Statins and LDL – Cholesterol – Primary Prevention What’s fact in 2012
Many studies have over the past 20 years reported beneficial effects of statin administration in secondary cardiovascular disease prevention and the large Cholesterol Treatment Trialists’ (CTT) Collaboration meta-analysis of individual data published in 2010 (170 000 individuals in 21 trials of statin regimens vs control and 5 trials comparing intensive vs less intensive regimens) has endorsed this view.1
Indeed, lowering low-density lipoprotein (LDL) cholesterol by 1 mmol/L can reduce the incidence of major vascular events (myocardial infarction [MI], coronary death, stroke, or coronary revascularization) by approximately 20%. Despite these beneficial effects in secondary prevention, doubts exist as to the true role of statins in primary prevention. These agents can have important side effects and studies have not completely reassured clinicians of the overall net benefit of statins in low-risk subjects.2,3
The CTT have now reported their findings4 regarding the role of statins in primary prevention, which will most certainly have important clinical implications.
The study – This new meta-analysis—funded by the British Heart Foundation, the UK Medical Research Council, Cancer Research UK, the European Community Biomed Programme, the Australian National Health and Medical Research Council, and the National Heart Foundation (Australia)—included individual participant data from 22 trials of statin vs control (n=134 537;median follow-up 4.8 years) and 5 trials of higher vs lower statin dosage (n=39 612; median follow-up 5.1 years).
End points were: major cardiovascular events, including nonfatal MI and coronary death), stroke, and coronary revascularization. Subjects in the study were subdivided into 5 categories: baseline 5-year major vascular event risk (no statin or low-intensity statin) <5%, ≥5% to <10%, ≥10% to <20%, ≥20% to <30%, ≥30%. In each of these categories, the rate ratio (RR) per 1.0 mmol/L LDL-cholesterol reduction was assessed.
Main findings – Irrespective of age, gender, baseline LDL cholesterol, and previous vascular disease, LDL-cholesterol lowering with a statin was associated with a reduction in major vascular events (RR 0.79; 95% confidence interval [CI] 0.77-0.81; per every 1.0 mmol/L reduction). Of interest, the proportional reduction in events was at least as big in the two lowest risk categories as in the higher risk categories. In the lowest risk categories, statins reduced major events (RR 0.57; 99% CI 0.36-0.89; P=0.0012; and RR 0.61; 99% CI 0.50-0.74; P<0.0001) and number of coronary revascularizations (P<0.0001). In individuals without a history of cardiovascular disease, statins reduced both vascular mortality (RR 0.85; 95% CI 0.77-0.95) and all-cause mortality (RR 0.91; 95% CI 0.85-0.97). Regarding stroke, the reduction in risk in subjects with <10% 5-year risk of major events was similar to that in higher risk categories (P for trend=0.3). IMPORTANTLY reduction in LDL cholesterol with a statin did not increase the incidence of cancer, cancer mortality, or other non-vascular mortality.
Implications of these findings
This recent study supports the notion that statins may be more than useful in primary prevention. Of note, in individuals with a 5-year risk of major vascular events <10%, each 1 mmol/L reduction in LDL cholesterol produced an absolute reduction in events of approximately 11 per 1000 over 5 years. This finding is important because 50% of all vascular events occur among individuals without previous vascular disease, who are considered to represent a low-risk category.5
Another relevant issue is that the benefits reported in the study exceed the known risks associated with statin therapy. These, however, should not be underestimated when consideration is given to the use of statins in low-risk patients. Statins are associated with dose-related increased risk of myopathy (0.5 per 1000 over 5 years) and rhabdomyolysis (incidence ≈0.1 per 1000 over 5 years).6 The risk of hemorrhagic stroke—particularly in the Asian population—was also higher in some previous studies,7 but the present meta-analysis showed an overall reduction in the risk of stroke. Sattar et al8 have suggested that statins might be associated with a proportional increase in the diagnosis of diabetes mellitus (~10%), but the incidence of diabetes observed in the primary prevention trials was 5% over 5 years (absolute excess 0.1% per year). Thus the beneficial effects reported in the recent CTT meta-analysis4 largely exceeded the potential harm of a slight increase in the incidence of diabetes.
As also discussed in the article,4 long-term follow-up statin trials have shown that the absolute reductions in major vascular events increase while the statin treatment is continued1 and these benefits persist for at least 5 years after the treatment has stopped.
The Lancet meta-analysis4 contributes importantly to the current debate regarding whether statins are truly beneficial in primary prevention and its findings are likely to influence forthcoming international guidelines.
1. Cholesterol Treatment Trialists’ (CTT) Collaboration; Baigent C, Blackwell L, Emberson J, et al.Lancet. 2010;376:1670-1681.
2. Ray KK, Seshasai SR, Erqou S, et al. Arch Intern Med. 2010;170:1024-1031.
3. Redberg RF, Katz M, Grady D. Arch Intern Med. 2011;171:1594.
4. Cholesterol Treatment Trialists’ (CTT) Collaborators. Lancet. 2012 May 16. Epub ahead of print.doi:10.1016/S0140-6736(12)60367-5.
5. Kerr AJ, Broad J, Wells S, Riddell T, Jackson R. Heart. 2009;95:125-129.
6. Armitage J. Lancet. 2007;370:1781-1790.
7. Cheung BM, Lam KS. Lancet. 2010;376:1622-1624.
8. Sattar N, Preiss D, Murray HM, et al. Lancet. 2010;375:735-742.