CLEAR Outcomes: Bempedoic Acid Reduces Limb Events in PAD

In statin-intolerant patients who have PAD, even those with no prior limb events, a cholesterol-lowering agent is associated with reductions in major cardiovascular events as well as major adverse limb events (MALE), according to a subgroup analysis from the CLEAR Outcomes trial.

Compared with those randomized to placebo, patients with PAD who received bempedoic acid (Nexletol; Esperion), an ATP citrate lyase inhibitor, had a 36% lower risk of MALE and 45% fewer total MALE over the study period.

“Effects appeared early, at 6 months of treatment, and continued over time, resulting in a meaningful reduction during follow-up,” write Marc P. Bonaca, MD (University of Colorado Anschutz Medical Campus, Aurora), and colleagues in a paper published today in Circulation.

To TCTMD, Bonaca said that to date the strongest data linking LDL-reducing therapies to benefits in PAD and fewer major adverse limb events has come from PCSK9 inhibitors. 

“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,” he wrote in an email.

In 2024, the US Food and Drug Administration approved expanded labeling for both bempedoic acid and bempedoic acid/ezetimibe (Nexlizet) to include a new indication for cardiovascular risk reduction in both primary and secondary prevention settings. Support for the decision came from the main CLEAR Outcomes trial, which showed that high-risk patients unable to tolerate statin therapy had a 13% lower relative risk of the primary composite endpoint of cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization. Compared with statins, bempedoic acid is associated with a lower risk of muscle-related adverse events.

In two subsequent subgroup analyses from the trial, the advantage for bempedoic acid held firm in those with no prior cardiovascular event and in patients with and without diabetes.

Commenting on the latest subgroup analysis for TCTMD, Seth S. Martin, MD (Johns Hopkins University School of Medicine, Baltimore, MD), said he views the data as being in line with the beneficial results seen with the PCSK9 inhibitor evolocumab (Repatha; Amgen) in the PAD subgroup of the FOURIER trial.

“Here we have yet another LDL-lowering therapy that’s been directly shown to reduce risk in patients with PAD,” he said. “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.”

Furthermore, Martin said, the CLEAR Outcomes findings represent “even more data that tells us we should all be out there doing everything we can to implement the 2026 dyslipidemia guideline that has very clear recommendations around the use of both statin and nonstatin therapies, including in patients with PAD.”

CLEAR Reductions Seen

CLEAR Outcomes randomized 13,970 patients to bempedoic acid 180 mg or placebo. For the subgroup analysis, Bonaca and colleagues looked at the 1,624 trial participants (mean age 63.9 years; 56.3% female) who had PAD at baseline. Like all others in the trial, those in the PAD subgroup were considered intolerant to statins. The investigators defined that as being unable or unwilling to take statin therapy due to muscle-related adverse effects associated with starting treatment that resolved when it was stopped.

At baseline, mean LDL-cholesterol level was 139.0 mg/dL in patients with and without PAD. The use of background lipid-lowering therapy also was similar, with 21.0% of those with PAD and 22.9% without PAD taking a very low-dose statin and 11.6% and 11.5%, respectively, taking ezetimibe.

After 6 months, the mean percent change in LDL-cholesterol levels in PAD patients was 23.6% with bempedoic acid and 1.0% with placebo. This correlated with a difference between groups over the duration of the trial of 22.2 mg/dL, which was consistent with the main study results.

Over a median of 40.6 months, the rate of MALE was 8.3% in PAD patients on placebo and 5.8% in those on bempedoic acid (P = 0.018).

The primary endpoint of time to first MACE or MALE was reduced in the overall cohort, with consistent effects in those with PAD (HR 0.82; 95% CI 0.64-1.04) and those without PAD (HR 0.87; 95% CI 0.79-0.86) at baseline, albeit with a lack of statistical significance in the PAD group. Additionally, total MACE or MALE was reduced by 29%, with consistent and statistically significant effects in those with and without PAD.

These results are a good reminder that PAD is a form of atherosclerotic cardiovascular disease. Seth S. Martin

Bonaca and colleagues note that despite the PAD population who were enrolled in the trial being relatively low risk due to nearly three-quarters of them having no prior limb events, “the incidence of MALE was high”—around 2.5% of patients had at least one such event and there were approximately four MALE per 100-patient years when including recurrent events. When this finding was combined with total broader CV composites, the overall effect of bempedoic acid was large in absolute terms at around 1.9 per 100 patient-years.

Rates of treatment-emergent adverse events were comparable among PAD patients on bempedoic acid versus placebo. As in the main CLEAR Outcomes trial, those on bempedoic acid had a higher rate of gout than those on placebo (2.9% vs 1.3%), as well as a higher incidence of hyperuricemia (10.7% vs 5.4%).

Importantly, the CLEAR Outcomes investigators say the emergence of MALE in patients who were not known to have PAD at baseline, when “coupled with the absence of universal screening for PAD, supports the observation that PAD is underdiagnosed.” 

With known PAD patients accounting for only about 12% of the entire study cohort, the subgroup analysis is not adequately powered to demonstrate significant differences between treatment arms for the primary endpoint, they add. Nevertheless, they say the findings serve as a reminder that “in patients with symptomatic PAD, even in the chronic setting, rates of MALE are significant particularly when recurrent events are considered.”

To TCTMD, Martin said the data also are a reminder that many conditions fall under the rubric of atherosclerotic cardiovascular disease (ASCVD). “Given that the benefits of lipid-lowering therapy extend throughout the continuum of ASCVD risk, to me it makes sense that we would see these clinical benefits across the spectrum of PAD risk,” he added.

“This is especially important when we consider that PAD has historically received less clinical attention than coronary artery disease,” Martin continued. “There are major gaps in implementing evidence-based, guideline-directed care, and PAD is a really important example of those gaps. So, I do hope that these data not only increase confidence around use of LDL-lowering therapy for patients with PAD, . . . [but also] inspire greater action that closes the gaps in guideline implementation.”

Bonaca said future trials “should and are considering major adverse limb events as components of primary endpoint composites, as clinically important and modifiable events that are relevant to patients and a broad spectrum of providers.”