Association Between Sodium-Glucose Cotransporter 2 Inhibitors and Lower Extremity Amputation Among Patients With Type 2 Diabetes

Abstract

IMPORTANCE 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. OBJECTIVE 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 PARTICIPANTSA 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.EXPOSURES 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.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% 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.

Sodium‐glucose co‐transporter‐2 inhibitor use and risk of lower‐extremity amputation: Evolving questions, evolving answers

“…Second, we showed that canagliflozin‐only analyses yielded higher HR estimates versus DPP‐4 inhibitor and SU initiators, but lower HR estimates versus non‐metformin, non‐SGLT2 inhibitor initiators. This last result is more consistent with the canagliflozin‐specific HR estimates observed by Yuan et al and Ryan et al Third, analyses using ITT follow‐up typically yielded HR estimates closer to the null than those using as‐treated approaches, which may have contributed to the observed differences between Yuan et al and Ryan et al, versus Chang et al, Adimadhyam et al, and the present study. Fourth, our subgroup analyses showed that excluding patients with prior amputation and prior CKD reduced HR estimates, whereas excluding patients with baseline insulin use increased HR estimates.…”

“…In the present study, which was planned and prespecified in 2017 prior to publication of other pharmaco‐epidemiological analyses, we observed a similarly elevated risk of LEA among SGLT2 inhibitor initiators versus DPP‐4 inhibitor comparators, and a similar null result versus initiators of all non‐metformin, non‐SGLT2 inhibitor GLDs (aHR 1.02, 95% CI 0.54‐1.93). However, results from the SU and non‐SGLT2 inhibitor comparisons were both substantively different from the results obtained by Chang et al, who made their comparisons against a suite of older GLDs including metformin, SUs and thiazolidinediones (aHR 2.12, 95% CI 1.19‐3.77). We attribute these differences to our simultaneous inclusion of insulin (typically a marker of more severe diabetes and higher amputation risk) and exclusion of metformin (often prescribed to patients with less severe diabetes and lower amputation risk) in the non‐SGLT2 inhibitor comparator group, which mirrors a commonly used comparator in previous studies …”

“…By contrast, also using MarketScan CCAE, Chang et al (aHR 1.50, 95% CI 0.85‐2.67) and Adimadhyam et al (aHR 1.38, 95% CI 0.83‐2.31) have suggested the possibility of increased LEA risk associated with new use of SGLT2 inhibitor agents, versus new use of DPP‐4 inhibitors. However, low event counts and more rigid cohort exclusions in both studies contributed to limited precision and CIs that contained the null.…”

“…In response, the US Food and Drug Administration issued a bulletin regarding amputation risk in May 2016 and a drug‐labelling change in July 2017 . Recently, several observational studies have sought to corroborate this finding in broader populations, with mixed conclusions …”

Sodium glucose cotransporter 2 inhibitors and risk of genital mycotic and urinary tract infection: A population‐based study of older women and men with diabetes

“…Evidence of cardio‐protection from SGLT2 inhibitors relative to other agents has led to a dramatic increase in use of these agents in recent years; thus, our findings are highly relevant as they identify another population‐based risk associated with use of SGLT2 inhibitors that should be carefully weighed against the benefits. While other reported risks associated with use of SGLT2 inhibitors are rare and severe, that is, euglycaemic ketoacidosis, lower limb amputations and acute kidney injury, genital mycotic infections are a common risk with use of SGLT2 inhibitors that affects both women and men.…”