Novel oral non-statin lipid-lowering therapy for patients with high and very high CV risk

Statins have remained the cornerstone of lipid-lowering therapy for several decades. However, a substantial proportion of patients fail to achieve guideline-recommended LDL-cholesterol targets, while one in 10–12 patients have statin intolerance. At the 31^st Annual Scientific Congress of the Hong Kong College of Cardiology (HKCC ASC 2023), Professor Ulrich Laufs of the Department of Cardiology, Leipzig University Hospital, Germany, presented evidence on bempedoic acid, a novel, first-in-class treatment for statin-intolerant patients at high risk of cardiovascular (CV) events, which is available as a single agent or as a fixed-dose combination (FDC) with ezetimibe.

Lowering LDL-C reduces atherosclerosis
LDL-C plays a causal role in endothelial dysfunction, contributing to the formation and subsequent rupture of atherosclerotic plaque. “The extent of vascular damage correlates with the level of LDL-C and the duration of exposure [ie, cholesterol-years],” pointed out Laufs. [www.ncbi.nlm.nih.gov/books/NBK343489; Eur Heart J 2020;41:1157-1163]

“A 50 percent reduction in LDL-C level from baseline, beginning in early adulthood, would prevent 60–90 percent of CV events later in life,” he continued.

However, in real-world clinical practice, the majority of patients do not reach guideline-recommended LDL-C goals. The multinational observational SANTORINI study showed that only 20 percent of high- and very-high-risk patients were treated to target. Among patients receiving combination therapy, only 32 percent were at LDL-C goals. [Lancet Reg Health Eur 2023;29:100624]

One in every 10–12 patients with hypercholesterolaemia has statin intolerance. [Eur Heart J 2022;43:3213-3223] “Given the large number of patients treated with statins, statin-associated muscle symptoms represent a significant clinical challenge,” added Laufs. “Besides, low rates of LDL-C goal attainment with currently available lipid-lowering therapies warrant additional treatment options, especially for patients at higher CV risk.”

Bempedoic acid: First-in-class inhibitor of cholesterol biosynthesis
Bempedoic acid is a novel oral inhibitor of adenosine triphosphate (ATP)–citrate lyase (ACLY). It acts upstream of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase – the target for statin therapy – and thereby inhibits both cholesterol and fatty acid synthesis pathways in the liver. ACLY inhibition leads to LDL-receptor upregulation and subsequent LDL particle clearance from blood, resulting in reduction of LDL-C levels and, eventually, a reduced risk of atherosclerosis. [Nat Commun 2016;7:13457]

Bempedoic acid is a prodrug that requires activation by the very long-chain acyl-CoA synthetase-1 (ASCVL1) enzyme, which is expressed primarily in the liver and not in skeletal muscle. Hence, there is minimal risk of muscle-related adverse effects. In a pooled analysis of four phase III clinical trials of patients not on statins (n=394), the incidence of muscle-associated symptoms among patients receiving bempedoic acid was comparable to that in the placebo group (26.4 per 100 person-years vs 28.6 per 100 person-years). [J Clin Lipidol 2022;16:286-297]

Efficacy of bempedoic acid
In a pooled analysis (n=3,623) of four randomized phase III clinical trials, bempedoic acid monotherapy lowered mean LDL-C levels from baseline at week 12 by 17.8 percent vs placebo when added to maximally tolerated statin therapy in patients with atherosclerotic cardiovascular disease (ASCVD), heterozygous familial hypercholesterolemia (HeFH), or both. Bempedoic acid monotherapy also lowered LDL-C levels by 24.5 percent vs placebo in patients with statin intolerance. (Figure 1) [JAMA Cardiol 2020;5:1124-1135]

In addition, bempedoic acid monotherapy significantly reduced median high-sensitivity C-reactive protein (hs-CRP; a well-established CV biomarker for CVD) from baseline at week 12 in ASCVD and/or HeFH patients on statins (difference vs placebo: -18.1 percent; p<0.001) and statin-intolerant patients (difference vs placebo: -27.4 percent; p<0.001). [JAMA Cardiol 2020;5:1124-1135; Curr Pharm Des 2021;27:263-275]

Reduction of CV events with bempedoic acid
In the CLEAR Outcomes trial among 13,970 high- and very-high-risk statin-intolerant patients, bempedoic acid reduced the relative risk of the primary composite endpoint of four-component major adverse cardiac events (MACE; CV death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization) by 13 percent vs placebo after a median follow-up of 40.6 months (hazard ratio, 0.87; 95 percent confidence interval [CI], 0.79–0.96; p=0.004). (Figure 2) [N Engl J Med 2023;388:1353-1364]

“The two lines continued to diverge over time, demonstrating the increase in treatment benefit with each additional year of exposure to bempedoic acid,” noted Laufs. (Figure 2)

Efficacy of FDC
With the FDC of bempedoic acid plus ezetimibe, mean LDL-C levels at week 12 can be reduced by 38.0 percent on top of statins and by 39.2 percent in statin-naïve patients vs placebo (both p<0.001). [Eur J Prev Cardiol 2020;27:593-603; J Clin Lipidol 2022;16:286-297]

At week 12, the FDC significantly reduced median hs-CRP in patients with high CVD risk on maximally tolerated statin therapy (difference vs placebo: -46.1 percent; p<0.001) and patients not receiving statins (difference vs placebo: -68.8 percent; p=0.007). [Eur J Prev Cardiol 2020;27:593-603; J Clin Lipidol 2022;16:286-297]

A simulation study evaluated the impact of bempedoic acid on LDL-C target attainment in German patients (n=105,577) at risk of CV events. “Adding bempedoic acid to statin plus ezetimibe nearly doubled the rate of LDL-C goal attainment in patients at high [69.4 percent vs 40.4 percent] and very high [59.1 percent vs 30.4 percent] CV risk,” noted Laufs. “For the remaining patients not at goal, a proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitor should be considered.” [PLoS One 2022;17:e0276898]

Final thoughts
Bempedoic acid, a novel first-in-class inhibitor of cholesterol biosynthesis, is appropriate for patients not at LDL-C goal despite optimal treatment with statin plus ezetimibe or those who cannot tolerate statins. “Early bempedoic acid/ezetimibe FDC therapy can promote better efficacy, greater tolerability, and most importantly, better medication adherence,” concluded Laufs.