CrossFit | Is Statin-Modified Reduction in Lipids the Most Important Preventive Therapy for Cardiovascular Disease?

Is Statin-Modified Reduction in Lipids the Most Important Preventive Therapy for Cardiovascular Disease?

ByCrossFitJuly 14, 2020

Question: Do the benefits of statins outweigh the harms in primary prevention?

Takeaway: Aseem Malhotra and Simon Capewell argue the magnitude of benefit from the use of statins in primary prevention among low-risk individuals is minimal, and the evidence of harm is common and significant. They further argue dietary changes lead to greater benefits with fewer side effects and primary prevention efforts ought to focus principally on encouraging diets demonstrated to improve insulin resistance and cardiovascular risk.

This 2016 publication presents a debate for and against the use of statins, particularly in primary prevention. Richard Dobbs introduces the debate, noting there is likely no question in medicine more studied and continually more mired in disagreement. Proponents of the use of statins cite large prospective trials, such as those of the Cholesterol Treatment Trialists (CTT) collaboration, which indicate statin use reduces cardiovascular risk and mortality with few adverse effects. Those against statin usage argue the benefits of statins are minimal in lower-risk patients. They also argue the design of trials such as those of the CTT collaboration systematically leads to underreporting of adverse effects.

Maceij Banach and Dmitri P Mikhailidis argue for preventive use of statins. Citing data from the PROVE-IT and IMPROVE-IT trials, they claim statins have been shown to consistently reduce cardiovascular risk and all-cause mortality with risk reductions in primary endpoints exceeding 50% (1). Data from these and other trials (including trials of PCSK-9 inhibitors) suggest benefits persist even when LDL-C is brought below 70 mg/dL (2). In primary prevention, CTT group analyses suggest there are small (approximately or less than 10%) but statistically significant reductions in cardiovascular risk and all-cause mortality among statin users compared to nonusers (3); evidence of benefit is correlated with improvement in cholesterol levels. Regarding adverse event rates, they acknowledge as much as 15% of the population may be “statin intolerant” and have a negative reaction to statins upon first exposure, but through dose and drug management, a statin regimen that minimizes side effects can be found for most of these patients in the clinic (4). Finally, they review a variety of pleiotropic benefits statins may have (i.e., in addition to their effect on cholesterol), which are generally supported by preliminary evidence.

Aseem Malhotra and Simon Capewell argue against the preventive use of statins. They do not dispute the benefits of statins in secondary prevention (5) — that is, to prevent a second heart attack. Instead, they argue that closer inspection of data gathered by the CTT and other groups suggests individuals at low risk of cardiovascular disease (i.e., those with a ≤ 20% 10-year cardiovascular risk) receive no reduction in overall or cardiovascular mortality from statin use (6). Similar data has shown statin use will prevent a heart attack in only one of 140 of these low-risk individuals (NNT = 140) — a small enough fraction that any statin-related benefits must be carefully compared to potential harms (7).

The majority of statin data is drawn from industry-funded trials, and these trials must be closely inspected to detect any potential areas of bias. In many major statin trials, a significant share of recruited subjects are excluded before the trial begins. In the Heart Protection Study, 36% of patients were excluded this way (8), and many of these excluded subjects may have experienced statin-related side effects in the past. As a result, the study included a subject population no longer representative of the general population. Community studies have indicated half of statin users discontinue the drug within a year, and nearly two-thirds of these discontinuations are due to side effects (9). Members of the CTT leadership have acknowledged they may have underestimated side effect burden by failing to solicit patients for all possible side effects (10). The higher rates seen in these community studies are consistent with RCT data indicating 40% of female statin users report exertion-related fatigue on statins (11). Pfizer’s own patient materials note side effects in “up to 1 in 10 patients” (12).

In cardiovascular primary prevention, dietary interventions have been shown to have a greater preventive impact and fewer side effects than statins. Larger trials have indicated dietary changes can reduce cardiovascular risk by 30% without side effects in primary prevention (13). In that setting, the benefit associated with eating an apple per day is equivalent to that of taking a statin (14). While statins may have some pleiotropic effects, these are poorly understood; dietary changes, conversely, improve lipid profile, insulin resistance, weight, inflammation, and a variety of other factors linked to cardiovascular disease and other associated conditions (15). Taken together, this evidence indicates efforts to effectively prevent cardiovascular disease need to focus not on increasing the use of statins or reducing cholesterol levels further through pharmacotherapy but instead on dietary changes that have been shown to reduce risk of cardiovascular disease and overall mortality.


  1. Lipids, blood pressure and kidney update 2014; 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines; Time for new indications for statins?; Guidelines for the management of dyslipidaemias The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS); Benefit of early statin therapy in patients with acute myocardial infarction who have extremely low low-density lipoprotein cholesterol; Intensive statin therapy and the risk of hospitalization for heart failure after an acute coronary syndrome in the PROVE IT-TIMI 22 study; Lipid, blood pressure and kidney update 2013
  2. Dysfunctional HDL: A novel important diagnostic and therapeutic target in cardiovascular disease?; EUROASPIRE IV: A European Society of Cardiology survey on the lifestyle, risk factor and therapeutic management of coronary patients from 24 European countries; Statin underuse and low prevalence of LDL-C control among U.S. adults at high risk of coronary heart disease; Objectives and methodology of Romanian SEPHAR II Survey. Project for comparing the prevalence and control of cardiovascular risk factors in two East-European countries: Romania and Poland
  3. Neutrophil superoxide anion generation during atorvastatin and fluvastatin therapy used in coronary heart disease primary prevention; Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins; The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials; Statins and all-cause mortality in high-risk primary prevention: a meta-analysis of 11 randomized controlled trials involving 65,229 participants; Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein; Statin therapy and new-onset diabetes: molecular mechanisms and clinical relevance
  4. The role of fibrate treatment in dyslipidemia: an overview; Statin intolerance — An attempt at a unified definition. Position paper from an International Lipid Expert Panel
  5. NNT: Statins given for 5 years for heart disease prevention (with known heart disease)
  6. Should people at low risk of cardiovascular disease take a statin?
  7. Making sense of health statistics; Choosing wisely in the UK: The Academy of Medical Royal Colleges’ initiative to reduce the harms of too much medicine
  8. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: A randomised placebo-controlled trial
  9. Predictors of nonadherence to statins: A systematic review and meta-analysis; Statin usage: Understanding statin use in America and gaps in education. The USAGE survey
  10. Statins expert calls for safety checks over the drug; Misinterpretation of trial evidence on statin adverse effects may harm patients
  11. Effects of statins on energy and fatigue with exertion: Results from a randomized controlled trial
  12. Pfizer Limited: Lipitor 10 mg, 20 mg, 40 mg, 80 mg Tablets. Package leaflet: Information for the user
  13. Primary prevention of cardiovascular disease with a Mediterranean diet
  14. A statin a day keeps the doctor away: comparative proverb assessment modelling study
  15. Nutriceuticals as antithrombotic agents; Relationship of insulin resistance and related metabolic variables to coronary artery disease: A mathematical analysis

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