Bempedoic acid has similar CV benefits as statins when normalized to degree of LDL-c lowering

Applying the methodology of the Cholesterol Treatment Trialists’ Collaboration to CLEAR Outcomes trial data showed bempedoic acid and statins led to comparable reductions of major vascular and coronary events per 1 mmol/L reduction in LDL-c.

This summary is based on the publication of Lincoff AM, Ray KK, Sasiela WJ, et al. - Comparative Cardiovascular Benefits of Bempedoic Acid and Statin Drugs. J Am Coll Cardiol. 2024 Jul 9;84(2):152-162. doi: 10.1016/j.jacc.2024.04.048

Introduction and methods

Background

Bempedoic acid, an adenosine triphosphate citrate lyase (ACL) inhibitor, blocks cholesterol synthesis upstream of HMG-CoA reductase . Unlike statins, bempedoic acid is a prodrug that is activated in the liver. In the recent CLEAR (Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen) Outcomes trial, bempedoic acid treatment resulted in a 21% decrease in LDL-c levels at 6 months compared with placebo and a 13% relative reduction in the risk of MACE [1].

In 2010, the Cholesterol Treatment Trialists’ Collaboration (CTTC) reported that for every 1 mmol/L (38.7 mg/dL) reduction in LDL-c levels achieved with statin therapy over 1 year, the risk of major vascular events is reduced by 22% [2].

Aim of the study

The authors examined whether the relationship between LDL-c lowering and CV benefits achieved with bempedoic acid is similar to that observed with statins when normalized per unit change in LDL-c level.

Methods

The CLEAR Outcomes trial was an international, multicenter, double-blind, placebo-controlled, event-driven, phase 3 RCT in which 13,970 statin-intolerant patients with pre-existing CVD (secondary prevention cohort) or elevated CVD risk (primary prevention cohort) and LDL-c ≥100 mg/dL (≥2.6 mmol/L) were randomized to oral bempedoic acid 180 mg once daily or placebo. At the time of randomization, 3174 patients (22.7%) were on statins. Median follow-up duration was 40.6 months (Q1–Q3: 37.1–46.2).

For the current analysis, the authors applied the CTTC methodology to outcomes of patients in the CLEAR Outcomes trial, using the CTTC composite endpoints “major vascular event” (defined as coronary heart disease death, nonfatal MI, fatal or nonfatal stroke, or coronary revascularization) and “major coronary event” (defined as coronary heart disease death or nonfatal MI).

Main results

• At 12 months, a first CTTC-defined major vascular event had occurred in 703 of 6992 patients (10.1%) in the bempedoic acid group and 816 of 6978 patients (11.7%) in the placebo group (HR: 0.85; 95%CI: 0.77–0.94).
• When normalized per 1 mmol/L reduction in LDL-c level, the HR for the first major vascular event was 0.75 (95%CI: 0.63–0.90). This was comparable to the rate ratio (RR) of 0.78 (95%CI: 0.76–0.80) per 1 mmol/L LDL-c reduction reported for statins in the CTTC 2010 meta-analysis [2].
• The incidence rate of the first CTTC-defined major coronary event at 12 months was 4.8% in the bempedoic acid group and 5.9% in the placebo group (HR: 0.81; 95%CI: 0.70–0.93), corresponding to an HR per 1 mmol/L LDL-c reduction of 0.69 (95%CI: 0.54–0.89). In comparison, the RR per 1 mmol/L LDL-c reduction for statins in the 2010 CTTC meta-analysis was 0.76 (95%CI: 0.73–0.78) [2].
• Similar normalized risk reductions for bempedoic acid and statins were seen for nonfatal MI and coronary revascularization but not coronary heart disease death or fatal or nonfatal stroke.
• In the primary prevention cohort (n=4206), the HR for the major vascular event composite endpoint per 1 mmol/L LDL-c reduction was 0.55 (95%CI: 0.35–0.86), compared with an RR per 1 mmol/L LDL-c reduction of 0.75 (95%CI: 0.70–0.80) in statin-treated patients with no vascular disease in an updated CTTC meta-analysis from 2012 [3].
• In the secondary prevention cohort (n=9764), the HR for the major vascular event composite endpoint per 1 mmol/L LDL-c reduction was 0.79 (95%CI: 0.66–0.96), compared with an RR per 1 mmol/L LDL-c reduction of 0.80 (95%CI: 0.77–0.82) in statin-treated patients with pre-existing vascular disease in the 2012 CTTC meta-analysis [3].
• A sensitivity on-treatment analysis in the per-protocol population of the CLEAR Outcomes trial (n=13,820) showed greater risk reductions for all CV endpoints compared with the intention-to-treat analysis. However, when normalized to LDL-c reductions at 12 months, the HRs were similar in the intention-to-treat and on-treatment per-protocol analyses.

Conclusion

Applying the CTTC methodology to CLEAR Outcomes trial data demonstrated that bempedoic acid reduced the risk of major vascular and coronary events in patients with or at high risk of CVD to a similar extent as statins for a given absolute magnitude of LDL-c lowering. The authors’ take-away message, therefore, is: “While statins remain the first-line therapy in cardiovascular disease prevention, treatment with bempedoic acid can provide significant reductions in cardiovascular risk among patients who cannot achieve desired LDL-c levels with statins, including those [who] are unable or unwilling to tolerate guideline-recommended doses of statins or who fail to experience sufficient LDL-c lowering despite intensive statin therapy.”

Find this article online at J Am Coll Cardiol.

References

1. Nissen SE, Lincoff AM, Brennan D, et al. Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. N Engl J Med. 2023;388(15):1353–1364.
2. Baigent C, Blackwell L, Emberson J, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376(9753):1670–1681.
3. Mihaylova B, Emberson J, Blackwell L, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012;380(9841):581–590.