1.1 The ketogenic diet is safe and more effective than other diets

1 Toffler Alvin Future Shock. 2 Aurora S.

Stouffer G.A.

Kucharska-Newton A.M.

Qamar A.

Vaduganathan M.

Pandey A.

Caughey M.C. Twenty-year trends and sex differences in young adults hospitalized with acute myocardial infarction: the ARIC community surveillance study. 3 Cohen E.

Cragg M.

deFonseka J.

et al. Statistical review of US macronutrient consumption data, 1965-2011: Americans have been following dietary guidelines, coincident with the rise in obesity. It has been said that: “The illiterate of the 21st century will not be those who cannot read and write, but those who cannot learn, unlearn, and relearn.” [] Despite nearly 50 years of clinging to the dogma that saturated fat is detrimental to health, that total cholesterol is associated with mortality, and despite developing extremely effective therapies to reduce cholesterol, we continue to see an ever-expanding epidemic of obesity, diabetes, and increasing incidence of coronary heart disease (CHD). Reversing decades of decreasing coronary heart disease incidence and prevalence, for the past decade trends are now increasing, especially in those under 50 years-male and female []. Lead by the United States Department of Agriculture, we have developed healthy food guidelines globally that counsel us to reduce fat intake, particularly saturated fat, in order to reduce our future risk of heart disease ( https://health.gov/dietaryguidelines/2015/guidelines/ ). Our population has listened and supported by the food industry has reduced our intake of fat, and particularly saturated fats, and as a consequence increased our consumption of carbohydrates which of course are broken down into sugars in our bodies []. There has been a direct correlation with the reduction of fat intake and the increase in carbohydrate intake with the obesity epidemic and the concordant increase in type II diabetes that we have witnessed over the past several decades ( https://www.cdc.gov/obesity/data/prevalence-maps.html ).

4 Keys A. Diet and the epidemiology of coronary heart disease. 5 Harcombe Z.

Baker J.S.

Cooper S.M.

Davies B.

Sculthorpe N.

DiNicolantonio J.J.

Grace F. Evidence from randomised controlled trials did not support the introduction of dietary fat guidelines in 1977 and 1983: a systematic review and meta-analysis. 6 Siri-Tarino P.W.

Sun Q.

Hu F.B.

Krauss R.M. Meta-analysis of prospective cohort studies evaluating the association of saturated fat with cardiovascular disease. 7 Ascherio I.

Katan M.B.

Zock P.L.

Stampfer M.J.

Willett W.C. Trans fatty acids and coronary heart disease. Dr. Ancel Keys, the most influential nutrition scientist in modern history, was an effective proponent of the so-called “diet heart hypothesis” []. Yet, the diet heart hypothesis remains in search of evidence-based validation. There was no evidence from randomized control trials to support the concept that fat is harmful at the time of the introduction of food guidelines in the late 1970s and early 1980s, nor has any more evidence that saturated fats are harmful accumulated since []. There is universal agreement that trans fats are detrimental to health and these have been phased out of foods as a consequence [].

8 Kabir Z.

Connolly G.N.

Clancy L.

Koh H.K.

Capewell S. Coronary heart disease death and decreased smoking prevalence in Massachusetts,1993–2003. 2 Aurora S.

Stouffer G.A.

Kucharska-Newton A.M.

Qamar A.

Vaduganathan M.

Pandey A.

Caughey M.C. Twenty-year trends and sex differences in young adults hospitalized with acute myocardial infarction: the ARIC community surveillance study. 3 Cohen E.

Cragg M.

deFonseka J.

et al. Statistical review of US macronutrient consumption data, 1965-2011: Americans have been following dietary guidelines, coincident with the rise in obesity. There is evidence that the decades-long trend to reduce the incidence and prevalence of CHD is ending. Decreased CHD rates have been largely attributed to successful public policy which reduced smoking rates across the Western world []. Unfortunately, over the past decade, we have seen that trend reverse. The incidence of CHD has been increasing. Even more concerning is the finding that premature myocardial infarction in subjects in their 40s and 50s occur often in patients with obesity, hypertension, and diabetes mellitus []. This is despite Americans following the low-fat recommendations since the 1980's with the consequence of consuming more carbohydrates and the population gaining more weight than ever before []. Indeed, unlike smoking, nutritional guidelines appear to have been a public policy failure.

9 Ramsden C.E.

Zamora D.

Majchrzak-Hong S.

Faurot K.R.

Broste S.K.

Frantz R.P.

Hibbeln J.R. Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment (1968-73). What was the evidence that has created the past half century of nutritional advice? Indeed, it was shaky from the start. The principle proponent of the diet heart hypothesis, Dr. Ancel Keys and his team, performed the Minnesota Coronary Experiment from 1968 to 1972 replacing the standard American diet of the time which was approximately 45% fat with polyunsaturated oils, chiefly linoleic acid, and demonstrated as predicted that there was a decrease in total cholesterol []. Unfortunately, there was no change in mortality, although there was a signal of increased mortality in patients at highest risk, over age 65. However, because the investigators did not believe their own results, it was not until 2016 that these results were published. Had they been published at the time and associated with the totality of other evidence, it is quite probable that the guidelines to reduce fat and increase carbohydrates in the diet would not have been accepted and we might have avoided the current epidemic of obesity and diabetes.

10 Gómez-Hernández A.

Beneit N.

Díaz-Castroverde S.

Escribano Ó. Differential role of adipose tissues in obesity and related metabolic and vascular complications. 11 Tahara N.

Kai H.

Yamagishi S.

Mizoguchi M.

Nakaura H.

Ishibashi M.

Kaida H.

Baba K.

Hayabuchi N.

Imaizumi T. Vascular inflammation evaluated by [18F]-fluorodeoxyglucose positron emission tomography is associated with the metabolic syndrome. 12 Pyörälä M.

Miettinen H.

Laakso M.

Pyörälä K. Hyperinsulinemia predicts coronary heart disease risk in healthy middle-aged men: the 22-year follow-up results of the Helsinki Policemen Study. Why is obesity such a major risk factor for CHD? It is most likely secondary to the development of visceral obesity, associated with hyperinsulinemia/insulin resistance, leading to enhanced local and systemic production of inflammatory cytokines/adipokines, and the ensuing dyslipidemia characterized by high-circulating triglycerides and low HDL []. Inflammation in vessel walls leads to medium vessel hypertrophy and hypertension that is present in 80% of overweight and obese individuals. Inflammation in small and medium arteries of the legs, kidneys and the heart leads to peripheral arterial disease, nephrosclerosis and CHD. A heightened systemic inflammatory state leads to insulin resistance and higher circulating insulin levels. Higher fasting insulin levels have been associated with higher risk of CHD in subjects without overt diabetes mellitus [].

13 Penson P.E.

Long D.L.

Howard G.

Toth P.P.

Muntner P.

Howard V.J.

Safford M.M.

Jones S.R.

Martin S.S.

Mazidi M.

Catapano A.L.

Banach M. Associations between very low concentrations of low density lipoprotein cholesterol, high sensitivity C-reactive protein, and health outcomes in the Reasons for Geographical and Racial Differences in Stroke (REGARDS) study. 14 Yang J.S.

Gerber J.N.

You H.J. Association between fasting insulin and high-sensitivity C reactive protein in Korean adults. In cardiovascular science there has been increasing interest in inflammation as an explanation for the so called “residual risk” after patients’ LDL cholesterol is controlled by statins. The REGARD registry showed that patients with an LDL cholesterol ≤1.8 mmol/L who had a high-sensitivity CRP (hsCRP) serum level ≥ 2 mg/L had a higher stroke risk, as well as all-cause and CHD mortality than patients with a hsCRP level <2 mg/L []. The higher the fasting insulin the greater the likelihood of having an elevated hsCRP; at least one study showed that patients with an insulin level greater than 15 uIU/mL had a 30% greater risk of having an hsCRP ≥ 2 mg/dl [].

15 Otvos J.D.

Mora S.

Shalaurova I.

Greenland P.

Mackey R.H.

Goff Jr., D.C. Clinical implications of discordance between low-density lipoprotein cholesterol and particle number. 16 Toth P.P.

Grabner M.

Punekar R.S.

Quimbo R.A.

Cziraky M.J.

Jacobson T.A. Cardiovascular risk in patients achieving low-density lipoprotein cholesterol and particle targets. 17 Manickam P.

Rathod A.

Panaich S.

Hari P.

Veeranna V.

Badheka A.

Jacob S.

Afonso L. Comparative prognostic utility of conventional and novel lipid parameters for cardiovascular disease risk prediction: do novel lipid parameters offer an advantage?. 18 Hulthe J.

Bokemark L.

Wikstrand J.

Fagerberg B. The metabolic syndrome, LDL particle size, and atherosclerosis: the Atherosclerosis and Insulin Resistance (AIR) study. 19 Krauss R.M.

Blanche P.J.

Rawlings R.S.

Fernstrom H.S.

Williams P.T. Separate effects of reduced carbohydrate intake and weight loss on atherogenic dyslipidemia. Perspectives on better understanding lipid profile and CHD risk are changing. It is now recognized that it is not simply the LDL cholesterol, but the composition of the lipoprotein that more accurately determines risk []. Again, there is a relationship between LDL particle size and obesity and insulin resistance []. Patients with high small dense LDL particles have a much higher risk of CHD events compared with those who have larger more buoyant LDL particles. This situation often creates a discordance with patients with lower LDL cholesterols levels but higher particle counts demonstrating a higher risk of CHD events, while patients with higher LDL cholesterol but lower particle counts have a lower risk of events. Macronutrient studies have shown that a diet high in saturated fatty acids actually increases LDL particle size compared to low-fat high carbohydrate diets that guidelines have encouraged the public to consume [].

20 Maiolino G.

Rossitto G.

Caielli P.

Bisogni V.

Rossi G.P.

Calò L.A. The role of oxidized low-density lipoproteins in atherosclerosis: the myths and the facts. 21 Ali W.

Kushwaha U.P.

Wamique M.

Vishwakarma P.

Tasleem M.

et al. Oxidized LDL as a biomarker in metabolic syndrome. Thus, it appears that LDL must be modified to become atherogenic []. How it is packaged by its lipoprotein moiety and how that package is modified in the circulation and vessel wall determines its role in atherosclerosis. Modified or oxidized LDL has less affinity for LDL receptors and, therefore, longer circulation times. In the vessels wall, scavenger receptors on macrophages have a higher affinity for oxidized LDL leading to increased uptake, foam cell transformation and apoptosis, essential ingredients for the formation of vulnerable atherosclerotic plaques. Oxidized LDL concentrations are higher in insulin resistance, the metabolic syndrome, and diabetes mellitus type 2 [].

22 King G.L.

Park K.

Li Q. Selective insulin resistance and the development of cardiovascular diseases in diabetes: the 2015 Edwin Bierman Award Lecture. Insulin, itself, has a dichotomous impact on the vessel wall. In metabolically healthy individuals in an insulin sensitive state, low levels of insulin are associated with healthy nitric oxide production, vasodilation, lower monocyte adhesion, lower local and systemic inflammation, and less oxidative stress. In the metabolically unwell patient with chronically high insulin levels due to insulin resistance, insulin exerts the opposite effect once it interacts with its receptor, increasing levels of plasminogen activator-1, and endothelin leading to a pro-vasoconstrictive state, smooth muscle proliferative state and a milieu that promotes migration of monocytes and smooth muscle cells [].

23 Sackner-Bernstein J.

Kanter D.

Kaul S. Dietary intervention for overweight and obese adults: comparison of low-carbohydrate and low-fat diets. A Meta-Analysis. 24 Schauer P.R.

Bhatt D.L.

Kirwan J.P.

et al. Bariatric surgery versus intensive medical therapy for diabetes — 5-year outcomes. 25 Sarah J.

Hallberg S.J.

McKenzie A.L.

Williams P.T.

et al. Effectiveness and safety of a novel care model for the management of type 2 diabetes at 1 year: an open-label, non-randomized, controlled study. 26 Bhanpuri N.H.

Hallberg S.J.

Williams P.T.

et al. Cardiovascular disease risk factor responses to a type 2 diabetes care model including nutritional ketosis induced by sustained carbohydrate restriction at 1 year: an open label, non-randomized, controlled study. Is there a way to reverse the diabetes and obesity epidemic? Certainly, the last 5–10 years of research have suggested that low carbohydrate, high-fat diets are associated with significantly greater weight loss compared with low-fat diets in head to head randomized control trials []. Similarly, for patients most metabolically unwell, those with diabetes mellitus type 2, the most effective treatment has been bariatric surgery []. Can obesity, a lifestyle disease, only be reversed by surgical intervention? More research is confirming that very low carbohydrate diets can effectively reverse the metabolic abnormalities of patients with diabetes mellitus type 2. Compared with low fat diets, carbohydrate restriction produces significantly greater reduction in hemoglobin A1c, and weight loss in patients with diabetes mellitus type 2. In a non-randomized clinical trial in patients with type 2 diabetes mellitus, 262 patients received a very low carbohydrate diet and 87 controls received a diet based on standard guidelines []. The intervention group was treated with a ketogenic diet with blood measurements confirming nutritional ketosis, with beta-hydroxybutyrate levels between 0.4 and 0.6 mmol/L. Patients lost between 10 and 15% of body weight. Inflammatory responses, as measured by hsCRP and white blood cell count, decreased significantly while they did not change or continued to increase in the usual care group. Virtually every important biomarker changed in a positive direction including triglycerides, HDL, small dense LDL particle count, and, most importantly, the 10-year risk of atherosclerotic cardiovascular disease decreased despite an increasing LDL cholesterol level. Indeed, the observation that LDL-C rises but its apolipoprotein B (apoB) does not, suggests that the particles have favorably transformed, which is confirmed by the increase in LDL particle size and the dramatic fall in the far more atherogenic small dense LDL-P. This would portend an event free advantage for those treated with a ketogenic diet. Conversely, in the usual care group, virtually every biomarker continued to deteriorate over follow-up including the predicted 10-year risk of cardiovascular events []. The LDL cholesterol, however, decreased. Unfortunately, the usual care low-fat diet also further reduced LDL particle size in these metabolically challenged diabetic patients. Have we been focusing on the wrong biomarker of risk? Is there any wonder why we have considered type 2 diabetes mellitus to be a largely progressive irreversible disease? Not surprisingly, in the intervention cohort, average hemoglobin A1c decreased from baseline 7.6%–6.3% at one year. From a cost perspective, medication utilization was dramatically reduced with half the patients completely discontinuing insulin, and all coming off sulfonylureas as opposed to the usual care group where insulin doses and sulfonylurea use continued to increase.

It is time for a paradigm shift in the thinking about risk factors for CHD. The epidemiological experiment to decrease fat in the diet has failed and has only made the population sick. We are seeing the adverse outcomes of misguided dogma that focused only on LDL cholesterol levels. It has been too simplistic and has led to an increased prevalence of heart disease in young people, who have been exposed to the toxic refined carbohydrate diet for their entire lives. It is sugar and processed carbohydrates that lead to insulin resistance, and then to a pro-inflammatory state that leads to many chronic conditions of our era, including hypertension, peripheral arterial disease, CHD, atrial fibrillation, heart failure with or without preserved ejection fraction, chronic renal insufficiency among many others. With 7/10 adults and 4/10 children, now overweight or obese, we need an urgent call to action to use science and not dogma to drive recommendations. Recommendations should not be based on nutritional and scientific bias. Indeed, we are now seeing the convergence of environmentalism, animal rights activism, plant-based dietism using weak association data to drive policy agenda. If we don't get this right, we will continue to witness an ever-expanding epidemic of obesity and its consequences in the population, with escalating astronomical costs both to individuals and to society. It is time for transparent science to drive agendas not dogma.