CLEAR substudies show benefit of bempedoic acid in three high-risk populations
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The cholesterol benefits of bempedoic acid plus background therapy were consistent across subgroups of patients with hypertension, metabolic syndrome and renal impairment, researchers reported.
At the National Lipid Association (NLA) Scientific Sessions, researchers presented three substudies of the CLEAR trials that evaluated the efficacy and safety of bempedoic acid (Nexletol, Esperion Therapeutics) for LDL lowering across several different patient populations.
Data were pooled from the phase 3 CLEAR Harmony, CLEAR Wisdom, CLEAR Serenity and CLEAR Tranquility trials, in which patients were randomly assigned to bempedoic acid 180 mg or placebo once daily plus stable background lipid-lowering therapy for 12 weeks.
In the CLEAR Harmony trial, researchers found that patients with atherosclerotic CVD and/or heterozygous familial hypercholesterolemia experienced significant decreases in LDL without a higher incidence of overall adverse events when assigned to bempedoic acid plus maximally tolerated statin therapy compared with placebo.
In CLEAR Wisdom, once-daily therapy bempedoic acid lowered LDL after 12 weeks compared with placebo in patients at high risk for CV events already receiving maximally tolerated statin and other lipid-lowering therapy.
Results of a prior pooled analysis of the CLEAR trials, published in JAMA Cardiology, showed that 12 weeks of once-daily bempedoic acid for patients with ASCVD and/or heterozygous familial hypercholesterolemia had a percentage change in LDL from baseline of –16% compared with 1.8% in the placebo arm (difference, –17.8 percentage points; 95% CI, –19.5 to –16; P < .001).
Each of the three posters presented at the NLA Scientific Sessions were subanalyses of the data from the CLEAR trials and assessed the effects of bempedoic acid in patients with hypertension, metabolic syndrome and renal impairment.
Bempedoic acid was generally well tolerated and had a safety profile similar to placebo in all three subanalyses.
The most common treatment emergent adverse events were reported in the renal function substudy and included urinary tract infection, anemia, diarrhea, arthralgia, nasopharyngitis, myalgia and fatigue.
Bempedoic acid in hypertension
In their CLEAR subanalysis, Cardiology Today Editorial Board Member Keith C. Ferdinand, MD, FACC, FAHA, FASPC, FNLA, professor of medicine in the John W. Deming department of medicine at Tulane University School of Medicine, and colleagues evaluated the efficacy and safety of bempedoic acid for patients with hypercholesterolemia and hypertension.
This study included data from the prior pooled analysis, including 2,825 patients with hypertension and 798 without, as well as data from a 6-week, randomized, double-blind, parallel-group phase 2 bempedoic acid study, which included 71 patients with hypertension and 72 without. The majority of patients included were white.
Ferdinand and colleagues reported that the mean percent LDL change at week 12 was significant (P < .0001) regardless of the patients’ hypertension status (P for interaction = .3697).
Moreover, in patients with BP between 140/90 mm Hg and 180/110 mm Hg, bempedoic acid had no effect on systolic BP or diastolic BP at week 6; however, generalization of these findings are limited due to the high proportion of white participants, according to the researchers.
Bempedoic acid in metabolic syndrome
In a second CLEAR subanalysis, Michael D. Shapiro, DO, Fred M. Parrish Professor of Cardiology and Molecular Medicine and director of the Center for Prevention and Cardiovascular Disease at Wake Forest University School of Medicine, and colleagues assessed the efficacy and safety of bempedoic acid on glycemic parameters in patients with metabolic syndrome at baseline.
“Metabolic syndrome has been associated with a twofold increased risk of developing atherosclerotic cardiovascular disease,” Shapiro and colleagues wrote on a poster. “The effect of bempedoic acid as a lipid-lowering therapy in patients with metabolic syndrome has not been established.”
Researchers also assessed the percent changes in high-sensitivity C-reactive protein, fasting plasma glucose and HbA1c at 12 weeks in patients with metabolic syndrome assigned to bempedoic acid or placebo.
Shapiro and colleagues reported that the mean percent LDL change at week 12 was significant (P < .0001), regardless of the patients’ metabolic syndrome status and was even more pronounced in those with metabolic syndrome compared with those without it (P for interaction = .0472).
Moreover, the median difference in high-sensitivity CRP at 12 weeks was significant regardless of metabolic syndrome status (P for all < .0001; P for interaction = .965).
The mean percent change in HbA1c (0.07; 95% CI, 0.1 to 0.04; P < .0001) and fasting plasma glucose was significant for patients with metabolic syndrome taking bempedoic acid (2.4; 95% CI, 4 to 0.9; P = .002) and was not significant for patients without metabolic syndrome (P for interaction for HbA1c = .0003; P for interaction for fasting plasma glucose = .002).
Bempedoic acid in renal impairment
For the third poster, Peter P. Toth, MD, PhD, FAHA, FESC, FACC, director of preventive cardiology at CGH Medical Center in Sperling, Illinois; professor of clinical family and community medicine at University of Illinois College of Medicine in Peoria; professor of medicine at Michigan State University College of Osteopathic Medicine in East Lansing, and colleagues conducted an analysis of safety and efficacy of bempedoic acid in patients with impaired renal function.
A total of 2,833 patients with impaired renal function were included in this study, of whom 81% had stage 2 renal function and 19% had stage 3a+b renal function.
“Renal impairment and elevated levels of LDL-C are both associated with cardiovascular risk. Patients with chronic kidney disease (CKD) are also at high risk of medication adverse events, possibly due to reduced renal excretion, as well as the likelihood of polypharmacy and high propensity for comorbidities,” Toth and colleagues wrote on a poster. “Lowering LDL-C reduces the risk of cardiovascular events in patients with CKD. Statins are utilized to lower LDL-C in this population; however, patients may not reach lipid goals without additional lipid-lowering therapies.”
Similar to the other subanalyses, Toth and colleagues reported that the mean percent LDL change at week 12 was significant (P < .0001), regardless of the patients’ stage of renal impairment and was similar across stages (P for interaction = .4442).
The mean percent change in total cholesterol (P for interaction = .7371), non-HDL (P for interaction = .6843), apolipoprotein B (P for interaction = .8706) and high-sensitivity CRP (P for interaction = .2173) were significant irrespective of renal impairment at 12 weeks.
Over a 52-week period, mean creatine level varied 7% or less in either the bempedoic acid or placebo arms, and 0.3% of patients in the bempedoic acid arm experienced a creatinine increase of more than 1 mg/dL at any time point.
References:
- Banach M, et al. JAMA Cardiol. 2020;doi:10.1001/jamacardio.2020.2314.
- Goldberg AC, et al. Late-Breaking Clinical Trials IV. Presented at: American College of Cardiology Scientific Session; March 16-18, 2019; New Orleans.
- Ray KK, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1803917.
- Shapiro MD, et al. Abstract 34. Presented at: National Lipid Association Scientific Sessions; June 2-5, 2022; Scottsdale, Arizona (hybrid meeting).
- Toth PP, et al. Abstract 32. Presented at: National Lipid Association Scientific Sessions; June 2-5, 2022; Scottsdale, Arizona (hybrid meeting).
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Ferdinand KC, et al. Abstract 33. Presented at: National Lipid Association Scientific Sessions; June 2-5, 2022; Scottsdale, Arizona (hybrid meeting).
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