The positives of statin use include reduced risk of cardiovascular events, and long-term safety and efficacy data, but statins are also associated with muscle discomfort and pain
Long-term statin data
Statins have reached a prominent place in the control of cardiovascular risk. The original trials in the 1990s showing the effectiveness of statins in reducing cardiovascular risk in coronary heart disease1,2 have been followed by long-term safety and efficacy trials.3–6 These extended follow-up studies have shown a legacy effect, with improved survival and a substantial reduction in cardiovascular outcomes for up to 20 years.3–6 In addition, long-term statin use does not increase the incidence of cancer or death from noncardiovascular causes.5,6 These studies support the wider adoption of statins in primary and secondary prevention strategies.
Trial findings: HOPE-3
The Heart Outcomes Prevention Evaluation (HOPE)-3 trial results7–10 published in 2016, provide further evidence for the role of statins in primary prevention strategies. HOPE-3 was a double-blind, randomized, placebo-controlled trial with a 2-by-2 factorial design enrolling 12,705 men (≥55 years) and women (≥60 years) of intermediate risk of cardiovascular events. Participants were randomly assigned to receive rosuvastatin 10 mg/day or placebo and were also randomly assigned to receive antihypertensive treatment with candesartan 16 mg/day plus hydrochlorothiazide 12.5 mg/day or placebo for a median treatment period of 5.6 years. Treatment with rosuvastatin resulted in a 24% lower risk of cardiovascular events, no increase in diabetes or cancers, but an excess of muscle symptoms, compared with placebo.7 Antihypertensive therapy did not significantly lower the risk of cardiovascular events, although subgroup analysis showed that those in the upper third for systolic blood pressure (˃143.5 mmHg) who took active treatment had a significantly lower cardiovascular risk than those receiving placebo.8 The combination of rosuvastatin, candesartan and hydrochlorothiazide was associated with a significantly lower rate of cardiovascular events than dual placebo in participants of intermediate risk who did not have cardiovascular disease.9
The relative risk reduction (RRR) of rosuvastatin in this primary intervention trial was 24%. In absolute terms, this was a reduction in the rate of cardiovascular events from 4.8% (over a period of 5.6 years) in the placebo group to 3.7% in the rosuvastatin group. These data are in agreement with those of a meta-analysis of randomized trials of statin therapy, which led to an RRR of 25% for cardiovascular events in a primary-prevention population.11 Taken together, these data make a strong case for statin treatment in patients with intermediate risk who do not yet have cardiovascular disease.
The potential gain in cardiovascular risk reduction seen in trials should be weighed against the discomfort due to muscle symptoms in individual patients. In the HOPE-3 trial, more participants in the rosuvastatin group than in the placebo group had muscle pain or weakness (5.8% versus 4.7%), although there was no significant difference between the two groups in the number of participants who permanently discontinued their assigned treatment because of muscle symptoms (1.3% versus 1.2%).7
Statins and low density lipoproteins
Is the reduction in low density lipoprotein (LDL) with statins relative to the degree of cardiovascular risk reduction? The HOPE-3 trial was not designed to answer this question, with the statin given independently of the pre-treatment cholesterol or LDL level. Statin treatment was still associated with a 26.5% reduction in LDL cholesterol level. Recent guidelines12,13 recommend a risk-based approach to statin use rather than an approach that is based primarily on LDL cholesterol levels.
The IMPROVE-IT trial14 studied the impact of reducing LDL-cholesterol levels in patients with acute coronary syndrome by adding ezetimibe to standard treatment of 40 mg simvastatin. The combined ezetimibe/simvastatin treatment led to a 22% lower LDL cholesterol concentration than placebo/simvastatin. However, the RRR in cardiovascular events was only 6%. These results suggest that LDL reduction may not be the only mechanism by which statins reduce cardiovascular risk. Pharmacological research in the past two decades has suggested pleiotropic effects of statins beyond LDL cholesterol reduction, including anti-oxidative, anti-inflammatory and anti-fibrotic effects.15,16
New insights from pharmacological studies and clinical trials suggest new paradigms for statin use in primary cardiovascular risk prevention. Statin use may offer benefits even in patients with intermediate cardiovascular risk without overt cardiovascular disease – benefits partly independent of LDL cholesterol reduction. Since hypertension is a major contributor to overall cardiovascular risk, the use of a statin should be considered in hypertensive patients. However, the decision to use a statin should be based upon estimates of risk reduction versus adverse effects in the individual.17,18
- Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383–1389.Shepherd J, et al.
- Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia: West of Scotland Coronary Prevention Study Group. N Engl J Med 1995;333:1301–1307.
- Pedersen TR, et al. Follow-up study of patients randomized in the Scandinavian Simvastatin Survival Study (4S) of cholesterol lowering. Am J Cardiol 2000;86:257–262.
- Ford I, et al. Long-term follow-up of the West Scotland Coronary Prevention Study Group. N Engl J Med 2007;357:1477–1486.
- Ford I, et al. Long-term safety and efficacy of lowering low-density lipoprotein cholesterol with statin therapy. 20-Year follow-up of West of Scotland Coronary Prevention Study. Circulation 2016;133:1073–1080.
- Hague WE, et al. Long-term effectiveness and safety of pravastatin in patients with coronary heart disease: sixteen years of follow-up of the LIPID study. Circulation 2016;133:1851–1860.
- Yusuf S, et al. Cholesterol lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med 2016;374:2021–2031.
- Lonn EM, et al. Blood-pressure lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med 2016;374:2009–2020.
- Yusuf S, et al. Blood-pressure and cholesterol lowering in persons without cardiovascular disease. N Engl J Med 2016;374:2032–2043.
- Cushman WC, Goff DC Jr. More HOPE for prevention with statins. N Engl J Med 2016;374:2085–2087.
- Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376:1670–1681.
- Stone NJ, 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. Circulation 2014;129:Suppl2:S1–S45.
- Nayor M, Vasan RS. Recent update to the US Cholesterol Treatment Guidelines: a comparison with international guidelines. Circulation 2016;133:1795–1806.
- Cannon CP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;372:2387–2397.
- Liao JK, Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol 2005;45:89–118.
- Kudo S, et al. SmgGDS as a crucial mediator of the inhibitory effects of statins on cardiac hypertrophy and fibrosis: novel mechanism of the pleiotropic effects of statins. Hypertension 2016;67:878–889.
- Thanassoulis G, et al. Individualized statin benefit for determining statin eligibility in the primary prevention of cardiovascular disease. Circulation 2016;133:1574–1581.
- Robinson JG, Ray K. Moving toward the next paradigm for cardiovascular prevention. Circulation 2016;133:1533–1536.