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August 18, 2026Circulation
Bempedoic Acid and First and Recurrent Limb Outcomes in Statin-Intolerant Patients With Peripheral Artery Disease: Insights From the CLEAR Outcomes Trial
Key result
Bempedoic acid cuts major adverse limb events ~36% vs placebo in statin-intolerant PAD patients.
- HR 0.64
- 95% CI 0.44-0.93
- P=0.018
- n=13,970
Why the study?
Whether bempedoic acid reduces the risk of major adverse limb events in patients with peripheral artery disease was unknown.
Does bempedoic acid 180 mg reduce major adverse limb events and major adverse cardiovascular events in statin-intolerant patients with peripheral artery disease?
Key Points
- To determine whether bempedoic acid reduces first and recurrent major adverse limb events (MALEs) in statin-intolerant patients with peripheral artery disease (PAD).
- In the CLEAR Outcomes trial, 13,970 statin-intolerant patients were randomized to receive bempedoic acid 180 mg daily or placebo between December 2016 and August 2019, including 1,624 patients with baseline PAD (mean age 63.9 years, 56.3% female).
- Blinded vascular specialists independently adjudicated MALEs (worsening symptoms requiring revascularization, chronic limb-threatening ischemia, and acute limb ischemia), evaluating time-to-first event and total events over a median follow-up of 40.6 months.
- In patients with baseline PAD, bempedoic acid reduced first MALEs by 36% compared to placebo (8.3% event rate; HR 0.64 [95% CI, 0.44–0.93]; P=0.018) and reduced total MALEs by 45% (RR 0.55 [95% CI, 0.35–0.85]; P=0.007).
- Total composite MACE-4 or MALE events were significantly reduced overall (RR 0.81 [95% CI, 0.73–0.90]), demonstrating consistent treatment efficacy in patients with PAD (RR 0.71 [95% CI, 0.54–0.95]) and without PAD (RR 0.82 [95% CI, 0.73–0.92]).
Study Design
Type
RCT (n=13,970)
Blinding
Blinded
Randomization
Randomized
Multicenter
Yes
Structured PICO
Does bempedoic acid 180 mg reduce major adverse limb events and major adverse cardiovascular events in statin-intolerant patients with peripheral artery disease?
P
Population
13,970 statin-intolerant patients (including 1,624 with peripheral artery disease at baseline, mean age 63.9 years, 56.3% female) randomized to bempedoic acid or placebo, followed for a median of 40.6 months.
I
Intervention
Bempedoic acid 180 mg
C
Comparator
Placebo
O
Outcome
MACE-4, defined as death resulting from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularizationcomposite
Main Result
Hazard Ratio: 0.64 (95% CI 0.44–0.93)
p-value: p=0.018
Bempedoic acid significantly reduces the risk of first and recurrent major adverse limb events in statin-intolerant patients with peripheral artery disease.
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“The consistent benefits seen in the current study with bempedoic acid underscore the importance of focusing on LDL targets for our high-risk vascular patients, and that combination therapies are going to be needed to achieve those goals in a significant number of patients.”
SSSeth S. MartinCardiologist, Johns Hopkins University School of Medicine
“Here we have yet another LDL-lowering therapy that's been directly shown to reduce risk in patients with PAD. These results are a good reminder that PAD is a form of atherosclerotic cardiovascular disease. These are particularly high-risk patients and there is a clinically significant reduction in cardiovascular outcomes.”
Implication
Supports bempedoic acid for limb-event prevention in statin-intolerant PAD; extends LDL-C lowering benefit to MALEs in this subgroup.
Abstract
BACKGROUND: Patients with peripheral artery disease (PAD) are at high risk of major adverse limb events (MALEs) and major adverse cardiovascular events (MACEs). Recently, bempedoic acid was shown to reduce MACEs in primary and secondary prevention patients. Whether bempedoic acid reduces the risk of MALE in patients with PAD is unknown. METHODS: CLEAR Outcomes (Cholesterol Lowering via Bempedoic Acid [ETC1002], an ACL-Inhibiting Regimen) randomized 13 970 patients to bempedoic acid 180 mg or placebo from December 22, 2016, to August 14, 2019. The trial primary end point was MACE-4, defined as death resulting from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization. A clinical history of PAD was reported by investigators at baseline. Two blinded vascular medicine specialists independently adjudicated MALEs, including adverse events indicating worsening PAD symptoms leading to revascularization, chronic limb-threatening ischemia, and acute limb ischemia. Outcomes were assessed as time to first event and total (including recurrent) events with a negative binomial approach. RESULTS: A total of 1624 of the enrolled patients (mean±SD age, 63.9±9.9 years; 915 [56.3%] female) had PAD at baseline. In patients with PAD in the placebo group, 69 (8.3%) had MALEs over a median of 40.6 months, with rate of recurrent events of 4.0%/y. Bempedoic acid reduced the risk of MALEs by 36% (hazard ratio, 0.64 [95% CI, 0.44–0.93]; P =0.018) Bempedoic acid reduced total MALEs by 45% (relative risk, 0.55 [95% CI, 0.35–0.85]; P =0.007). First MACE-4 or MALE was reduced overall by 13% (hazard ratio, 0.87 [95% CI, 0.80–0.95]) with consistent effects with PAD (hazard ratio, 0.82 [95% CI, 0.64–1.04]) and without PAD (hazard ratio, 0.87 [95% CI, 0.79–0.86]; P interaction =NS) but not statistically significant within the PAD subgroup alone. Total MACE-4 or MALE was reduced (relative risk, 0.81 [95% CI, 0.73–0.90]) overall with consistent effects in PAD (relative risk, 0.71 [95% CI, 0.54–0.95]) and without PAD (relative risk, 0.82 [95% CI, 0.73–0.92]; P interaction =NS). CONCLUSIONS: Patients with PAD are at high risk of MALEs and MACEs. Bempedoic acid reduces both MACEs and MALEs in patients with atherosclerotic vascular disease, with notable absolute benefits in patients with PAD. These findings support (1) the importance of lowering low-density lipoprotein cholesterol in patients with PAD to reduce overall vascular risk and (2) the benefits of bempedoic acid in this population.
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Cite This Study
Bonaca et al. (2026) conducted an RCT in Peripheral artery disease (PAD) and statin intolerance (n=13,970). Bempedoic acid vs. Placebo was evaluated on Major adverse limb events (MALEs) (HR 0.64, 95% CI 0.44-0.93, p=0.018). Bempedoic acid reduced the risk of major adverse limb events by 36% in statin-intolerant patients with peripheral artery disease (HR 0.64; 95% CI 0.44-0.93; P=0.018).