Cardiology Pharmaceuticals

Two Sides to Bempedoic Acid’s Primary Prevention Impact

A Cleveland Clinic-led study stunned the ADA 2023 crowd this week, showing that bempedoic acid (Esperion’s Nexletol) significantly reduced future cardiovascular events among people with high CVD risks who had never experienced a major cardiac event. 

The JAMA-published subanalysis of the 14k-patient CLEAR Outcomes trial looked at a subgroup 4,206 primary prevention patients (high CVD risks, diabetes, no previous CV events, statin-intolerant, 59% women) who were randomized to either take bempedoic acid (180 mg daily oral) or a placebo.

The bempedoic acid group achieved a 21.3% average LDL-C reduction versus placebo at six months (-30.2 mg/dL, 142.5 mg/dL at baseline), and had 21.5% lower HSCRP levels at 12 months (2.4 mg/L at baseline). 

Those “modest” cholesterol reductions appeared to drive significant outcome improvements over 40 months:

  • 30% reduced risk of MACE 4 (5.3% vs 7.6% – CV death, MI, stroke, or coronary revascularization) — the primary endpoint
  • 36% reduced risk of MACE 3 (4.0% vs. 6.4% – CV death, MI, or stroke)
  • 39% reduced risk of nonfatal myocardial infarction (1.4% vs. 2.2%)
  • 39% reduced risk of cardiovascular death (1.8% vs. 3.1%)
  • 27% reduced risk of all-cause mortality (3.6% vs. 5.2%)

These subanalysis results far surpassed those from the overall CLEAR Outcomes trial, which showed a much smaller 13% reduction in MACE 4 among both primary and secondary prevention patients, and didn’t reduce all-cause mortality.

The authors called the study a “wake-up call” for physicians, noting that less than half of U.S. adults who are candidates for primary prevention lipid-lowering therapy actually receive it, including many patients who can’t or don’t want to take statins.

However, the corresponding JAMA editorial and critics on CardioTwitter suggest that these results might be “too good to be true” (e.g. statistical issues, implausible differences from CLEAR trial results), and the editorial emphasized that bempedoic acid should be viewed as a “good plan B” rather than a statin substitute. 

The Takeaway

At least within this particular subanalysis group, bempedoic acid massively reduced high-risk patients’ risk of experiencing their first CV event, while underscoring the overall importance of primary LDL-C reduction (regardless of medication). 

However, commentary from study authors and the cardiology community suggests that it might take even stronger evidence and some big changes (new guidelines, lower costs, more education/outreach) in order to meaningfully expand adoption of preventative LDL-C reduction therapies — especially beyond statins.

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