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Assessing the clinical benefits of drugs for dyslipidaemia
A recent editorial in the New England Journal of Medicine1 highlights several challenging issues in the development of new treatments for lipid disorders. There is now uncertainty regarding the regulatory approach of approving drugs on the basis of favourable lipid effects and evaluating clinical benefit after approval.
In numerous trials and several meta-analyses of outcome trials, the reduction of low-density lipoprotein (LDL) cholesterol has been shown to be associated with outcome benefit.2–4 Most of these studies have been performed with statins. The first demonstration of efficacy in lowering LDL cholesterol to reduce cardiovascular morbidity, however, was achieved with bile acid sequestrants.5 A reduction of LDL cholesterol by 1 mmol/L results in a 20% reduction of cardiovascular events regardless of its baseline levels.3,4 LDL cholesterol is one of the best validated end points in medicine. Therefore, while the benefit of reducing LDL-cholesterol can be quantified, the benefit risk assessment of new interventions to reduce LDL-cholesterol is mainly influenced by the risk profile of a new drug. In the ILLUMINATE trial, torcetrapib failed to demonstrate benefit despite a 25% reduction in LDL cholesterol, because an increase in blood pressure induced by torcetrapib could not offset the benefit in reducing LDL cholesterol.6
In the absence of a safety signal, the expected benefit of a new intervention can be realised in the target population through long-term trials with clinical end points, to be conducted post-authorisation.
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1. Hiatt WR, Smith RJ. Assessing the clinical benefits of lipid disorder drugs. N Engl J Med 2014;370:396–99. http://dx.doi.org/10.1056/NEJMp1313866
2. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383–9.
3. Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366:1267–78. http://dx.doi.org/10.1016/S0140-6736(05)67394-1
4. Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170000 participants in 26 randomised trials. Lancet 2010;376:1670–81. http://dx.doi.org/10.1016/S0140-6736(10)61350-5
5. Tyroler HA. Cholesterol and cardiovascular disease. An overview of Lipid Research Clinics (LRC) epidemiologic studies as background for the LRC Coronary Primary Prevention Trial. Am J Cardiol 1984;54:14C–19C. http://dx.doi.org/10.1016/0002-9149(84)90851-8
6. Bartler PJ, Caulfield M, Eriksson, M et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007;357:2109–22. http://dx.doi.org/10.1056/NEJMoa0706628