Comparisons of new-onset peripheral arterial disease in Type 2 diabetes mellitus patients exposed to SGLT2I, DPP4I or GLP1a: a population-based cohort study

Abstract Background Sodium-glucose cotransporter-2 inhibitors (SGLT2I) have been suggested to have beneficial effects against atherosclerotic cardiovascular disease. The comparative risks of new onset peripheral arterial disease (PAD) between SGLT2Is, dipeptidyl peptidase-4 inhibitors (DPP4Is) and glucagon-like peptide-1 receptor agonist (GLP1a) remain unknown. Objective This real-world study aims to compare the risks of PAD upon exposure to SGLT2I and dipeptidyl peptidase-4 inhibitors (DPP4I). Methods This was a retrospective population-based cohort study of patients with type-2 diabetes mellitus (T2DM) on either SGLT2I or DPP4I between 1st January 2015 and 31st December 2020 using a territory-wide registry in Hong Kong. The primary outcome was new-onset PAD. The secondary outcome was all-cause mortality. Propensity score matching (1:1 ratio) using the nearest neighbour search was performed. Multivariable Cox regression was applied to identify significant associations. A three-arm sensitivity analysis including the GLP1a cohort was conducted. Results This cohort included 75470 T2DM patients (median age: 62.3 years old [SD: 12.8]; 55.79 % males). The SGLT2I and DPP4I groups consisted of 28753 patients and 46717 patients, respectively. After matching, 186 and 256 patients suffered from PAD in the SGLT2I and DPP4I groups respectively, over a median follow-up of 5.6 years. SGLT2I use was associated with lower risks of PAD (Hazard ratio [HR]: 0.85; 95% Confidence Interval [CI]: 0.67-0.98) compared to DPP4I use after adjustments for demographics, comorbidities, medications, renal function, and diabetic laboratory tests. Similar associations were observed in subgroup analyses in male patients above 65 years old, with hypertension, and low HbA1c levels. In the sensitivity analysis, SGLT2I was not associated with lower risks of PAD compared to GLP1a (HR: 0.88; 95% CI: 0.65-1.18). The results remained consistent in the competing risk and the sensitivity analyses. Conclusions SGLT2I use amongst T2DM patients was associated with lower risks of new-onset PAD and PAD-related outcomes when compared to DPP4I after adjustments. Illustrated Abstract