R3i Editorials

R3i editorials, created by members of the R3i board, focus on addressing the persistent challenges of residual cardiovascular risk. These editorials serve to educate healthcare professionals about emerging insights and therapeutic strategies related to lipid-related risk factors, such as triglyceride-rich lipoproteins and lipoprotein(a).

September 2024
PROMINENT trial suggests new hope for diabetes-related lower-extremity complications
Prof. Jean-Charles Fruchart, Prof. Michel Hermans, Prof. Pierre Amarenco

Diabetes-related complications (both macrovascular and microvascular) have a devastating impact on people with diabetes. As diabetes prevalence escalates worldwide, projected to increase by almost 50% by 2045 (1), the burden of diabetes complications will also escalate. A major focus has been on managing and preventing macrovascular complications, given that people with diabetes have a 3-fold higher risk of developing cardiovascular disease (1). However, microvascular complications associated with hyperglycemia such as diabetic retinopathy, diabetic kidney disease and diabetes-related lower-extremity complications are also prevalent. Compared with people without diabetes, those with diabetes are at 10-fold higher risk of kidney disease, a third will develop some form of vision loss during their lifetime, and a lower limb is lost due to amputation every 30 seconds worldwide (2). 

Diabetes-related lower-extremity complications are especially devastating. According to the Global Burden of Disease Study 2016, these complications represent a large and growing contributor to the global disability burden, affecting an estimated 131 million people with nearly 17 million years lived with disability (3). Up to one-third of patients with chronic limb ischemia (which underlies lower-extremity complications) will develop foot ulceration in their lifetime and 1 in 5 will ultimately undergo lower-extremity amputation (4). If diagnosis is delayed or patients experience rapid progression, the risk of major amputation and mortality is even higher (5,6). Treatment options are limited, and no medical therapy has demonstrated clinical benefit. 

With this scenario, recent insights from the Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Participants with Diabetes (PROMINENT) suggest new hope. As discussed in this month’s Landmark article, the PROMINENT investigators undertook a secondary analysis to evaluate the effect of the selective peroxisome proliferator-activated receptor alpha modulator (SPPARM-α) pemafibrate on the incidence of lower extremity ischemic ulceration or gangrene in 10,497 patients with type 2 diabetes mellitus, mild-to-moderate hypertriglyceridemia (triglyceride level, 200 to 499 mg/dL), and low high-density lipoprotein cholesterol levels (≤ 40 mg/dL) (7). The primary outcome was incident lower extremity ischemic ulceration or gangrene (8).

Over a median follow-up of 3.3 years, treatment with pemafibrate was associated with 37% reduction (hazard ratio 0.63, 95% confidence interval [CI] 0.41–0.95; p=0.03) in the incidence of lower ischemic extremity ulceration or gangrene. Analysis of the effect of pemafibrate on the components of the primary outcome showed a 53% reduction in the risk of gangrene (p=0.01), as well as 32% reduction in ulcer (8). These findings generally align with results from the Fenofibrate Intervention and Event Lowering Diabetes (FIELD) study, in which treatment with fenofibrate, a relatively weak peroxisome proliferator-activated receptor alpha (PPAR-α) agonist, was associated with 36% reduction in the risk of non-traumatic limb amputations (predominantly minor amputations) compared with placebo (9). 

A key question arising from this exploratory analysis from PROMINENT is the disparity between the neutral effect of pemafibrate (against a background of high-intensity statin treatment) on macrovascular events as seen in the main trial versus clinical benefit on lower-extremity vascular complications (7, 8). While this analysis does not provide insights into the underlying mechanism(s), this distinction may relate to the role of PPAR-α in regulating several processes impacted by microvascular injury, including apoptosis, inflammation, prostaglandin metabolism, and lipotoxicity (10), as well as potential lipid-independent mechanisms (11, 12). This question merits further study. 

With a large – and growing – unmet clinical need, these findings suggest new hope for reducing the devastating impact of lower-extremity complications in people with diabetes. Although these secondary results from PROMINENT warrant corroboration in other studies, the potential implications are important for patients, their caregivers, clinicians and wider society.

References

  1. International Diabetes Federation. Facts and figures. Available at https://idf.org/about-diabetes/diabetes-facts-figures/
    2. International Diabetes Federation. Diabetes complications. Available at https://idf.org/about-diabetes/diabetes-complications/
    3. Zhang Y, Lazzarini PA, McPhail SM, et al. Global disability burdens of diabetes-related lower-extremity complications in 1990 and 2016. Diabetes Care 2020;43:964-74.
    4. Armstrong DG, Boulton AJM and Bus SA. Diabetic foot ulcers and their recurrence. N Engl J Med 2017;376:2367-75.
    5. McDermott K, Fang M, Boulton AJM, Selvin E, Hicks CW. Etiology, epidemiology, and disparities in the burden of diabetic foot ulcers. Diabetes Care 2023;46:209-21.
    6. Ahmed ME, Mohammad KMK, Mahadi SI and Widyatalla AH. Management of diabetic ulcers of the dorsum of the foot and distal leg ulcers. J Wound Care 2022;31:941-5.
    7. Das Pradhan A, Glynn RJ, Fruchart JC, et al. Triglyceride lowering with pemafibrate to reduce cardiovascular risk. N Engl J Med 2022;387:1923-34.
    8. 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;84:408-10.
    9. 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.
    10. Hiukka A, Maranghi M, Matikainen N and Taskinen MR. PPARalpha: an emerging therapeutic target in diabetic microvascular damage. Nat Rev Endocrinol 2010;6:454-63.
    11. Kawanishi H, Ohashi K, Ogawa H, Otaka N, Takikawa T, Fang L, Ozaki Y, Takefuji M, Murohara T and Ouchi N. A novel selective PPARalpha modulator, pemafibrate promotes ischemia-induced revascularization through the eNOS-dependent mechanisms. PLoS One 2020;15:e0235362.
    12. Katayama A, Yamamoto Y, Tanaka K, Matsubara K, Sugitani M, Fujihara S, Harada S, Kaetsu Y, Yoshida A and Hisatome I. Fenofibrate enhances neovascularization in a murine ischemic hindlimb model. J Cardiovasc Pharmacol 2009;54:399-404.