Bempedoic Acid Reduces LDL Cholesterol, Risk of Cardiovascular Events Among Patients With Statin Intolerance

AUTHOR:
Michael J. Bloch, MD
Associate Professor, University of Nevada School of Medicine
Medical Director, Renown Vascular Care, Renown Institute for Heart and Vascular Health
President, Blue Spruce Medical Consultants, PLLC

For my entire career, statins have been a cornerstone therapy for the prevention of cardiovascular (CV) events in persons with elevated CV risk. But a significant number of high-risk patients, perhaps as many as 10%, are either unable or unwilling to take statins at the moderate or high doses that have been proven to be effective in reduction of CV events.

Bempedoic acid is a unique therapy that blocks cholesterol synthesis by inhibiting ATP-citrate lyase upstream from the enzyme targeted by statins. Like statin therapy, bempedoic acid inhibits cellular production of cholesterol, which leads to increased transcription of low-density lipoprotein (LDL) receptors to bring cholesterol into the cell and clear LDL cholesterol from the blood stream. In contrast to statin therapy, bempedoic acid is considered a prodrug that is only activated in liver cells and not in other cells, such as muscle cells that may be responsible for many of the adverse effects of statin therapy, both real and perceived. In several previous studies, bempedoic acid has been demonstrated to decrease low-density lipoprotein cholesterol (LDL-C) by 17% to 28% alone or in combination with other lipid-lowering agents. Based on these data, bempedoic acid has been approved by FDA to lower LDL-C, but its effects on CV outcomes were unknown, and most formularies have limited access to only the highest risk patients with atherosclerotic CV disease or familial hypercholesterolemia.

The CLEAR Outcomes study was designed to test the hypothesis that bempedoic acid would decrease CV events in high-risk patients who were unwilling or unable to take evidence-based doses of statin therapy. To be included in the study, high risk was defined as either having had a previous CV event (secondary prevention cohort) or clinical risk factors that put the patient at high risk for a future CV event (primary prevention cohort). Eligible patients had to report being unable or unwilling to receive moderate- or high-dose statins because of an adverse event that had started or worsened during statin therapy or resolved or decreased after discontinuation of statin-therapy. Patients were required to provide written confirmation that they were intolerant to statins and that statins were the preferred agents for lowering CV risk. Site investigators were required to confirm and acknowledge these statements for each patient. Patients who were taking low-intensity statins or other lipid-lowering therapies were permitted to take part in the study and remain on the background therapy throughout its course. Patients who successfully completed a 4-weeks using the  single-blind placebo were randomly assigned to receive either bempedoic acid 180mg daily or matching placebo. The primary endpoint was a four-component composite of major CV events–nonfatal myocardial infarction (MI), nonfatal stroke, coronary revascularization, or CV death.

A total of 13,970 patients were randomly assigned (6692 to bempedoic acid and 6678 to placebo). The mean age was 65.5 years, 48.2% were female, 45.6% had diabetes, and 69.9% had a history of a previous CV event. The mean baseline LDL-C was 139.0 mg/dl; 22.7% were taking low intensity statin; and 11.5% were taking ezetimibe. Very few patients were taking PCSK9 inhibitor monoclonal antibodies (PCSK9i mAb). Patients were followed for a mean of 40.6 months. After 6 months of therapy, LDL-C was 21.1% lower in in the bempedoic acid group (mean 107 mg/dl) vs placebo (mean 136 mg/dl). C-reactive protein levels were 21.6% lower in the bempedoic acid group.

The primary endpoint resulted in 11.7% of the bempedoic acid group as compared with 13.3% in the placebo group for a significant between-group difference of 13%. The secondary endpoint of CV death, nonfatal stroke, and nonfatal MI was 15% lower in the bempedoic acid group. A significant benefit was seen in both the primary and secondary prevention cohort, and it appeared that the effect was modestly more pronounced in the primary prevention cohort. There were no significant differences in risk of CV death or mortality as solitary endpoints. The overall incidence of all adverse events, serious adverse events, and events leading to discontinuation of study drug were no different between study groups. Specifically, there was no difference in the rates of reported musculoskeletal problems. The incidence of increased levels of transaminases and uric acid were modestly higher in the bempedoic acid group. The incidence of cholelithiasis was higher in the bempedoic acid group than the placebo group (2.2% vs 1.2%), a finding that had not been seen in previous studies of this agent.

Statins should remain first-line therapy for reducing CV risk in patients with elevated LDL-C for both primary and secondary prevention. While we do not necessarily need patients to sign an attestation in clinical practice as was done in this clinical trial, we should continue to stress to our patients that statins are the preferred agents. Except for inpatients who have very severe adverse effects, a retrial of a different statin agent is usually warranted before moving to non-statin medications. Additionally, we should try to maintain the maximally tolerated statin dose in our at-risk patients, even if that requires very low doses and/or less than daily administration. However, “clear outcomes” demonstrate that multiple non-statin therapies, including ezetimibe, PCSK9i mAb, and now bempedoic acid, also robustly reduce CV events.

Given its effectiveness, tolerability, and relatively low cost, ezetimibe will likely remain the first-choice agent in higher-risk patients not at the LDL-C goal, despite maximally tolerated statin therapy. Interestingly, the CV outcome studies with pcsk9i mAb only included secondary prevention patients who were on moderate- or high-dose statin therapy. The CLEAR Outcomes study demonstrates that bempedoic acid reduces events even in patients who are “statin intolerant” and extends those results to high-risk primary prevention patients. Given their more potent effect on LDL-C, PSCK9i mAb will remain an important option for patients whose LDL-C remains far from the optimal target, despite maximally tolerated statin therapy +/- ezetimibe. But their cost, current FDA-approved indication, and formulary limitations will likely continue to limit their utilization to secondary prevention. If the FDA will adjust its indication based on these results (and formularies will change their utilization criteria), bempedoic acid should become a more widely utilized alterative for secondary-prevention patients who are relatively close to the LDL-C target, despite maximally tolerated statin therapy and the large number of high-risk primary prevention patients who are unable or unwilling to take statin therapy.

Want more expert perspective? Read our full Q&A interview with lead author, Steven E. Nissen, MD.

Additional Resource: Nissen SE, Lincoff AM, Brennan D, et al; CLEAR Outcomes Investigators. Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. N Engl J Med. 2023. doi: 10.1056/NEJMoa2215024.