Insights from PROMINENT: Pemafibrate reduces the risk of ulcer or gangrene in type 2 diabetes
patients
September 2024
These findings from the PROMINENT trial suggest that pemafibrate may offer therapeutic potential
for reducing lower-extremity ischemic ulceration and gangrene in patients with type 2 diabetes.
Marinho LL, Everett BM, Aday AW, et al. Effect of pemafibrate on diabetic foot ulceration and
gangrene. An exploratory analysis from PROMINENT. J Am Coll Cardiol 2024;84:408-410.
STUDY SUMMARY
| Objective: | To evaluate the effect of pemafibrate on the adjudicated outcome of incident lower- extremity ischemic ulceration or gangrene using prospective data from the Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Participants with Diabetes (PROMINENT) trial. |
| Study design: | Secondary analysis of PROMINENT, a randomized, double-blind, placebo-controlled trial. |
| Study population: | PROMINENT included 10,479 patients with type 2 diabetes mellitus (T2DM), mild-to- moderate hypertriglyceridemia (triglyceride level 200 to 499 mg/dL), low high-density lipoprotein cholesterol levels (≤ 40 mg/dL) and controlled low-density lipoprotein cholesterol levels with guideline-directed lipid lowering therapy (nearly two-thirds on high-intensity statins). Overall, 15% of patients had a history of baseline peripheral artery disease (PAD). |
| Main study variable |
Primary outcome: The primary efficacy outcome of this analysis was physician- |
| Methods: | All reported events were initially adjudicated by the trial’s Clinical Endpoints Committee as presence or absence of new or worsening PAD. In addition, two independent cardiologists with expertise in PAD conducted a second adjudication to capture additional information including ulcer location and presence or absence of gangrene at clinical presentation. The data were analysed on an intention-to-treat basis using Kaplan-Meier curves and unadjusted log-rank P values to compare the cumulative incidence of first ulcer or gangrene between randomly allocated treatment groups. Cox proportional-hazards models, stratified by sex, history of cardiovascular disease, and baseline statin treatment was used to analyse time to first occurrence of ulcer or gangrene in the two treatment groups. Data were also analysed separately for first occurrence of ulcer or first occurrence of gangrene. |
RESULTS
The median follow-up in PROMINENT was 3.3 years (interquartile range 2.5 to 4.0 years).
Treatment with pemafibrate was associated with a 37% relative reduction in the risk of
the primary composite outcome (Table 1). When analysed for component endpoints,
pemafibrate was associated with a statistically significant reduction in the risk of gangrene
(Hazard ratio 0.47, 95% confidence interval [CI] 0.25–0.87; p=0.01), as well as a
directionally lower incidence of ulcer (n= 62; Hazard ratio 0.68, 95% CI, 0.41–1.12; p=0.13).
Table 1. Effect of pemafibrate on lower extremity ischemic ulceration or gangrene in
PROMINENT
| Pemafibrate | Placebo | ||
| No. of events | 35 | 56 | |
| Incidence (per 1000 person-years) |
2.1 | 3.4 | 0.63 (0.41–0.95) p=0.03 |
| Authors’ conclusion: | In patients with T2DM, mild-to-moderate hypertriglyceridemia, and low levels of high- density lipoprotein cholesterol on guideline directed lipid lowering therapy, pemafibrate significantly reduced the risk of lower-extremity ischemic ulceration or gangrene, a finding that merits further prospective investigation among patients at high risk of developing this disease. |
COMMENT
PAD and hyperglycemia are the primary drivers of foot ulceration. It has been estimated that 20-30%
of diabetes patients have PAD, although this may be even higher among older patients (1). Major
nontraumatic lower-extremity amputation is a morbid complication of longstanding or poorly
controlled diabetes and/or end-stage PAD, conferring a substantial burden to patients and their
caregivers. Despite a declining incidence of lower-extremity amputations during the 1990s and
2000s, rates have plateaued or increased in the past decade, posing a major challenge to healthcare
systems (2). This scenario highlights an unmet clinical need for new medical treatments to prevent
the severe complications associated with diabetic lower-extremity disease.
This latest analysis from the PROMINENT trial suggests therapeutic potential for pemafibrate. In this
report, pemafibrate treatment was associated with 37% relative risk reduction for lower-extremity
ischemic ulcer or gangrene, common precursors to amputation. The findings also align with data
from the Fenofibrate Intervention and Event Lowering Diabetes (FIELD) study, in which fenofibrate, a
relatively weak peroxisome proliferator-activated receptor alpha agonist, reduced the incidence of
minor amputations in type 2 diabetes patients (3). While the authors acknowledge the limitations of
their data, including exclusion of patients with severe PAD from PROMINENT, and the lack of data
relating to aggravating factors such as progressive neuropathy, co-infection, foot deformity, and
access to podiatric care or pre-emptive vascular intervention in the trial, the magnitude of the
treatment effect associated with pemafibrate provides a rationale for further study.
| References | 1. Barnes JA, Eid MA, Creager MA, et al. Epidemiology and risk of amputation in patients with diabetes mellitus and peripheral artery disease. Arterioscler Thromb Vasc Biol 2020;40:1808–17. 2. McDermott KM, Srinivas T, Abularrage CJ. Multidisciplinary approach to decreasing major amputation, improving outcomes, and mitigating disparities in diabetic foot and vascular disease. Semin Vasc Surg 2023;36:114-21. 3. Rajamani K, Colman PG, Li LP, et al. Effect of fenofibrate on amputation events in people with type 2 diabetes mellitus (FIELD study): a prespecified analysis of a randomised controlled trial. Lancet 2009;373:1780-8. |
| Key words | Key words: PROMINENT trial; pemafibrate; peripheral artery disease; ulcer; gangrene. |
