The Ketogenic Diet as a Treatment for Metabolic Syndrome

The Ketogenic Diet for Metabolic Syndrome

Metabolic Syndrome (MetS) can be viewed as a set of symptoms of insulin resistance. Taken together, those symptoms signify a threat of heart disease, diabetes, cancer, and other diseases that appear to be different manifestations of a common cause. That common cause is likely to be insulin resistance.

This hypothesis is supported by evidence that ketogenic diets not only normalize insulin sensitivity and the symptoms of MetS, but they treat (or have promise in treating) many MetS-associated diseases.

In light of this, it seems plausible that adopting a ketogenic diet will significantly improve your chances of avoiding these diseases in the first place.

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In brief

  • Metabolic Syndrome is a cluster of symptoms, not a disease. Those symptoms are useful to class together, because their association with a variety of different diseases strongly suggests a common cause. In other words, it has provided us with a compelling hypothesis.
  • If there were a common cause, then a therapy that treats that cause should help them all. Moreover, it should reduce the symptoms of Metabolic Syndrome itself. Further, treatments that work for one but not the others should be considered inferior, “band-aid” treatments.
  • A ketogenic diet improves Metabolic Syndrome. Also, for every disease associated with MetS that we have investigated, a keto diet has either been shown to help, has shown preliminary evidence in its favour, or has not been sufficiently tested to rule out.
  • This supports the hypothesis that those diseases have a common cause, and that a ketogenic diet addresses it.

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What is Metabolic Syndrome?

Metabolic Syndrome is a cluster of symptoms that commonly occur together and indicate increased risk of cardiovascular disease (CVD), type 2 diabetes (T2D), cancer, and other diseases. Clinically, to be diagnosed with MetS, you have to score above (or in the case of HDL, below) a healthy threshold in at least 3 of the following 5 measurements: waist size, fasting blood glucose, blood pressure, triglycerides, and HDL. All of these are associated with insulin resistance, although some are more predictive than others 1, 2, 3 , and so metabolic syndrome might be more accurately described as insulin resistance syndrome (and it sometimes is) 4, 5.

Just as with any such measure, it can be misleading to draw a threshold at such a particular point. The cost of ignoring warning signs because they fall below a threshold may be worse than the benefit of giving a special diagnosis to those who have multiple symptoms, each of which could be recognized as warranting treatment on its own 6.

Nonetheless, it is useful to have a name for a set of associations for two reasons.

  1. It allows us to recognize the commonalities in symptoms of a variety of disease states which is suggestive of common mechanisms.
  2. It promotes the insight that any treatment that is purported to improve risk of CVD or T2D ought to have a beneficial impact on all of the associated symptoms. If it doesn't, there is a risk that it is a band-aid solution that temporarily hides the problem rather than fixing it.

Because these symptoms so often occur together, and because they are all risk factors for a group of diseases which in turn are risk factors for each other, it is the contention of many scientists that they have a common cause. Some argue that this common cause is obesity itself. A separate cause is postulated for obesity, which then is supposed to cause the other risk factors. However, other researchers, ourselves among them, believe that obesity and the other symptoms have a common cause related to insulin signalling. For this reason, we have grouped together several diseases which appear to have insulin signalling at their root, and which have elevated risk in the presence of Metabolic Syndrome symptoms. These diseases include (but are not limited to) cardiovascular disease 7, type 2 diabetes 8, polycystic ovarian syndrome 9, Alzheimer's disease 10, and cancer. 11.

In other words, we believe that Metabolic Syndrome is not itself a disease, but is a class of warning signs associated with the progression of several other diseases. If this is true, then when you treat the underlying cause of these symptoms, they will all normalize together, and the risk of all associated diseases will simultaneously be reduced.

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Ketogenic diets treat insulin resistance and therefore are expected to treat all diseases that have Metabolic Syndrome as a symptom.

The following is just a sample of evidence showing that not only does a keto diet address the symptoms of MetS itself, but also those conditions associated with it. This is not meant to be comprehensive — there are many more supporting experiments in each category!

  • Carbohydrate restriction has a more favorable impact on the metabolic syndrome than a low fat diet12.
  • A ketogenic diet favorably affects serum biomarkers for cardiovascular disease in normal-weight men 13.
  • In addition to decreasing body weight and improving glycemia, a ketogenic diet can be effective in decreasing antidiabetic medication dosage 14 .
  • In a pilot study, a ketogenic diet led to significant improvement in weight, percent free testosterone, LH/FSH ratio, and fasting insulin in women with obesity and PCOS over a 24 week period 15 .
  • An oral ketogenic compound, AC-1202, was tested in subjects with probable Alzheimer's disease, and resulted in a significant improvement to cognitive scores 16.
  • It seems a reasonable possibility that a very-low-carbohydrate diet could help to reduce the progression of some types of cancer, although at present the evidence is preliminary 17.

* * *


  • The ketogenic diet is a powerful therapy that exerts its healing effect in a wide variety of conditions that may seem superficially unrelated.
  • These conditions are linked by their connection to insulin resistance, and therefore their association with MetS.
  • This supports not only the hypothesis that a keto diet treats MetS, but also that insulin resistance is the underlying cause of many devastating diseases, and that the way a keto diet is treating those is by intercepting and correcting the underlying cause.

* * *


1 Evidence type: observational analysis Evidence type:
Insulin resistance in aging is related to abdominal obesity. Kohrt WM, Kirwan JP, Staten MA, Bourey RE, King DS, Holloszy JO. Diabetes. 1993 Feb;42(2):273-81.

(emphasis ours)


Studies have shown that insulin resistance increases with age, independent of changes in total adiposity. However, there is growing evidence that the development of insulin resistance may be more closely related to abdominal adiposity. To evaluate the independent effects of aging and regional and total adiposity on insulin resistance, we performed hyperinsulinemic euglycemic clamps on 17 young (21-33 yr) and 67 older (60-72 yr) men and women. We assessed FFM and total and regional adiposity by hydrodensitometry and anthropometry. Insulin-stimulated GDRs at a plasma insulin concentration of approximately 450 pM averaged 45.6 +/- 3.3 mumol.kg FFM-1 x min-1 (mean +/- SE) in the young subjects, 45.6 +/- 10.0 mumol.kg FFM-1 x min-1 in 24 older subjects who were insulin sensitive, and 23.9 +/- 11.7 mumol.kg FFM-1 x min-1 in 43 older subjects who were insulin resistant. Few significant differences were apparent in skin-fold and circumference measurements between young and insulin-sensitive older subjects, but measurements at most central body sites were significantly larger in the insulin-resistant older subjects. Waist girth accounted for > 40% of the variance in insulin action, whereas age explained only 10-20% of the total variance and < 2% of the variance when the effects of waist circumference were statistically controlled. These results suggest that insulin resistance is more closely associated with abdominal adiposity than with age."]

2 Evidence type: retrospective observation
Use of waist circumference to predict insulin resistance: retrospective study. Wahrenberg H, Hertel K, Leijonhufvud BM, Persson LG, Toft E, Arner P. BMJ. 2005 Jun 11;330(7504):1363-4. Epub 2005 Apr 15.

In the multiple regression model, waist circumference was the strongest regressor of the five significant covariates (standardised partial regression coefficients: waist circumference β1 = 0.37; log-plasma triglycerides β2 = 0.23; systolic blood pressure β3 = 0.10, high density lipoprotein cholesterol β4 = -0.09; and body mass index β5 = 0.15 (P < 0.001)).

3 Evidence type: observational analysis
Biomarkers in Fasting Serum to Estimate Glucose Tolerance, Insulin Sensitivity, and Insulin Secretion Allison B. Goldfine, Robert W. Gerwien, Janice A. Kolberg, Sheila O’Shea, Sarah Hamren, Glenn P. Hein, Xiaomei M. Xu, and Mary Elizabeth Patti Clinical Chemistry 57:2 326–337 (2011)

A subset of 5 markers was associated with insulin sensitivity (assessed using the dynamic CISI measure): fasting glucose, insulin, Fas ligand, complement C3, and PAI-1. As shown in Fig. 3C, 91% of variance between predicted and observed CISI values was accounted for by these 5 markers alone (P 0.0001). In addition, a bootstrap R 2 value of 0.90 (IQR 0.83–0.94) indicates that the model could be expected to perform well on an independent data set. By comparison, HOMA-IR, a widely accepted estimate of insulin resistance based on fasting glucose and insulin, explained 88% of the variance of the dynamic measure of insulin sensitivity.

4 Evidence type: observation
A.D.A.M. Medical Encyclopedia.

Metabolic syndrome; Insulin resistance syndrome; Syndrome X

5 Evidence type: observation
Diabetes Health Center Insulin Resistance and Diabetes

If you have pre-diabetes or diabetes, chances are that you’ve heard of the medical term insulin resistance syndrome or metabolic syndrome. Insulin resistance or metabolic syndrome describes a combination of health problems that have a common link — an increased risk of diabetes and early heart disease.

6 Evidence type: observation
The metabolic syndrome: is this diagnosis necessary? Gerald M Reaven. Am J Clin Nutr June 2006 vol. 83 no. 6 1237-1247

The goal of diagnosing the metabolic syndrome is to identify persons at increased risk of CVD. Because each component that makes up the versions of the metabolic syndrome increases CVD risk (34, 36, 37, 62, 68, 69), it seems prudent to treat any of these abnormalities that are present. Furthermore, it would not be too surprising that the more abnormalities present in any given person, the greater would be his or her risk of CVD. The question can be raised, however, as to whether identifying a person as having metabolic syndrome necessarily indicates that he or she is at greater risk of CVD than is a person who may not qualify for that designation. This did not seem to be the case when the ATP III criteria were applied to the Framingham Study database (117); a recent report pointed out that persons meeting any 2 criteria were at no less risk than were those meeting 3 criteria. Indeed, it would be possible to describe a number of prototypic clinical situations in which a person with 1 or 2 abnormalities would be at greater risk of CVD than would a patient who met the metabolic syndrome diagnostic criteria.

7 Evidence type: retrospective observation
The Metabolic Syndrome and Total and Cardiovascular Disease Mortality in Middle-aged Men. Hanna-Maaria Lakka, MD, PhD; David E. Laaksonen, MD, MPH; Timo A. Lakka, MD, PhD; Leo K. Niskanen, MD, PhD; Esko Kumpusalo, MD, PhD; Jaakko Tuomilehto, MD, PhD; Jukka T. Salonen, MD, PhD JAMA. 2002;288(21):2709-2716. doi:10.1001/jama.288.21.2709.

The metabolic syndrome, a concurrence of disturbed glucose and insulin metabolism, overweight and abdominal fat distribution, mild dyslipidemia, and hypertension, is associated with subsequent development of type 2 diabetes mellitus and cardiovascular disease (CVD).


The prevalence of the metabolic syndrome ranged from 8.8% to 14.3%, depending on the definition. There were 109 deaths during the approximately 11.4-year follow-up, of which 46 and 27 were due to CVD and CHD, respectively. Men with the metabolic syndrome as defined by the NCEP were 2.9 (95% confidence interval [CI], 1.2-7.2) to 4.2 (95% CI, 1.6-10.8) times more likely and, as defined by the WHO, 2.9 (95% CI, 1.2-6.8) to 3.3 (95% CI, 1.4-7.7) times more likely to die of CHD after adjustment for conventional cardiovascular risk factors. The metabolic syndrome as defined by the WHO was associated with 2.6 (95% CI, 1.4-5.1) to 3.0 (95% CI, 1.5-5.7) times higher CVD mortality and 1.9 (95% CI, 1.2-3.0) to 2.1 (95% CI, 1.3-3.3) times higher all-cause mortality. The NCEP definition less consistently predicted CVD and all-cause mortality. Factor analysis using 13 variables associated with metabolic or cardiovascular risk yielded a metabolic syndrome factor that explained 18% of total variance. Men with loadings on the metabolic factor in the highest quarter were 3.6 (95% CI, 1.7-7.9), 3.2 (95% CI, 1.7-5.8), and 2.3 (95% CI, 1.5-3.4) times more likely to die of CHD, CVD, and any cause, respectively.


Cardiovascular disease and all-cause mortality are increased in men with the metabolic syndrome, even in the absence of baseline CVD and diabetes.

8 Evidence type: retrospective observation
Risks for All-Cause Mortality, Cardiovascular Disease, and Diabetes Associated With the Metabolic Syndrome: A summary of the evidence. Earl S. Ford, MD, MPH Diabetes Care July 2005 vol. 28 no. 7 1769-1778

For studies that used the exact NCEP definition of the metabolic syndrome, random-effects estimates of combined relative risk were 1.27 (95% CI 0.90–1.78) for all-cause mortality, 1.65 (1.38–1.99) for cardiovascular disease, and 2.99 (1.96–4.57) for diabetes. For studies that used the most exact WHO definition of the metabolic syndrome, the fixed-effects estimates of relative risk were 1.37 (1.09–1.74) for all-cause mortality and 1.93 (1.39–2.67) for cardiovascular disease; the fixed-effects estimate was 2.60 (1.55–4.38) for coronary heart disease.

CONCLUSIONS—These estimates suggest that the population-attributable fraction for the metabolic syndrome, as it is currently conceived, is ∼6–7% for all-cause mortality, 12–17% for cardiovascular disease, and 30–52% for diabetes.

9 Evidence type: retrospective observation
Prevalence and Characteristics of the Metabolic Syndrome in Women with Polycystic Ovary Syndrome. Teimuraz Apridonidze, Paulina A. Essah, Maria J. Iuorno and John E. Nestler. The Journal of Clinical Endocrinology & Metabolism April 1, 2005 vol. 90 no. 4 1929-1935

The polycystic ovary syndrome (PCOS) is characterized by insulin resistance with compensatory hyperinsulinemia. Insulin resistance also plays a role in the metabolic syndrome (MBS). We hypothesized that the MBS is prevalent in PCOS and that women with both conditions would present with more hyperandrogenism and menstrual cycle irregularity than women with PCOS only.

We conducted a retrospective chart review of all women with PCOS seen over a 3-yr period at an endocrinology clinic. Of the 161 PCOS cases reviewed, 106 met the inclusion criteria. The women were divided into two groups: 1) women with PCOS and the MBS (n = 46); and 2) women with PCOS lacking the MBS (n = 60).

Prevalence of the MBS was 43%, nearly 2-fold higher than that reported for age-matched women in the general population. Women with PCOS had persistently higher prevalence rates of the MBS than women in the general population, regardless of matched age and body mass index ranges.

10 Evidence type: retrospective observation
Association of metabolic syndrome with Alzheimer disease: A population-based study. M. Vanhanen, PhD, K. Koivisto, MD, PhD, L. Moilanen, MD, PhD, E. L. Helkala, PhD, T. Hänninen, PhD, H. Soininen, MD, PhD, K. Kervinen, MD, PhD, Y. A. Kesäniemi, MD, PhD, M. Laakso, MD, PhD and J. Kuusisto, MD, PhD Neurology September 12, 2006 vol. 67 no. 5 843-847

Of the study subjects, 418 (43.6%) had MetS. Probable or possible AD was diagnosed in 45 subjects (4.7%). AD was more frequently detected in subjects with MetS than in subjects without MetS (7.2 vs 2.8%; p < 0.001). The prevalence of AD was higher in women with MetS vs women without the syndrome (8.3 vs 1.9%; p < 0.001), but in men with MetS, the prevalence of AD was not increased (3.8 vs 3.9%; p = 0.994). In univariate logistic regression analysis, MetS was significantly associated with AD (odds ratio [OR] 2.71; 95% CI 1.44 to 5.10). In multivariate logistic regression analysis including also apolipoprotein E4 phenotype, education, age, and total cholesterol, MetS was significantly associated with AD (OR 2.46; 95% CI 1.27 to 4.78). If only nondiabetic subjects were included in the multivariate analysis, MetS was still significantly associated with AD (OR 3.26; 95% CI 1.45 to 7.27).

11 Evidence type: review and meta-analysis
Metabolic syndrome and risk of cancer: a systematic review and meta-analysis. Esposito K, Chiodini P, Colao A, Lenzi A, Giugliano D. Diabetes Care. 2012 Nov;35(11):2402-11. doi: 10.2337/dc12-0336.

RESULTS: We analyzed 116 datasets from 43 articles, including 38,940 cases of cancer. In cohort studies in men, the presence of metabolic syndrome was associated with liver (relative risk 1.43, P < 0.0001), colorectal (1.25, P < 0.001), and bladder cancer (1.10, P = 0.013). In cohort studies in women, the presence of metabolic syndrome was associated with endometrial (1.61, P = 0.001), pancreatic (1.58, P < 0.0001), breast postmenopausal (1.56, P = 0.017), rectal (1.52, P = 0.005), and colorectal (1.34, P = 0.006) cancers. Associations with metabolic syndrome were stronger in women than in men for pancreatic (P = 0.01) and rectal (P = 0.01) cancers. Associations were different between ethnic groups: we recorded stronger associations in Asia populations for liver cancer (P = 0.002), in European populations for colorectal cancer in women (P = 0.004), and in U.S. populations (whites) for prostate cancer (P = 0.001).

CONCLUSIONS: Metabolic syndrome is associated with increased risk of common cancers; for some cancers, the risk differs betweens sexes, populations, and definitions of metabolic syndrome.

12 Evidence type: controlled experiment
Carbohydrate restriction has a more favorable impact on the metabolic syndrome than a low fat diet. Volek JS, Phinney SD, Forsythe CE, Quann EE, Wood RJ, Puglisi MJ, Kraemer WJ, Bibus DM, Fernandez ML, Feinman RD. Lipids. 2009 Apr;44(4):297-309. doi: 10.1007/s11745-008-3274-2. Epub 2008 Dec 12.


We recently proposed that the biological markers improved by carbohydrate restriction were precisely those that define the metabolic syndrome (MetS), and that the common thread was regulation of insulin as a control element. We specifically tested the idea with a 12-week study comparing two hypocaloric diets (approximately 1,500 kcal): a carbohydrate-restricted diet (CRD) (%carbohydrate:fat:protein = 12:59:28) and a low-fat diet (LFD) (56:24:20) in 40 subjects with atherogenic dyslipidemia. Both interventions led to improvements in several metabolic markers, but subjects following the CRD had consistently reduced glucose (-12%) and insulin (-50%) concentrations, insulin sensitivity (-55%), weight loss (-10%), decreased adiposity (-14%), and more favorable triacylglycerol (TAG) (-51%), HDL-C (13%) and total cholesterol/HDL-C ratio (-14%) responses. In addition to these markers for MetS, the CRD subjects showed more favorable responses to alternative indicators of cardiovascular risk: postprandial lipemia (-47%), the Apo B/Apo A-1 ratio (-16%), and LDL particle distribution. Despite a threefold higher intake of dietary saturated fat during the CRD, saturated fatty acids in TAG and cholesteryl ester were significantly decreased, as was palmitoleic acid (16:1n-7), an endogenous marker of lipogenesis, compared to subjects consuming the LFD. Serum retinol binding protein 4 has been linked to insulin-resistant states, and only the CRD decreased this marker (-20%). The findings provide support for unifying the disparate markers of MetS and for the proposed intimate connection with dietary carbohydrate. The results support the use of dietary carbohydrate restriction as an effective approach to improve features of MetS and cardiovascular risk.

13 Evidence type: non-randomized experiment
A Ketogenic Diet Favorably Affects Serum Biomarkers for Cardiovascular Disease in Normal-Weight Men. Matthew J. Sharman, William J. Kraemer, Dawn M. Love, Neva G. Avery, Ana L. Gómez, Timothy P. Scheett, and Jeff S. Volek. J. Nutr. July 1, 2002 vol. 132 no. 7 1879-1885

The primary objective of this study was to examine how healthy normolipidemic, normal-weight men respond to a ketogenic diet in terms of fasting and postprandial CVD biomarkers. Ketogenic diets have been criticized on the grounds they jeopardize health (8); however, very few studies have directly evaluated the effects of a ketogenic diet on fasting and postprandial risk factors for CVD. Subjects consumed a diet that consisted of 8% carbohydrate (<50 g/d), 61% fat, and 30% protein. Adaptation to this ketogenic diet resulted in significant reductions in fasting TAG (−33%), postprandial lipemia after a fat-rich meal (−29%), and fasting insulin concentrations (−34%). There were significant increases in LDL particle size, and no change in the oxidative LDL concentrations. There was a significant increase in HDL cholesterol at wk 3 after the ketogenic diet. Collectively, the responses in serum lipids, insulin and lipid subclasses to the ketogenic diet were favorable in terms of overall CVD risk profile.

14 Evidence type: controlled but not randomized experiment
Effect of low-calorie versus low-carbohydrate ketogenic diet in type 2 diabetes. Hussain TA, Mathew TC, Dashti AA, Asfar S, Al-Zaid N, Dashti HM. Nutrition. 2012 Oct;28(10):1016-21. doi: 10.1016/j.nut.2012.01.016. Epub 2012 Jun 5.

Three hundred and sixty-three overweight and obese participants were recruited from the Al-Shaab Clinic for a 24-wk diet intervention trial; 102 of them had type 2 diabetes. The participants were advised to choose LCD [low calorie diet] or LCKD [low carb ketogenic diet], depending on their preference. Body weight, body mass index, changes in waist circumference, blood glucose level, changes in hemoglobin and glycosylated hemoglobin, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, uric acid, urea and creatinine were determined before and at 4, 8, 12, 16, 20, and 24 wk after the administration of the LCD or LCKD. The initial dose of some antidiabetic medications was decreased to half and some were discontinued at the beginning of the dietary program in the LCKD group. Dietary counseling and further medication adjustment were done on a biweekly basis.


The LCD and LCKD had beneficial effects on all the parameters examined. Interestingly, these changes were more significant in subjects who were on the LCKD as compared with those on the LCD.

15 Evidence type: pilot study
The effects of a low-carbohydrate, ketogenic diet on the polycystic ovary syndrome: A pilot study. John C Mavropoulos, William S Yancy, Juanita Hepburn and Eric C Westman Nutrition & Metabolism 2005, 2:35

(Emphasis ours)

Eleven women with a body mass index >27 kg/m2 and a clinical diagnosis of PCOS were recruited from the community. They were instructed to limit their carbohydrate intake to 20 grams or less per day for 24 weeks. Participants returned every two weeks to an outpatient research clinic for measurements and reinforcement of dietary instruction. In the 5 women who completed the study, there were significant reductions from baseline to 24 weeks in body weight (-12%), percent free testosterone (-22%), LH/FSH ratio (-36%), and fasting insulin (-54%). There were non-significant decreases in insulin, glucose, testosterone, HgbA1c, triglyceride, and perceived body hair. Two women became pregnant despite previous infertility problems.

16 Evidence type: randomized, double-blind, placebo-controlled, multicenter trial
Study of the ketogenic agent AC-1202 in mild to moderate Alzheimer's disease: a randomized, double-blind, placebo-controlled, multicenter trial. Samuel T Henderson, Janet L Vogel, Linda J Barr, Fiona Garvin, Julie J Jones and Lauren C Costantini. Nutrition & Metabolism 2009, 6:31

AC-1202 significantly elevated a serum ketone body (β-hydroxybutyrate) 2 hours after administration when compared to Placebo. In each of the population groups, a significant difference was found between AC-1202 and Placebo in mean change from Baseline in ADAS-Cog score on Day 45: 1.9 point difference, p = 0.0235 in ITT; 2.53 point difference, p = 0.0324 in per protocol; 2.6 point difference, p = 0.0215 in dosage compliant. Among participants who did not carry the APOE4 allele (E4(-)), a significant difference was found between AC-1202 and Placebo in mean change from Baseline in ADAS-Cog score on Day 45 and Day 90. In the ITT population, E4(-) participants (N = 55) administered AC-1202 had a significant 4.77 point difference in mean change from Baseline in ADAS-Cog scores at Day 45 (p = 0.0005) and a 3.36 point difference at Day 90 (p = 0.0148) compared to Placebo. In the per protocol population, E4(-) participants receiving AC-1202 (N = 37) differed from placebo by 5.73 points at Day 45 (p = 0.0027) and by 4.39 points at Day 90 (p = 0.0143). In the dosage compliant population, E4(-) participants receiving AC-1202 differed from placebo by 6.26 points at Day 45 (p = 0.0011, N = 38) and 5.33 points at Day 90 (p = 0.0063, N = 35). Furthermore, a significant pharmacologic response was observed between serum β-hydroxybutyrate levels and change in ADAS-Cog scores in E4(-) subjects at Day 90 (p = 0.008).

17 Evidence type: review of experiments and case-studies
Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets. A Paoli, A Rubini, J S Volek and K A Grimaldi. European Journal of Clinical Nutrition (2013) 67, 789–796; doi:10.1038/ejcn.2013.116; published online 26 June 2013

[I]t seems a reasonable possibility that a very-low-carbohydrate diet could help to reduce the progression of some types of cancer, although at present the evidence is preliminary. In the 1980s, seminal animal studies by Tisdale and colleagues demonstrated that a ketogenic diet was capable to reduce tumour size in mice, whereas more recent research has provided evidence that ketogenic diets may reduce tumour progression in humans, at least as far as gastric and brain cancers are concerned. Although no randomized controlled trials with VLCKD have yet been conducted on patients and the bulk of evidence in relation to the influence of VLCKD on patient survival is still anecdotal, a very recent paper by Fine et al. suggests that the insulin inhibition caused by a ketogenic diet could be a feasible adjunctive treatment for patients with cancer. In summary, perhaps through glucose ‘starvation’ of tumour cells and by reducing the effect of direct insulin-related actions on cell growth, ketogenic diets show promise as an aid in at least some kind of cancer therapy and is deserving of further and deeper investigation—certainly the evidence justifies setting up clinical trials.


The medical-grade diet

This post is based on a talk we gave at BSidesLV on August 1st, 2013. You can also watch the video (20 minutes long).

In the face of a severe medical condition, typical dietary therapies have little or no power. The ketogenic diet, however, has proven potency. Here's how it's different.

In brief

  • Ketogenic diets are uniquely powerful among dietary therapies. They have been shown to have profound medical effects on serious conditions, especially in the brain.
  • These effects may be beneficial even if you aren't currently sick.
  • This power is accessible to practically anyone.

Diets are weak medicine

If someone tells you they know of a diet that treats a serious medical condition, you ought to be skeptical.

We don't mean a diet that restricts something you are allergic to or intolerant of — yes, we can prevent retardation in phenylketonurics by avoiding phenylalanine, and if you have gluten intolerance, avoiding gluten is a no-brainer.

However, if someone tells you that you can follow their diet and stop taking medication for a formidable disease like bipolar disorder, or that it would cure a progressive terminal disease like Alzheimer's or cancer, you would probably think that person was a quack. That's because dietary therapies for major diseases don't typically withstand scientific scrutiny. When tested in clinical trials, they show no significant results, or weak results at best.

Diets might help you feel better or might slightly improve your chances, but they are unlikely to cause the sort of profound changes in your body that can completely reverse the course of a major disease.

The ketogenic diet is an exception.

Ketogenic diets are strong medicine

The ketogenic diet is currently used by doctors to treat a major illness, not as an “alternative therapy” — but as a standard, proven medical practice. It is now recognized by neurologists that ketogenic diets are at least as effective as the best anti-epileptic drugs. Around 15% of epilepsy patients who are put on a keto diet by their neurologist become completely seizure free. About a third have a 90% reduction in seizures, and a third have better than a 50% reduction in seizures 1. That's state-of-the-art treatment for that disease.

A keto diet induces a distinct, favourable metabolic state

As we described in our article on keto-adaptation, a ketogenic diet shifts your metabolism from relying mostly on glucose for fuel, to relying mostly on fuels derived from fat (including ketone bodies — a fuel used by all human bodies, but used in greater quantities when on a keto diet). This change has extensive effects at both the cellular level, and the whole-body level.

It causes profound effects in the brain. Although the mechanisms aren't fully understood, it is well-established that ketogenic diets are neuroprotective against a variety of insults. That is, they protect against different kinds of brain damage. For example, in animal experiments, those animals on a ketogenic diet sustain significantly less brain damage after artificially induced stroke 2 or trauma 3. It even protects against damage from nerve gas 4.

Ketogenic diets also improve conditions associated with heart disease and diabetes, such as high triglycerides and low HDL (“good cholesterol”) 5, insulin resistance 6, and obesity. 7

Moreover, there is preliminary evidence that ketogenic diets are effective against other serious conditions, including bipolar disorder 8, Alzheimer's disease 9, and cancer 10.

Finally, on a keto diet your energy supply is managed more directly by your body. So it makes sense that energy, focus, and mood would become more stable. This has been reported anecdotally and we've previously given a possible explanation for it.

Try this at home!

Ketogenic diets are safe. Like starting an exercise program, starting a keto diet doesn't require a prescription or the supervision of a doctor, except in special cases footnote †. It's not difficult to do (though there are some common pitfalls). The potential benefits are high and the evidence for those benefits is strong. As we argue in How to Judge a Health Practice, this is a rare and valuable combination of qualities.


  • Ketogenic diets are recognized as being at least as powerful as drugs in at least one major clinical condition, and there is reason to believe they are useful against others.
  • The effects may be beneficial even if you currently consider yourself to be healthy. Perhaps you could be even more healthy!
  • It's easy and practical to try a ketogenic diet yourself.

footnote †

Like starting an exercise program, starting a keto diet is safe for healthy people. However, if you have a dangerous or unstable medical condition—for example you are in danger of having a heart attack or you have bipolar disorder—you should of course consult your doctor before doing something like starting an exercise program or a keto diet.

Also, of course, you should always consult a doctor before discontinuing a medication or changing your dosage. This is particularly relevant to keto diet, because for some conditions the diet could cause you to need less of your medication, such as for blood pressure, diabetes, epilepsy, or bipolar. Therefore, if you go on a keto diet and keep taking the same dosage of your medication, then you may end up taking too much medication for your needs, which itself could be dangerous. On the other hand, reducing or discontinuing your medication could be dangerous. Therefore, if you are currently taking a medication, you should consult your doctor before starting a keto diet.

This is not because keto diet is unsafe! At least, no more so than exercising. It's just that if you have a dangerous or unstable medical condition or you are taking prescription medications, then you have to be extra careful about making changes.


1 Evidence type: review of clinical reports
Neal EG, Cross JH. Efficacy of dietary treatments for epilepsy. J Hum Nutr Diet. 2010 Apr;23(2):113-9. doi: 10.1111/j.1365-277X.2010.01043.x.

There have been two systematic reviews on the efficacy of the KD. The first included 11 studies published since 1970 (Lefevre & Aronson, 2000). Using a combined analysis of outcome data, the authors reported 15.8% of children to be seizure free and 55.8% to have a greater than 50% reduction in seizures, and it was concluded that there was sufficient evidence to determine that the diet is efficacious in children with intractable epilepsy. A more recent review of 14 studies arrived at the same conclusion (Keene, 2006), reporting an average of 15.6% of a total collective population of 972 patients to be seizure free after 6 months, with 33% having a greater than 50% seizure reduction. A statistical meta-analysis of 19 studies and a total of 1084 patients (Henderson et al., 2006) found the diet reduced seizures by >90% in one-third of the patients, regardless of age or seizure type; the pooled odds ratio of treatment success among patients staying on the diet relative to those discontinuing was 2.25.

2 Evidence type: review of controlled animal experiments
Carl E. Stafstrom and Jong M. Rho. The Ketogenic Diet as a Treatment Paradigm for Diverse Neurological Disorders Front Pharmacol. 2012; 3: 59. Published online 2012 April 9. Prepublished online 2012 January 25. doi: 10.3389/fphar.2012.00059

To date, no clinical trials of the KD have been performed in patients with stroke, but several animal studies of hypoxia-ischemia support the potential beneficial effect of the diet. Most of these models entail pre-treatment with the KD (or with BHB), resulting in decreased structural and functional damage from the stroke.

3 Evidence type: review of controlled animal experiments
Carl E. Stafstrom and Jong M. Rho. The Ketogenic Diet as a Treatment Paradigm for Diverse Neurological Disorders Front Pharmacol. 2012; 3: 59. Published online 2012 April 9. Prepublished online 2012 January 25. doi: 10.3389/fphar.2012.00059

Several recent animal studies support this idea [that dietary therapy might ameliorate brain injury and possibly, long-term consequences such as epilepsy], and investigators have principally focused on ketone bodies (Prins, 2008a). Using a controlled cortical impact (CCI) injury model, Prins et al. (2005) showed that pre-treatment with a KD significantly reduced cortical contusion volume in an age-related manner that correlated with maturation-dependent differences in cerebral metabolism and ketone utilization. Later, they showed that cognitive and motor functioning was also improved with KD treatment (Appelberg et al., 2009). Further, using a weight drop model, Hu et al. (2009) showed that the KD pre-treatment reduced Bcl-2 (also known as Bax) mRNA and protein levels 72 h after trauma, indicating that apoptotic neurodegeneration could be prevented with this diet. Consistent with these observations, it was found that fasting – which shares the key feature of ketosis with the KD – led to significant tissue sparing in brain following CCI injury, and that again ketosis (with improved mitochondrial functioning) rather than the relative hypoglycemia seen with fasting was the important determinant of neuroprotection (Davis et al., 2008).

4 Evidence type: controlled animal experiments
Jeffrey L. Langston, Todd M. Myers Diet composition modifies the toxicity of repeated soman exposure in rats. Neurotoxicology. 2011 Jun;32(3):342-9. doi: 10.1016/j.neuro.2011.03.001. Epub 2011 Mar 17.

Differences in toxicity as a function of diet composition became apparent during the first week. Specifically, rats fed the glucose-enriched diet showed pronounced intoxication during Week 1, resulting in imperfect survival, weight loss, and deteriorated avoidance performance relative to all other groups. All rats fed the glucose-enriched diet died by the end of exposure Week 2. In contrast, only 10% of animals fed the standard diet died by the end of Week 2. Also in Week 2, weight loss and disrupted avoidance performance were apparent for all groups except for those fed the ketogenic diet. This differential effect of diet composition became even more striking in Week 3 when survival in the standard and choline diet groups approximated 50%, whereas survival equaled 90% in the ketogenic diet group.

5 Evidence type: controlled clinical trial and review of past trials
Westman EC, Yancy WS Jr, Olsen MK, Dudley T, Guyton JR. Effect of a low-carbohydrate, ketogenic diet program compared to a low-fat diet on fasting lipoprotein subclasses. Int J Cardiol. 2006 Jun 16;110(2):212-6. Epub 2005 Nov 16.

Recent research implicates dietary carbohydrates, especially refined carbohydrates, as a risk factor for cardiovascular disease [1]. In recent studies, a low-carbohydrate, ketogenic diet (LCKD) led to weight loss and improvements in high-density lipoprotein cholesterol (HDL-C) and serum triglyceride over a 6- to 12-month period [2], [3], [4] and [5]. Because obesity, low HDL-C, and elevated triglyceride are recognized as cardiovascular risk factors, and can be made worse by a low-fat/high-carbohydrate diet [6], [7] and [8], an LCKD might be a candidate treatment for these conditions.


Triglyceride is increasingly thought to be important in the pathogenesis of atherosclerosis, and treatments that lower triglyceride and raise HDL-cholesterol have been shown to reduce major coronary events [38] and [39]. High triglyceride levels promote the formation of small LDL by a process of cholesterol ester/triglyceride exchange and subsequent lipase action on triglyceride-enriched LDL [40]. Small HDL appear to be formed by a similar process and are then cleared from the circulation more rapidly than large HDL [41]. Based on the findings of this study, the reduction of dietary carbohydrate should be evaluated as a treatment for hypertriglyceridemia, low HDL-C, and ultimately atherosclerosis.

6 Evidence type: small clinical trial
Boden G, Sargrad K, Homko C, Mozzoli M, Stein TP. Effect of a low-carbohydrate diet on appetite, blood glucose levels, and insulin resistance in obese patients with type 2 diabetes. Ann Intern Med. 2005 Mar 15;142(6):403-11.

(Emphasis ours)

On the low-carbohydrate diet, mean energy intake decreased from 3111 kcal/d to 2164 kcal/d. The mean energy deficit of 1027 kcal/d (median, 737 kcal/d) completely accounted for the weight loss of 1.65 kg in 14 days (median, 1.34 kg in 14 days). Mean 24-hour plasma profiles of glucose levels normalized, mean hemoglobin A1c decreased from 7.3% to 6.8%, and insulin sensitivity improved by approximately 75%. Mean plasma triglyceride and cholesterol levels decreased (change, -35% and -10%, respectively).

7 Evidence type: meta-study of controlled trials
Hession M, Rolland C, Kulkarni U, Wise A, Broom J. Systematic review of randomized controlled trials of low-carbohydrate vs. low-fat/low-calorie diets in the management of obesity and its comorbidities. Obes Rev. 2009 Jan;10(1):36-50. doi: 10.1111/j.1467-789X.2008.00518.x. Epub 2008 Aug 11.

(Emphasis ours)

Note that these studies were on low carb diets that were not even necessarily so low as to be ketogenic.


There are few studies comparing the effects of low-carbohydrate/high-protein diets with low-fat/high-carbohydrate diets for obesity and cardiovascular disease risk. This systematic review focuses on randomized controlled trials of low-carbohydrate diets compared with low-fat/low-calorie diets. Studies conducted in adult populations with mean or median body mass index of > or =28 kg m(-2) were included. Thirteen electronic databases were searched and randomized controlled trials from January 2000 to March 2007 were evaluated. Trials were included if they lasted at least 6 months and assessed the weight-loss effects of low-carbohydrate diets against low-fat/low-calorie diets. For each study, data were abstracted and checked by two researchers prior to electronic data entry. The computer program Review Manager 4.2.2 was used for the data analysis. Thirteen articles met the inclusion criteria. There were significant differences between the groups for weight, high-density lipoprotein cholesterol, triacylglycerols and systolic blood pressure, favouring the low-carbohydrate diet. There was a higher attrition rate in the low-fat compared with the low-carbohydrate groups suggesting a patient preference for a low-carbohydrate/high-protein approach as opposed to the Public Health preference of a low-fat/high-carbohydrate diet. Evidence from this systematic review demonstrates that low-carbohydrate/high-protein diets are more effective at 6 months and are as effective, if not more, as low-fat diets in reducing weight and cardiovascular disease risk up to 1 year. More evidence and longer-term studies are needed to assess the long-term cardiovascular benefits from the weight loss achieved using these diets.

8 Evidence type: case studies
James R. Phelps, Susan V. Siemers & Rif S. El-Mallakh The ketogenic diet for type II bipolar disorder. Neurocase: The Neural Basis of Cognition DOI: 10.1080/13554794.2012.690421

Successful mood stabilizing treatments reduce intracellular sodium in an activity-dependent manner. This can also be achieved with acidification of the blood, as is the case with the ketogenic diet. Two women with type II bipolar disorder were able to maintain ketosis for prolonged periods of time (2 and 3 years, respectively). Both experienced mood stabilization that exceeded that achieved with medication; experienced a significant subjective improvement that was distinctly related to ketosis; and tolerated the diet well. There were no significant adverse effects in either case. These cases demonstrate that the ketogenic diet is a potentially sustainable option for mood stabilization in type II bipolar illness. They also support the hypothesis that acidic plasma may stabilize mood, perhaps by reducing intracellular sodium and calcium.

Evidence type: review of hypotheses and controlled animal experiments
Carl E. Stafstrom and Jong M. Rho. The Ketogenic Diet as a Treatment Paradigm for Diverse Neurological Disorders Front Pharmacol. 2012; 3: 59. Published online 2012 April 9. Prepublished online 2012 January 25. doi: 10.3389/fphar.2012.00059

Mood stabilizing properties of the KD have been hypothesized (El-Mallakh and Paskitti, 2001), but no clinical studies have been conducted as of this writing. The potential role of the KD in depression has been studied in the forced choice model of depression in rats, which led to a beneficial effect similar to that afforded by conventional antidepressants (Murphy et al., 2004; Murphy and Burnham, 2006).

9 Evidence type: review of human and animal experiments
Carl E. Stafstrom and Jong M. Rho. The Ketogenic Diet as a Treatment Paradigm for Diverse Neurological Disorders Front Pharmacol. 2012; 3: 59. Published online 2012 April 9. Prepublished online 2012 January 25. doi: 10.3389/fphar.2012.00059

Clinical studies to date have been equivocal but promising. A randomized double-blind, placebo-controlled trial of a MCT KD resulted in significantly improved cognitive functioning in APOε4-negative patients with AD but not in patients with a APOε4 mutation (Henderson et al., 2009). In this study, the primary cognitive end-points measured were the mean change from baseline in the AD Assessment Scale-Cognitive subscale, and global scores in the AD Cooperative Study – Clinical Global Impression of Change (Henderson et al., 2009). This significant clinical improvement was considered to be secondary to improved mitochondrial function, since ketone bodies (specifically, beta-hydroxybutyrate or BHB) have been shown to protect against the toxic effects of β-amyloid on neurons in culture (Kashiwaya et al., 2000). Alternatively, the KD may actually decrease amounts of β-amyloid deposition (VanderAuwera et al., 2005).


[T]here is growing evidence that the KD may be an effective treatment for AD through a variety of metabolism-induced mechanisms that reduce oxidative stress and neuroinflammation, and enhance bioenergetic profiles – largely through enhanced mitochondrial functioning.

10 Evidence type: plausible mechanism and case studies
Seyfried TN, Marsh J, Shelton LM, Huysentruyt LC, Mukherjee P. Is the restricted ketogenic diet a viable alternative to the standard of care for managing malignant brain cancer? Epilepsy Res. 2012 Jul;100(3):310-26. doi: 10.1016/j.eplepsyres.2011.06.017. Epub 2011 Aug 31.


Malignant brain cancer persists as a major disease of morbidity and mortality. The failure to recognize brain cancer as a disease of energy metabolism has contributed in large part to the failure in management. As long as brain tumor cells have access to glucose and glutamine, the disease will progress. The current standard of care provides brain tumors with access to glucose and glutamine. The high fat low carbohydrate ketogenic diet (KD) will target glucose availability and possibly that of glutamine when administered in carefully restricted amounts to reduce total caloric intake and circulating levels of glucose. The restricted KD (RKD) targets major signaling pathways associated with glucose and glutamine metabolism including the IGF-1/PI3K/Akt/Hif pathway. The RKD is anti-angiogenic, anti-invasive, anti-inflammatory, and pro-apoptotic when evaluated in mice with malignant brain cancer. The therapeutic efficacy of the restricted KD can be enhanced when combined with drugs that also target glucose and glutamine. Therapeutic efficacy of the RKD was also seen against malignant gliomas in human case reports. Hence, the RKD can be an effective non-toxic therapeutic option to the current standard of care for inhibiting the growth and invasive properties of malignant brain cancer.