[Skip to Content]
[Skip to Content Landing]
Original Investigation
September 2018

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

Author Affiliations
  • 1Center for Drug Safety and Effectiveness, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
  • 2Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
  • 3Department of Family Medicine and Community Health, University of Massachusetts Medical School, Worcester
  • 4Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
  • 5Division of General Internal Medicine, Department of Medicine, Johns Hopkins Medicine, Baltimore, Maryland
JAMA Intern Med. 2018;178(9):1190-1198. doi:10.1001/jamainternmed.2018.3034
Key Points

Question  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?

Findings  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.

Meaning  Sodium-glucose cotransporter 2 inhibitors may be associated with increased risk of amputation compared with some oral treatments for 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 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.

Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words
    ×