Bempedoic Acid in PAD

Peripheral artery disease (PAD) is a common but often under recognized form of atherosclerotic cardiovascular disease (ASCVD). Bempedoic acid provides a statin-independent option that lowers both cardiovascular and limb events in statin-intolerant patients with PAD.

A subgroup analysis of the CLEAR Outcomes trial assessed bempedoic acid (Nexletol) in 1,624 statin-intolerant PAD patients (from 13,970 total randomized to bempedoic acid 180 mg daily or placebo).

Baseline LDL cholesterol was 139 mg/dL. At 6 months, LDL fell by 23.6% with bempedoic acid vs 1% with placebo. Over a median 40.6-month follow-up, bempedoic acid reduced first major adverse limb events (MALE) by 36% and total MALE by 45%, with event rates of 5.8% vs 8.3%. Benefits were seen by 6 months and continued throughout follow-up. Combined cardiovascular and limb events were also reduced, showing benefit beyond prevention of myocardial infarction and stroke.

Nearly three-quarters of PAD patients had no prior major limb event, yet still had meaningful event rates. This highlights PAD as a high-risk ASCVD condition even without prior revascularization or critical limb ischemia.

These results align with the overall CLEAR Outcomes trial, where bempedoic acid reduced the primary composite cardiovascular endpoint by 13%. The drug inhibits ATP citrate lyase, lowering LDL cholesterol and generally causing fewer muscle-related side effects than statins. Overall safety was similar to placebo, although hyperuricemia and gout occurred more often.

In summary, these findings support treating PAD as established ASCVD and using intensive LDL lowering to reduce both cardiovascular and limb risk. Statins remain first-line when tolerated, but statin-intolerant patients should receive nonstatin therapies such as bempedoic acid, ezetimibe, or PCSK9-targeted agents, guided by LDL levels, risk, and treatment goals.

Clinical takeaway: In statin-intolerant patients with PAD, clinicians should proactively initiate nonstatin LDL-lowering therapy—particularly bempedoic acid—to reduce not only cardiovascular events but also major limb complications, reinforcing PAD as a high-risk ASCVD condition requiring aggressive lipid management.