R3i Editorials

July 2024
Action needed on peripheral artery disease – any hints from PROMINENT?
Prof. Jean-Charles Fruchart, Prof. Michel Hermans, Prof. Pierre Amarenco

Peripheral artery disease (PAD) is an escalating challenge. Global estimates suggest that >200 million individuals worldwide are living with PAD, with over 40% of this burden in low to middle income countries (1,2). Not only are these individuals at risk of adverse limb outcomes, but they are also at high risk of cardiovascular events (3). Among patients with type 2 diabetes mellitus, PAD is one of the most prevalent initial vascular complications (4); the risk of PAD is also higher and more severe in this group than in the general population (5). Despite this, the risk of PAD in this patient population is underappreciated, with patients typically underdiagnosed and undertreated.  

The management of PAD encompasses both non-pharmacologic strategies and pharmacologic interventions (3). Novel therapies have demonstrated clinical benefits in terms of reduction of both cardiovascular and adverse limb outcomes, such as the proprotein convertase subtilisin/kexin type 9 inhibitors, and sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists, and these findings have been translated to recent updates to clinical guidelines for the management of PAD (3). Despite this, implementation in clinical practice remains suboptimal. Furthermore, there is an unmet clinical need for therapeutic options to prevent the downstream consequences associated with PAD, including lower extremity ulceration and related gangrene, both of which adversely impact patient quality of life. 

The Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Participants with Diabetes (PROMINENT) trial suggested that pemafibrate may have therapeutic potential in PAD. Despite neutral results for the primary outcome (4-point major adverse cardiovascular events, i.e. nonfatal myocardial infarction, ischaemic stroke, coronary revascularization, or death from cardiovascular causes), the incidence of the secondary endpoint of new or worsening PAD was lower in the pemafibrate group versus the placebo group (136 vs. 158 patients with events, hazard ratio [95% confidence interval] 0.87 [0.69–1.09]) (6). 

Preliminary data from a secondary analysis (currently only available as an abstract) indicate that pemafibrate reduced the relative risk of lower extremity ischaemic ulceration or gangrene by 37%, although absolute numbers with these events were small (35 patients in the pemafibrate group vs. 56 in the placebo group) (7). Although potential mechanisms have yet to be fully defined, disparities in the results of PROMINENT (for the primary endpoint vs. PAD events) may relate to differences in the effects of pemafibrate on the large blood vessels versus the microvasculature. In support, the peroxisome proliferator-activated receptor alpha (PPARα) agonist fenofibrate was shown to reduce lower extremity distal amputation in the Fenofibrate Intervention and Event Lowering Diabetes (FIELD) study (8). The underlying mechanisms implicated in this benefit include effects on angiogenesis, neovascularization and wound healing (9,10). Additionally, genetic causal inference methods have identified up to 10 biomarkers representative of key pathways in PAD pathophysiology, including those involved in lipoprotein regulation, which suggest potential causal association (11).

We need to await detailed information regarding this secondary analysis from PROMINENT. However, the preliminary results are encouraging, in suggesting a possible therapeutic role for pemafibrate on PAD in patients with type 2 diabetes mellitus. Given the lack of therapeutic options for preventing chronic limb-threatening ischaemic complications associated with PAD, these findings merit further study. With the burden of PAD expected to escalate as the population ages, obesity rates increase and diabetes becomes more prevalent, this gap in PAD management warrants new attention. 

References

  1. Song P, Rudan D, Zhu Y, et al. Global, regional and national prevalence and risk factors for peripheral artery disease in 2015: an updated systematic review and analysis. Lancet Global Health 2019;7:e1020-30.
  2. GBD 2019 Peripheral Artery Disease Collaborators. Global burden of peripheral artery disease and its risk factors, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Global Health 2023;11: E1553-E1565. 
  3. Gornik HL, Aronow HD, Goodney PP, et al. 2024 ACC/AHA/AACVPR/APMA/ABC/SCAI/SVM/SVN/SVS/SIR/VESS Guideline for the Management of Lower Extremity Peripheral Artery Disease. J Am Coll Cardiol 2024;doi.org/10.1016/j.jacc.2024.02.013.
  4. Shah AD, Langenberg C, Rapsomaniki E, et al. Type 2 diabetes and incidence of cardiovascular diseases: a cohort study in 1.9 million people. Lancet Diabetes Endocrinol 2015;3:105–13.
  5. Nativel M, Potier L, Alexandre L, et al. Lower extremity arterial disease in patients with diabetes: a contemporary narrative review. Cardiovasc Diabetol 2018;17(1):138.
  6. 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.
  7. Marino L, Everett BM, Aday AY, et al. Pemafibrate reduces incidence of lower extremity ischemia ulcer and gangrene: evidence from PROMINENT. Abstract 23102. . Circulation 2023;148:e282–e317.
  8. 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.
  9. Yuan J, Tan JTM, Rajamani K et al. Fenofibrate rescues diabetes-related impairment of ischemia-mediated angiogenesis by PPARalpha-independent modulation of thioredoxin-interacting protein. Diabetes 2019;68:1040-53.
  10. Deng Y, Han X, Yao Z, et al. PPARalpha agonist stimulated angiogenesis by improving endothelial precursor cell function via a NLRP3 Inflammasome pathway. Cell Physiol Biochem 2017;42:2255-66.
  11. Sharma P, Klarin D, Voight BF, et al. Evaluation of plasma biomarkers for causal association with peripheral artery disease. Arterioscler Thromb Vasc Biol 2024;44:1114–23.