Dyslipidaemia in 2015: Advances in treatment of dyslipidaemia

Abstract

inal, randomized, controlled trials (RCTs) published in 2015 have far-reaching implications for the management of cholesterol levels. In the past 3 decades, cholesterol-lowering therapy has been dominated by statins. These drugs reduce LDL-cholesterol (LDL-C) levels with few adverse effects. RCTs document their efficacy in reducing atherosclerotic cardiovascular disease (ASCVD). Several statins are now available as inexpensive, generic drugs. Statins are the standard of care for secondary prevention of ASCVD, and are being used increasingly in primary prevention. They inhibit cholesterol synthesis and reduce hepatic cholesterol content, which increases expression of LDL receptors and lowers serum LDL-C level. Highintensity statins can reduce LDL-C levels by up to 60%. Two other drugs, ezetimibe and inhibitors of proprotein convertase subtilisin/ kexin type 9 (PCSK9), also lower LDL-C levels through their actions on LDL receptors (FIG. 1). A meta-analysis by the Cholesterol Treatment Trialists’ (CTT) Collaboration showed that statin therapy is equally efficacious in reducing major cardiovascular events in men as in women1. In this analysis, relative risk of vascular events was reduced by 22% in men and by 16% in women for every 1.0 mmol/l (38.6 mg/dl) decrease in LDL-C level. No adverse effects on cancer or non cardiovascular mortality were found in either men or women. This meta-analysis confirms that for every 1% reduction in the LDL-C level, the risk of events related to ASCVD is reduced by ~1%. statins. Ezetimibe primarily acts on the intestine, and has no known systemic effects (FIG. 1). The findings of this trial strongly support the ‘cholesterol hypothesis’, which had been blurred to some extent by claims of pleio tropism of statins. The authors of an editorial accompanying the publication of findings from the IMPROVE-IT trial also regarded the reduction in LDL-C level as the dominant action of statins, and proposed the principle of “the lower, the better”3 when assessing levels of LDL-C. The CTT investigators favoured estimating benefits in terms of percentage LDL-C lowering (“the more, the better”1), whereas the results of the IMPROVE-IT trial seemingly support a shift in emphasis to decreasing LDL-C to very low levels (“the lower, the better”3). An opportunity to test this new hypothesis presented itself with the introduction of a new class of drugs. Inhibition of PCSK9 by monoclonal antibodies allows greater expression of LDL receptors, which in turn lowers serum LDL-C concentrations (FIG. 1). Two reports published in 2015 document the efficacy of PCSK9 inhibitors for reducing the LDL-C level, and findings strongly suggest that they also decrease the risk of cardiovascular events4,5. Consequently, a 50% decrease in LDL-C level with high-intensity statins should reduce the risk of ASCVD by ~50%, a benefit that applies equally to men and women. However, the findings sparked another question, namely whether further reduction in LDL-C levels, beyond those achieved by treatment with highintensity statins, would yield an additional reduction in risk. To address this question, investigators performed the randomized, controlled IMPROVE-IT trial2, in which the combination of simvastatin (40 mg) and ezetimibe (10 mg) was compared with simvastatin (40 mg) and placebo. A total of 18,144 patients, hospitalized for an acute coronary syndrome event within the preceding 10 days and who had an LDL-C level of 1.3–3.3 mmol/l, were recruited into the IMPROVE-IT trial, regardless of previous treatment with statins. The mean LDL-C level was 53.7 mg/dl (1.4 mmol/l) in patients receiving combination therapy, and 69.5 mg/dl (1.8 mmol/l) in those receiving statin monotherapy. Compared with statin therapy alone, combined therapy signifi cantly reduced the risk of future ASCVD events by 6%. The investigators estimated that to achieve a reduction in ASCVD events, the number-needed-to-treat was ~51, regarded as justifiable by many experts. Beyond the practical use of ezetimibe in combination with statins, the results of the IMPROVE-IT trial demonstrate that risk is reduced proportionately to the reduction in LDL-C level, unrelated to pleiotropic effects of DY S L I P I DA E M I A I N 2 0 1 5

DOI: 10.1038/nrcardio.2015.208
0204020162017
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@article{Grundy2016DyslipidaemiaI2, title={Dyslipidaemia in 2015: Advances in treatment of dyslipidaemia}, author={Scott M. Grundy}, journal={Nature Reviews Cardiology}, year={2016}, volume={13}, pages={74-75} }