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• Low carbohydrate diet SHOULD be recommended for patients diagnosed with familial hypercholesterolaemia and metabolic syndrome
  David M Diamond, Abdullah A Alabdulgader, Michel de Lorgeril, Zoe Harcombe, Malcolm Kendrick, Aseem Malhotra, Blair J O'Neill, Uffe Ravnskov, Sherif Sultan and Jeff Volek
  Published on: 23 March 2022

• Published on: 23 March 2022

  Low carbohydrate diet SHOULD be recommended for patients diagnosed with familial hypercholesterolaemia and metabolic syndrome

  • David M Diamond, Professor University of South Florida, Tampa, FL USA
  • Other Contributors:
    • Abdullah A Alabdulgader, Congenital Cardiologist/Electrophysiologist
    • Michel de Lorgeril, Cardiologist
    • Zoe Harcombe, Independent Researcher
    • Malcolm Kendrick, General Practitioner
    • Aseem Malhotra, Cardiologist
    • Blair J O'Neill, Cardiologist
    • Uffe Ravnskov, Medical Doctor
    • Sherif Sultan, Vascular Surgeon
    • Jeff Volek, Registered Dietitian and Professor

  Pawlak1 critiqued our challenge to conventional dietary guidelines for people diagnosed with familial hypercholesterolaemia (FH)2. Indeed, his criticism was so incriminatory that he stated our recommendation “constitutes malpractice”. Considering the gravity of his claim, especially as it is levied against co-authors who are mostly MDs, it is important to disclose what we actually recommended, and to point out the flawed evidence Pawlak used to claim that we have committed malpractice.

  First, Pawlak misunderstood the purpose of our paper. We did not question “the efficacy of low-saturated fat, low-cholesterol diet to reduce LDL cholesterol”, as he stated. We provided strong support for the hypothesis that factors other than LDL-C, such as smoking, hypercoagulation and hyperinsulinemia, have a potent influence on the incidence of coronary events in FH that dwarfs that of LDL-C3. For example, in our Figure 4 we illustrated the findings of Gaudet et al.4, who demonstrated that FH people without obesity or insulin resistance had no greater rate of coronary heart disease (CHD) than non-FH people. In contrast, obese, insulin-resistant FH people had over 7 times greater incidence of CHD than non-FH people. Moreover, in recent work we have elaborated on the extensive, but largely ignored, literature demonstrating that factors other than LDL-C, such as increased levels of coagulation factors, explain why only a subset of FH individuals develop premature CHD5. Finally, we in...

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  Pawlak1 critiqued our challenge to conventional dietary guidelines for people diagnosed with familial hypercholesterolaemia (FH)2. Indeed, his criticism was so incriminatory that he stated our recommendation “constitutes malpractice”. Considering the gravity of his claim, especially as it is levied against co-authors who are mostly MDs, it is important to disclose what we actually recommended, and to point out the flawed evidence Pawlak used to claim that we have committed malpractice.

  First, Pawlak misunderstood the purpose of our paper. We did not question “the efficacy of low-saturated fat, low-cholesterol diet to reduce LDL cholesterol”, as he stated. We provided strong support for the hypothesis that factors other than LDL-C, such as smoking, hypercoagulation and hyperinsulinemia, have a potent influence on the incidence of coronary events in FH that dwarfs that of LDL-C3. For example, in our Figure 4 we illustrated the findings of Gaudet et al.4, who demonstrated that FH people without obesity or insulin resistance had no greater rate of coronary heart disease (CHD) than non-FH people. In contrast, obese, insulin-resistant FH people had over 7 times greater incidence of CHD than non-FH people. Moreover, in recent work we have elaborated on the extensive, but largely ignored, literature demonstrating that factors other than LDL-C, such as increased levels of coagulation factors, explain why only a subset of FH individuals develop premature CHD5. Finally, we included in our paper a review of the literature demonstrating that elderly people with the highest levels of LDL-C show either an equal or lower rate of mortality than people with the lowest LDL-C6. Other work, as well, has shown that FH people at 70 years of age have a significantly lower 10 year mortality rate compared to the general population7. Therefore, we find no reason to recommend that FH people reduce their LDL-C levels with diet or medication.

  The primary purpose of our paper was to point out that low cholesterol, low saturated fat diets have been recommended to FH individuals for over 80 years, without any evidence of benefit. Indeed, we stated in our paper that diets that are low in fat are therefore high in carbohydrates, which may promote an atherogenic biomarker profile. What we did recommend was that FH individuals with components of the metabolic syndrome, e.g., excess weight, hypertension, hyperinsulinemia or hyperglycemia, would benefit from a diet low in carbohydrates. Support for this recommendation is based in the vast literature on clinical trials utilizing the low carbohydrate diet (LCD), which has shown its effectiveness in improving CHD-sensitive biomarkers, at a level equal to or superior to low fat diets8. The well-established benefits of an LCD in improving CHD-sensitive biomarkers supported our recommendation that a clinical trial should be performed with LCD only in FH individuals with components of the metabolic syndrome or excess hypercoagulation markers.

  Second, based on the findings of 3 publications, two of them conducted on non-FH rodents and one in non-FH people, Pawlak claimed that our recommendation of the LCD for FH would “exacerbate atherosclerosis”. It is therefore important to assess whether the findings of these three papers justify his concern that the LCD is inherently atherogenic.

  Two studies Pawlak cited were conducted on genetically manipulated mice designed to model human atherosclerosis9 10. Research on a rodent model of a human disease should be scrutinized closely to satisfy criteria in which the methods and biomarker outcomes are comparable to the human condition. These two studies do not satisfy these criteria. The diets of the animals are unlike a typical diet a human would consume, in general, and certainly do not match the diet of someone on an LCD. In the Foo et al.,9 study, the food was composed of sugar (8.4%), corn starch (3.6%), casein protein (45%) and milkfat (43%). This diet has no relevance to human nutrition, with one of numerous flaws being that an LCD is typically composed of 20-25% protein, 60-70% fat and 10-15% carbohydrates. Indeed, a diet that contains more protein than fat is likely to make a person ill. The second study by Kostogrys et al.,10 as well, contained a diet for the rodents with a dietary composition that no human should consume; it contained 52% protein, 12% sugar, 5% corn starch, 21% fat (butter), and the remainder as cellulose and minerals. Confirmation that these findings are unrelated to human research on LCD is that in both studies the mice developed hypertriglyceridemia, an effect that does not happen in people on LCD8. These rodent studies, therefore, have no translational value toward understanding LCD effects on CHD.

  Animal research that is more relevant to mechanisms underlying premature CHD in FH individuals is provided by the Watanabe rabbit model of FH, which has high cholesterol, elevated coagulation factors (Factor VIII and fibrinogen) and develops human-like atherosclerosis.11 12 It is of value that the development of atherosclerosis in the Watanable rabbit was prevented by probucol, a medication which also reduces cardiovascular events in FH people.13 Most importantly, probucol reduced coagulation factor levels without lowering their high cholesterol.12

  Pawlak cited a 20 year old clinical study that he asserted documented “the progression and the severity of CAD” (coronary artery disease) in people on an LCD. The problems with this cited study are so extensive they could fill a textbook on flawed scientific methods. First, the repeated blood work and cardiac imaging in this year-long intervention study would have had a very high cost, but no funding source was mentioned in the paper. Second, subjects were given dietary guidance, but the study did not include a registered dietician. Third, it is stated that each individual was questioned regarding dietary habits, but there is no record of what the subjects consumed. Specifically, there is no quantification of the categories, macronutrients or amount of food the subjects in the two groups ate. Fourth, there is a vague, unsubstantiated statement that a subset of patients adopted a ‘high-protein diet’, which, in theory, is equivalent to an LCD. However, there is no confirmation as to whether the ‘high-protein diet’ as described by Fleming was an LCD. Fifth, this author published related work with the same dietary program that demonstrated an increase in triglycerides in subjects on a high fat diet. The finding that people on the high fat diet developed hypertriglyceridemia is inconsistent with every other study on LCD effects on triglycerides. Overall, the work by Fleming is flawed at every level of analysis, and his findings have not been replicated by any LCD study.

  The fact that Pawlak has depended on three fatally flawed studies to justify his claims that an LCD is harmful provides strong support for our contention that there is no high caliber research that demonstrates the LCD is harmful. A relevant year-long study conducted at Stanford University demonstrated that the LCD was equal or superior to other diets, including a low saturated fat (Ornish) diet, in terms of cardiovascular biomarker risk outcomes.14

  Finally, Pawlak praised the effects of a low-fat, vegetarian diet in improving cardiovascular health, citing work by Ornish et al.15 However, the Ornish work was not solely a diet study. It involved an experimental group that was prescribed an intensive lifestyle intervention that included a low fat, vegetarian diet, as well as aerobic exercise sessions, stress management training, smoking cessation, group psychosocial support, and they were told to avoid sugar consumption. Control subjects were given no interventions other than to follow routine advice from their personal physicians. The multi-factorial nature of the intervention group does not permit the conclusion that any one factor, such as diet, was causally related to the outcomes of the study. It should be noted, as well, that despite the intensive lifestyle intervention in the experimental group, there was no difference in hard cardiovascular outcomes, such as the incidence of myocardial infarctions, coronary artery bypass grafts or death, between the two groups.

  In conclusion, Pawlak has failed to justify his charge that we have committed malpractice by recommending that FH individuals with components of metabolic syndrome should follow a carbohydrate restricted diet.

   
  1. Pawlak R. Low carbohydrate diets should NOT be recommended for patients with familiar hypercholesterolaemia. BMJ-Evidence Based Medicine 2020.
  2. Diamond DM, Alabdulgader AA, de Lorgeril M, et al. Dietary Recommendations for Familial Hypercholesterolaemia: an Evidence-Free Zone. BMJ Evid Based Med 2020.
  3. Ravnskov U, de Lorgeril M, Diamond DM, et al. LDL-C does not cause cardiovascular disease: a comprehensive review of the current literature. Expert Rev Clin Pharmacol 2018;11(10):959-70.
  4. Gaudet D, Vohl MC, Perron P, et al. Relationships of abdominal obesity and hyperinsulinemia to angiographically assessed coronary artery disease in men with known mutations in the LDL receptor gene. Circulation 1998;97(9):871-77.
  5. Ravnskov U, de Lorgeril M, Kendrick M, et al. Inborn coagulation factors are more important cardiovascular risk factors than high LDL-cholesterol in familial hypercholesterolemia. Med Hypotheses 2018;121:60-63.
  6. Ravnskov U, Diamond DM, Hama R, et al. Lack of an association or an inverse association between low-density-lipoprotein cholesterol and mortality in the elderly: a systematic review. Bmj Open 2016;6(6).
  7. Mundal L, Sarancic M, Ose L, et al. Mortality among patients with familial hypercholesterolemia: a registry-based study in Norway, 1992-2010. J Am Heart Assoc 2014;3(6):e001236.
  8. Diamond DM, O'Neill BJ, Volek JS. Low carbohydrate diet: are concerns with saturated fat, lipids, and cardiovascular disease risk justified? Curr Opin Endocrinol Diabetes Obes 2020;27(5):291-300.
  9. Foo SY, Heller ER, Wykrzykowska J, et al. Vascular effects of a low-carbohydrate high-protein diet. Proc Natl Acad Sci U S A 2009;106(36):15418-23.
  10. Kostogrys RB, Franczyk-Zarow M, Maslak E, et al. Low carbohydrate, high protein diet promotes atherosclerosis in apolipoprotein E/low-density lipoprotein receptor double knockout mice (apoE/LDLR(-/-)). Atherosclerosis 2012;223(2):327-31.
  11. Watanabe Y. Serial inbreeding of rabbits with hereditary hyperlipidemia (WHHL-rabbit). Atherosclerosis 1980;36(2):261-8.
  12. Mori Y, Wada H, Nagano Y, et al. Hypercoagulable state in the Watanabe heritable hyperlipidemic rabbit, an animal model for the progression of atherosclerosis. Effect of probucol on coagulation. Thromb Haemost 1989;61(1):140-3.
  13. Yamashita S, Hbujo H, Arai H, et al. Long-term probucol treatment prevents secondary cardiovascular events: a cohort study of patients with heterozygous familial hypercholesterolemia in Japan. J Atheroscler Thromb 2008;15(6):292-303.
  14. Gardner CD, Kiazand A, Alhassan S, et al. Comparison of the Atkins, Zone, Ornish, and LEARN diets for change in weight and related risk factors among overweight premenopausal women. Jama-Journal of the American Medical Association 2007;297(9):969-77.
  15. Ornish D, Scherwitz LW, Billings JH, et al. Intensive lifestyle changes for reversal of coronary heart disease. JAMA 1998;280(23):2001-7.

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  Conflict of Interest:
  DMD is a member of the science advisory board for Anutra and has received honoraria from Pruvit.
  ZH receives royalties for books/content on diet and health.
  MK receives royalties for books on cholesterol and related medical issues.
  AM donates royalties from his diet book to charity.
  UR receives royalties for books on diet and cholesterol.
  JSV receives royalties for low-carbohydrate nutrition books. He is founder, consultant, and stockholder of Virta Health Corp.; a member of the advisory boards for Atkins Nutritionals Inc., UCAN Co., Ketone Sciences, and Axcess Global; and has received honoraria from Metagenics and Pruvit.
  

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