Statins remain the cornerstone for the primary and secondary prevention and cardiovascular events in patients with hypercholesterinaemia and hypertriglyceridemia. |
Ezetimibe, alirocumab, evolocumab, icosapent ethyl and fenofibrate are second-line treatment alternatives as add-on treatment to statin or as monotherapy for statin-intolerant patients with dyslipidaemia. |
Notable emerging lipid-lowering treatments include bempedoic acid, the siRNA PCSK9 inhibitor inclisiran, the ANGPTL3 inhibitor evinacumab, the MTP inhibitor lomitapide, the ApoB-100 inhibitor mipomersen and the ApoC-III degradation molecules volanesorsen and olezarsen, as well as the Lp(a) inhibitors pelcarsen and olpasiran. |
1 Introduction
2 Established Pharmaceutical Therapies
2.1 Statins
2.2 Ezetimibe
2.3 PCSK9 Inhibitors
2.4 Fibrates
2.5 Omega-3 Fatty Acids
2.6 Other Drugs
3 Emerging Pharmaceutical Therapies
3.1 Bempedoic Acid
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The CLEAR Tranquillity trial evaluated bempedoic acid compared with placebo in 269 patients receiving ezetimibe as background therapy [132]. Relative to placebo, bempedoic acid reduced LDL-C by − 29%, non-HDL-C by − 24%, total cholesterol by − 18%, ApoB-100 by −19% and hsCRP by − 31%.
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The CLEAR Serenity trial randomized 345 statin-intolerant patients with hypercholesterolemia to receive bempedoic acid or placebo [127]. Bempedoic acid lowered LDL-C by − 21%, non-HDL-C by − 18%, total cholesterol by − 15%, ApoB-100 by − 15% and hsCRP by − 24%.
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The CLEAR Wisdom trial randomized 779 patients with atherosclerosis or heterozygous familial hypercholesterolemia (HeFH) to receive bempedoic acid or placebo [129]. Bempedoic acid reduced LDL-C by − 17%, non-HDL by − 13%, total cholesterol by − 11%, ApoB-100 by −13% and hsCRP by − 9% compared with placebo.
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The CLEAR Harmony trial assessed bempedoic acid’s safety and efficacy in 2230 statin-treated patients with atherosclerosis or HeFH compared with placebo [130]. Relative to placebo, bempedoic acid reduced LDL-C by − 16%, non-HDL-C by − 13%, total cholesterol by − 11%, ApoB-100 by − 12% and hsCRP by − 22%. The incidence of adverse events was similar across both interventional groups, yet a higher percentage discounted treatment with bempedoic acid than placebo (10.9% versus 7.1%). Gout was more frequently observed among patients treated with bempedoic acid (1.2% versus 0.3%).
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The CLEAR Outcomes trial randomized 13,970 patients with established or high risk for CVD, intolerance to statins, and LDL-C level ≥ 100 mg/dL to receive bempedoic acid (180 mg daily) or placebo [131]. Bempedoic acid reduced the risk of MACE by − 13% (HR 0.87, 95% CI 0.79–0.96, p = 0.004) and resulted in a − 21.1% greater reduction in LDL-C levels compared with placebo [133]. A higher frequency of gout (3.1% versus 2.1%) and cholelithiasis (2.2% versus 1.2%) was observed with bempedoic acid than with placebo [133].
3.2 Inclisiran
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The phase 3 ORION-10 and ORION-11 trials evaluated inclisiran compared with placebo across a total of 1561 and 1617 patients with atherosclerosis or an atherosclerotic CVD risk-equivalent, respectively [137]. Compared with placebo, inclisiran reduced LDL-C levels by − 52% and − 50%, respectively.
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These results were confirmed in the phase 3 ORION-9 trial which showed a − 48% LDL-C reduction of inclisiran relative to placebo among 482 patients with HeFH [138].
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Results of the ORION-9, ORION-10, and ORION-11 trials were consistent in pooled patient- and trial-level meta-analyses [140, 141]. Across all three trials, LDL-C reductions amounted to −51%. Except for injection site rejections, patients were not at an increased risk for any adverse events. In contrast to the other PCSK9 inhibitors, inclisiran does not induce the expression of auto-antibodies according to results from the ORION-1 trial [142].