Pemafibrate reduces microvascular complications of PAD and T2D 

Participants from the PROMINENT trial with type 2 diabetes (T2D) and mixed dyslipidaemia who were treated with pemafibrate had a mean 37% reduction in ischaemic ulcerations or gangrene related to peripheral artery disease (PAD). According to the authors of this post-hoc analysis, these findings are in line with prior studies indicating that PPAR-α agonists have a positive effect on distal small vessel complications in T2D and PAD. 

“Prior studies indicate that PPAR-α agonists may reduce diabetic limb vascular complications in patients with T2D,” according to Dr Aruna Pradhan (Brigham and Women’s Hospital, MA, USA) [1]. In the previously published, randomised-controlled, phase 3 PROMINENT trial, the PPAR-α agonist pemafibrate did not outperform placebo in reducing cardiovascular events in a population of patients with T2D and mixed hyperlipidaemia [2]. “We did see an interesting, but non-significant, trend concerning new or worsening PAD,” added Dr Pradhan. The current post-hoc analysis hypothesised that pemafibrate reduced clinical ischaemic ulceration and gangrene, which are considered microvascular and micro-organ complications of PAD [2].

In the subpopulation of PROMINENT participants with ulcers or gangrene (n=91), pemafibrate was associated with significantly lower rates of ulcers and gangrene as compared with placebo (HR 0.63; 95% CI 0.41–0.96; P=0.03) after a median follow-up of 3.4 years. Both ulcers (HR 0.65; 95% CI 0.38–1.11) and gangrene (HR 0.49; 95% CI 0.27–0.87) were lower with pemafibrate treatment, whereas other PAD outcomes, such as PAD admission, revascularisation, or major amputation, were not significantly lower (HR 0.89; 95% CI 0.70–1.13).

“Reducing the risk of amputation (due to ulcers or gangrene) is complicated because there is a very heterogeneous biology,” said Prof. Marc Bonaca (University of Colorado, CO, USA), who discussed the trial outcomes. Different mechanisms are at play in large artery ischaemia and microvascular disease. “In microvascular disease, we do not really understand the biology, particularly in the context of diabetes. There are no therapeutic options.” However, promising data is emerging for several agents. Prof. Bonaca mentioned the GLP-1 agonist liraglutide and the PPAR-α agonist fenofibrate. “The current results are a confirmation of the findings that we saw for fenofibrate,” he said. Other studies are needed to further unravel the mechanisms that are behind the effects of these agents.

1. 
   
   1. Marinho LL, et al. Pemafibrate reduces incidence of lower extremity ischaemic ulcer and gangrene: evidence from PROMINENT. FS07, AHA Scientific Sessions 2023, 11–13 November, Philadelphia, USA.
   2. Pradhan AD, et al. N Engl J Med 2022;387:1923–1934.

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Posted on 29 January, 202423 April, 2024