Study Suggests Bempedoic Acid Could Find Role in Primary Prevention

Steve Nissen, MD
Credit: Cleveland Clinic

New data from the 83rd Scientific Sessions of the American Diabetes Association (ADA 2023) suggests bempedoic acid could prove useful in a primary prevention role for people with statin intolerance.

A subgroup analysis of a primary prevention cohort within the CLEAR Outcomes trial, results of the study come just more than 3 months after the initial presentation of the trial at the American College of Cardiology (ACC) 2023 scientific sessions and suggest use of bempedoic acid was associated with a 30% reduction in relative risk of the primary MACE endpoint in adjusted analyses.^1,2

“We know early prevention measures are critical to slowing the progression of heart disease, especially for people with comorbidities like diabetes,” said the study’s lead author Steven E. Nissen MD, chief academic officer of the Heart, Vascular, and Thoracic Institute at Cleveland Clinic.³ “Unfortunately, less than half of patients in the US similar to the study patient population are being treated with cholesterol-lowering drugs – leaving them at risk. The results presented today are a wake-up call for the clinical community that patients with risk factors for coronary disease and high cholesterol, particularly those with diabetes, should be treated with a cholesterol-lowering drug.”

Leading up to the presentation at the American College of Cardiology 2023 scientific sessions and simultaneous publishing in the New England Journal of Medicine, CLEAR Outcomes was amongst the most anticipated trials in lipid management in recent memory. A 13,970-person trial, the study was the first to demonstrate a benefit on 4-point major adverse cardiovascular events (MACE) with a lipid-lowering therapy.²

Results of the study presented at ACC 2023 suggested primary endpoint event was significantly lower with bempedoic acid (11.7%) than with placebo therapy (13.3%) (Hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.79-0.96; P=.004). Investigators pointed out the analyses also indicated use of bempedoic acid was associated with reductions in the incidences of a composite of death from cardiovascular causes, nonfatal stroke, or nonfatal myocardial infarction (HR, 0.85; 95% CI, 0.76-0.96; P = .006), fatal or nonfatal myocardial infarction (HR, 0.77; 95% CI, 0.66-0.91; P = .002); and coronary revascularization (HR, 0.81; 95% CI, 0.72-0.92; P = .001).²

At ADA 2023, Nissen presented data from a primary prevention subgroup within the CLEAR Outcomes trial, which included 4206 of the 13,970 included in the overall trial. Among this cohort, 2100 received bempedoic acid and 2106 received matching placebo therapy. The overall cohort included in the subgroup analysis had a mean age of 68 years, 59% were female, and 66% had diabetes. Investigators highlighted use of bempedoic acid was associated with a mean reduction in LDL-C of 30.2 mg/dL and hsCRP reduction of 0.56 mg/L compared to placebo therapy.¹

The primary outcome of interest for the trial was the first occurrence of any component of a MACE composite, which included cardiovascular death, nonfatal myocardial infarction (MI), nonfatal stroke, or coronary revascularization.¹

Upon analysis, results indicated use of bempedoic acid was associated with a 30% reduction in relative risk of a primary endpoint event in adjusted analyses, which included a median follow-up of 39.9 months (aHR, 0.70; 95% CI, 0.55-0.89; P = .002). Further analysis suggested use of bempedoic acid was associated with a reduction in risk when using a composite of cardiovascular death, MI, or stroke (HR, 0.64; 95% CI, 0.48-0.84; P < .001) and when assessing cardiovascular death (HR, 0.61; 95% CI, 0.41-0.92), and all-cause mortality (HR, 0.73; 95% CI, 0.54-0.98).¹

Investigators pointed out there was no significant effect on risk of stroke or coronary revascularization. Additionally, analysis of safety endpoints suggested use of bempedoic acid was associated with an increased incidence of gout (2.6% vs 2.0%), cholelithiasis (2.5% vs 1.1%), and increases in serum creatinine, uric acid, and hepatic enzyme levels relative to placebo therapy.¹

In an editorial published in JAMA, Dhruv Kazi, MD, associate director of the Smith Center for Outcomes Research and director of the Cardiac Critical Care Unit at Beth Israel Deaconess Medical Center, highlighted the significance of the CLEAR Outcomes results demonstrating the benefit of bempedoic acid but cautioned clinicians they should still consider statins as first-line therapy in patients who can tolerate use.⁴

“Given these strengths and limitations of the analysis, how do clinicians incorporate bempedoic acid into clinical practice? Bempedoic acid is an effective therapeutic option for appropriately selected statin-intolerant individuals who would have met the eligibility criteria for the study based on elevated predicted risk of cardiovascular events, presence of high levels of coronary calcium, or concurrent diabetes,” Kazi wrote.⁴ “But even in this higher-risk group, bempedoic acid should not be considered a substitute for statins, which remain the first-line therapy for primary prevention for several reasons.”

References:

1. Nissen SE, Menon V, Nicholls SJ, et al. Bempedoic Acid for Primary Prevention of Cardiovascular Events in Statin-Intolerant Patients. JAMA. Published online June 24, 2023. doi:10.1001/jama.2023.9696
2. Campbell P. Bempedoic acid reduces risk of mace by 13%, but proves no benefit on cardiovascular death. HCP Live. March 4, 2023. Accessed June 24, 2023. https://www.hcplive.com/view/bempedoic-acid-reduces-risk-of-mace-by-13-but-proves-no-benefit-on-cardiovascular-death.
3. Cholesterol lowering drug shown to cut major heart-related events and risk of death from heart disease by one-third for statin-intolerant patients. Cholesterol Lowering Drug Shown to Cut Major Heart-Related Events and Risk of Death from Heart Disease by One-Third for Statin-Intolerant Patients | ADA. June 24, 2023. Accessed June 24, 2023. https://diabetes.org/newsroom/press-releases/2023/cholesterol-lowering-drug-shown-cut-major-heart-related-events-and-risk-death-heart-disease-one-third-statin-intolerant-patients.
4. Kazi DS. Bempedoic Acid for High-Risk Primary Prevention of Cardiovascular Disease: Not a Statin Substitute but a Good Plan B. JAMA. Published online June 24, 2023. doi:10.1001/jama.2023.9854