Statins and safety: can we finally be reassured?

Statins have revolutionised modern cardiovascular treatment by producing a striking reduction in coronary risk. In 2005, the Cholesterol Treatment Trialists’ (CTT) collaboration reported a meta-analysis of 14 random ised trials (including about 90 000 patients) of statin versus placebo that recorded a 20% relative risk reduc tion in major vascular events (comprising coronary death, nonfatal myocardial infarction, coronary revas cu lar isation, or stroke) per 1 mmol/L decrease in LDL cholesterol. Findings of other studies subsequently showed the additional benefi t of intensive-dose over standard-dose statin treatment. Although the benefi t of statins in these trials was overwhelmingly positive, data for long-term effi cacy and tolerability were typically restricted to 5 years, and the safety of prolonged treatment with these HMG-CoA reductase inhibitors, especially in elderly patients, was questioned. Findings of observational studies (not randomised and, thus, subject to confounding) suggest diminished rates of prostate cancer associated with statin use, yet a 50% higher risk of colorectal cancer with more than 5 years of statin treatment. Furthermore, confl icting fi ndings indicate an association between very low total or LDL cholesterol concentrations and higher rates of cancers and non-vascular mortality and morbidity. For this reason, data from randomised trials of statin treatment with extended follow-up of patients were examined to address these concerns and investigate the therapeutic and safety implications of prolonged statin therapy. In a meta-analysis of 26 randomised controlled trials (21 trials of statin vs placebo and fi ve of highdose vs standard-dose statin), consisting of more than 160 000 participants, researchers investigated safety and long-term effi cacy of statins. With median follow-up of 4·8–5·1 years, intensive statin regimens (compared with placebo) reduced LDL by 0·51 mmol/L at 1 year and produced an additional highly signifi cant 15% risk reduction in major fi rst vascular events, comprising coronary death or non-fatal myocardial infarction (relative risk reduction 13%), coronary revascularisation (19%), and ischaemic stroke (16%). All-cause mortality was reduced by 10% per 1·0 mmol/L reduction in LDL cholesterol and was attributable largely to reductions in coronary death. Despite the low LDL concentrations achieved, deaths due to cancer or non-vascular causes (relative risk 0·97) or cancer incidence (1·00) did not diff er. Nonetheless, critics continue to suggest that statins could increase risk for cancers that take longer than 5 years to emerge clinically. This idea prompted additional studies with extended post-trial followup. The West of Scotland Coronary Prevention Study (WOSCOPS), in which 6595 men with hypercholesterolaemia without a history of myocardial infarction were randomly allocated 40 mg daily of pravastatin or placebo from 1989 to 1991, was a 5-year study. Survivors were followed up for about 10 additional years after the trial, for a total followup period of about 15 years. The results of the original 8 Caplin ME, Buscombe JR, Hilson AJ, Jones AL, Watkinson AF, Burroughs AK. Carcinoid tumour. Lancet 1998; 352: 799–805. 9 Ramage JK, Ahmed A, Ardill J, et al. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs). Gut 2011; published online Nov 3. DOI:10.1136/ gutjnl-2011-300831.