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Pemafibrate was tied to potential prevention of leg and foot ulcers in type 2 diabetes, a silver lining to the PROMINENT trial's otherwise disappointing cardiovascular results.

In an exploratory analysis, pemafibrate was tied to significantly reduced lower extremity ischemic ulceration or gangrene compared with placebo (2.1 vs 3.4 per 1,000 person-years, HR 0.63, 95% CI 0.41-0.96) over a median 3.4 years of follow-up, according to Aruna Pradhan, MD, of Brigham and Women's Hospital and Harvard University in Boston, and colleagues.

While several subgroups appeared particularly vulnerable to developing ischemic ulceration or gangrene -- namely people with a history of diabetic foot disease, baseline peripheral artery disease (PAD), or retinopathy -- the PPAR-α modulator did not show evidence of any heterogeneity in this treatment effect, the authors reported in the .

Meanwhile, there are very few therapies available for ischemic foot ulcers in diabetes. No medication is known to reduce ischemic lower extremity ulceration, according to Pradhan's group.

"The current data raise the possibility that pemafibrate offers a therapeutic approach for reducing lower extremity ischemic ulceration and gangrene, findings consistent with prior evidence of benefit for PPAR-α agonists on other diabetic microvascular complications, including minor amputation and diabetic retinopathy," Pradhan and colleagues wrote.

This would mean some redemption after the investigators had been unable to prove a cardiovascular benefit to pemafibrate, the main goal in PROMINENT, despite the agent clearly reducing triglycerides and various other lipids.

"The results of this exploratory analysis are promising. This is particularly important because it comes on the heels of potentially for reduction in risk for foot-level amputation," said podiatric surgeon David Armstrong, DPM, MD, PhD, of Keck Medicine of USC, Los Angeles, who was not involved with the study.

"Having a medically-based therapy to reduce risk for lower extremity complications like diabetic foot ulcers (which occur every second around the world) could yield significant public health benefits," Armstrong told MedPage Today in an email.

Diabetic foot ulcers can be caused by nerve damage, immune system dysfunction, and PAD. These ulcers are a leading cause of major lower extremity amputation, and their prevalence is increasing despite efforts at prevention and early treatment.

For now, diabetes specialist Andrew Boulton, MD, of University of Manchester, England, and immediate past president of the International Diabetes Federation, called the concept of pemafibrate for diabetic foot ulcers "interesting but unproven."

He said one issue was that there was no counting of neuro-ischemic ulcers in the present analysis. He also highlighted the use of subjective PAD endpoints in the study, as well as the lack of assessment for neuropathy that would be expected to affect some of the endpoints.

Moving forward, the PROMINENT authors said they are anticipating two placebo-controlled trials: one testing pemafibrate for acute healing of existing diabetic foot ulcerations, and the other testing the drug for prevention of recurrent ulcers in those with recently healed wounds.

PROMINENT was a double-blind trial that had participants randomized to pemafibrate 0.2 mg orally twice daily or placebo. Included were 10,497 people with type 2 diabetes, mild to moderate hypertriglyceridemia, and HDL cholesterol levels ≤40 mg/dL. This was also a population in which participants were all either on statin therapy or had LDL cholesterol level <100 mg/dL at enrollment.

Baseline characteristics were similar between the two study groups.

Investigators said that incident PAD events were subject to blind adjudication. This covered new or worsening intermittent claudication, rest pain, lower extremity ischemic ulceration (including gangrene), lower extremity revascularization, or major amputation in the setting of ankle brachial index ≤0.9 or another marker of PAD.

For the present analysis, Pradhan's group also relied on a separate blind adjudication of ulcer and gangrene events. Incident ischemic ulceration was defined as the new occurrence of lower extremity ulceration or gangrene, accompanied by diagnostic testing indicative of new or worsening obstructive PAD.

Limitations of PROMINENT include the modest number of total events and uncertain generalizability of results to other populations, Pradhan's team acknowledged.

"These findings provide strong impetus for further prospective investigations of pemafibrate to reduce lower limb ulceration risk, especially among those with prior foot disease and other high-risk characteristics for ulceration and gangrene," the authors wrote.

Boulton advised that ulcer prevention would be the "better," more feasible outcome to study going forward. Plus, the current ulcer recurrence rate is so high that "if you can show you prevent recurrence, that would be a step forward."

In contrast, he said, proving an ulcer healing benefit is "tricky" and subject to many confounding variables -- notably the patients who have kept walking on their wounds to the dismay of decades of trialists.

"If you give them holy water, they're not going to heal. You keep walking on ulcers, they're not going to heal," Boulton commented in an interview. "These people have lost the gift of pain. They will walk on it."

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