Bempedoic acid a good lipid-lowering alternative in select populations

The first‐in‐class ATP–citrate lyase inhibitor bempedoic acid (BA) appears useful in the treatment of hypercholesterolaemia, yielding significant reductions in total cholesterol, low-density lipoprotein cholesterol (LDL-C), non–high-density lipoprotein cholesterol (non–HDL-C), apolipoprotein B (ApoB), and high‐sensitivity C‐reactive protein (hs‐CRP), with an acceptable safety profile, according to the results of a meta-analysis.

“BA is a valuable treatment option for patients with statin intolerance, not able to receive an adequate lipid‐lowering treatment, and for patients with high cardiovascular risk, not reaching desired target of LDL-C despite a maximally tolerated lipid‐lowering treatment, including both statin and ezetimibe,” the investigators said.

A once‐daily, oral lipid-lowering drug, BA suppresses cholesterol synthesis by inhibiting the ATP–citrate lyase. This triggers upregulation of LDL receptor expression in the liver and, in turn, increases clearance of LDL particles and lowers LDL‐C. The mechanism of action differs from other lipid‐lowering therapies, including statins, which target statin reductase, and ezetimibe, which prevents intestinal cholesterol absorption. [J Lipid Res 2013;54:134-151; Eur Heart J 2016;37:2999-3058]

In the current meta-analysis, the investigators summarized evidence from seven randomized controlled trials evaluating the safety and efficacy of 180‐mg BA in patients with hypercholesterolaemia, with a mean study duration of 25 weeks.

Three studies involved patients with high cardiovascular risk and/or heterozygous familial hypercholesterolaemia receiving maximally tolerated statin therapy alone or in combination with other lipid‐lowering drugs; two studies included statin-intolerant patients; and two studies enrolled hypercholesterolaemia patients on maximally tolerated statin therapy. The total population comprised 2,767 BA‐treated patients and 1,469 controls.

Pooled data revealed that compared with control, 12 weeks of treatment with BA led to greater reductions in LDL-C (mean difference [MD], −17.5 percent; p<0.001; I², 80.3 percent), total cholesterol (MD, −10.9 percent; p<0.001; I², 62.5 percent), non–HDL-C (MD, −12.3 percent; p<0.001; I², 63.4 percent), and ApoB (MD, −10.6 percent; p<0.001; I², 52.2 percent). [J Am Heart Assoc 2020;doi:10.1161/JAHA.119.016262]

Hs‐CRP also hit a significant low with BA (MD, −13.2 percent; p<0.001; I², 69.0 percent), a finding that points to its positive effect on overall cardiovascular risk profile, in light of the recognized role of the biomarker for predicting cardiovascular event, the investigators pointed out. [Atherosclerosis 2017;259:75-82]

Results were consistent in a subgroup analysis. Notably, BA decreased LDL-C by about 20 percent in patients with high cardiovascular risk and in those with statin intolerance. In comparison, the drug conferred a greater effect on non–HDL‐C, ApoB, and hs‐CRP in statin‐intolerant patients vs high‐risk patients.

“This is likely caused by the lack of an adequate treatment in the large majority of statin‐intolerant patients, thus making BA treatment proportionally more efficacious,” the investigators noted.

With respect to safety, BA and control treatment had similar rates of any adverse events (AEs), serious AEs, and muscle‐related AEs. Among BA-treated patients, there was a higher incidence of treatment discontinuation due to AEs (odds ratio [OR], 1.393; p=0.005; I², 0 percent), of gout flare (OR, 3.2; p=0.002; I², 0 percent), and of modest but significant uric acid elevations (MD, 0.7 mg/dL; p<0.01; I², 77.6 percent), but a lower frequency of new‐onset diabetes mellitus (OR, 0.691; p=0.032; I², 0 percent).

“We found a trend toward statistical significance for the association between an increasing age and an increased rate of muscle‐related AEs and drug discontinuation because of AEs,” which the investigators attributed to the potential presence of comorbid diseases or compliance problems associated with ageing.

They acknowledged that the relevance of the meta-analysis may be limited by the relatively small number of individuals studied and short‐term exposure to BA, so additional investigations are needed to address this.