How to Approach Dyslipidemia in the Primary Prevention Setting: Are Statins Overused?
The first U.S. guidelines for the primary prevention of cardiovascular disease (CVD) were published in Circulation in 1997.1 As noted by the authors, "Primary prevention refers to guidance given to persons with no known cardiovascular disease."1 What is perhaps most striking about this initial article is its brevity, three pages. At the time, only two randomized, placebo-controlled trials (RCTs) of dyslipidemic therapies had been published: The Lipid Research Clinics Coronary Prevention trial2 and the West of Scotland trial3 (WOSCOPS). Only the latter compared statin to placebo. Subsequently, three other primary prevention RCTs comparing statin to placebo were published, the results of which led to further updates and the expansion of the indications for treating healthy high-risk people with statins.
The most recent guidelines, which address both primary and secondary prevention and are 85 pages in length, were published in 20134 and ignited a storm of controversy. The new guidelines expanded the indications for treating healthy people with statins, based on a new risk-calculator, which was attacked as flawed,5 (overestimating risk by anywhere from 75% to 150%) and suggested statin treatment for anyone with a 10-year event (heart attack or stroke) risk of 7.5% or more. The number of additional people who could be treated with statins for primary prevention (after the recommended clinician patient risk discussion) based on these recommendations by most estimates exceeds 10 million in the United States alone.
Randomized, placebo-controlled, double-blind clinical trials are the gold standard of clinical research. What can we say about the absolute risk reduction that resulted when statins were compared to placebo in primary prevention trials during which participants were followed for pre-determined endpoints?
In WOSCOPS, a study limited to hypercholesterolemic men, there was an absolute risk reduction (ARR) of 2.4% in the composite primary endpoint of non-fatal myocardial infarction (MI) or coronary heart disease (CHD) death over an average follow-up of 4.9 years. From these results, we can calculate that 42 men would have to be treated for almost five years to prevent one nonfatal MI/CHD death (the number needed to treat [NNT]).
In AFCAPS/TexCAPS6, the average follow-up was 5.2 years, and there was an ARR of 2% in the composite primary endpoint, yielding an NNT of 50 over five years. In this study, the endpoint consisted of fatal or nonfatal MI, unstable angina (UA) or sudden cardiac death. Revascularization was a secondary endpoint and for this endpoint the ARR was 1.6%.
It is important to point out that both the diagnosis of unstable angina and the need for revascularization are not "hard" endpoints but are diagnoses/medical decisions driven by the symptom of chest pain. Statins have a well-known vasodilatory effect due to an improvement in coronary endothelial function,7 making inclusion of these occurrences as endpoints suspect, since the placebo does not improve endothelial function and is also prone to bias, as this is a subjective endpoint. Despite this, the occurrence of UA and the need for revascularization were included in the composite endpoint of other statin RCTs.The first statin RCT to include women showed interesting sex-specific differences in results.8 Women, who made up 15% of the study population, showed no significant benefit in either the primary endpoint or any of its constituents. This lack of statin benefit for women would be found in other primary prevention trials as well.
In the ASCOT-LLA9 study there was an ARR of 1.1% in the composite primary endpoint of non-fatal MI/fatal CHD over an average follow-up of 3.3 years. This yields an NNT of 91 over about three years to prevent one event. Women showed no benefit. In fact, there were 19 endpoints among the 979 women randomized to statin and 17 endpoints among the 963 women randomized to placebo.
JUPITER10 was the largest statin primary prevention trial and found an ARR of 0.6% over a median follow up of 1.9 years. The primary endpoint was a composite of MI, stroke, arterial revascularization, hospitalization for UA or death from cardiovascular causes. When the results in women were published separately in 2010,11 there was a significant reduction in the primary endpoint in women randomized to rosuvastatin versus placebo. Among the components of the primary endpoint, however, only arterial revascularization, or the combination of arterial revascularization or hospitalization for UA were significantly reduced. There was no statistically significant difference between women randomized to statin or placebo in the rates of the individual endpoints of fatal or non-fatal MI, fatal or non-fatal stroke, death from CVD or total mortality. However, the hazard ratio for women was 0.54 (CI 0.37-0.80; p = 0.002). Both men and women treated with rosuvastatin had a higher HbA1c at 12 months, and a higher incidence of physician-reported diabetes was observed in women compared to men. A subsequent analysis of the JUPITER data showed that statin therapy accelerated the diagnosis of diabetes by six weeks on average.
Summarizing these four primary prevention trials, with over 41,000 participants, of whom almost 10,000 were women, the absolute risk reduction achieved by statin treatment for periods of about two to five years ranged from 0.6% to 2.4% in the overall study populations. No primary prevention trial showed that statins reduce the incidence of hard endpoints in women. In addition, a meta-analysis of 11 RCTs that compared statin to placebo in high-risk primary prevention found no evidence of benefit on all-cause mortality.12
These underwhelming results must be balanced against the well-known adverse events associated with statin use. RCTs comparing statin to placebo have found an increased risk of new onset diabetes in people randomized to statins. A meta-analysis of 13 statin trials including 91,140 participants found that the relative risk of diabetes was increased 9% among those randomized to statins (absolute risk increase 0.4%).13 However, the Women's Health Initiative, a prospective observational study of healthy postmenopausal women, found that among women taking statins at baseline. 9.9% developed diabetes compared to 6.4% who were not taking statins for an absolute risk increase of 3.52% and a hazard ratio, unadjusted, of 1.71, (1.48 after multivariate adjustment).14 The highest relative risk, 1.89, was found among women with a normal body mass index. It is possible that the true increase in diabetes risk from taking statins may be greater than what was found by review of clinical trial data, but more recent data indicates that the risk of diabetes is more pronounced in those individuals with at least two components of the metabolic syndrome.
Simvastatin, atorvastatin and rosuvastatin increase fasting serum insulin levels and decrease insulin sensitivity as determined by the Quantitative Insulin Sensitivity Check Index or the Homeostasis Model Assessment of Insulin Resistance (HOMA_IR).15 This diabetogenic effect of statins appears to be related to statin dose and the degree of attained cholesterol lowering. Groups at greater than average risk of diabetes when treated with statins include women, the elderly, and Asians. It is supremely ironic that drugs that have been touted as reducing the risk of heart disease in healthy women (despite lack of evidence of benefit in RCTs) actually increase a woman's risk of the most potent risk factor for developing CVD, diabetes mellitus. Nevertheless, those women who developed a blood sugar increase above 125 mg/dL in JUPITER had significantly fewer cardiovascular events on statin therapy. On the other hand, there was no benefit of statin therapy in the women with diabetes in the CARDS trial. The long-term implications of medication associated hyperglycemia are still unclear.
Myalgias are often reported in people taking statins. While statin-associated rhabdomyolysis is rare and usually self-limited with discontinuation, Mammen and his colleagues have reported on a rare autoimmune muscle disorder precipitated by statins in which markedly elevated creatine phosphokinase (CPK) levels persist for months after cessation of statins.16 In addition, there are single nucleotide polymorphisms (SNPs) affecting the SLCO1B1 gene that increase the risk of statin myopathy between four- and 17-fold. These were found in 15% of the population of the United Kingdom where the study took place,17 but they seem to only be of prognostic importance mainly in subjects on simvastatin.
There are other reported adverse events that have been attributed to statins, including cognitive dysfunction,18 neuropathy,19 cataracts,20 liver injury,21 and congenital defects among children born to women who were exposed to statins during pregnancy,22 but space limitations preclude going into them in this article. Suffice it to say that the use of statins for primary prevention provides little benefit, while increasing the risk of serious adverse events, including the onset of diabetes.
How then should we approach the treatment of dyslipidemia in the primary prevention setting? Are there data from RCTs on dietary interventions in high-risk people without established vascular disease? The PREDIMED trial results were published in 2013;23 7,447 people (57% women) aged 55 to 80 years who were at high risk for CVD (more than 70% had dyslipidemia) were randomized to three arms: a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with mixed nuts, or a control diet (advice to reduce dietary fat).
The primary endpoint was the rate of major CVD events (MI, stroke or CVD death), and the trial was stopped after a median follow-up of 4.8 years. The primary endpoint occurred in 96 of 2,543 people in the first group, 83 of 2,454 people in the second group and 109 of 2,450 people in the control diet for an absolute risk reduction of 0.8% and a relative risk reduction of 30%. Of the components of the primary endpoint, only stroke achieved statistical significance on its own. No adverse effects of the diet were reported.
In caring for our patients we must focus not only on dyslipidemia but on overall cardiac risk. In this author's opinion, the first step in treating dyslipidemia in the setting of primary prevention should be intensive lifestyle modification with detailed dietary instruction in the Mediterranean Diet, and specific exercise prescriptions commensurate with patient capability. While time-intensive, this effort can be rewarding for doctor and patient. Given the minimal benefit, and real risks of statin treatment, a lifestyle-centered approach seems most likely to fulfill our primary obligation, primum non nocere, or first do no harm.
- Grundy, SM Balady GJ, Criqui MH, et al. Guide to primary prevention of cardiovascular diseases. Circulation 1997;95:2329-31.
- Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial Results. JAMA 1984;251:351-64.
- Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Eng J Med 1995;333:1301-7.
- Stone NJ, Robinson J, Lichtenstein AH, et al. 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. J Am Coll Cardiol 2014;63:2889-934.
- Ridker PM, Cook NR. Statins: new American guidelines for prevention of cardiovascular disease. Lancet 2013;382:1762-5.
- Downs JR, Clearfield M, Weis S et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. JAMA 1998;279:1615-22.
- Treasure CB, Klein JL, Weintraub WS, et al. Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease. N Engl J Med 1995;332:481–7.
- Walsh JME, Pignone M. Drug treatment of hyperlipidemia in women. JAMA 2004;291:2243-52.
- Sever PS, Dahlof B, Poulter NR et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial – Lipid Lowering Arm (ASCOT-LLA): a multicenter randomized controlled trial. Lancet 2003;361:1149-58.
- Ridker PM, Danielson E, Fonseca FAH, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195-2207.
- Mora S, Glynn RJ, Hsia J, et al. Statins for the primary prevention of cardiovascular events in women with elevated high-sensitivity C-reactive protein or dyslipidemia. Circulation 2010;121:1069-77.
- Ray KK, Seshasai SR, Erquo S, et al. Statins and all-cause mortality in high-risk primary prevention: a meta-analysis of 11 randomized controlled trials involving 65,229 participants. Arch Intern Med 2010;170:1024-31.
- Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative met-analysis of randomized statin trials. Lancet 2010;375:735-42.
- Culver AL. Ockene IS, Balasubramanian R, et al. Statin use and risk of diabetes mellitus in postmenopausal women in the Women's Health Initiative. Arch Intern Med 2012;172:144-52.
- Goldstein MR, Mascitelli L. Do statins cause diabetes? Curr Diab Rep 2013;13:381-90.
- Mammen AL, Chung T, Christopher-Stine L, et al. Autoantibodies against 3-hydroxyl-3-methylglutaryl-coenzyme A reductase in patients with statin-associated autoimmune myopathy. Arthritis Rheum 2011;63:713-21.
- The SEARCH Collaborative Group. SLCO1B1 variants and statin-induced myopathy: a genome-wide study. New Engl J Med 2008;359:789-99.
- Muldoon MF, Barger SD, Ryan CM, et al. Effects of lovastatin on cognitive function and psychological well-being. Am J Med 2000;108:538-46.
- Gaist D, Jeppesen U, Andersen M, et al. Statins and risk of polyneuropathy a case control study. Neurology 2002;58:1333-1337.
- Hippisley-Cox J, Coupland C. Unintended effects of statins in men and women in England and Wales: population based cohort study using the QResearch Data Base. BMJ 2010;340:c2197.
- Russo MW, Hoofnagle JH, Gu J, et al. Spectrum of statin hepatotoxicity: experience of the drug-induced liver injury network. Hepatology 2014;60: 679-8.
- Edison RJ, Muenke M. Mechanistic and epidemiologic considerations in the evaluation of adverse birth outcomes following gestational exposure to statins. Am J Med Genet A 2004;131A:287-298.
- Estruch R, Rios E, Salas-Salvado J, et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013;368:1279-90.
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