Bempedoic acid and the future of statin alternatives
August 4, 2023
Dyslipidemia, one of Australia’s silent killers
Hyperlipidemia, a significant contributor to cardiovascular disease and death, is a pressing health concern in Australia. Statins, or 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors, are a primary line of defence in the fight against hyperlipidemia. For every 1.0 mmoL/L reduction in low-density lipoprotein (LDL)-cholesterol facilitated by statins, there is a 21% decrease in the occurrence of major vascular incidents and a 9% drop in overall mortality. Given their considerable clinical effectiveness and an exceptional safety record, statins have become a common prescription among Australians.
While statin therapy serves as the cornerstone for lipid-lowering treatments, helping prevent atherosclerotic cardiovascular disease (ASCVD), it does not always meet the patient-specific LDL-C targets, even with high dosages. Moreover, a subset of patients—between 5% to 10%—are intolerant to statins, mainly due to muscle-related side effects. Unfortunately, discontinuing statin treatment due to side effects poses another danger: an elevated risk of vascular incidents and mortality.
Statin side effects
Almost all statins carry the risk of musculoskeletal side effects, with myalgia being the most frequently observed. More serious conditions like myositis are less common but are associated with an increase in creatine kinase (CK). Rhabdomyolysis, the most severe musculoskeletal outcome linked with statins, is characterised by a CK surge beyond 10 times the normal upper limit, coupled with myoglobinuria, renal dysfunction, and abnormal serum electrolytes.
Severe musculoskeletal side effects from statin drugs, overall, are relatively rare. Nevertheless, the incidence of myopathy varies in literature, ranging from 0.1-10%, due to differences in definitions, data collection methods, and reporting bias. For instance, a study by Khan et al. (2015) analysed over 10,000 statin users in the United States and found that myalgia was a leading cause of statin discontinuation, with over 60% of patients who had stopped therapy citing musculoskeletal side effects. All major statin trials, including large meta-analyses, conclude that severe musculoskeletal side effects from statin use are infrequent, and the overarching benefits of statin therapy generally outweigh this minor risk.
Historically, statin-intolerant patients have had limited therapeutic alternatives. Ezetimibe achieves only modest reductions in LDL-C levels, and proprotein convertase subtilisin/kexin type 9 inhibitors are recommended for primary prevention exclusively in cases of diagnosed heterozygous familial hypercholesterolemia. The recent approval of bempedoic acid, a new lipid-lowering agent with fewer muscle-related side effects compared to statins, presents an exciting development.
The outlook of bempedoic acid
Bempedoic acid is a promising lipid-lowering drug recently approved for treating dyslipidemia. This ATP citrate lyase inhibitor reduces LDL cholesterol levels and is linked with a low rate of muscle-related adverse events, making it an attractive alternative for those who are statin-intolerant or refuse to take them due to side effects. However, its impact on cardiovascular outcomes is yet to be definitively determined.
Manufactured and marketed as Nexletol by US-based Esperion Therapeutics, bempedoic acid received FDA approval in 2020 for treating adults with heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular disease (ASCVD) who require further LDL cholesterol lowering. The landmark study leading to this approval, published in the New England Journal of Medicine, was sponsored by Esperion Therapeutics.
Preclinical trials and completed Phase II and III clinical trials have shown encouraging safety and efficacy results across various patient groups, including those intolerant to statins. Bempedoic acid is currently under evaluation in a cardiovascular outcomes trial to assess its impact on major cardiovascular events in patients at high cardiovascular disease risk or with statin intolerance.
As a prodrug, bempedoic acid requires activation in the body, primarily in the liver via an enzyme called ACSVL1. As this enzyme is primarily located in the liver and to a lesser extent in the kidneys, but not present in muscle or fat tissues, bempedoic acid remains inactive in skeletal muscle tissue, thus significantly reducing the likelihood of muscle-related side effects associated with statins. This unique characteristic enhances its appeal for patients experiencing statin-related side effects or those unwilling to take statins.
The future of statin-alternative therapies
The recent endorsement by the FDA of bempedoic acid, both as a standalone treatment and in a fixed-dose combination with ezetimibe, will reshape the future of lipid management, particularly for patients with established ASCVD or HeFH who are already on the highest tolerable dose of statins but require further LDL-C reduction. Backed by data from five clinical trials across a range of patient demographics—including those with ASCVD, HeFH, high risk for ASCVD, and statin intolerant individuals—bempedoic acid is poised to play a crucial role as an additional non-statin option in the quest to maximise cardiovascular risk-reduction therapy.
However, when incorporating this new agent into treatment strategies, a thorough review of each patient’s statin therapy and coadministration is still essential for a few reasons. Firstly, it’s important to determine if the statin treatment has been escalated to the maximum bearable dosage to ensure optimal LDL-C control based on the individual’s needs. Secondly, a patient’s history of statin intolerance needs to be scrutinised, and their tolerance for any dose of statin evaluated. If a patient is unable to tolerate any dose of statin, they will likely need to rely on a combination of non-statin treatments (like bempedoic acid plus ezetimibe) to achieve LDL-C reduction comparable to what a moderate-intensity statin could offer. Clinical trials have shown that this combination can lower LDL-C levels by 36%. As standalone therapies, bempedoic acid and ezetimibe have been found to reduce LDL-C levels by 15–23% and 13–20%, respectively. Lastly, for patients on simvastatin or lovastatin, it’s crucial to maintain dose restrictions of no more than 20 mg daily for simvastatin or 40 mg daily for lovastatin when used in combination with bempedoic acid.
Although more research is needed to support the direct substitute of statin-based therapies in the treatment of dyslipidemia and associated cardiovascular risks, bempedoic acid proves an exciting pharmacological alternative to improve adherence and outcomes.
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