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

May 22, 2025Journal of the American Heart Association

New cases of artery disease in type 2 diabetes patients using three different diabetes medicines

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Abstract

SGLT2 inhibitors are associated with a lower risk of new-onset peripheral artery disease compared to DPP4 inhibitors in patients with type 2 diabetes.

Among 75,470 patients with type 2 diabetes, 186 developed peripheral artery disease (PAD) in the SGLT2 inhibitor group and 256 in the DPP4 inhibitor group over a median follow-up of 5.6 years.
The hazard ratio for developing PAD with SGLT2 inhibitors compared to DPP4 inhibitors was 0.79, indicating a potential protective effect.
This association remained significant after controlling for factors such as demographics, comorbidities, medications, renal function, and glycemic tests.
No significant difference in PAD risk was observed between SGLT2 inhibitors and glucagon-like peptide-1 receptor agonists.

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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 75 470 patients with type 2 diabetes (median age, 62.3±12.8 years; 55.79% men). The SGLT2I and DPP4I groups consisted of 28 753 patients and 46 717 patients, respectively. After matching, 186 and 256 patients had 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], 0.79 [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.

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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

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