OBJECTIVES : To quantify the association between oral Type 2 diabetes medication use, foot and leg amputation, and other vascular outcomes, including peripheral arterial disease, critical limb ischemia, osteomyelitis and ulcer.

METHODS : Retrospective, new user design cohort study using Truven MarketScan Commercial Claims and Encounters data from September 2012 and September 2015. We focused on 2.0 million commercially insured individuals and used propensity score weighting to balance baseline differences among groups. Sensitivity analyses varied statistical models, assessed the effect of combining DPP-4 inhibitors and GLP-1 agonists as a single referent group, and adjusted for baseline use of older oral agents. Exposures of interest were new use of SGLT-2s alone, dipeptidyl peptidase-4 [DPP-4] inhibitors alone, glucagon-like peptide-1 [GLP-1] agonists alone, or other anti-diabetic agents (any combination of sulfonylurea, metformin, or thiazolidinediones). Outcomes and measures of interest were foot and leg amputation defined by validated ICD-9 and CPT codes.

RESULTS : Of 2.0 million potentially eligible individuals, a total of 933,073 were included in the final analyses, including 38,692 (4.2%) new SGLT-2 inhibitor users, 101,408 (10.9%) new DPP-4 inhibitor users, and 37,932 (4.1%) new GLP-1 agonist users. After propensity score weighting and adjustment for demographics, severity of diabetes, comorbidities and medications, there was a non-statistically significant increased risk of amputation associated with new use of SGLT-2 inhibitors compared with DPP-4 inhibitors (adjusted hazard ratio [aHR] 1.50, 95% confidence interval [CI] 0.85-2.67) and GLP-1 agonists (aHR 1.47, CI 0.64-3.36). SGLT-2 inhibitor use was associated with amputation compared with sulfonylureas, metformin, or thiazolidinediones (aHR 2.12, CI 1.19-3.78). These results persisted in sensitivity analyses.

CONCLUSIONS : SGLT-2 inhibitors may be associated with increased risk of amputation compared with some oral Type 2 diabetes treatments. Further observational studies are needed with extended follow-up and larger sample sizes given the importance of the primary outcome of interest.