduced triglyceride in adults with T2DM compared with regular diet (MD, -24.10 mg/dL; 95% CI, -33.93 to -14.27, MCID threshold 7.96 mg/dL) [ 14 , 35 ], and (4) KD for 12 months was associated with increased LDL-C in adults with T2DM compared with regular diet (MD, 6.35 mg/dL; 95% CI, 2.02 to 10.69, MCID threshold 3.87 mg/dL) [ 14 , 35 ]. In addition, there were 4 statistically significant associations supported by moderate-quality evidence: (1) KD for 3 months was associated with reduced HbA 1c in adults with T2DM compared with regular diet (MD, -0.61%; 95% CI, -0.82 to -0.40, MCID threshold 0.5%) [ 14 , 35 ], (2) VLCKD for 4–6 weeks was associated with reduced body weight in T2DM adults with overweight or obesity compared with a low-fat diet or regular diet (MD, -9.33 kg; 95% CI, -15.45 to -3.22, MCID threshold 4.40 kg) [ 14 , 15 ], (3) K-LCHF for 4–6 weeks was associated with reduced respiratory exchange ratio in athletes compared with a high-carbohydrate diet (SMD, -2.66; 95% CI, -3.77 to -1.54) [ 39 ], and (4) K-LCHF for 11–24 weeks was associated with increased total cholesterol in athletes compared with regular diet (MD, 1.32 mg/dL; 95% CI, 0.64 to 1.99) [ 14 , 17 ].

Types of KD showed different effects on health outcomes with changes more than the MCID thresholds in different populations (Fig.  2 ). KD or MAD for 3–16 months was associated with a 5-times higher proportion of children and adolescents with refractory epilepsy achieving seizure frequency reduction ≥ 50% from baseline compared with a regular diet (RR, 5.11; 95% CI, 3.18 to 8.21) [ 16 ]. In healthy participants, K-LCHF for 3–12 weeks could reduce body weight by 3.68 kg (95% CI, -4.45 to -2.90) but also significantly reduced muscle mass by 1.27 kg (95% CI, -1.83 to -0.70, MCID threshold 1.10 kg) [ 14 , 26 , 38 ]. In adults with T2DM, KD for 3–12 months was found to have significant associations with changes more than the MCID thresholds, including reduction of triglyceride and HbA 1c ; however, KD for 12 months led to a clinically meaningful increase in LDL-C by 6.35 mg/dL (95% CI, 2.02 to 10.69, MCID threshold 3.87 mg/dL) [ 14 , 35 ]. In adults with overweight or obesity and/or metabolic syndrome, VLCKD for 4–6 weeks demonstrated a clinically meaningful weight loss of 9.33 kg (95% CI, -15.45 to -3.22, MCID threshold 4.40 kg) [ 14 , 15 ]. VLCKD for 3–96 weeks led to a clinically meaningful improvement in BMI, body weight, waist circumference, triglyceride, fat mass, and insulin resistance, while preserving muscle mass [ 42 ].

Associations of Types of Ketogenic Diet with Health Outcomes. Abbreviations: BMI, body mass index, DBP, diastolic blood pressure; GRADE, Grading of Recommendations, Assessment, Development, and Evaluations; HbA 1c , hemoglobin A 1c ; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, homeostatic model of insulin resistance; LDL-C, low-density lipoprotein cholesterol; SBP, systolic blood pressure; TEI, total energy intake

Excluding RCTs with small sizes in 7 associations found that the strength of evidence of one association was downgraded to very low quality, i.e., KD for 12 months, and the increase of LDL-C in adults with T2DM compared with a control diet. Another association was downgraded to low quality, i.e., KD for 12 months and the reduction of triglyceride in adults with T2DM compared with the control diet (Additional file 2 : Table S6). The remaining associations retained the same rank.

This umbrella review was performed to systematically assess the potential associations of KD and health outcomes by summarizing the evidence from meta-analyses of RCTs. Sensitivity analyses were performed to provide additional evidence from high-quality RCTs, which further increased the reliability of results. We identified 115 associations of KD with a wide range of outcomes. Most associations were rated as low and very low evidence according to the GRADE criteria because of serious imprecision and large heterogeneity in findings, and indirectness due to a mix of different interventions and comparators.

Our findings showed that KD or MAD resulted in better seizure control in children and adolescents with medication-refractory epilepsy (approximately a third of cases) for up to 16 months [ 10 , 11 , 16 ]. Anti-epileptic mechanisms of KD remain unknown but are likely multifactorial. Enhanced mitochondrial metabolism and an increase in ketone bodies or reduction in glucose across the blood–brain barrier resulted in synaptic stabilization [ 48 , 49 , 50 ]. Other mechanisms include an increase in gamma-aminobutyric acid (GABA) [ 51 ], more beneficial gut microbiome [ 52 ], less pro-inflammatory markers [ 53 ], and epigenetic modifications (e.g. beta-hydroxybutyrate [beta-OHB]) [ 54 ].

In adults, KD was associated with improved anthropometric measures, cardiometabolic parameters, and exercise performance. Our findings, however, demonstrated differences in the level of associations with type of KD. On the one hand, VLCKD is very effective in producing weight loss while preserving muscle mass in adults with overweight or obesity, with specific benefits on anthropometric and cardiometabolic parameters [ 15 , 42 ]. On the other hand, a significant portion of the weight loss seen in K-LCHF was due to muscle mass loss [ 17 , 38 ]. Overall KD was negatively associated with reduced muscle mass and increased LDL-C and total cholesterol.

Our findings demonstrated that KD could induce a rapid weight loss in the initial phase of 6 months, after which time further weight loss was hardly achieved [ 35 ]. Furthermore, weight loss induced by KD is relatively modest and appears comparable to other dietary interventions that are effective for short-term weight loss, e.g., intermittent fastingand Mediterranean diet [ 55 , 56 , 57 ].

KD is one of the dietary interventions employed by individuals to achieve rapid weight loss, which usually comes with reduced muscle mass [ 58 ]. However, KD has been hypothesized to preserve muscle mass following weight loss based on several mechanisms, including the protective effect of ketones and its precursors on muscle tissue [ 59 , 60 , 61 ], and increased growth hormone secretion stimulated by low blood glucose to increase muscle protein synthesis [ 58 , 62 , 63 ].

With regards to KD effects on lipid profiles, our results demonstrate an effective reduction in serum triglyceride levels with 3 months of lowered dietary carbohydrate intake, with even further reduction by month 12 [ 35 ]. Triglyceride levels are consistently shown to decrease after KD. Acute ketosis (beta-OHB ≈ 3 mM) due to ketone supplementation also shows decreases in triglycerides, indicating a potential effect of ketones on triglycerides independent of weight loss. One possible mechanism is the decreased very low-density lipoprotein content in the plasma due to low insulin levels. Due to a lack of insulin, lipolysis increases in fat cells [ 2 , 13 , 15 ]. Of note, the converse has also been observed as a phenomenon known as carbohydrate-induced hypertriglyceridemia, whereby higher dietary carbohydrate intake leads to higher serum triglycerides levels, potentially mediated by changes in triglyceride clearance and hepatic de novo lipogenesis rates [ 64 ]. Though our aggregate results also confirm an increase in LDL-C and total cholesterol with KD and K-LCHF, respectively, it is important to note that an increase in either of these levels does not necessarily signify a potentially deleterious cardiovascular end-point. This qualification derives from the fact that LDL particles are widely heterogeneous in composition and size, with small dense LDL particles being significantly more atherogenic than larger LDL particles [ 65 ]. Our observed aggregate effect of KD on cholesterol levels does not account for the difference in LDL particle size, nor does it distinguish the sources of dietary fat, which can also be a significant effector of LDL particle size distribution and metabolism [ 66 ].

Most RCTs of KD were conducted in patients with a limited group of participants, such as those with overweight, obesity, metabolic syndrome, cancer, and refractory epilepsy. In addition, most outcomes measured were limited to only surrogate outcomes. Thus, more clinical trials with a broader scope in populations and outcomes associated with KD would expand the role of KD in a clinical setting. For example, participant selection could be expanded from previous trials to include elderly patients, nonalcoholic fatty live disease (NAFLD) patients, and polycystic ovarian syndrome patients. Outcomes of interest of could be expanded to include (1) clinical outcomes such as cardiovascular events and liver outcomes, (2) short- and long-term safety outcomes such as adverse events (e.g., gastrointestinal, neurological, hepatic, and renal), eating disorder syndrome, sleep parameters, lipid profiles, and thyroid function and (3) other outcomes such as adherence and quality of life. More importantly, long-term studies are needed to investigate the sustainability of the clinical benefits of KD.

Our findings are useful to support the generation of evidence-based recommendations for clinicians contemplating use of KD in their patients, as well as for the general population. We further emphasize the importance of consultation with healthcare professionals before utilizing KD and any other dietary interventions. We demonstrated the benefits of KD on various outcomes in the short term. However, these improvements may prove difficult to sustain in the long term because of challenges in adherence. As for any diet interventions to achieve sustainable weight loss, factors of success include adherence, negative energy balance, and high-quality foods. Thus, communication and education with KD practitioners are important to ensure their adherence to the diet. Some individuals might benefit from switching from KD to other dietary interventions to maintain long-term weight loss.

Limitations

This umbrella review has several limitations. Firstly, we focused on published meta-analyses which confined us from assessing the associations of KD on outcomes and populations that were not included in existing meta-analyses. Secondly, most of the included meta-analyses were rated with AMSTAR-2 as critically low confidence, mainly due to a lack of study exclusion reasons, unexplained study heterogeneity, and unassessed publication bias. However, these domains unlikely affected our findings. Thirdly, we could not perform a dose–response analysis to understand the effects of different levels of carbohydrate intake on health outcomes because of insufficient details of carbohydrate intake reported in the meta-analyses. Fourthly, most RCTs of KD were limited to a relatively small number of participants with a short-term follow-up period, which limited our assessment of sustained beneficial effects after stopping KD. Lastly, due to decreased adherence, carbohydrate intake most likely increased across the course of the trials. For example, subjects in the KD arm of the A TO Z Weight Loss Study [ 67 ], started with a carbohydrate intake < 10 g/day but ended at 12 months with a carbohydrate intake accounting for 34% of TEI. In the DIRECT trial, subjects in the KD group started with carbohydrate intake of 20 g/day and ended at 12 months with 40% of TEI from carbohydrate intake [ 68 ]. Thus, we cannot be certain how the precise degree of ketosis contributed to the beneficial effects noted.

Beneficial associations of practicing KD were supported by moderate- to high-quality evidence, including weight loss, lower triglyceride levels, decreased HbA 1c , RER, and decreased seizure frequency. However, KD was associated with a clinically meaningful increase in LDL-C. Clinical trials with long-term follow-up are warranted to investigate whether these short-term effects of KD will translate to beneficial effects on more long-term clinical outcomes such as cardiovascular events and mortality.

Availability of data and materials

All data generated or analysed during this study are included in this published article and its supplementary information files.

Abbreviations

Beta-hydroxybutyrate

Body mass index

Diastolic blood pressure

Gamma-aminobutyric acid

High-density lipoprotein cholesterol

Hemoglobin A 1c

Homeostatic model assessment of insulin resistance

Ketogenic low-carbohydrate high-fat diet

Ketogenic diets

Low-density lipoprotein cholesterol

Modified Atkins diet

Minimally clinically important difference

Nonalcoholic fatty liver disease

Randomized clinical trials

Respiratory exchange ratio

Systolic blood pressure

Type 2 diabetes mellitus

Total energy intake

Very low-calorie ketogenic diet

Maximal oxygen consumption

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The authors would like to acknowledge Thunchanok Ingkaprasert and Wachiravit Youngjanin for their editorial assistance.

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Chanthawat Patikorn, Pantakarn Saidoung, Sajesh K. Veettil & Nathorn Chaiyakunapruk

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Method S1. Data extraction. Table S1. Difference from original review protocol. Table S2. Search strategy. Table S3. Excluded studies with reasons.  Table S4. Quality assessment. Table S5. Summary of associations. Table S6. Sensitivity analyses. 

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Patikorn, C., Saidoung, P., Pham, T. et al. Effects of ketogenic diet on health outcomes: an umbrella review of meta-analyses of randomized clinical trials. BMC Med 21 , 196 (2023). https://doi.org/10.1186/s12916-023-02874-y

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Review article, ketogenic diets and chronic disease: weighing the benefits against the risks.

• 1 Physicians Committee for Responsible Medicine, Washington, DC, United States
• 2 Brenda Davis Nutrition Consulting, Kelowna, BC, Canada
• 3 Department of Medicine, New York University Grossman School of Medicine, New York, NY, United States
• 4 Department of Medicine, New York City Health + Hospitals/Bellevue, New York, NY, United States
• 5 College of Liberal and Professional Studies, University of Pennsylvania, Philadelphia, PA, United States
• 6 School of Public Health, Loma Linda University, Loma Linda, CA, United States
• 7 Adjunct Faculty, Department of Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, United States

Very-low-carbohydrate ketogenic diets have been long been used to reduce seizure frequency and more recently have been promoted for a variety of health conditions, including obesity, diabetes, and liver disease. Ketogenic diets may provide short-term improvement and aid in symptom management for some chronic diseases. Such diets affect diet quality, typically increasing intake of foods linked to chronic disease risk and decreasing intake of foods found to be protective in epidemiological studies. This review examines the effects of ketogenic diets on common chronic diseases, as well as their impact on diet quality and possible risks associated with their use. Given often-temporary improvements, unfavorable effects on dietary intake, and inadequate data demonstrating long-term safety, for most individuals, the risks of ketogenic diets may outweigh the benefits.

Introduction

Very-low-carbohydrate (ketogenic) diets have been promoted for weight loss and, less commonly, for other health reasons. This review summarizes the effects of a ketogenic diet on health conditions for which it has been promoted, as well as potential long-term effects on health.

The term “ketogenic diet” generally refers to a diet that is very low in carbohydrate, modest in protein, and high in fat. This mix of fuels aims to induce ketosis , or the production of ketone bodies that serve as an alternate energy source for neurons and other cell types that cannot directly metabolize fatty acids. Urinary ketone levels are often used as an indicator of dietary adherence ( 1 ).

Various ketogenic diets have been studied, as shown in Table 1 . The best defined and studied is sometimes called a “classic” ketogenic diet, referring to a very-low-carbohydrate diet that is generally medically supervised, with a 4:1 or 3:1 ratio, by weight, of dietary fat to combined dietary protein and carbohydrate ( 2 ).

Table 1 . Macronutrient composition of ketogenic diets.

Other variants allow more protein or carbohydrate ( 2 ). Ketogenic diets as typically implemented in scientific studies limit dietary carbohydrate to <50 g per day with varying amounts of fat and protein ( 3 , 4 ). “Low-carbohydrate diets” refer to carbohydrate intake below the recommended dietary allowance of 130 g/day ( 3 ), which may not be low enough to induce ketosis ( 5 ).

Effects on Nutrient Metabolism

During prolonged fasting, some tissues, such as muscle, can directly metabolize free fatty acids released from adipose stores. However, much of this fatty acid is converted into ketones in the liver, which can fuel otherwise-obligate glucose consumers like neurons, minimizing mobilization of body protein for gluconeogenesis. However, to induce the liver to make ketones in the fed state, carbohydrate intake must be minimized and fat intake increased. Protein utilization is also altered on a ketogenic diet; the body shunts as much protein as possible to gluconeogenesis, while the minimum necessary amount is used for tissue repair.

Effects on Diet Quality

Extreme carbohydrate restriction can profoundly affect diet quality, typically curtailing or eliminating fruits, vegetables, whole grains, and legumes and increasing consumption of animal products. Very-low-carbohydrate diets may lack vitamins, minerals, fiber, and phytochemicals found in fruits, vegetables, and whole grains ( 6 – 8 ). Low-carbohydrate diets are often low in thiamin, folate, vitamin A, vitamin E, vitamin B6, calcium, magnesium, iron, and potassium ( 9 ). In the absence of multivitamin supplements, individuals on low-carbohydrate diets are at risk of frank nutritional deficiencies ( 10 ). Even when consuming only nutrient-dense foods, a 4:1 ketogenic diet is reported to have multiple micronutrient shortfalls, often lacking in vitamin K, linolenic acid, and water-soluble vitamins excluding vitamin B12 ( 11 ).

Ketogenic diets are typically low in fiber needed not only for healthful intestinal function but also for microbial production of beneficial colonic short-chain fatty acids ( 12 ), which enhance nutrient absorption, stimulate the release of satiety hormones, improve immune function, and have anti-inflammatory and anti-carcinogenic effects ( 13 , 14 ). Inadequate intake of these microbiota-accessible carbohydrates found in plant cell walls also increases gut permeability, as bacteria extract the carbon they need from the mucus membrane that protects the gastrointestinal tract instead of fiber ( 15 ). The relative abundance of certain health-promoting, fiber-consuming bacteria has been found to be reduced in children consuming a ketogenic diet for epilepsy ( 16 ). It has been suggested that supplementation of ketogenic diets with fiber and non-digestible carbohydrates might be advisable ( 16 ), although data to confirm that supplementation could counteract the effects of very-low-carbohydrate diets on the gut microbiota are lacking.

Intake of other protective dietary components may also be insufficient, such as phytochemicals (e.g., flavanones and anthocyanins), which are not typically included in multivitamins and for which specific intake targets have not been established. Low-carbohydrate diets are also typically high in saturated fat and cholesterol ( 10 ).

Effects of Ketogenic Diets by Condition

Seizure disorders.

Worldwide, the lifetime prevalence of epilepsy is 7.6 per 1,000 people ( 17 ). According to a 2018 Cochrane Review, most affected individuals can eliminate seizures with medication, but about 30% cannot. Some one-third to one-half of people with drug-resistant epilepsy can reduce seizure frequency by at least 50% with a ketogenic diet ( 18 ). The lack of glucose available to fuel neurons is a possible mechanism for action ( 19 ).

Long-term adherence is challenging, as food choices are limited and adverse effects are common ( 18 ). Micronutrient supplementation is required. Potential health risks accompany the long-term use of such a diet, as described below. Research has shown that modified versions of the ketogenic diet allowing for more carbohydrates have also been somewhat effective in seizure reduction ( 19 ). Most studies have not been long term, large scale, nor conducted with adult participants; therefore, more research is needed.

Obesity and Weight Management

Ketogenic diets can induce weight loss ( 20 – 23 ). In a 2020 meta-analysis of 38 studies lasting 6–12 months and including 6,499 participants, low-carbohydrate diets, defined here as <40% of energy from carbohydrate, led to a small weight loss, compared with low-fat diets, defined as <30% of energy from fat (mean difference −1.30 kg; 95% CI, −2.02 to −0.57), with considerable variability between individuals and between studies. More than half of included studies met criteria for a general ketogenic diet, as defined in Table 1 , for part or all of the low-carbohydrate intervention ( 24 ).

It has been proposed that weight loss on ketogenic diets may be due to reduced appetite ( 25 ), an effect also seen in those following balanced, very-low-energy diets (<800 kcal/day). Since ketosis occurs on both types of diets, though to a lesser degree with very-low-energy diets, it is speculated that ketosis itself may decrease hunger ( 26 ). However, findings from a recent trial by Hall et al. suggest that a low-fat vegan diet (10% energy from fat) may be more effective than a ketogenic diet in suppressing appetite ( 27 ). Energy expenditure has also been shown to increase on a ketogenic diet, at least in short-term studies ( 27 , 28 ).

In controlled trials, low-carbohydrate diets appear no more effective than other diets that similarly restrict calories ( 29 ), nor are they more effective than other dietary interventions, such as low-fat vegetarian diets, at inducing weight loss ( 30 , 31 ). A 2013 meta-analysis of randomized controlled trials testing very-low-carbohydrate ketogenic diets (≤50 g carbohydrate/day or ≤10% kcal from carbohydrates) against diets based on modest reductions in fat intake (<30% kcal from fat) for at least 1 year found that ketogenic diets led to marginally more weight loss than reduced-fat diets (weighted mean difference: −0.91 kg; 95% CI, −1.65 kg to −0.17 kg, p = 0.02). However, no statistically significant difference in amount of weight lost was seen between the 2 diets in trials following people for at least 2 years ( 3 ).

A 2017 meta-analysis of 9 trials echoed these findings. In studies <12 months long, low-carbohydrate diets (<130 g carbohydrate/day or <26% kcal from carbohydrates) were seen to lead to greater weight loss in people with type 2 diabetes relative to normal- or high-carbohydrate control diets (weighted mean difference: −1.18 kg; 95% CI, −2.32 kg to −0.04 kg; p = 0.04). No advantage was seen relative to control diets in studies of longer duration (weighted mean difference: −0.24 kg; 95% CI, −2.18 kg to 1.7 kg; p = 0.81) ( 32 ).

At least initially, ketogenic diets may slow fat loss. In a 2016 metabolic ward study by Hall et al., 17 overweight or obese men were provided a baseline diet (50% carbohydrate, 35% fat, and 15% protein, as a percent of energy) for 4 weeks, then a ketogenic diet (5% carbohydrate, 80% fat, 15% protein) for 4 weeks. For 2 weeks after switching from the baseline diet to the ketogenic diet, participants' weight loss accelerated—but fat loss slowed. The authors attributed the additional weight loss primarily to loss of body water. However, loss of body protein may have contributed; urinary nitrogen levels increased through day 11 on the ketogenic diet. In the final 2 weeks on the ketogenic diet, participants' rates of body weight and fat loss rebounded to a rate comparable to that on the baseline diet. As a result, study participants required 4 weeks on a ketogenic diet to lose the same average 0.5 kg of fat lost in the final 2 weeks on a baseline diet. It is not clear whether these effects have longer-term consequences ( 28 ).

The 2021 metabolic ward study by Hall et al. tested the effects of both an animal-based ketogenic diet (76% energy from fat, 10% carbohydrate) and a plant-based, low-fat diet (75% carbohydrate, 10% fat) on 20 weight-stable adults, mean age 29.9 years, mean BMI 27.8 kg/m 2 ( 27 ). Participants were randomized to each diet, which they consumed ad libitum for 2 weeks before immediately crossing over to the other diet. Ad libitum energy intake was 689 kcal/day lower on the low-fat, plant-based diet as compared to the ketogenic diet ( p < 0.0001). Reported hunger and satisfaction were similar between groups. Both diets induced weight loss: 1.77 ± 0.32 kg ( p < 0.0001) for the ketogenic diet vs. 1.09 ± 0.32 kg ( p = 0.003) for the low-fat diet. However, most of the weight lost on the ketogenic diet came from fat-free mass (-1.61 ± 0.27 kg; p < 0.0001); this was not the case with the low-fat diet (−0.16 ± 0.27 kg; p = 0.56). Fat mass did not significantly change during either the first or second week of the ketogenic diet, while the low-fat diet led to significant losses in body fat after both the first and second weeks. This suggests that low-fat, plant-based diets may control appetite better than ketogenic diets. These results also add to evidence suggesting that the rapid initial weight loss observed on ketogenic diets is due predominantly to loss of fat-free mass (e.g., body water, glycogen, protein, and contents of the gastrointestinal tract) ( 27 ).

Type 1 Diabetes

Although ketogenic diets can improve glycemia in pediatric patients with type 1 diabetes, they are generally not used in this population due to the risk of malnutrition, failure to thrive, reduced bone density, hyperlipidemia, poor sleep, amenorrhea, and hypoglycemia. In addition, mood and behavior may be adversely affected ( 33 ).

In adults with type 1 diabetes, both favorable and unfavorable outcomes have been observed. A small study of 11 adults with type 1 diabetes reported that a ketogenic diet improved blood glucose control ( 34 ). However, the ketogenic diet triggered more frequent and extreme hypoglycemic episodes (6.3 episodes per week compared to 1–2 episodes per week typically reported for those following conventional or otherwise unspecified diets). The majority of participants also developed dyslipidemia. Lipid changes are of particular concern in individuals with diabetes, who are already at heightened risk of cardiovascular events ( 34 ).

A comprehensive review strongly discouraged sustained ketosis or hyperketonemia in individuals with type 1 diabetes ( 35 ). Due to metabolic irregularities associated with type 1 diabetes, ketone production is elevated, and ketone clearance is diminished. Individuals with elevated ketones are at increased risk for complications of the microvasculature, brain, kidney, and liver compared to those with normal ketone levels. In type 1 diabetes, hyperketonemia is associated with oxidative stress, inflammation, non-alcoholic fatty liver disease, and insulin resistance ( 35 ).

Type 2 Diabetes

Ketogenic diets depress appetite, promote weight loss, reduce blood glucose values, and decrease HbA1c in the short term ( 21 , 36 – 43 ). Some studies have reported improved insulin sensitivity ( 40 ); the effect appears to be dependent on loss of fat mass ( 44 ). In the abovementioned metabolic ward study in which 17 overweight or obese men were provided a baseline diet (50% carbohydrate) for 4 weeks and then a ketogenic diet (5% carbohydrate) for 4 weeks, during the ketogenic diet phase, total cholesterol, low-density lipoprotein cholesterol (LDL-C), and C-reactive protein increased significantly, while fasting insulin and triglycerides decreased. While on the ketogenic diet, insulin sensitivity was impaired when participants were challenged with a baseline diet meal (50% carbohydrates) ( 45 ).

In the 2021 metabolic ward trial by Hall et al. comparing the effects of an animal-based ketogenic diet and a plant-based, low-fat diet, the plant-based diet had a greater glycemic load and predictably resulted in higher postprandial glucose and insulin levels than the ketogenic diet. However, glucose tolerance, as determined by an oral glucose tolerance test at the end of each phase, was compromised during the ketogenic phase (average 2-h glucose was 142.6 mg/dL) compared to the plant-based phase (average 2-h blood glucose was 108.5 mg/dL). In addition, high-sensitivity C-reactive protein, a marker of inflammation, was substantially higher while on the ketogenic diet compared to the plant-based diet (2.1 vs. 1.2 mg/L; p = 0.003), although not significantly different from baseline ( 27 ).

Another low-carbohydrate diet trial that followed individuals for 1 year found that insulin sensitivity was improved at 6 months but returned to baseline at 1 year ( 22 ). In healthy men, a ketogenic diet (83% fat and 2% carbohydrate) reduced insulin's ability to suppress endogenous glucose production ( 46 ).

A recent meta-analysis showed that reductions in hemoglobin A1c achieved with carbohydrate-restricted diets typically wane after a few months and that such diets are not more effective than other diets ( 47 ).

In other clinical trials with ketogenic diets, diabetes medications are frequently reduced or eliminated ( 21 , 36 – 43 ). The beneficial effects of ketogenic diets for people with type 2 diabetes are attributable primarily to weight loss, with benefits appearing to wane over time ( 48 , 49 ). Few additional negative impacts on global measures of health have been reported in short-term studies on type 2 diabetes ( 21 , 37 , 40 ). Long-term effects have not been elucidated ( 49 ).

The prospective Nurses' Health Study found no link between diets lower in carbohydrate and incident type 2 diabetes in women, although those consuming the most vegetable protein and fat had an 18% lower risk ( 50 ). The Health Professionals Follow-Up Study found that men consuming diets low in carbohydrate and high in animal protein and fat had a 37% higher risk of being diagnosed with type 2 diabetes than those who scored lowest for this diet style. Those emphasizing vegetable protein and fat on low-carbohydrate diets did not experience increased risk, and for men under 65 years of age, diabetes risk was 22% lower ( 51 ).

Dietary staples in ketogenic diets include concentrated fats, meat, poultry, fish, eggs, and cheese, all of which have been associated with increased diabetes risk ( 52 – 56 ). These foods can be high in saturated fat, cholesterol, chemical contaminants, pro-oxidants such as heme iron, and inflammatory compounds such as N-glycolylneuraminic acid (Neu5Gc) and endotoxins. Conversely, foods consistently associated with reduced diabetes risk, including fruits, legumes, whole grains, and several vegetables, are minimized or eliminated ( 52 – 56 ).

Non-alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is a serious condition where excess fat is stored in hepatocytes, causing steatosis, which can progress to non-alcoholic steatohepatitis and increase the risk of hepatocellular carcinoma ( 57 – 60 ). Worldwide, the prevalence of NAFLD in adults is estimated to be 25.2%, ranging from a low of 13.5% in Africa to a high of 31.8% in the Middle East, with North America at 24.1% ( 61 ). The risk of NAFLD is significantly higher in individuals who have obesity or type 2 diabetes (43–92%) ( 57 , 58 , 62 ).

Hepatic triacylglycerol comes from three sources: de novo lipogenesis, primarily from glucose; lipolysis of stored triglyceride from adipose tissue; and diet-derived fats ( 58 ). Most (60–80%) triglyceride is from adipose tissue, 15% is from diet, and 5% is from de novo lipogenesis in healthy people. Triglyceride from de novo lipogenesis is much higher (26%) in individuals with NAFLD ( 63 ). Fat derived from de novo lipogenesis and adipose tissue is accelerated by insulin resistance ( 63 ).

Several clinical trials have compared low-fat and low-carbohydrate hypocaloric diets in overweight or obese adults and found similar reductions in intrahepatic fat ( 64 – 66 ). Ketogenic diets typically increase intake of saturated fat, cholesterol, and animal protein, all of which are associated with insulin resistance, oxidative stress, and an exacerbated flow of free fatty acids to hepatocytes ( 57 , 62 , 63 , 67 ).

In epidemiological studies, diets high in saturated fat, trans fat, simple sugars, and animal protein (especially from red and processed meat) ( 57 ) and low in dietary fiber and omega-3 fatty acids ( 62 , 68 ) are thought to contribute to NAFLD. In the Rotterdam Study, those consuming the most animal protein were 54% more likely to have NAFLD than those consuming the least (OR 1.54, 95% CI, 1.20–1.98) ( 68 ). Dietary components associated with reduced NAFLD risk include whole grains, nuts and seeds, monounsaturated fats, omega-3 fatty acids, vegetable protein, prebiotic fiber, probiotics, resveratrol, coffee, taurine, and choline ( 57 ). In the Tzu Chi Health Study, replacing one serving of soy with fish (or meat) was associated with a 12–13% increased risk of NAFLD. Whole grain intake had an inverse relationship with NAFLD, and those following a vegetarian diet had a 21% lower risk of NAFLD ( 69 ).

Lifestyle modifications, particularly diet change, weight loss, and exercise, are the primary modality for treating NAFLD ( 57 , 62 , 63 ). Lifestyle interventions that promote weight loss have been found to reduce liver fat and improve aminotransferase concentrations and insulin sensitivity ( 48 , 57 , 58 , 62 , 63 , 68 ). It has been suggested that achieving ketosis may have a benefit in ameliorating fatty liver ( 63 ), but the studies supporting this are limited and typically also restrict energy intake. Long-term safety and specific clinical outcomes have not been determined.

Some have suggested ketogenic diets for cancer patients ( 70 ) based on the so-called “Warburg effect,” whereby cancer cells increase glucose uptake and upregulate glycolysis even in the presence of oxygen, preferentially fermenting glucose to lactate ( 71 ). By nearly eliminating available glucose, ketogenic diets theoretically stress cancer cells.

Few clinical trials have tested this. A 2018 systematic review of ketogenic diets for the management of gliomas found no randomized clinical trials and just 6 published case series/reports. While the authors could not evaluate the effectiveness of ketogenic diets for cancer survival, they noted that minimal adverse events were reported, suggesting ketogenic diets may be safe in this population ( 72 ).

A 2020 systematic review analyzed 13 studies of ketogenic diets as a complementary therapy for standard treatments in a variety of cancers. Studies analyzed were small ( n = 2–44); 9 were prospective and 6 were controlled, but just 2 were randomized, and ketogenic diet prescriptions differed between studies. Diet-related adverse events were uncommon and mostly minor, and the diet had a beneficial effect on body composition. Findings were mixed for both overall survival and progression-free survival; beneficial effects were seen in four studies ( 73 ). A possible explanation for the lack of a consistent survival benefit is demonstrated in in vitro research suggesting that ketone utilization by cancer cells increases expression of genes associated with high metastatic potential ( 74 ). Given potential benefits for body composition, large, well-designed, randomized clinical trials are needed to determine the safety and effectiveness of ketogenic diets in cancer treatment ( 72 , 73 ).

Long-term data on cancer outcomes with ketogenic diets are lacking. However, food components typical of a ketogenic diet, such as red and processed meats, are linked to increased cancer risk ( 75 – 77 ). Whole grains, fruits, and vegetables are linked to a lower risk of both cancer and all-cause mortality ( 78 , 79 ), yet, with the exception of non-starchy vegetables, these foods are commonly avoided on ketogenic diets. For example, in one study of a ketogenic diet for type 2 diabetes, researchers encouraged unlimited meat, poultry, seafood, and eggs, while cutting intake of whole grains, fruits, and starchy vegetables and limiting intake of salad vegetables and non-starchy vegetables ( 21 ).

Alzheimer's Disease

By 2050, it is projected that 13.8 million people in the U.S. will have Alzheimer's disease (AD) ( 80 ). Given the brain's inability to efficiently utilize glucose in AD, some have proposed ketones as an alternate fuel source for these individuals ( 81 ). As reviewed by Włodarek in 2019, small trials have found that increasing blood ketones by supplementing with medium-chain triglycerides does improve some measures of cognitive function in AD, although not necessarily in those with the APOEε4 genotype ( 82 ).

No long-term data on ketogenic diets for AD are available, although small, short-term trials have been conducted. A 3-month, weight-maintaining ketogenic diet intervention improved cognition in subjects with mild-to-moderate AD ( n = 15), but improvements were lost after a 1-month washout period ( 83 ). A 6-week trial of a ketogenic diet in subjects with mild cognitive impairment led to improved memory relative to a control diet (50% of energy from carbohydrates); follow-up data were not available. However, the ketogenic diet was substantially lower in calories, which may have independently reduced insulin resistance ( 84 ). In a 2020 review of short-term ketogenic diet and ketone supplement studies in older adults, including those with no dysfunction, mild cognitive impairment, and AD, 6 of 9 controlled trials with clinical endpoints found significant cognitive improvements in the intervention groups, while other trials did not. Whether cognitive gains would be maintained upon discontinuation of the diet/supplement remains unknown due to lack of long-term follow-up ( 85 ).

Saturated fat intake, which typically increases on a ketogenic diet, is strongly associated with AD risk. In the Chicago Health and Aging Project, high saturated fat intake was linked to a 2- to 3-fold increased risk of incident AD ( 86 ). A 2016 review of international data found that consuming meats, eggs, high-fat dairy such as butter and cheese, and sweets was linked to an increased risk of AD ( 87 ). Aside from sweets, consumption of these foods generally increases on a ketogenic diet.

Polyphenol-rich plant foods such as fruits and vegetables are associated with lower AD risk ( 88 ) and diets focusing on whole plant foods and limiting animal foods and processed foods, such as the MIND diet, are proven to reduce AD risk ( 89 ). Thus, by providing ketones that can be metabolized by neurons in AD, a ketogenic diet could improve symptoms in the short term, but the diet's nutritional profile could increase risk over the long-term in healthy individuals.

Cardiovascular Disease

The effect of low-carbohydrate diets on plasma lipid concentrations is a major concern. It has long been established that weight loss by any means causes a reduction in total cholesterol of about 2 mg/dL per kilogram lost ( 90 ). However, low-carbohydrate diets are often an exception to that rule. In a 2002 6-month study of a very-low-carbohydrate “Atkins” diet by Westman et al., 12 (29%) of the 41 participants had LDL-C elevations. The average increase was 18 mg/dL ( 91 ). In a similar 6-month study by Yancy, 30% of participants had LDL-C increases > 10% ( 92 ).

In a trial published in 2003 by Foster et al., LDL-C rose 6.2% in a group of low-carbohydrate dieters at 3 months ( 22 ). For comparison, LDL-C dropped by 11.1% during this same time period in participants following a conventional low-calorie diet. In a 2004 1-year study, those on a low-carbohydrate diet increased their mean LDL-C from 112 to 120 mg/dL ( 93 ). In 2018, Hallberg ( 94 ) reported a mean 10% rise in LDL-C in individuals following low-carbohydrate diets, an elevation that persisted during 2 years of follow-up ( 95 ). A recent meta-analysis of 5 studies showed that, in individuals with type 2 diabetes, ketogenic diets led to, on average, no substantial change in LDL-C ( 96 ).

It is important to note that changes reported in group means do not reflect the change for any given individual. In the 2002 study cited above, while the mean LDL-C increase was 18 mg/dL, one participant's LDL-C concentration increased from 123 to 225 mg/dL ( 91 ). In the Yancy study, one participant's LDL-C increased from to 219 mg/dL. Another experienced an LDL-C rise from 184 to 283 mg/dL, and a third developed chest pain and was subsequently diagnosed with coronary heart disease ( 92 ). In the Foster study, the standard deviation for the change in LDL-C was 20.4%, indicating that while LDL-C decreased for some, for many participants, LDL-C rose dramatically ( 22 ).

Negative effects on blood lipids have also been seen in healthy individuals. A 2018 pilot study of young, fit adults (average age 31) found that 12 weeks on a ketogenic diet led to a weight loss of 3.0 kg in the ketogenic group, with no significant weight change in the control group. However, despite significant weight loss, LDL-C increased by 35% in the ketogenic group ( p = 0.048), from 114 mg/dL at baseline to 154 mg/dL at 12 weeks ( 97 ).

Some have suggested that LDL-C or LDL particle concentration elevations are of no concern if the increase is mainly in larger LDL particles. There are two problems with this rationale: First is the problem of heterogeneity noted above (i.e., individuals may have significant worsening of their lipid profiles that are not reflected by mean figures). Second, LDL is potentially atherogenic regardless of particle size ( 98 , 99 ). Data supporting this concern come from the Women's Health Study, a randomized, placebo-controlled trial of low-dose aspirin and vitamin E. As part of the study, LDL particle size was assessed. The hazard ratio for incident cardiovascular disease associated with large LDL particles was 1.44 (indicating a 44% increased risk). For small LDL, it was 1.63 (a 63% increased risk). Both were highly statistically significant. In other words, large LDL particles were strongly atherogenic, albeit less so than small LDL ( 100 ).

It has also been proposed that the risk elevation associated with increased LDL-C concentrations may be neutralized to the extent that high-density lipoprotein cholesterol (HDL-C) also rises. However, both Mendelian randomization trials and studies using HDL-elevating agents have not shown benefit regarding cardiovascular risk. In the former category are studies that have examined individuals with naturally occurring genetic variants associated with elevated plasma HDL-C concentrations. These genetic traits are not associated with reduced risk of myocardial infarction unless they also reduce LDL-C ( 101 ).

Treatment-induced HDL-C elevations were examined in a meta-analysis of 108 studies including 299,310 participants, which found no associated reduction in the risk of coronary heart disease events, coronary disease mortality, or total mortality ( 102 ). The LDL-C/HDL-C ratio was not a better predictor of cardiovascular outcomes than LDL-C alone, and the authors recommended using LDL-C, rather than HDL-C or a ratio of the two, as the therapeutic target.

Kidney Health

The evidence of the renal-specific effects of ketogenic diets is limited but worth noting, especially in the context of the unclear long-term benefits of such diets for diabetes and obesity ( 103 ). For those without chronic kidney disease (CKD), one of the biggest potential risks of the ketogenic diet is the development of kidney stones, a finding that has been frequently noted in the pediatric epilepsy literature ( 104 , 105 ). The ketogenic diet's emphasis on high-fat, animal-based foods while excluding many fruits and vegetables promotes a urinary milieu for kidney stones. Dietary animal protein consumption is a well-established promoter of kidney stones ( 106 ). The acidosis caused by the ketogenic diet may also encourage stone formation by lowering urinary citrate and pH levels while increasing urinary calcium levels.

Another potential risk of animal-based ketogenic diets for those without CKD is the development of CKD through the consumption of animal fat and protein. In observational studies of populations eating Western diets, high animal fat consumption, as is common with ketogenic diets, has been associated with increased risk of developing albuminuria ( 107 ). In a prospective study of nearly 12,000 people over 23 years, high animal protein consumption was associated with a 23% increased hazard ratio of incident CKD ( 108 ). Other observational studies of animal protein have shown similar findings ( 109 , 110 ).

For those with CKD, the high protein content in some ketogenic diets is of concern. While “classic” ketogenic diets are not necessarily high in protein, those used for weight loss often meet the definition of a high-protein diet (>1.5 g/kg/d) by encouraging dieters to consume 1.2–2.0 g/kg/d. Compared to control diets with higher protein content, low protein consumption has been associated with a reduction in the rate of kidney function decline in a meta-analysis of 14 randomized controlled trials ( 111 ). High protein consumption facilitates hyperfiltration, a phenomenon of increased blood flow to the glomerulus, which is thought to lead to long-term damage in those with CKD ( 112 ). Finally, the acid load from the ketogenic diet may worsen metabolic acidosis and kidney disease in those with CKD ( 113 ). The ketogenic diet's acid load comes from the foods consumed (especially those from animal-based sources), ketoacids associated with ketone production, and from the lack of natural alkali found in fruits and vegetables that are often avoided in the ketogenic diet. As such, the ketogenic diet requires further research regarding its long-term renal safety in those with and without CKD.

Pre-pregnancy and Pregnancy

Approximately 40% of pregnancies in the United States are unplanned ( 114 ). Low-carbohydrate diets followed prior to conception or during the periconceptual period are associated with an increased risk of birth defects and gestational diabetes, respectively.

The National Birth Defects Prevention Study found that women who reported consuming low-carbohydrate diets in the year prior to conception (daily carbohydrate intake ≤5th percentile of control mothers, or ~95 g carbohydrate/day) were 30% more likely to have an infant with a neural tube defect (95% CI, 1.02–1.67), specifically anencephaly (OR 1.35; 95% CI, 0.90–2.02) and spina bifida (OR 1.28; 95% CI, 0.95–1.72) ( 115 ). For unplanned pregnancies in particular, effect estimates for carbohydrate-restricted diets showed an 89% increased risk of neural tube defects (95% CI, 1.28–2.79) ( 115 ).

Use of folate supplements may not mitigate the risk seen with low-carbohydrate diets. In the above study, there was no effect measure modification by folic acid supplement use ( 115 ). A 2019 study conducted using data that predated the era of folate-fortified grain products also found an increase in neural tube defects in the offspring of women consuming low-carbohydrate diets in the periconceptual period (OR 2.0; 95% CI, 1.2–3.4), suggesting other factors were contributing ( 116 ).

A prospective cohort study evaluating gestational diabetes risk scored women's diets for adherence to a low-carbohydrate diet pattern and dietary fat source. After adjusting for multiple variables including BMI, women consuming the least carbohydrate had a 27% higher risk of gestational diabetes compared to those consuming the most (RR 1.27; 95% CI, 1.06–1.51, p = 0.03). A stronger association was seen for women following a low-carbohydrate diet pattern high in animal products; they had a 36% higher risk of gestational diabetes (RR 1.36; 95% CI, 1.13–1.64, p = 0.003). A vegetable-based low-carbohydrate dietary pattern was not associated with increased risk ( 117 ).

Adverse Effects of Ketogentic Diets

The most restrictive ketogenic diets used for epilepsy can cause fatigue, headache, nausea, constipation, hypoglycemia, and acidosis, especially within the first few days to weeks of following the diet ( 2 ). Dehydration, hepatitis, pancreatitis, hypertriglyceridemia, hyperuricemia, hypercholesterolemia, hypomagnesemia, and hyponatremia can also occur ( 82 , 118 ).

A study of 300 users of online forums found that self-administered ketogenic diets may be accompanied by a temporary cluster of symptoms frequently termed “keto flu,” which includes headache, fatigue, nausea, dizziness, “brain fog,” gastrointestinal discomfort, decreased energy, feeling faint, and heartbeat alterations ( 119 ). In endurance athletes, 3.5 weeks on a ketogenic diet led to unfavorable effects on markers of bone modeling and remodeling ( 120 ).

Longer-term effects can include decreased bone mineral density, nephrolithiasis, cardiomyopathy, anemia, and neuropathy of the optic nerve ( 82 , 121 ). Ketogenic diets have low long-term tolerability, and are not sustainable for many individuals ( 48 , 49 ). Diets low in carbohydrate have also been associated with an increased risk of all-cause mortality ( 122 ), although recent data suggest that lower-carbohydrate diets can be linked to either higher or lower mortality risk, depending on the quality of the carbohydrate they contain and whether they rely more on animal protein and saturated fat or plant protein and unsaturated fat, respectively ( 123 ).

Ketogenic diets reduce seizure frequency in some individuals with drug-resistant epilepsy. These diets can also reduce body weight, although not more effectively than other dietary approaches over the long term or when matched for energy intake. Ketogenic diets can also lower blood glucose, although their efficacy typically wanes within the first few months.

Very-low-carbohydrate diets are associated with marked risks. LDL-C can rise, sometimes dramatically. Pregnant women on such diets are more likely to have a child with a neural tube defect, even when supplementing folic acid. And these diets may increase chronic disease risk: Foods and dietary components that typically increase on ketogenic diets (eg, red meat, processed meat, saturated fat) are linked to an increased risk of CKD, cardiovascular disease, cancer, diabetes, and Alzheimer's disease, whereas intake of protective foods (eg, vegetables, fruits, legumes, whole grains) typically decreases. Current evidence suggests that for most individuals, the risks of such diets outweigh the benefits.

Author Contributions

LC and NDB contributed to the organization of the manuscript, reviewed, and approved the submitted version. LC composed the outline and drafted the manuscript. LC, BD, SJ, MJ, JP, MN, and NDB wrote sections of the manuscript. All authors had full access to data and revised and approved the manuscript for publication.

This work was funded by the Physicians Committee for Responsible Medicine.

Conflict of Interest

LC is an employee of the Physicians Committee for Responsible Medicine in Washington, DC, a non-profit organization providing educational, research, and medical services related to nutrition. LC also declares that a trust for her benefit previously held stock in 3M, Abbot Labs, AbbVie, Johnson and Johnson, Mondelez, Nestle, and Walgreens; she is the author of a food and nutrition blog, Veggie Quest; and she is former publications editor and current chair for the Women's Health Dietetic Practice Group within the Academy of Nutrition and Dietetics. MJ and JP received compensation from the Physicians Committee for Responsible Medicine while working on this manuscript. MN is an employee of the Physicians Committee for Responsible Medicine. NDB is an Adjunct Professor of Medicine at the George Washington University School of Medicine. He serves without compensation as president of the Physicians Committee for Responsible Medicine and Barnard Medical Center in Washington, DC, non-profit organizations providing educational, research, and medical services related to nutrition. He writes books and articles and gives lectures related to nutrition and health and has received royalties and honoraria from these sources.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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123. Shan Z, Guo Y, Hu FB, Liu L, Qi Q. Association of low-carbohydrate and low-fat diets with mortality among US adults. JAMA Intern Med . (2020) 180:513–23. doi: 10.1001/jamainternmed.2019.6980

Keywords: ketogenic diet, very-low-carbohydrate diet, low-carbohydrate diet, obesity, disease prevention

Citation: Crosby L, Davis B, Joshi S, Jardine M, Paul J, Neola M and Barnard ND (2021) Ketogenic Diets and Chronic Disease: Weighing the Benefits Against the Risks. Front. Nutr. 8:702802. doi: 10.3389/fnut.2021.702802

Received: 29 April 2021; Accepted: 10 June 2021; Published: 16 July 2021.

Reviewed by:

Copyright © 2021 Crosby, Davis, Joshi, Jardine, Paul, Neola and Barnard. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Lee Crosby, LCrosby@pcrm.org

The Ketogenic Diet: Evidence for Optimism but High-Quality Research Needed

Affiliation.

• 1 New Balance Foundation Obesity Prevention Center, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
• PMID: 31825066
• PMCID: PMC7269727
• DOI: 10.1093/jn/nxz308

For >50 y, dietary guidelines in the United States have focused on reducing intakes of saturated and total fat. However, rates of obesity and diabetes rose markedly throughout this period, with potentially catastrophic implications for public health and the economy. Recently, ketogenic diets have received substantial attention from the general public and nutrition research community. These very-low-carbohydrate diets, with fat comprising >70% of calories, have been dismissed as fads. However, they have a long history in clinical medicine and human evolution. Ketogenic diets appear to be more effective than low-fat diets for treatment of obesity and diabetes. In addition to the reductions in blood glucose and insulin achievable through carbohydrate restriction, chronic ketosis might confer unique metabolic benefits of relevance to cancer, neurodegenerative conditions, and other diseases associated with insulin resistance. Based on available evidence, a well-formulated ketogenic diet does not appear to have major safety concerns for the general public and can be considered a first-line approach for obesity and diabetes. High-quality clinical trials of ketogenic diets will be needed to assess important questions about their long-term effects and full potential in clinical medicine.

Keywords: Alzheimer disease; cancer; cardiovascular disease; diabetes; ketogenic diet; ketones; low-carbohydrate diet; low-fat diet; obesity; vegan diet.

Copyright © The Author(s) 2019.

• Blood Glucose / metabolism
• Diet, Ketogenic*
• Dietary Carbohydrates / administration & dosage
• Insulin / blood
• Insulin Resistance
• Nutrition Policy
• Obesity / diet therapy*
• Obesity / metabolism
• Weight Loss
• Blood Glucose
• Dietary Carbohydrates

Diet Review: Ketogenic Diet for Weight Loss

Finding yourself confused by the seemingly endless promotion of weight-loss strategies and diet plans? In this series , we take a look at some popular diets—and review the research behind them .

What is it?

The ketogenic or “keto” diet is a low-carbohydrate, fat-rich eating plan that has been used for centuries to treat specific medical conditions. In the 19 th century, the ketogenic diet was commonly used to help control diabetes. In 1920 it was introduced as an effective treatment for epilepsy in children in whom medication was ineffective. The ketogenic diet has also been tested and used in closely monitored settings for cancer, diabetes, polycystic ovary syndrome, and Alzheimer’s disease.

However, this diet is gaining considerable attention as a potential weight-loss strategy due to the low-carb diet craze, which started in the 1970s with the Atkins diet (a very low-carbohydrate, high-protein diet, which was a commercial success and popularized low-carb diets to a new level). Today, other low-carb diets including the Paleo, South Beach, and Dukan diets are all high in protein but moderate in fat. In contrast, the ketogenic diet is distinctive for its exceptionally high-fat content, typically 70% to 80%, though with only a moderate intake of protein.

How It Works

The premise of the ketogenic diet for weight loss is that if you deprive the body of glucose—the main source of energy for all cells in the body, which is obtained by eating carbohydrate foods—an alternative fuel called ketones is produced from stored fat (thus, the term “keto”-genic). The brain demands the most glucose in a steady supply, about 120 grams daily, because it cannot store glucose. During fasting, or when very little carbohydrate is eaten, the body first pulls stored glucose from the liver and temporarily breaks down muscle to release glucose. If this continues for 3-4 days and stored glucose is fully depleted, blood levels of a hormone called insulin decrease, and the body begins to use fat as its primary fuel. The liver produces ketone bodies from fat, which can be used in the absence of glucose. [1]

When ketone bodies accumulate in the blood, this is called ketosis. Healthy individuals naturally experience mild ketosis during periods of fasting (e.g., sleeping overnight) and very strenuous exercise. Proponents of the ketogenic diet state that if the diet is carefully followed, blood levels of ketones should not reach a harmful level (known as “ketoacidosis”) as the brain will use ketones for fuel, and healthy individuals will typically produce enough insulin to prevent excessive ketones from forming. [2] How soon ketosis happens and the number of ketone bodies that accumulate in the blood is variable from person to person and depends on factors such as body fat percentage and resting metabolic rate. [3]

What is ketoacidosis?

There is not one “standard” ketogenic diet with a specific ratio of macronutrients ( carbohydrates , protein , fat ). The ketogenic diet typically reduces total carbohydrate intake to less than 50 grams a day—less than the amount found in a medium plain bagel—and can be as low as 20 grams a day. Generally, popular ketogenic resources suggest an average of 70-80% fat from total daily calories, 5-10% carbohydrate, and 10-20% protein. For a 2000-calorie diet, this translates to about 165 grams fat, 40 grams carbohydrate, and 75 grams protein. The protein amount on the ketogenic diet is kept moderate in comparison with other low-carb high-protein diets, because eating too much protein can prevent ketosis. The amino acids in protein can be converted to glucose, so a ketogenic diet specifies enough protein to preserve lean body mass including muscle, but that will still cause ketosis.

Many versions of ketogenic diets exist, but all ban carb-rich foods. Some of these foods may be obvious: starches from both refined and whole grains like breads, cereals, pasta, rice, and cookies; potatoes, corn, and other starchy vegetables; and fruit juices. Some that may not be so obvious are beans , legumes, and most fruits. Most ketogenic plans allow foods high in saturated fat, such as  fatty cuts of meat , processed meats, lard, and butter, as well as sources of unsaturated fats , such as nuts, seeds, avocados, plant oils, and oily fish. Depending on your source of information, ketogenic food lists may vary and even conflict.

• Strong emphasis on fats at each meal and snack to meet the high-fat requirement. Cocoa butter, lard, poultry fat, and most plant fats (olive, palm, coconut oil) are allowed, as well as foods high in fat, such as avocado, coconut meat, certain nuts (macadamia, walnuts, almonds, pecans), and seeds (sunflower, pumpkin, sesame, hemp, flax).
• Some dairy foods may be allowed. Although dairy can be a significant source of fat, some are high in natural lactose sugar such as cream, ice cream, and full-fat milk so they are restricted. However, butter and hard cheeses may be allowed because of the lower lactose content.
• Protein stays moderate. Programs often suggest grass-fed beef (not grain-fed) and free-range poultry that offer slightly higher amounts of omega-3 fats, pork, bacon, wild-caught fish, organ meats, eggs, tofu, certain nuts and seeds.
• Most non-starchy vegetables are included: Leafy greens (kale, Swiss chard, collards, spinach, bok choy, lettuces), cauliflower, broccoli, Brussels sprouts, asparagus, bell peppers, onions, garlic, mushrooms, cucumber, celery, summer squashes.
• Certain fruits in small portions like berries. Despite containing carbohydrate, they are lower in “net carbs”* than other fruits.
• Other: Dark chocolate (90% or higher cocoa solids), cocoa powder, unsweetened coffee and tea, unsweetened vinegars and mustards, herbs, and spices.

Not Allowed

• All whole and refined grains and flour products, added and natural sugars in food and beverages, starchy vegetables like potatoes, corn, and winter squash.
• Fruits other than from the allowed list, unless factored into designated carbohydrate restriction. All fruit juices.
• Legumes including beans, lentils, and peanuts.
• Although some programs allow small amounts of hard liquor or low carbohydrate wines and beers, most restrict full carbohydrate wines and beer, and drinks with added sweeteners (cocktails, mixers with syrups and juice, flavored alcohols).

*What Are Net Carbs? “Net carbs” and “impact carbs” are familiar phrases in ketogenic diets as well as diabetic diets. They are unregulated interchangeable terms invented by food manufacturers as a marketing strategy, appearing on some food labels to claim that the product contains less “usable” carbohydrate than is listed. [6] Net carbs or impact carbs are the amount of carbohydrate that are directly absorbed by the body and contribute calories. They are calculated by subtracting the amount of indigestible carbohydrates from the total carbohydrate amount. Indigestible (unabsorbed) carbohydrates include insoluble fibers from whole grains, fruits, and vegetables; and sugar alcohols, such as mannitol, sorbitol, and xylitol commonly used in sugar-free diabetic food products. However, these calculations are not an exact or reliable science because the effect of sugar alcohols on absorption and blood sugar can vary. Some sugar alcohols may still contribute calories and raise blood sugar. The total calorie level also does not change despite the amount of net carbs, which is an important factor with weight loss. There is debate even within the ketogenic diet community about the value of using net carbs.

Programs suggest following a ketogenic diet until the desired amount of weight is lost. When this is achieved, to prevent weight regain one may follow the diet for a few days a week or a few weeks each month, interchanged with other days allowing a higher carbohydrate intake.

The Research So Far

The ketogenic diet has been shown to produce beneficial metabolic changes in the short-term. Along with weight loss, health parameters associated with carrying excess weight have improved, such as insulin resistance, high blood pressure, and elevated cholesterol and triglycerides. [2,7] There is also growing interest in the use of low-carbohydrate diets, including the ketogenic diet, for type 2 diabetes. Several theories exist as to why the ketogenic diet promotes weight loss, though they have not been consistently shown in research: [2,8,9]

• A satiating effect with decreased food cravings due to the high-fat content of the diet.
• A decrease in appetite-stimulating hormones, such as insulin and ghrelin, when eating restricted amounts of carbohydrate.
• A direct hunger-reducing role of ketone bodies—the body’s main fuel source on the diet.
• Increased calorie expenditure due to the metabolic effects of converting fat and protein to glucose.
• Promotion of fat loss versus lean body mass, partly due to decreased insulin levels.

The findings below have been limited to research specific to the ketogenic diet: the studies listed contain about 70-80% fat, 10-20% protein, and 5-10% carbohydrate. Diets otherwise termed “low carbohydrate” may not include these specific ratios, allowing higher amounts of protein or carbohydrate. Therefore only diets that specified the terms “ketogenic” or “keto,” or followed the macronutrient ratios listed above were included in this list below. In addition, though extensive research exists on the use of the ketogenic diet for other medical conditions, only studies that examined ketogenic diets specific to obesity or overweight were included in this list. ( This paragraph was added to provide additional clarity on 5.7.18. )

• A meta-analysis of 13 randomized controlled trials following overweight and obese participants for 1-2 years on either low-fat diets or very-low-carbohydrate ketogenic diets found that the ketogenic diet produced a small but significantly greater reduction in weight, triglycerides, and blood pressure, and a greater increase in HDL and LDL cholesterol compared with the low-fat diet at one year. [10] The authors acknowledged the small weight loss difference between the two diets of about 2 pounds, and that compliance to the ketogenic diet declined over time, which may have explained the more significant difference at one year but not at two years (the authors did not provide additional data on this).
• A systematic review of 26 short-term intervention trials (varying from 4-12 weeks) evaluated the appetites of overweight and obese individuals on either a very low calorie (~800 calories daily) or ketogenic diet (no calorie restriction but ≤50 gm carbohydrate daily) using a standardized and validated appetite scale. None of the studies compared the two diets with each other; rather, the participants’ appetites were compared at baseline before starting the diet and at the end. Despite losing a significant amount of weight on both diets, participants reported less hunger and a reduced desire to eat compared with baseline measures. The authors noted the lack of increased hunger despite extreme restrictions of both diets, which they theorized were due to changes in appetite hormones such as ghrelin and leptin, ketone bodies, and increased fat and protein intakes. The authors suggested further studies exploring a threshold of ketone levels needed to suppress appetite; in other words, can a higher amount of carbohydrate be eaten with a milder level of ketosis that might still produce a satiating effect? This could allow inclusion of healthful higher carbohydrate foods like whole grains, legumes, and fruit. [9]
• A study of 39 obese adults placed on a ketogenic very low-calorie diet for 8 weeks found a mean loss of 13% of their starting weight and significant reductions in fat mass, insulin levels, blood pressure, and waist and hip circumferences. Their levels of ghrelin did not increase while they were in ketosis, which contributed to a decreased appetite. However during the 2-week period when they came off the diet, ghrelin levels and urges to eat significantly increased. [11]
• A study of 89 obese adults who were placed on a two-phase diet regimen (6 months of a very-low-carbohydrate ketogenic diet and 6 months of a reintroduction phase on a normal calorie Mediterranean diet) showed a significant mean 10% weight loss with no weight regain at one year. The ketogenic diet provided about 980 calories with 12% carbohydrate, 36% protein, and 52% fat, while the Mediterranean diet provided about 1800 calories with 58% carbohydrate, 15% protein, and 27% fat. Eighty-eight percent of the participants were compliant with the entire regimen. [12] It is noted that the ketogenic diet used in this study was lower in fat and slightly higher in carbohydrate and protein than the average ketogenic diet that provides 70% or greater calories from fat and less than 20% protein.

Potential Pitfalls

Following a very high-fat diet may be challenging to maintain. Possible symptoms of extreme carbohydrate restriction that may last days to weeks include hunger, fatigue, low mood, irritability, constipation, headaches, and brain “fog.” Though these uncomfortable feelings may subside, staying satisfied with the limited variety of foods available and being restricted from otherwise enjoyable foods like a crunchy apple or creamy sweet potato may present new challenges.

Some negative side effects of a long-term ketogenic diet have been suggested, including increased risk of kidney stones and osteoporosis, and increased blood levels of uric acid (a risk factor for gout). Possible nutrient deficiencies may arise if a variety of recommended foods on the ketogenic diet are not included. It is important to not solely focus on eating high-fat foods, but to include a daily variety of the allowed meats, fish, vegetables, fruits, nuts, and seeds to ensure adequate intakes of fiber, B vitamins, and minerals (iron, magnesium, zinc)—nutrients typically found in foods like whole grains that are restricted from the diet. Because whole food groups are excluded, assistance from a registered dietitian may be beneficial in creating a ketogenic diet that minimizes nutrient deficiencies.

Unanswered Questions

• What are the long-term (one year or longer) effects of, and are there any safety issues related to, the ketogenic diet?
• Do the diet’s health benefits extend to higher risk individuals with multiple health conditions and the elderly? For which disease conditions do the benefits of the diet outweigh the risks?
• As fat is the primary energy source, is there a long-term impact on health from consuming different types of fats (saturated vs. unsaturated) included in a ketogenic diet?
• Is the high fat, moderate protein intake on a ketogenic diet safe for disease conditions that interfere with normal protein and fat metabolism, such as kidney and liver diseases?
• Is a ketogenic diet too restrictive for periods of rapid growth or requiring increased nutrients, such as during pregnancy, while breastfeeding, or during childhood/adolescent years?

Bottom Line

Available research on the ketogenic diet for weight loss is still limited. Most of the studies so far have had a small number of participants, were short-term (12 weeks or less), and did not include control groups. A ketogenic diet has been shown to provide short-term benefits in some people including weight loss and improvements in total cholesterol, blood sugar, and blood pressure. However, these effects after one year when compared with the effects of conventional weight loss diets are not significantly different. [10]

Eliminating several food groups and the potential for unpleasant symptoms may make compliance difficult. An emphasis on foods high in  saturated fat  also counters recommendations from the Dietary Guidelines for Americans and the American Heart Association and may have adverse effects on blood LDL cholesterol. However, it is possible to modify the diet to emphasize foods low in saturated fat such as olive oil, avocado, nuts, seeds, and fatty fish.

A ketogenic diet may be an option for some people who have had difficulty losing weight with other methods.  The exact ratio of fat, carbohydrate, and protein that is needed to achieve health benefits will vary among individuals due to their genetic makeup and body composition. Therefore, if one chooses to start a ketogenic diet, it is recommended to consult with one’s physician and a dietitian to closely monitor any biochemical changes after starting the regimen, and to create a meal plan that is tailored to one’s existing health conditions and to prevent nutritional deficiencies or other health complications. A dietitian may also provide guidance on reintroducing carbohydrates once weight loss is achieved.

A modified carbohydrate diet following the Healthy Eating Plate model may produce adequate health benefits and weight reduction in the general population. [13]

• Low-Carbohydrate Diets
• David Ludwig clears up carbohydrate confusion
• The Best Diet: Quality Counts
• Other Diet Reviews
• 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 Aug;67(8):789.
• Paoli A. Ketogenic diet for obesity: friend or foe?. Int J Environ Res Public Health . 2014 Feb 19;11(2):2092-107.
• Gupta L, Khandelwal D, Kalra S, Gupta P, Dutta D, Aggarwal S. Ketogenic diet in endocrine disorders: Current perspectives. J Postgrad Med . 2017 Oct;63(4):242.
• von Geijer L, Ekelund M. Ketoacidosis associated with low-carbohydrate diet in a non-diabetic lactating woman: a case report. J Med Case Rep . 2015 Dec;9(1):224.
• Shah P, Isley WL. Correspondance: Ketoacidosis during a low-carbohydrate diet. N Engl J Med . 2006 Jan 5;354(1):97-8.
• Marcason W. Question of the month: What do “net carb”, “low carb”, and “impact carb” really mean on food labels?. J Am Diet Assoc . 2004 Jan 1;104(1):135.
• Schwingshackl L, Hoffmann G. Comparison of effects of long-term low-fat vs high-fat diets on blood lipid levels in overweight or obese patients: a systematic review and meta-analysis. J Acad Nutr Diet . 2013 Dec 1;113(12):1640-61.
• Abbasi J. Interest in the Ketogenic Diet Grows for Weight Loss and Type 2 Diabetes. JAMA . 2018 Jan 16;319(3):215-7.
• Gibson AA, Seimon RV, Lee CM, Ayre J, Franklin J, Markovic TP, Caterson ID, Sainsbury A. Do ketogenic diets really suppress appetite? A systematic review and meta‐analysis. Obes Rev . 2015 Jan 1;16(1):64-76.
• 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 Oct;110(7):1178-87.
• 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 Jul;67(7):759.
• Paoli A, Bianco A, Grimaldi KA, Lodi A, Bosco G. Long term successful weight loss with a combination biphasic ketogenic mediterranean diet and mediterranean diet maintenance protocol. Nutrients . 2013 Dec 18;5(12):5205-17.
• Hu T, Mills KT, Yao L, Demanelis K, Eloustaz M, Yancy Jr WS, Kelly TN, He J, Bazzano LA. Effects of low-carbohydrate diets versus low-fat diets on metabolic risk factors: a meta-analysis of randomized controlled clinical trials. Am J Epidemiol . 2012 Oct 1;176(suppl_7):S44-54.

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• Published: 30 November 2020

Effect of the ketogenic diet on glycemic control, insulin resistance, and lipid metabolism in patients with T2DM: a systematic review and meta-analysis

• Xiaojie Yuan 1   na1 ,
• Jiping Wang 1   na1 ,
• Shuo Yang 2   na1 ,
• Mei Gao 2 ,
• Lingxia Cao 2 ,
• Xumei Li 1 ,
• Dongxu Hong 1 ,
• Suyan Tian 3 &
• Chenglin Sun   ORCID: orcid.org/0000-0003-3570-1918 1 , 2  

Nutrition & Diabetes volume  10 , Article number:  38 ( 2020 ) Cite this article

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• Type 2 diabetes

At present, the beneficial effect of the ketogenic diet (KD) on weight loss in obese patients is generally recognized. However, a systematic research on the role of KD in the improvement of glycemic and lipid metabolism of patients with diabetes is still found scarce.

This meta-study employed the meta-analysis model of random effects or of fixed effects to analyze the average difference before and after KD and the corresponding 95% CI, thereby evaluating the effect of KD on T2DM.

After KD intervention, in terms of glycemic control, the level of fasting blood glucose decreased by 1.29 mmol/L (95% CI: −1.78 to −0.79) on average, and glycated hemoglobin A1c by 1.07 (95% CI: −1.37 to −0.78). As for lipid metabolism, triglyceride was decreased by 0.72 (95% CI: −1.01 to −0.43) on average, total cholesterol by 0.33 (95% CI: −0.66 to −0.01), and low-density lipoprotein by 0.05 (95% CI: −0.25 to −0.15); yet, high-density lipoprotein increased by 0.14 (95% CI: 0.03−0.25). In addition, patients’ weight decreased by 8.66 (95% CI: −11.40 to −5.92), waist circumference by 9.17 (95% CI: −10.67 to −7.66), and BMI by 3.13 (95% CI: −3.31 to −2.95).

KD not only has a therapeutic effect on glycemic and lipid control among patients with T2DM but also significantly contributes to their weight loss.

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Introduction.

Diabetes mellitus (DM) is the world’s leading cause for motility and morbidity, and the disease has become a major public health burden worldwide. It is estimated that the prevalence of diabetes in adults worldwide is over 300 million, and it will increase by 55% by 2035 1 . Obesity or overweight is one of the essential risk factors for diabetes and contributes to a twice-higher risk to develop DM 2 , 3 . Thus, dietary therapy aiming at weight loss is typically recommended in clinical practice 4 . Due to the fact that diabetes and its complications affect many aspects of physiology, the benefits of weight reduction are not limited to glycemic control but are also related to many cardiovascular risk factors such as blood pressure, high-density lipoprotein (HDL), total cholesterol (TC) and triglyceride (TG) 2 .

Medical nutrition, as part of the comprehensive treatment of DM with obesity with a primary goal of weight reduction, is the most simple, effective and economical choice of intervention. The dietary approach for body weight reduction can be obtained from many strategies, including a low-calorie diet, a very low-calorie diet, high-protein diet, and so on. Ketogenic diet (KD), which contains a very low level of carbohydrates (<55 g/d) with the main energy sources of lipid and protein, and which causes ketosis and simulates the physiological state of fasting, has been well reported to be effective for weight loss and glycemic control 4 , 5 , 6 , 7 , 8 , 9 . Previous meta-analyses have proved the efficacy of KD in body weight reduction 2 , 10 , 11 ; however, systemic reviews on the effect of KD on weight reduction and glycolipid metabolism in patients with DM are still limited. Westman et al. 12 and Partsalaki et al. 13 demonstrated that KD improved type 2 diabetes mellitus (T2DM) by reducing the glycemic response caused by carbohydrate and improving potential insulin resistance. Leonetti et al. 14 and Walton et al. 15 reported reduced TG and TC with increased HDL levels after KD consumption for a lipid profile. However, controversies are still existing; studies revealed that a low-carbohydrate, high-fat diet may exacerbate the lipid profile in patients with diabetes, although glycemic control improved with hypoglycemic medications 16 , 17 , 18 . Therefore, the purpose of the current review was to conduct a meta-analysis on the effects of a KD in patients with diabetes.

Considering the potential benefits of KD in diabetes management and weight reduction, and considering fasting blood glucose and glycated hemoglobin A1c (HbA1c) as common biomarkers for long-term glycemic control, HDL, LDL, TC, and TG levels are included in the current analysis to determine the changes of metabolic disorders in glucose and lipid metabolism. In addition, the homeostatic model assessment of insulin resistance (HOMA-IR) is considered as a reflection of insulin resistance reversal.

Materials and methods

Literature search.

In this meta-analysis, only studies published in English were considered, which were identified by searching the PubMed and MEDLINE databases. The keywords used for this literature search are T2DM or diabetes mellitus, ketogenic diet, obesity, and human. The search was finished on September 20, 2019. This meta-analysis was planned and performed according to the Preferred Reporting Items for Systemic Reviews (PRISM) guideline (Fig. 1 ).

Only studies published in English were considered, which were identified by searching the PubMed and MEDLINE databases. The keywords used for this literature search are T2DM or diabetes mellitus, ketogenic diet, obesity, and human. The search was finished on September 20, 2019.

Inclusive/exclusive criteria

Studies that met the following inclusive criteria were included: (1) the disease of interest is type II diabetes; (2) the therapeutic diet under consideration is KD; (3) the study was carried out on humans; animal experiments are not included; and (4) the summary statistics of the mean difference between before and after KD (if both means for before and after measurements are available, then we took the difference of these two statistics to obtain the desired mean difference), their corresponding standard error or 95% CI (according to this, the standard error was calculated) or p values (according to this, the corresponding t statistics and subsequently the standard error were calculated) are available.

Exclusive criteria: (1) case report studies were excluded; (2) meta-analysis or review studies were excluded; (3) studies on other diseases rather than type II diabetes were excluded; and (4) if only the respective mean and standard errors were available, such studies were excluded given it is hard to get an accurate estimation for the standard error of mean difference (since both measurements were on the same patient, they should be correlated to each other, and hence it is impossible to estimate this correlation).

Statistical analysis

The effects of KD on type II diabetes were estimated by the mean difference after KD versus before KD and their corresponding 95% CIs in random-effects meta-analysis models or fixed-effect meta-analysis models. To determine which model should be used, heterogeneity among studies was evaluated by the Cochrane’s Q statistic corresponding p values and the I 2 statistics. If the p value was <0.05 and I 2  > 0.5, a random-effect meta-analysis model was used. Otherwise, a fixed-effect meta-analysis model was chosen. Additionally, potential bias was assessed by using funnel plots, in which effect sizes versus standard errors were diagrammed. All statistical analysis was carried out in the R software, version 3.5 ( www.r-project.org ) 19 , 20 , 21 .

There are 13 studies included in this meta-analysis; the details of these 13 studies are presented in Table 1 . In total, 567 subjects were included in the final meta-analysis. From the perspective of glucose metabolism, lipid metabolism, and weight control, the effects of KD on T2DM were systemically reviewed by comparing the after-intervention measures with before-intervention measures of several biomarkers for the same patient. The variables used to surrogate for carbohydrate metabolism are included fasting glucose level and HbA1c; for lipid metabolism TC, TG, HDL and LDL; and for weight loss body weight, BMI and waist circumference. For all variables except BMI and waist, random-effect models were adopted according to the Q statistic p value and I 2 statistics.

Using the meta-analysis method, we found that the fasting blood glucose level was decreased 1.29 mmol/l (95% CI: −1.78 to −0.79) after the intervention of KD, compared to before such an intervention (based on ten articles that have the summary statistics for the difference between after- and before-intervention measures). As far as HbA1c is concerned, we found that the reduced proportion of HbA1c is more significant after the KD implementation, with a difference of −1.07% (95% CI: −1.37 to −0.78), which is regarded as the ideal therapeutic effect of drugs that is possible to be achieved on HbA1c. The forest plots for these two carbohydrates metabolism indices are given in Fig. 2 .

The reduced proportion of HbA1c is more significant after the KD implementation, which is regarded as the ideal therapeutic effect of drugs that is possible to be achieved on HbA1c.

In this study, eight articles investigated the effect of KD on the lipid metabolism of diabetic patients, but only five papers analyzed total cholesterol. It can be seen that after KD consumption, TG decreased by 0.72 mmol/L (95% CI: −1.01 to −0.43), TC decreased by 0.33 mmol/L (95% CI: −0.66 to −0.01), and LDL decreased by 0.05 mmol/L (95% CI: −0.25 to −0.15). On the other hand, HDL increased by 0.14 mmol/L (95% CI: 0.03−0.25). The forest plots for these four biomarkers are shown in Fig. 3 .

It can be seen that after KD consumption, TG, TC, and LDL decreased. On the other hand, HDL increased.

Regarding weight loss, many studies have demonstrated that KD has a positive effect by providing effective control over obesity. The results of our meta-analysis are consistent with previous results. Specifically, the average weight decreased by 8.66 kg (95% CI: −11.40 to −5.92), waist circumference reduced by 9.17 cm (95% CI: −10.67 to −7.66) and BMI reduced by 3.13 kg/m 2 (95% CI: −3.31 to −2.95), as shown in Fig. 4 .

Many studies have demonstrated that KD has a positive effect by providing effective control over obesity; our findings were consistent with the previous reports.

The American Diabetes Society (ADA) recommended physical activity, dietary management, and medical intake and other approaches should be applied simultaneously to manage blood glucose levels, and other abnormal metabolic factors. KD showed numerous health benefits to patients with T2DM 22 , 23 . KD provides energy through fat oxidation. When the human body experienced extreme hunger or very limited carbohydrate, the ketone body was produced and released to circulation by hepatic transformation of fatty acids 24 , 25 . Nutritional ketosis is different from severe pathological diabetic ketosis; the blood ketone body remained at 0.5−3.0 mmol/L with reduced blood glucose and normal blood pH, with no symptoms in nutritional ketosis 26 .

The possible mechanism for the health benefit of KD on patients with T2DM is that the extreme restriction of carbohydrate reduces the intestinal absorption of mono-saccharide, which leads to lower blood glucose level and reduces the fluctuation of blood glucose, and its effectiveness on regulating glucose metabolism was confirmed by a large body of evidence 27 , 28 . The current study analyzed 13 studies from literature focusing on diabetic patients; the results showed that the reduction of blood glucose ranges from 0.62 to 5.61 mmol/L. Higher reduction amplitudes were reported by Dashti 29 and Leonetti et al. 14 of 5.61 mmol/L (weight random 3.0%) and 3.87 mmol/L (weight random 1.2%), respectively; other reductions in blood glucose were all lower than 1.8 mmol/L. The possible reason for the higher reduction found in these two studies could be the higher blood glucose level included in the studies, and also that the average blood glucose concentration was above 10.0 mmol/L, leading to the possibility of a larger reduction; however, their contribution to the overall effect estimations in the meta-analysis was low. The average changes in fasting blood glucose after the KD consumption among the selected studies were −1.29 mmol/L, indicating the effectiveness of the KD in lowering fasting blood glucose.

No studies included in this meta-analysis evaluated the effect of KD on postprandial glucose level; unlike medications, dietetic therapy showed a long-term effect on glucose regulation 4 , 16 , and HbA1c was analyzed to evaluate the long-term effect of KD. HbA1c effectively reflects the blood glucose control in the past 2−3 months in patients with diabetes. It is reported that the risk of cardiac infarction and micro-vascular complications reduced by 14% and 37%, respectively, when HbA1c reduced by 1%. Therefore, the HbA1c level showed essential clinical significance in evaluating the blood glucose control, revealing the potential problems in the treatment and thereby guiding the therapeutic schedule 30 , 31 . Eight of the selected studies showed a reduction of HbA1c after KD consumption, the changes ranging from −0.6% to −3.3%; HbA1c reduced <1.5% in the majority of the studies included in the current analysis besides the study conducted by Walton (−3.3%; weight random 5.1%) 15 . The possible explanation for such strong improvement of HbA1c could be that Walton’s study had enrolled a limited number of patients and thus the compliance of patients to KD therapy can be guaranteed. Moreover, the studied subjects were newly diagnosed diabetic patients who were under dietary management without taking glucose-lowering medications; newly diagnosed subjects persist well in the study. Considering the causal factors comprehensively, the above study showed an ideal reduction in HbA1c. The average reduction of HbA1c was 1.07 in the current analysis of the selected eight studies, indicating that dietary management may also achieve the ideal therapeutic effects of medication.

HOMA-IR is considered as an indicator to evaluate the status of insulin resistance. Insulin resistance as a clinical characteristic of T2DM is closely related to obesity. Improving insulin resistance is one of the major targets in diabetes treatment 32 , 33 , 34 . However, studies focusing on the role of KD in the improvement of insulin resistance in patients with diabetes are very limited; most of the studies focused on the effect in obese subjects 35 , 36 . For instance, a controlled clinical trial aiming at the effects of KD consumption in obese people without diabetes revealed that HOMA-IR decreased by about 2.0 after KD consumption for 6 weeks 37 . The current analysis showed consistent changes in the studies that included HOMA-IR evaluation, with reduction ranging from −0.4 to −3.4; the reason for the significant reduction of 3.4 in the study by Tay et al. 38 is that the population included was obese diabetic patients with BMI higher than 30 kg/m 2 . Obesity is closely related to insulin resistance; KD consumption is confirmed to be effective in reducing body weight, and it is expected that KD may improve insulin resistance in obese diabetic patients 39 . During the ketogenesis, the sensitivity of the insulin receptor is promoted; therefore, KD not only ensures the supply of basic nutrients but also maintains a negative balance of energy, and reduces the fluctuation and reduction of insulin secretion caused by reduced carbohydrate intake as well, which eventually leads to improved insulin sensitivity 40 , 41 , 42 , 43 .

Consumption of KD not only improved glucose metabolism, but a large body of evidence has reported that KD improved lipid metabolism as well. Hussain et al. 4 reported that KD reduced TG and TC, and increased HDL level, thus ameliorating the status of dyslipidemia. In the present study, eight studies included showed results of lipid metabolism in diabetic patients after KD consumption; however, only five analyzed the TC levels. The current results showed the mean reduction of TG was 0.72 mmol/L, TC was 0.33 mmol/L, and LDL was 0.05 mmol/L, while the increase of HDL was 0.14 mmol/L. The higher amplitude of variation occurred in the Dashti et al. study 29 . This study reported that TG reduced by 3.67 mmol/L, TC reduced by 1.88 mmol/L, and LDL reduced by 1.78 mmol/L, while HDL increased by 0.14 mmol/L. Changes in the amplitude of the lipid biomarkers were all at the higher end in the above study. Both glucose and lipid metabolism showed great improvement after KD consumption in such a study; the characteristics of subjects recruited were closely correlated. The study recruited 31 obese subjects with hyperglycemia, dyslipidemia, and BMI over 30 kg/m 2 . The baseline TG, TC, and LDL were higher than those of typical patients with T2DM, which may contribute to the significant changes after the intervention. Consumption of KD showed a significant therapeutic effect in common patients with T2DM, including the Dashti 29 study. Disorders of lipid metabolism are particularly strong among patients with insulin resistance in T2DM. Dyslipidemia is lipotoxic to cells, leading to and/or aggravating insulin resistance. Its typical manifestation is the increase of TG and free fatty acid (FFA) 44 , 45 , 46 , 47 . Increased FFA is an independent pathogenic factor for insulin resistance and can possibly increase the risk for cardiovascular diseases 48 , 49 . Therefore, the improvement of dyslipidemia is beneficial for not only regulating insulin sensitivity but also controlling the occurrence and progression of diabetic complications 50 , 51 .

Numerous studies have confirmed the role of KD consumption in weight reduction in obese patients 35 , 36 , 37 , 40 , 41 , 42 , 43 , 52 ; the current meta-analysis focused on the effect of KD on weight reduction in obese diabetic patients. The results showed the average reduction of body weight was 8.66 kg, waist circumference was 9.17 cm, and BMI was 3.22 kg/m 2 , which were consistent with previous studies in nondiabetic patients. We also found that KD reduced systolic blood pressure by 4.30 (95% CI: −7.02 to 1.58) and diastolic blood pressure by 5.14 (95% CI: −10.18 to 0.10) in patients with T2DM, which possibly benefit from the improvement of body weight 51 .

Besides the mediation of glucose and lipid metabolism, KD may also benefit other clinical symptoms in diabetic patients, including insomnia, chills, constipation, pruritus, numbness of limbs, hypopsia, fatty liver, hypertension, and reduced cardiac function.

The potential side effects of KD were only mentioned in two of the studies 14 , 41 included in the meta-analysis; thus it is impossible to perform a systematic review in terms of the risks associated with KD consumption. Specifically, Goday and Leonetti’s 14 , 41 study investigated the adverse reactions of KD. Goday et al. 41 mentioned that fatigue, headache, nausea and vomiting were more common in the KD diet group after a 2-week intervention, while constipation and orthostatic hypotension were more common after 10 weeks. It was revealed by Leonetti et al. 14 that in the early stages of applying the KD, patients reported a sense of hunger, but it could be significantly alleviated with the progress of the intervention. Even though headache, nausea, vomiting, constipation, diarrhea, and other symptoms were reported during the study, the symptoms were mild and lasted for a short time, not relating to clinical practice.

Limitations

Only 13 studies were included in the current analysis, with limited studies focusing on the effect of KD in patients with T2DM worldwide. For instance, no analysis was conducted on HOMA-IR even though there was a trend of improvement; also, very limited literature was available. All studies included in this meta-analysis were carried out among Caucasian diabetic patients (no East Asians included); however, the majority of East Asian diabetic patients showed insulin resistance with central obesity and defect in insulin secretion. Therefore, clinical trials conducted among East Asians are highly desirable to confirm whether there is an improvement in the secretion function of islet cells other than improved regulation of glucose and lipid metabolism. Moreover, the current study analyzed the data without assigning studies into time duration due to the limited number of studies and the missing data of insulin and lipid biomarkers; in addition, the duration of the follow-up was decentralized into days, months, and years. The available studies concerning the effects of ketogenic diet in patients with diabetes are very limited; it is impossible to summarize a similar follow-up interval for statistical analysis of time points. However, the current results suggested that ketogenic diet consumption contributed to therapeutic effects despite the length of the term of intervention. The analysis of the difference before and after the intervention may also give credit to the clinical efficacy of the diet therapy. In current clinical practice, a majority of the patients have to use a combination of multiple drugs to improve their glycolipid metabolism. Drug therapy is a heavy mental and economical burden to patients. Given the fact that most of the patients are confused regarding a proper dietary therapy plan, it is essential to recommend a feasible dietary therapy plan to transmit a positive message to both patients with diabetes and physicians majored in the area of diabetes.

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Acknowledgements

This study was supported by the Science Technology Department of Jilin Province (20180623006TC and 20200404213YY) and the Interdisciplinary Project of First Hospital of Jilin University (JDYYJC010) and Transformation Project of First Hospital of Jilin University (JDYYZH-1902019) and Education Department of Jilin Province (JJKH20190032KJ and JJKH20201081KJ).

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Department of Clinical Nutrition, First Hospital of Jilin University, 1 Xinmin Street, 130021, Changchun, Jilin, China

Xiaojie Yuan, Jiping Wang, Xumei Li, Dongxu Hong & Chenglin Sun

Department of Endocrinology and Metabolism, First Hospital of Jilin University, 1 Xinmin Street, 130021, Changchun, Jilin, China

Shuo Yang, Mei Gao, Lingxia Cao & Chenglin Sun

Division of Clinical Research, First Hospital of Jilin University, 1 Xinmin Street, 130021, Changchun, Jilin, China

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X.Y., J.W., S.Y., S.T. and C.S. were responsible for writing, M.G., L.C., X.L. and S.Y. were responsible for the literature collection and data management, D.H. and S.T. for statistical analysis, C.S. and S.T. are in charge of the overall research design and supervision.

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Yuan, X., Wang, J., Yang, S. et al. Effect of the ketogenic diet on glycemic control, insulin resistance, and lipid metabolism in patients with T2DM: a systematic review and meta-analysis. Nutr. Diabetes 10 , 38 (2020). https://doi.org/10.1038/s41387-020-00142-z

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Article Contents

• INTRODUCTION
• Acknowledgments

Impact of ketogenic diet on cardiovascular disease

• Article contents
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• Supplementary Data

Mohamed S Zaghloul, Santiago Elizondo-Benedetto, Mohamed A Zayed, Impact of ketogenic diet on cardiovascular disease, Nutrition Reviews , 2023;, nuad152, https://doi.org/10.1093/nutrit/nuad152

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A comprehensive review of the current literature was conducted to summarize the potential therapeutic and management roles of ketogenic diet (KD) for cardiovascular disease (CVD).

Consensus has not been reached on the optimal diet for individuals with cardiovascular risk factors. KDs are characterized by high-fat, low-carbohydrate, and appropriate protein content, and have gained popularity in recent years in the management of various conditions, including cardiovascular and metabolic diseases.

Original research, systematic reviews, and meta-analyses available in the PubMed, Web of Science, and Google Scholar databases were reviewed.

The current body of preclinical and clinical evidence on the efficacy of KD in the management of CVD remains limited. Specific applications of KD seem to suggest a positive impact on management of CVD. However, conflicting results and a lack of precise molecular and biochemical mechanisms of action provide ample opportunity for future investigation.

More multidisciplinary studies are needed to determine the true clinical benefit of KD in the management of CVD and so justify its expanded clinical use.

• cardiovascular diseases
• carbohydrates
• ketogenic diet

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Pilot study shows ketogenic diet improves severe mental illness

A small clinical trial led by Stanford Medicine found that the metabolic effects of a ketogenic diet may help stabilize the brain.

April 1, 2024 - By Nina Bai

A study led by researchers at Stanford Medicine showed that diet can help those with serious mental illness. nishihata

For people living with serious mental illness like schizophrenia or bipolar disorder, standard treatment with antipsychotic medications can be a double-edged sword. While these drugs help regulate brain chemistry, they often cause metabolic side effects such as insulin resistance and obesity, which are distressing enough that many patients stop taking the medications.

Now, a pilot study led by Stanford Medicine researchers has found that a ketogenic diet not only restores metabolic health in these patients as they continue their medications, but it further improves their psychiatric conditions. The results, published March 27 in Psychiatry Research , suggest that a dietary intervention can be a powerful aid in treating mental illness.

“It’s very promising and very encouraging that you can take back control of your illness in some way, aside from the usual standard of care,” said Shebani Sethi , MD, associate professor of psychiatry and behavioral sciences and the first author of the new paper.

Making the connection

Sethi, who is board certified in obesity and psychiatry, remembers when she first noticed the connection. As a medical student working in an obesity clinic, she saw a patient with treatment-resistant schizophrenia whose auditory hallucinations quieted on a ketogenic diet.

That prompted her to dig into the medical literature. There were only a few, decades-old case reports on using the ketogenic diet to treat schizophrenia, but there was a long track record of success in using ketogenic diets to treat epileptic seizures.

“The ketogenic diet has been proven to be effective for treatment-resistant epileptic seizures by reducing the excitability of neurons in the brain,” Sethi said. “We thought it would be worth exploring this treatment in psychiatric conditions.”

A few years later, Sethi coined the term metabolic psychiatry, a new field that approaches mental health from an energy conversion perspective.

Shebani Sethi

In the four-month pilot trial, Sethi’s team followed 21 adult participants who were diagnosed with schizophrenia or bipolar disorder, taking antipsychotic medications, and had a metabolic abnormality — such as weight gain, insulin resistance, hypertriglyceridemia, dyslipidemia or impaired glucose tolerance. The participants were instructed to follow a ketogenic diet, with approximately 10% of the calories from carbohydrates, 30% from protein and 60% from fat. They were not told to count calories.

“The focus of eating is on whole non-processed foods including protein and non-starchy vegetables, and not restricting fats,” said Sethi, who shared keto-friendly meal ideas with the participants. They were also given keto cookbooks and access to a health coach. 

The research team tracked how well the participants followed the diet through weekly measures of blood ketone levels. (Ketones are acids produced when the body breaks down fat — instead of glucose — for energy.) By the end of the trial, 14 patients had been fully adherent, six were semi-adherent and only one was non-adherent.

The participants underwent a variety of psychiatric and metabolic assessments throughout the trial.

Before the trial, 29% of the participants met the criteria for metabolic syndrome, defined as having at least three of five conditions: abdominal obesity, elevated triglycerides, low HDL cholesterol, elevated blood pressure and elevated fasting glucose levels. After four months on a ketogenic diet, none of the participants had metabolic syndrome.

On average, the participants lost 10% of their body weight; reduced their waist circumference by 11% percent; and had lower blood pressure, body mass index, triglycerides, blood sugar levels and insulin resistance.

“We’re seeing huge changes,” Sethi said. “Even if you’re on antipsychotic drugs, we can still reverse the obesity, the metabolic syndrome, the insulin resistance. I think that’s very encouraging for patients.”

The participants reported improvements in their energy, sleep, mood and quality of life.

The psychiatric benefits were also striking. On average, the participants improved 31% on a psychiatrist rating of mental illness known as the clinical global impressions scale, with three-quarters of the group showing clinically meaningful improvement. Overall, the participants also reported better sleep and greater life satisfaction.

“The participants reported improvements in their energy, sleep, mood and quality of life,” Sethi said. “They feel healthier and more hopeful.”

The researchers were impressed that most of the participants stuck with the diet. “We saw more benefit with the adherent group compared with the semi-adherent group, indicating a potential dose-response relationship,” Sethi said.

Alternative fuel for the brain

There is increasing evidence that psychiatric diseases such as schizophrenia and bipolar disorder stem from metabolic deficits in the brain, which affect the excitability of neurons, Sethi said.

The researchers hypothesize that just as a ketogenic diet improves the rest of the body’s metabolism, it also improves the brain’s metabolism.

“Anything that improves metabolic health in general is probably going to improve brain health anyway,” Sethi said. “But the ketogenic diet can provide ketones as an alternative fuel to glucose for a brain with energy dysfunction.”

Likely there are multiple mechanisms at work, she added, and the main purpose of the small pilot trial is to help researchers detect signals that will guide the design of larger, more robust studies.  

As a physician, Sethi cares for many patients with both serious mental illness and obesity or metabolic syndrome, but few studies have focused on this undertreated population.

She is the founder and director of the metabolic psychiatry clinic at Stanford Medicine.

“Many of my patients suffer from both illnesses, so my desire was to see if metabolic interventions could help them,” she said. “They are seeking more help. They are looking to just feel better.”

Researchers from the University of Michigan; the University of California, San Francisco; and Duke University contributed to the study.

The study was supported by Baszucki Group Research Fund, the Kuen Lau Fund and the Obesity Treatment Foundation.

About Stanford Medicine

Stanford Medicine is an integrated academic health system comprising the Stanford School of Medicine and adult and pediatric health care delivery systems. Together, they harness the full potential of biomedicine through collaborative research, education and clinical care for patients. For more information, please visit med.stanford.edu .

Hope amid crisis

Psychiatry’s new frontiers

In 1921, a distinguished physician at the Mayo Clinic suggested trying what he called a ketogenic diet, a high-fat diet designed to be so carbohydrate-deficient it could effectively mimic the fasting state. Oddly, the success of ketogenic diets against pediatric epilepsy seems to get conflated by keto diet proponents into suggesting it is beneficial for everyone.

By eschewing carbohydrates, you force your body to burn fat. And indeed, the amount of fat you burn shoots up when you eat a keto diet. At the same time, however, the fat you take in shoots up when you eat a keto diet. What happens to our overall body-fat balance? Body fat loss slows upon switching to the ketogenic diet.

Just looking at the scale, the ketogenic diet seems like a success, but what happens inside bodies tells a different story. On the keto diet, rates of body fat loss may slow by more than half, so most of what is lost is water. The reason less fat is burned on a ketogenic diet is presumably the same reason people who start fasting may start burning less fat: Without carbohydrates, the preferred fuel, our bodies start burning more of our own protein .

Inadequate intake of 17 micronutrients has been documented in those on ketogenic diets. Children have gotten scurvy, and some have even died from deficiency of the mineral selenium , which can cause sudden cardiac death. Bone fractures disproportionately plague children on ketogenic diets, along with growth stunting and kidney stones , and constipation is a frequently cited side effect. Keto diets have also been shown to reduce the richness and diversity of our gut flora , and all of that saturated fat can have a profound impact on the heart: A meta-analysis of four cohort studies following the diets, diseases, and deaths of more than a quarter million people found that those who eat lower-carb diets suffer a significantly higher risk of all-cause mortality, meaning they live, on average, significantly shorter lives.

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Keto diet may accelerate organ ageing

In mice, a ketogenic diet increases the build-up of zombie-like cells in the heart, kidney, lungs and brain, which can accelerate organ ageing and lead to health problems

By Grace Wade

17 May 2024

Research on the health effects of low-carbohydrate diets like keto has had mixed results

nadianb/Shutterstock

A ketogenic diet causes damaged cells to accumulate in the organs of mice. Their build-up suggests the keto diet may accelerate organ ageing, raising the risk of conditions like heart disease and cancer.

Although many people have adopted low-carbohydrate diets like keto for weight loss and controlling blood sugar , research on their health effects is mixed, with some studies finding they increase the risk of heart attacks.

We’re finally working out why the Mediterranean diet is so good for us

To learn more, David Gius at the University of Texas Health Science Center at San Antonio and his colleagues fed six mice a ketogenic diet for three weeks. More than 90 per cent of their calories came from fat and less than 1 per cent from carbohydrates. A control group ate a standard diet where 17 per cent of calories came from fat and 58 per cent came from carbohydrates.

The researchers then analysed heart, kidney, liver and brain tissue samples from the mice, looking for senescent cells. Senescence occurs when cells become too damaged to function, but instead of dying, they enter a zombie-like state. These cells linger in tissues, spewing toxins that stoke inflammation.

Animals on the ketogenic diet had significantly more senescent cells in their organs compared with those on a standard diet. For instance, their kidneys contained, on average, four times the amount of a marker of cellular senescence as those from animals fed a regular diet.

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Senescent cells increase with age. So, these findings suggest the keto diet might accelerate organ ageing, which would raise the risk of conditions like heart disease, cancer and type 2 diabetes. However, switching mice back to a standard diet decreased senescent cells.

“While the ketogenic diet is probably a good thing, [it is not for] everyone. And importantly, you need to take a break,” says Gius. “I think our paper really says we need to study this more rigorously.”

It isn’t clear how these experimental findings may translate to people, says Russell Jones at the Van Andel Institute in Michigan. “They’re running a 90 per cent fat diet, and that would be virtually impossible to adhere to as a human,” he says.

Journal reference:

Science Advances DOI: 10.1126/sciadv.ado1463

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A long-term ketogenic diet accumulates aged cells in normal tissues, new study shows

by University of Texas Health Science Center at San Antonio

A strict "keto-friendly" diet popular for weight loss and diabetes, depending on both the diet and individual, might not be all that friendly.

A new study led by researchers at The University of Texas Health Science Center at San Antonio (UT Health San Antonio) found that a continuous long-term ketogenic diet may induce senescence, or aged, cells in normal tissues, with effects on heart and kidney function in particular. However, an intermittent ketogenic diet, with a planned keto vacation or break, did not exhibit any pro-inflammatory effects due to aged cells, according to the research.

The findings have significant clinical implications suggesting that the beneficial effect of a ketogenic diet might be enhanced by planned breaks.

"To put this in perspective, 13 million Americans use a ketogenic diet, and we are saying that you need to take breaks from this diet or there could be long-term consequences," said David Gius.

Gius is lead author of the new study titled, "Ketogenic diet induces p53-dependent cellular senescence in multiple organs," published May 17 in the journal Science Advances .

Other authors also are with the Department of Radiation Oncology and Mays Cancer Center, as well as the Sam and Ann Barshop Institute for Longevity and Aging Studies, Center for Precision Medicine, School of Nursing, and Division of Nephrology in the Department of Medicine at UT Health San Antonio; and both the Houston Methodist Cancer Center and Houston Methodist Research Institute.

Too much of a good thing

A ketogenic diet, popularly known as keto-friendly, is a high-fat, low-carbohydrate diet that leads to the generation of ketones, a type of chemical that the liver produces when it breaks down fats. While a ketogenic diet improves certain health conditions and is popular for weight loss , pro-inflammatory effects also have been reported.

The new study shows that mice on two different ketogenic diets, and at different ages, induce cellular senescence in multiple organs, including the heart and kidney. However, this cellular senescence was eliminated by a senolytic, or a class of small molecules that can destroy senescence cells, and prevented by administration of an intermittent ketogenic diet regimen.

"As cellular senescence has been implicated in the pathology of organ disease, our results have important clinical implications for understanding the use of a ketogenic diet ," Gius said. "As with other nutrient interventions, you need to 'take a keto break.'"

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New UT Health San Antonio study reveals drawbacks of long-term ‘keto’ diet

Research suggests strict attention to ketogenic diet may affect heart, kidneys.

David Ibañez , Web - Managing Editor

SAN ANTONIO – If you’re a hardcore “keto” dieter, you may want to take a break from it.

According to a new study led by researchers at UT Health San Antonio , continuous long-term attention to the high-fat, low-carbohydrate diet popular for weight loss and diabetes may lead to the aging of cells in normal tissues, particularly affecting heart and kidney function.

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The study recommends dieters take an intermittent attitude by taking planned breaks.

“To put this in perspective, 13 million Americans use a ketogenic diet, and we are saying that you need to take breaks from this diet or there could be long-term consequences,” said David Gius, MD, PhD, assistant dean of research and professor with the Department of Radiation Oncology in the Joe R. and Teresa Lozano Long School of Medicine at UT Health San Antonio, and associate cancer director for translational research at the institution’s Mays Cancer Center.

Gius is the lead author of the study “Ketogenic diet induces p53-dependent cellular senescence in multiple organs,” which was published Friday in the journal Science Advances.

To read more about the study, click here .

Copyright 2024 by KSAT - All rights reserved.

About the Author

David ibañez.

David Ibañez has been managing editor of KSAT.com since the website's launch in October 2000.

Could a Low-Cal Keto Diet Help Ease Acne?

By Ernie Mundell HealthDay Reporter

WEDNESDAY, May 15, 2024 (HealthDay News) -- In a small pilot study, some young women looking to lose weight on a low-calorie keto diet got an unexpected benefit: Their acne began to clear up.

“These findings represent an opportunity to control a skin disease that affects most teenagers and many adults at some point in their lifetimes, causing distress, embarrassment, anxiety and low self-confidence among sufferers, robbing them of their quality of life,” said lead study author Luigi Barrea , of the Università Telematica Pegaso in Naples, Italy.

His team presented its findings Tuesday at the European Congress on Obesity on Vienna, Italy.

As Barrea's group explained, acne is thought to be a chronic inflammatory illness affecting what's known as the pilosebaceous unit: the hair follicle, hair shaft and nearby sebaceous gland. About 9% of the world's population is affected by acne, largely in the teenage years.

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According to the Italian researchers, acne has long been linked with obesity, perhaps because both conditions are tied to rising inflammation and oxidative stress.

Could the ketogenic diet fight that underlying inflammation and oxidative stress?

“While the role of diet in acne is inconclusive, the very low-calorie ketogenic diet is known for aiding weight loss and generating anti-inflammatory ketone bodies that provide energy when dietary carbohydrates are scarce, as well as promoting resistance against inflammatory and oxidative stress,” Barrea explained in a meeting news release. “We thought it would be worth exploring this potential treatment in acne.”

Their study was small: Just 31 young women (ages 18 to 30) who were obese and had moderate levels of acne.

All of the women embarked on 45 days of a very low-calorie ketogenic diet (just 700–800 kilocalories per day). In keeping with the keto regimen, 44% of calories came from fat, 43% from protein and just 13% from carbohydrates.

All of the women successfully completed the diet, with some mild "adverse effects" -- headaches, muscle weakness -- reported.

Weight-loss results were impressive. The women lost an average of about 8% of their body weight over the 45 days, with a similar percentage drop in their waistline measurements, Barrea's team reported.

Their acne improved as well: Measured by a standard "global acne grading scale," scores improved by an average of 41.5% over the course of the 45-day diet.

As well, "the participants also reported much better life satisfaction, with an average 45% improvement in their quality-of-life score," researchers reported.

Barrea's team said there was a scientific basis for the easing of acne. They found that markers for systemic inflammation, oxidative stress and gut microbiome health all improved. Improvements in inflammation and oxidative appeared to correlate with reductions in acne severity, the team said.

“In this small pilot trial, the 45-day very low-calorie ketogenic diet demonstrated notable improvements in acne severity that seemed to be attributable to the known antioxidant and anti-inflammatory effects of the diet," Barrea concluded.

He stressed however, that the study was very small and because these findings were presented at a medical meeting, they should be considered preliminary until published in a peer-reviewed journal.

However, “if confirmed in larger, more robust studies, the very low-calorie ketogenic diet could provide a valuable alternative to antibiotics and topical treatments to help the many thousands of people affected by acne," Barrea said.

More information

Find out more about acne and its treatments at the American Dermatological Association .

SOURCE: European Congress on Obesity, news release, May 14, 2024

Copyright © 2024 HealthDay . All rights reserved.

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