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SGLT-2 Inhibitors and Lower Extremity Amputation
Study Questions:
What is the association between the use of oral medication for type 2 diabetes and five outcomes (lower extremity amputation, peripheral arterial disease, critical limb ischemia, osteomyelitis, and ulcer)?
Methods:
The investigators conducted a retrospective cohort study using Truven Health Market Scan Commercial Claims and Encounters data on new users between September 1, 2012, and September 30, 2015. The study 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 dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) agonists as a single referent group, adjusted for baseline use of older oral agents, and included people with baseline amputation. New use of SGLT-2 inhibitors alone, DPP-4 inhibitors alone, GLP-1 agonists alone, or other antidiabetic agents (sulfonylurea, metformin hydrochloride, or thiazolidinediones) was the exposure of interest. The main outcomes measure was foot and leg amputation, defined by validated International Classification of Diseases, Ninth Revision and Current Procedural Terminology codes.
Results:
Among 2.0 million potentially eligible individuals, a total of 953,906 (516,046 women and 437,860 men; mean [SD] age, 51.8 [10.9] years) were included in the final analyses, including 39,869 new users of SGLT-2 inhibitors (4.2%), 105,023 new users of DPP-4 inhibitors (11.0%), and 39,120 new users of GLP-1 agonists (4.1%). The median observation time ranged from 99 days for new users of GLP-1 agonists to 127 days for those using metformin, sulfonylureas, and thiazolidinediones, while the crude incident rates ranged from 4.90 per 10,000 person-years for those using metformin, sulfonylureas, and thiazolidinediones to 10.53 per 10,000 person-years for new users of SGLT-2 inhibitors. After propensity score weighting and adjustment for demographics, severity of diabetes, comorbidities, and medications, there was a nonstatistically significant increased risk of amputation associated with new use of SGLT-2 inhibitors compared with DPP-4 inhibitors (adjusted hazard ratio, 1.50; 95% confidence interval [CI], 0.85-2.67) and GLP-1 agonists (adjusted hazard ratio, 1.47; 95% CI, 0.64-3.36). New use of SGLT-2 inhibitors was statistically significantly associated with amputation compared with sulfonylureas, metformin, or thiazolidinediones (adjusted hazard ratio, 2.12; 95% CI, 1.19-3.77). These results persisted in sensitivity analyses.
Conclusions:
The authors concluded that use of SGLT-2 inhibitors may be associated with increased risk of amputation compared with some oral treatments for type 2 diabetes.
Perspective:
This retrospective analysis using a large commercial claims database reports a nonstatistically significant increased risk of amputation associated with new use of SGLT-2 inhibitors compared with DPP-4 inhibitors and GLP-1 agonists. Furthermore, new use of SGLT-2 inhibitors was associated with a statistically significant greater likelihood of amputation compared with the use of three older oral diabetes medicines examined. These findings have clinical relevance since SGLT-2 inhibitors are now very commonly prescribed. There appears to be a need for additional data on risk of amputation with SGLT-2 inhibitors from passive surveillance systems to meta-analyses of large studies, including observational studies of vascular outcomes to make more informed decisions on choice of type 2 diabetes therapy.
Clinical Topics: Cardiovascular Care Team, Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Heart Failure and Cardiac Biomarkers
Keywords: Amputation, Diabetes Mellitus, Type 2, Dipeptidyl Peptidase 4, Dipeptidyl-Peptidase IV Inhibitors, Glucagon-Like Peptide 1, Metabolic Syndrome, Metformin, Osteomyelitis, Peripheral Arterial Disease, Primary Prevention, Risk, Sodium-Glucose Transport Proteins, Sulfonylurea Compounds, Thiazolidinediones, Ulcer, Vascular Diseases
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