Bempedoic acid safety analysis: Pooled data from four phase 3 clinical trials

Abstract

BACKGROUND: An ongoing need exists for safe and effective lipid-lowering therapies (LLTs) for patients unable to achieve desired lipid levels with current treatment options. OBJECTIVE: The objective of this study was to describe the safety profile of bempedoic acid, an oral, first-in-class, adenosine triphosphate (ATP)-citrate lyase inhibitor that significantly reduces low-density lipoprotein cholesterol (LDL-C) levels by 17.4%-28.5% vs placebo. METHODS: This was a pooled analysis of four phase 3, randomized (2:1), double-blind, placebocontrolled studies in patients with hypercholesterolemia who required additional LDL-C lowering, despite stable maximally-tolerated LLT. Patients received 180 mg of bempedoic acid (n 5 2424) or placebo (n 5 1197) once daily for 12 to 52 weeks. Assessments included treatment-emergent adverse events (TEAEs) and clinical laboratory tests. RESULTS: Of 3621 patients (the median drug exposure: 363 days), exposure-adjusted TEAE rates were 87.1/100 and 82.9/100 person-years (PY) for bempedoic acid and placebo, respectively. No single TEAE influenced the difference in rates. TEAEs leading to discontinuation occurred at rates of 13.4/ 100 and 8.9/100 PY for bempedoic acid vs placebo, with the most common cause being myalgia, which occurred less frequently with bempedoic acid vs placebo (1.5/100 vs 2.0/100 PY). Rates of myalgia and muscle weakness were comparable vs placebo. Bempedoic acid was associated with mild increases in blood urea nitrogen, creatinine, and uric acid and decreases in hemoglobin. These laboratory abnormalities were apparent by week 4, stable over time, and reversible after treatment cessation. Gout incidence was 1.6/100 vs 0.5/100 PY in the bempedoic acid vs placebo groups. New-onset diabetes/ hyperglycemia occurred less frequently with bempedoic acid vs placebo (4.7/100 vs 6.4/100 PY). The safety profile was consistent across subgroups. CONCLUSIONS: Bempedoic acid is generally safe and well tolerated among patients with hypercholesterolemia who require additional LLT.

Role of Bempedoic Acid in Clinical Practice

“…Other risk factors for tendon rupture include statin use [42,43], fluoroquinolone or systemic corticosteroid use, diabetes, gout, rheumatoid arthritis, renal failure, patients who are aged older than 60 years, being male, and history of tendon disorders [43][44][45][46][47]. In the phase 3 bempedoic acid trials, all the patients who developed tendon rupture or injury had one or more of these risk factors, including concomitant statins [40].…”

“…Overall, in the phase 3 studies, bempedoic acid was not associated with a clinically meaningful increase in the incidence of muscle-related AEs commonly reported with statin use, including myalgia and muscle weakness [ 40 ]. Among patients in the ASCVD and/or HeFH on statins pool, 51% of whom were taking high-intensity statins; muscle spasms (bempedoic acid, 3.6% and placebo, 2.3%), pain in the extremity (bempedoic acid, 3.0% and placebo, 1.7%), myalgia (bempedoic acid, 5.2% and placebo, 5.3%), and muscle weakness (bempedoic acid, 0.5% and placebo, 0.5%) were reported at the same incidence rate in patients treated with bempedoic acid or placebo [ 33 , 34 ].…”

“…The mean increase in uric acid at 12 weeks was 0.82 mg/dL for bempedoic acid vs −0.02 mg/dL for placebo. This increase was apparent within 4 weeks of treatment, was stable over time, and was reversible after withdrawal of drug [ 40 ]. A history of gout also appeared to increase the risk of gout with bempedoic acid; 14 (11.0%) of 127 patients with a history of gout developed acute gout while they received bempedoic acid compared with 2 (2.9%) of 69 patients with a history of gout who received placebo.…”

Lipid lowering with bempedoic acid added to a proprotein convertase subtilisin/kexin type 9 inhibitor therapy: A randomized, controlled trial

“…Bempedoic acid was associated with mild increases in blood urea nitrogen, creatinine, and uric acid and decreases in hemoglobin, which were reversible after treatment was stopped. 28 Patients treated with bempedoic acid had a higher rate of gout than did patients receiving placebo (1.6 per 100 patient-years vs 0.5 per 100 patient-years). 28 The incidence of gout was greatest among patients who had a history of gout or those who had elevated uric acid levels at baseline.…”

“…28 Patients treated with bempedoic acid had a higher rate of gout than did patients receiving placebo (1.6 per 100 patient-years vs 0.5 per 100 patient-years). 28 The incidence of gout was greatest among patients who had a history of gout or those who had elevated uric acid levels at baseline. It is possible that a similar incidence of laboratory abnormalities and gout associated with bempedoic acid treatment and more adverse reactions associated with evolocumab would have been observed in our study if it had been of longer duration.…”