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What is the association between the use of sodium-glucose cotransporter 2 inhibitors and lower extremity amputation, peripheral arterial disease, osteomyelitis, and venous ulceration among patients with type 2 diabetes?
In this population-based cohort study of commercially insured patients, the length of follow-up was relatively short, and amputations were rare. There was no statistically significantly increased risk of amputations associated with new use of sodium-glucose cotransporter 2 inhibitors compared with new use of dipeptidyl peptidase 4 inhibitors and glucagon-like peptide 1 agonists, although the hazard ratios were elevated, while new use of sodium-glucose cotransporter 2 inhibitors was associated with a statistically significant increased risk of amputation compared with use of metformin, sulfonylureas, and thiazolidinediones.
Sodium-glucose cotransporter 2 inhibitors may be associated with increased risk of amputation compared with some oral treatments for type 2 diabetes.
Results of clinical trials suggest that canagliflozin, a sodium-glucose cotransporter 2 (SGLT-2) inhibitor for treating type 2 diabetes, may be associated with lower extremity amputation.
To quantify the association between the use of oral medication for type 2 diabetes and 5 outcomes (lower extremity amputation, peripheral arterial disease, critical limb ischemia, osteomyelitis, and ulcer).
Design, Setting, and Participants
A retrospective cohort study was conducted using Truven Health MarketScan 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).
Main Outcomes and Measures
Foot and leg amputation, defined by validated International Classification of Diseases, Ninth Revision and Current Procedural Terminology codes.
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% 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 and Relevance
Use of SGLT-2 inhibitors may be associated with increased risk of amputation compared with some oral treatments for type 2 diabetes. Further observational studies are needed with extended follow-up and larger sample sizes.
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Accepted for Publication: April 20, 2018.
Corresponding Author: G. Caleb Alexander, MD, MS, Center for Drug Safety and Effectiveness, Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe St W6035, Baltimore, MD 21205 (email@example.com).
Published Online: August 13, 2018. doi:10.1001/jamainternmed.2018.3034
Author Contributions: Drs Chang and Alexander had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Chang, Singh, Baksh, Alexander.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Chang, Singh, Mansour, Baksh.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Chang, Singh.
Obtained funding: Alexander.
Administrative, technical, or material support: Mansour, Baksh, Alexander.
Conflict of Interest Disclosures: Dr Alexander reported serving as Chair of the US Food and Drug Administration’s Peripheral and Central Nervous System Advisory Committee, serving as a paid consultant to QuintilesIMS, serving on the Advisory Board of MesaRx Innovations, holding equity in Monument Analytics, and serving as a member of OptumRx’s Pharmacy and Therapeutics Committee. This arrangement has been reviewed and approved by the Johns Hopkins Bloomberg School of Public Health. Dr Singh reported attending advisory board meetings on the safety of diabetic drugs hosted by Janssen Pharmaceuticals (manufacturer of canagliflozin) and Eli Lilly & Co (manufacturer of dulaglutide) and was compensated for his time.
Funding/Support: This work was supported in part through contract number U01 FD004977-03 from the Johns Hopkins Center of Excellence in Regulatory Science and Innovation (Dr Alexander).
Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study, analysis or interpretation of the data, and preparation or final approval of the manuscript prior to publication.
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