In the EXSCEL trial, diabetic patients with peripheral artery disease had higher mortality and amputation rates, but weekly exenatide did not improve cardiovascular events or amputation rates compared to placebo regardless of PAD status.
HR 1.38Increased all-cause mortality in diabetic patients with PAD versus without PAD — highlighting the high-risk nature of this population
What the researchers found
Among 14,752 EXSCEL participants, 2,800 (19%) had PAD at baseline. PAD patients versus non-PAD patients had:
- Higher MACE rates: 13.6% vs 11.4% (adjusted HR 1.13, 95% CI 1.00-1.27, P=0.047)
- Higher all-cause mortality: adjusted HR 1.38 (95% CI 1.20-1.60, P<0.001)
- Higher LEA rates
Exenatide versus placebo showed no differences in MACE or lower-extremity amputation rates, regardless of PAD status. This means exenatide was neither beneficial nor harmful in this high-risk population.
Why it matters
Patients with both diabetes and PAD face extremely high cardiovascular risk and are at particular risk for lower-extremity amputation — a concern heightened after a diabetes drug (canagliflozin) was linked to increased amputation risk. This analysis provides safety reassurance that exenatide does not increase amputation risk in PAD patients. However, it also shows that exenatide does not provide the cardiovascular protection that newer GLP-1 agonists like semaglutide and liraglutide have demonstrated.
How the study worked
Post hoc analysis of the EXSCEL trial, a double-blind, placebo-controlled randomized trial evaluating once-weekly exenatide versus placebo in patients with type 2 diabetes. The primary endpoint was composite MACE (cardiovascular death, myocardial infarction, or stroke). This subgroup analysis assessed outcomes in patients with and without baseline PAD, with adjusted hazard ratios accounting for baseline characteristics.
What this study cannot tell us
This is a post hoc subgroup analysis, not a prespecified primary analysis, so it may be underpowered for detecting smaller treatment effects. PAD was defined by baseline medical history, which may undercount undiagnosed cases. Once-weekly exenatide is an older formulation; results may not apply to newer, more potent GLP-1 RAs. The null result for exenatide in PAD patients cannot be extrapolated to other GLP-1 drugs that have shown cardiovascular benefit.
How to read the evidence
This is a post hoc subgroup analysis from a large, well-conducted randomized controlled trial (EXSCEL, n=14,752). While the underlying trial is high-quality, post hoc analyses carry lower evidence strength than prespecified analyses.
When this study was published
Published in 2019 using EXSCEL trial data, this analysis predates the more recent cardiovascular outcome data for semaglutide and tirzepatide which have shown positive results.
The bigger picture
This analysis provides important context for understanding the heterogeneity of GLP-1 RA cardiovascular outcomes. While liraglutide (LEADER) and semaglutide (SUSTAIN-6) showed cardiovascular benefit, exenatide (EXSCEL) did not — and this subgroup analysis confirms the lack of benefit even in the highest-risk PAD population. This has contributed to the understanding that not all GLP-1 RAs are equivalent for cardiovascular protection, influencing guideline recommendations that favor specific agents.
Questions still open
- Would semaglutide or liraglutide show cardiovascular benefit in the PAD subpopulation, given their overall positive CVOT results?
- What explains the cardiovascular benefit heterogeneity among different GLP-1 receptor agonists?
- Should GLP-1 RA selection for diabetic PAD patients prioritize agents with demonstrated cardiovascular benefit?
Common questions
Why was amputation risk specifically studied with this diabetes drug?
If exenatide didn't help heart outcomes, does that mean GLP-1 drugs don't work for PAD patients?
Read the original research
Clinical Outcomes in Patients With Type 2 Diabetes Mellitus and Peripheral Artery Disease: Results From the EXSCEL Trial.
Circulation. Cardiovascular interventions, 12(12), e008018
Citation
Badjatiya, Anish; Merrill, Peter; Buse, John B; Goodman, Shaun G; Katona, Brian; Iqbal, Nayyar; Pagidipati, Neha J; Sattar, Naveed; Holman, Rury R; Hernandez, Adrian F; Mentz, Robert J; Patel, Manesh R; Jones, W Schuyler. (2019). Clinical Outcomes in Patients With Type 2 Diabetes Mellitus and Peripheral Artery Disease: Results From the EXSCEL Trial.. Circulation. Cardiovascular interventions, 12(12), e008018. https://doi.org/10.1161/CIRCINTERVENTIONS.119.008018