Statin-intolerant patients represent a difficult patient group to treat in lipid management. Now, with the CLEAR Outcomes study, it has been shown that a therapeutic option with a beneficial effect on the incidence of cardiovascular events is available for them with bempedoic acid.
Vascular atherosclerosis begins in young adulthood and progresses over decades. The disease is associated with significant morbidity and mortality due to coronary, cerebrovascular, and peripheral vascular disease. The basis of modern prevention and treatment of atherosclerosis is lowering serum cholesterol levels with 3-hydroxy-3-methylglutaryl coenzyme (HMG-CoA) reductase inhibitors (statins). Statins lower low-density lipoprotein (LDL) cholesterol levels, slow the progression of atherosclerosis, and reduce morbidity and mortality associated with coronary, cerebrovascular, and peripheral vascular events. High-intensity statin therapy is recommended for all patients with established atherosclerotic vascular disease and for patients at high risk for atherosclerotic vascular disease. Unfortunately, a substantial percentage (about 10%) of patients who would benefit from statins are unable or unwilling to take them, primarily because of muscle-related symptoms [1].
Bempedoic acid – New hope for cholesterol patients!?
Bempedoic acid is a prodrug: it must be converted by the very long-chain acyl-CoA synthetase 1 (ASCVL1) into a CoA thioester, which is the active metabolite. CoA thioester inhibits adenosine triphosphate citrate lyase, which is located upstream of HMG-CoA reductase in the cholesterol biosynthesis pathway (Fig. 1) [2]. By a different mechanism than statins, bempedoic acid inhibits the mevalonate pathway, leading to depletion of cellular cholesterol and subsequent upregulation of hepatic LDL receptors, thereby lowering circulating LDL cholesterol levels. Bempedoic acid therapy has theoretical advantages over the use of statins. Since bempedoic acid is a prodrug, it should only be active in tissues expressing ASCVL1. The liver contains abundant ASCVL1 and thus facilitates the lowering of cholesterol by bempedoic acid; in contrast, muscle tissue does not express ASCVL1. Thus, bempedoic acid may offer an advantage over statins in preventing myopathic symptoms or hyperglycemia because bempedoic acid is not expected to inhibit cholesterol or isoprenoid synthesis in muscle [2].
In multiple studies, bempedoic acid lowered LDL cholesterol levels by 17% to 28%, a result that led to approval by the Food and Drug Administration and the European Medicines Agency for this indication in 2020. However, data from randomized controlled trials on the effects of bempedoic acid on cardiovascular events have been lacking. The CLEAR Outcome Study now fills this gap by examining the effects of bempedoic acid on adverse cardiovascular events in a mixed population of patients for whom primary or secondary prevention is clinically indicated but who were unable or unwilling to take the guideline-recommended doses of statins [3].
Bempedoic acid and the prevention of cardiovascular disease
A total of 13,970 patients were randomized; 6992 were assigned to the bempedoic acid group and 6978 to the placebo group. Baseline characteristics of patients in the two study groups were similar. The mean age (± SD) was 65.5 ± 9.0 years, 6740 patients (48.2%) were female, 6373 (45.6%) had diabetes, 9764 (69.9%) had received prior cardiovascular treatment, 3174 (22.7%) were taking a statin, and 1612 (11.5%) were receiving ezetimibe. The mean LDL cholesterol level was 139.0 mg per deciliter (3.59 mmol per liter), the mean high-density lipoprotein cholesterol level was 49.5 mg per deciliter (1.28 mmol per liter), the mean triglyceride level was 159.0 mg per deciliter (1.80 mmol per liter), and the mean high-sensitivity C-reactive protein (CRP) level was 2.3 mg per liter. Patients were followed for a median of 40.6 months. The duration of exposure to bempedoic acid and placebo was similar, with patients receiving the assigned drug for 82.7% and 81.0% of the potential follow-up time, respectively. A complete assessment of the primary end point was available for 13,313 patients (95.3%), and vital status was available for 13,886 (99.4%).
The primary end point was a four-component composite of serious adverse cardiovascular events, defined as death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization, as determined by a time-to-first event analysis. Key secondary end points, also assessed in a time-to-first event analysis and tested in a hierarchical order, included a triple composite of death from cardiovascular causes, nonfatal stroke or nonfatal myocardial infarction, fatal or nonfatal myocardial infarction, coronary revascularization, fatal or nonfatal stroke, death from cardiovascular causes, and death from any cause.
Effect on LDL cholesterol and high-sensitivity CRP.
Effects of the study programs on LDL cholesterol and high-sensitivity CRP over time are shown in Figure 2. The mean LDL cholesterol level after 6 months of treatment with bempedoic acid was 107.0 mg per deciliter (2.77 mmol per liter) compared with 136.0 mg per deciliter (3.52 mmol per liter) on placebo, a difference of 29.2 mg per deciliter (0.76 mmol per liter); the observed difference in percent reduction was 21.1 percentage points (95% confidence interval [CI], 20.3-21.9) in favor of bempedoic acid. After six months, the reduction in LDL cholesterol levels, adjusted for missing data using a sample mixture model, was 20.3 percentage points. The time-averaged difference in LDL cholesterol reduction between the bempedoic acid and placebo groups, over the duration of the study was 22.0 mg per deciliter (0.57 mmol per liter); the difference in percent reductions was 15.9 percentage points in favor of bempedoic acid. Of patients in the placebo group, 15.6% received additional lipid-lowering therapy, compared with 9.4% of patients in the bempedoic acid group. At six months, the difference in the percent change in mean high-sensitivity CRP was -21.6 percentage points (95% CI, -23.7 to -19.6) in favor of bempedoic acid.
Cumulative Incidence of Cardiovascular Events
A primary endpoint event (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization) occurred in 819 patients (11.7%) in the bempedoic acid group and in 927 patients (13.3%) in the placebo group (hazard ratio, 0.87; 95% CI, 0.79-0.96; p=0.004). The risk of events related to the first three key secondary endpoints was significantly lower in the bempedoic acid group than in the placebo group. Death from cardiovascular causes, nonfatal stroke, or nonfatal myocardial infarction (the first major secondary endpoint) occurred in 575 patients (8.2%) in the bempedoic acid group and in 663 patients (9.5%) in the placebo group (hazard ratio, 0.85; 95% CI, 0.76-0.96; p=0.006). Fatal or nonfatal myocardial infarction (the second major secondary endpoint) occurred in 261 patients (3.7%) in the bempedoic acid group and in 334 patients (4.8%) in the placebo group (hazard ratio, 0.77; 95% CI, 0.66-0.91; p=0.002). Coronary revascularization (the third major secondary endpoint) occurred in 435 patients (6.2%) in the bempedoic acid group and in 529 patients (7.6%) in the placebo group (hazard ratio, 0.81; 95% CI, 0.72-0.92; p=0.001). The results for the other major secondary end points (fatal or nonfatal stroke, death from cardiovascular causes, and death from any cause) did not differ significantly between the bempedoic acid group and the placebo group.
Adverse events and safety-relevant laboratory findings
The overall frequency of adverse events, serious adverse events, and adverse events leading to discontinuation of the study program did not differ significantly between the bempedoic acid group and the placebo group. The frequency of investigator-reported predefined adverse events of special interest was similar in the two study groups, with the exception of increases in liver enzyme levels (4.5% in the bempedoic acid group versus 3.0% in the placebo group) and renal events (11.5% in the y bempedoic acid group versus 8.6% in the placebo group). Myalgias were reported in 5.6% of patients in the bempedoic acid group and in 6.8% of patients in the placebo group. Rhabdomyolysis was identified by investigators in eight patients (0.06%), two of whom (one in each study group) met diagnostic criteria for rhabdomyolysis. Increases in liver aminotransferase levels of more than three times the upper limit of the normal range occurred more frequently in the bempedoic acid group than in the placebo group, and the mean changes from baseline in creatinine and uric acid levels were greater in the bempedoic acid group. The incidence of hyperuricemia was higher in the bempedoic acid group than in the placebo group (10.9% vs. 5.6%), as was the incidence of gout (3.1% vs. 2.1%) and cholelithiasis (2.2% vs. 1.2%).
Benefits of bempedoic acid are now clearer
The compelling results of the CLEAR Outcomes study will and should increase the use of bempedoic acid in patients with established atherosclerotic vascular disease and in patients at high risk for vascular disease who cannot or will not take statins. However, it is premature to consider bempedoic acid as an alternative to statins. Given the overwhelming evidence for the vascular benefits of statins, clinicians should continue to strive to prescribe them at the maximum tolerated dose for appropriate patients, including those who have discontinued statins because of suspected side effects. Although bempedoic acid also lowers LDL cholesterol levels in patients taking statins, the clinical benefit of bempedoic acid in addition to standard statin therapy is unknown [1].
Two observations from the CLEAR outcomes study require further investigation. Given the pathobiology of atherosclerosis, the evidence of a greater effect of bempedoic acid in the primary prevention cohort than in the secondary prevention cohort is likely due to chance. However, it is plausible that patients may benefit more from early administration of bempedoic acid during the course of atherosclerotic disease or that concomitant therapies may reduce the benefit of bempedoic acid in the secondary prevention cohort. As the investigators note, this finding could be due to effective adjunctive therapy, excessively short treatment and observation periods, or the actual lack of an effect of bempedoic acid on mortality. Many individual studies on statins have also shown no effect of the drug on mortality; it was not until meta-analysis of several clinical trials that the effect of statins on mortality became clear [1].
Bempedoic acid has now been added to the list of evidence-based alternatives to statins for primary and secondary prevention in patients at high cardiovascular risk. The benefits of bempedoic acid are now clearer, and it is now the responsibility of clinicians to translate this information into better primary and secondary prevention for more high-risk patients who will benefit from fewer cardiovascular events as a result [1].
Literature:
- Alexander JH: Benefits of Bempedoic Acid – Clearer Now. N Engl J Med 2023; doi: 10.1056/NEJMe2301490.
- Keaney JF, Jr: Bempedoic Acid and the Prevention of Cardiovascular Disease. N Engl J Med 2023; doi: 10.1056/NEJMe2300793.
- Nissen SE, et al: Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients. N Engl J Med 2023; doi: 10.1056/NEJMoa2215024.
CARDIOVASC 2023; 22(2): 22-24
