Statins have become the gold standard pharmacological intervention to reduce the risk of atherosclerosis by inhibiting cholesterol biosynthesis and lowering levels of low-density lipoprotein cholesterol (LDLC). Recently, the clinical trials PROMINENT, REDUCE-IT and STRENGTH showed that the combination of statins and an anti-inflammatory agent that lowers LDLC and inflammation, as measured by the concentration of high-sensitivity C-reactive protein (hsCRP), is the most beneficial therapy for reducing atherosclerotic risk. However, it was unclear whether the levels of LDLC and hsCRP can predict the atherosclerotic risk in statin-intolerant individuals. In the CLEAR-Outcomes trial, Ridker et al. identified hsCRP as a reliable predictor for adverse cardiovascular events and death in statin-intolerant individuals with hyperlipidemia, and bempedoic acid as an effective treatment for lowering LDLC and hsCRP and the risk of adverse cardiovascular events.
The CLEAR-Outcome trial included 13,970 statin-intolerant patients who either had a previous cardiovascular event or were at high risk for cardiovascular events. The participants randomly received either 180 mg oral bempedoic acid or a placebo to evaluate the levels of LDLC and hsCRP over a median follow-up period of 40.6 months and their potential as predictors for adverse cardiovascular events or death. Bempedoic acid is an FDA-approved drug for patients with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who need to lower their cholesterol levels. The analyzed statin-intolerant patients showed median baseline LDLC concentrations ranging from 115 to 158.5 mg dl−1 and hsCRP concentrations ranging from 1.15 to 4.47 mg l−1. The researchers showed that the baseline level of hsCRP was significantly associated with the primary composite end point of future myocardial infarction, stroke, coronary revascularization or cardiovascular death and the end points of cardiovascular mortality and all-cause mortality, whereas the baseline LDLC quartile was less related to primary composite endpoints and neutral for cardiovascular mortality and all-cause mortality. The level of hsCRP above the median trial level was sufficient to increase the risks for the primary composite endpoint and — even more evident — the risk for cardiovascular mortality and all-cause mortality independent of the LDLC level, whereas the increase in LDLC above the median level did not increase the risk for adverse cardiovascular events or mortality. The treatment of statin-intolerant patients with bempedoic acid reduced the median hsCRP levels by 21.6% and reduced the mean LDLC levels by 21.1% at 6 months, and reduced the primary trial composite end point by 13%, compared with the placebo group. The results show that low-grade inflammation assessed by the level of hsCRP reflects the risk of future adverse cardiovascular events and cardiovascular death. They also highlight the importance of preventive treatments such as bempedoic acid to lower the levels of LDLC and hsCRP and reduce the risk of adverse cardiovascular events.
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