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Association Between Sodium-Glucose Cotransporter 2 Inhibitors and Lower Extremity Amputation Among Patients With Type
Hsien-Yen Chang1,2, Sonal Singh3, Omar Mansour1,4
1Center for Drug Safety and Effectiveness, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
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 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.
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.
Insights
New use of sodium-glucose cotransporter 2 (SGLT-2) inhibitors for type 2 diabetes showed a statistically significant increased risk of amputation compared to sulfonylureas, metformin, or thiazolidinediones.
Area of Science:
- Endocrinology
- Pharmacology
- Diabetology
Background:
- Type 2 diabetes management involves various oral medications.
- Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are a class of oral antidiabetic agents.
- Previous clinical trials suggested a potential association between SGLT-2 inhibitors and lower extremity amputation.
Purpose of the Study:
- To quantify the association between the use of oral type 2 diabetes medications and lower extremity amputation.
- To compare the risk of amputation among new users of SGLT-2 inhibitors versus other oral antidiabetic agents.
Main Methods:
- Retrospective cohort study using large commercial claims data (2.0 million individuals).
- Propensity score weighting was employed to balance baseline characteristics.
- New users of SGLT-2 inhibitors were compared with new users of dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptide 1 (GLP-1) agonists, and other oral agents (sulfonylurea, metformin, thiazolidinediones).
Main Results:
- New use of SGLT-2 inhibitors was not significantly associated with increased amputation risk compared to DPP-4 inhibitors or GLP-1 agonists.
- However, new use of SGLT-2 inhibitors was statistically significantly associated with a higher risk of amputation compared to sulfonylureas, metformin, or thiazolidinediones (aHR, 2.12; 95% CI, 1.19-3.77).
- These findings were consistent across sensitivity analyses.
Conclusions:
- The use of SGLT-2 inhibitors may be associated with an increased risk of lower extremity amputation compared to certain other oral type 2 diabetes treatments.
- Further research with longer follow-up and larger datasets is warranted to confirm these findings.
- This study highlights the importance of considering potential risks when prescribing SGLT-2 inhibitors.
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