CrossFit | The Cholesterol and Calorie Hypotheses Are Both Dead — It Is Time to Focus on the Real Culprit: Insulin Resistance

The Cholesterol and Calorie Hypotheses Are Both Dead — It Is Time to Focus on the Real Culprit: Insulin Resistance

ByCrossFitFebruary 10, 2020

What question does this article answer?
Do cholesterol levels or obesity predict heart disease and mortality risk more accurately than insulin resistance?
The current evidence suggests lowering cholesterol and/or reducing weight is neither necessary nor sufficient to prevent heart disease. The same evidence suggests reducing insulin resistance through diet and exercise more effectively prevents heart disease, with fewer side effects, than any existing pharmacological interventions.

In this 2017 editorial, Maryanne Demasi, Robert Lustig, and Aseem Malhotra argue that targeting insulin resistance, not obesity or cholesterol levels, will lead to the largest reductions in cardiovascular risk and mortality.Existing medical guidelines recommend an ever-growing share of the population — including, according to some prominent researchers, all Americans over 40 and some children as young as 8 — be given statins to reduce heart disease risk (1). The rationale for use of statins is that they lower LDL cholesterol (LDLC) levels and reduce heart disease incidence and mortality.

A growing body of evidence is critical both of statins and the “cholesterol hypothesis” linking elevated LDLC to increased cardiovascular risk (2). Forty-four RCTs testing various cholesterol-lowering medications found a successful reduction in LDLC did not reduce cardiovascular or overall mortality (3). The ACCELERATE trial, which tested the CETP inhibitor evacetrapib, found the drug reduced LDLC levels by 37% and more than doubled HDL cholesterol levels without reducing the number of cardiac events or deaths — results sufficiently disappointing to lead the funders to cease further drug development (ibid). Evolocumab was similarly found to reduce LDLC levels by 60% while reducing cardiovascular event rates by only 1.5% and not affecting overall mortality (4). Recent analyses have estimated the life-extending benefit of years of rigorous statin adherence to be an average of four days, and the effects are possibly negative in the elderly (5).

The Lyon Diet Heart Study, conversely, found counseling heart attack survivors to follow a Mediterranean diet prevented heart attack in 1 in 18 patients and death in 1 in 30 patients over four years, despite no change in LDLC (6).

Taken together, these results suggest cholesterol-lowering medications do little to improve cardiovascular or overall health, and lowering cholesterol is neither necessary nor sufficient to prevent heart attacks. Given the non-trivial side effects associated with statins, the authors suggest that in some populations, statins may be doing more harm than good (7).

Additionally, the American Heart Association and others have long argued for the replacement of dietary saturated fat with polyunsaturated fat, a recommendation rooted in the relative effects of these fats on blood cholesterol levels (8). This shift has pushed the Western diet toward widespread consumption of vegetable oils rich in omega-6 fatty acids, driving the ratio of omega-6 to omega-3 in Western diets from 1:1 (as seen in traditional populations) to as high as 20:1. Some evidence suggests this shift is proinflammatory, thereby increasing heart disease risk, and that the effectiveness of diets rich in omega-3s, such as the Mediterranean diet, may partially be due to their corrective impact on this fatty acid balance (9).

Insulin resistance has been more consistently linked to increased risk of heart disease (10). More than two-thirds of those hospitalized for heart attacks have metabolic syndrome, and a recent analysis estimated amelioration of insulin resistance could prevent a greater share of heart attacks than normalizing traditional risk factors such as cholesterol levels and blood pressure (11). Diets that reduce insulin resistance — namely, those that reduce consumption of refined grains and sugars — coupled with exercise have been linked to reduced heart disease risk and mortality (12). Insulin resistance also predicts heart disease risk more accurately than obesity, with 1 in 5 obese individuals found to be metabolically healthy and 2 in 5 normal-weight individuals metabolically unhealthy (13). Viewed through this lens, dietary recommendations that attempt to combat obesity by reducing fat consumption and increasing consumption of refined grains and sugars may unintentionally increase insulin resistance and heart disease risk (14).

The authors conclude that the weight of the evidence suggests diet and exercise interventions that target insulin resistance will reduce cardiovascular disease and mortality risk to a greater extent, and with fewer side effects, than existing drugs (15).


  1. Life-saving benefits of cholesterol-busting drugs outweigh risks; ABC’s catalyst program on cholesterol will kill people; Reduction of risk for cardiovascular disease in children and adolescents
  2. Industry sponsorship and research outcome; How statistical deception created the appearance that statins are safe and effective in primary and secondary prevention of cardiovascular disease; Beyond confusion and controversy, can we evaluate the real efficacy and safety of cholesterol-lowering with statins?
  3. Cholesterol paradox: A correlate does not a surrogate make; Time trends in statin utilization and coronary mortality in Western countries
  4. Evolocumab and clinical outcomes in patients with cardiovascular disease
  5. The effect of statins on average survival in randomized controlled trials, an analysis of end point postponement; Cardiovascular prevention among older adults: The ALLHAT-LLT randomized clinical trial
  6. Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease
  7. Recent flaws in evidence based medicine: statin effects in primary prevention and consequences of suspending the treatment
  8. Dietary fats and cardiovascular disease: A Presidential Advisory from the American Heart Association
  9. Higher omega-3 index is associated with increased insulin sensitivity and more favourable metabolic profile in middle-aged overweight men
  10. Dissecting the role of insulin resistance in the metabolic syndrome; Resistance to insulin-mediated glucose disposal as a predictor of cardiovascular disease
  11. The reliability and prognosis of in-hospital diagnosis of metabolic syndrome in the setting of acute myocardial infarction.; Relationship of insulin resistance and related metabolic variables to coronary artery disease: A mathematical analysis
  12. Effects of dietary fructose restriction on liver fat, de novo lipogenesis, and insulin kinetics in children with obesity; Systematic review and meta-analysis of dietary carbohydrate restriction in patients with type 2 diabetes; Saturated fat does not clog the arteries: Coronary heart disease is a chronic inflammatory condition, the risk of which can be effectively reduced from healthy lifestyle interventions; Minimum amount of physical activity for reduced mortality and extended life expectancy: a prospective cohort study
  13. Obesity, fat distribution, and weight gain as risk factors for clinical diabetes in men; Use of metabolic markers to identify overweight individuals who are insulin resistant; Phenotypic characterization of insulin-resistant and insulin-sensitive obesity; Discrimination between obesity and insulin resistance in the relationship with adiponectin; Increased heart failure risk in normal-weight people with metabolic syndrome compared with metabolically healthy obese individuals
  14. Toward a unifying hypothesis of metabolic syndrome; Isocaloric fructose restriction and metabolic improvement in children with obesity and metabolic syndrome; Short-term isocaloric fructose restriction lowers apoC-III levels and yields less atherogenic lipoprotein profiles in children with obesity and metabolic syndrome

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