Comparison of New-Onset Peripheral Artery Disease in Patients With Type 2 Diabetes Exposed to Sodium-Glucose Cotransporter-2 Inhibitors, Dipeptidyl Peptidase-4 Inhibitors, or Glucagon-Like Peptide-1 Agonists: A Population-Based Cohort Study

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2Is), dipeptidyl peptidase-4 inhibitors (DPP4Is), and glucagon-like peptide-1 receptor agonists have been associated with improved cardiovascular outcomes and prognosis. The comparative risks of new-onset peripheral artery disease (PAD) between these medications remain unknown. This real-world study compared the risks of PAD in patients exposed to SGLT2I and DPP4I. METHODS AND RESULTS: This was a retrospective population-based cohort study of patients with type 2 diabetes on either an SGLT2I or a DPP4I between January 1, 2015, and December 31, 2015, using a territory-wide database from Hong Kong. The primary outcome was new-onset PAD. The secondary outcomes were cardiovascular hospitalization, cardiovascular death, and all-cause death. Propensity score matching (1:1 ratio) using the nearest neighbor search was performed. Multivariable Cox regression with time-weighted variables was used to identify significant associations. A 3-arm analysis including the glucagon-like peptide-1 receptor agonist cohort was conducted. This cohort included 75470 patients with type 2 diabetes (median age, 62.3±12.8years; 55.79% men). The SGLT2I and DPP4I groups consisted of 28753 patients and 46717 patients, respectively. After matching, 186 and 256 patients had PAD in the SGLT2I and DPP4I groups, respectively, over a median follow-up of 5.6years. SGLT2I use was associated with lower risks of PAD (hazard ratio [HR], 0.79 [95% CI, 0.66–0.93]) compared with DPP4I use after adjusting for demographics, comorbidities, medications, renal function, and glycemic tests. The association remained consistent regardless of sex, age, and other metabolic diseases. In the 3-arm analysis, the risk of PAD was not statistically different between SGLT2Is and glucagon-like peptide-1 receptor agonists (HR, 1.18 [95% CI, 0.52–2.68]). The results remained consistent in the competing risk and the sensitivity analyses. CONCLUSIONS: SGLT2I use among patients with type 2 diabetes was associated with lower risks of new-onset PAD and PAD-related outcomes when compared with DPP4Is after adjustments.