Sodium–Glucose Cotransporter 2 Inhibitors and the Risk of Below-Knee Amputation: A Multicenter Observational Study

Abstract

Reports of amputations associated with sodium-glucose cotransporter 2 (SGLT2) inhibitors have been inconsistent. We aimed to compare the risk of below-knee amputation with SGLT2 inhibitors versus dipeptidyl peptidase 4 (DPP-4) inhibitors among patients with type 2 diabetes. RESEARCH DESIGN AND METHODSThis multicenter observational study used administrative health care databases from seven Canadian provinces and the U.K. Incident SGLT2 inhibitor users were matched to DPP-4 inhibitor users using a prevalent new-user design and timeconditional propensity scores. Cox proportional hazards models were used to estimate site-specific adjusted hazard ratios (HR) and corresponding 95% CIs of incident below-knee amputation for SGLT2 inhibitor versus DPP-4 inhibitor users. Random effects meta-analyses were used to pool the site-specific results. RESULTSThe study cohort included 207,817 incident SGLT2 inhibitor users matched to 207,817 DPP-4 inhibitor users. During a mean exposed follow-up time of 11 months, the amputation rate was 1.3 per 1,000 person-years among SGLT2 inhibitor users and 1.5 per 1,000 person-years among DPP-4 inhibitor users. The adjusted HR of below-knee amputations associated with SGLT2 inhibitor use compared with DPP-4 inhibitor use was 0.88 (95% CI 0.71-1.09). Similar results were obtained in stratified analyses by specific SGLT2 inhibitor molecule. CONCLUSIONSIn this large multicenter observational study, there was no association between SGLT2 inhibitor use and incident below-knee amputations among patients with type 2 diabetes compared with DPP-4 inhibitor use. While these findings provide some reassurance, studies with a longer duration of follow-up are needed to assess potential long-term effects.Sodium-glucose cotransporter 2 (SGLT2) inhibitors are the newest antidiabetic agents for type 2 diabetes management (1). They inhibit the SGLTs on renal proximal tubules, leading to glucosuria. This effect not only lowers glycemia but also induces weight loss and blood pressure reduction (2). Indeed, randomized placebo-controlled trials have shown that SGLT2 inhibitors also decrease the risk of cardiovascular outcomes (3,4) and heart failure (3-5). Current guidelines from the American Diabetes Association

Risk of lower extremity amputations in patients with type 2 diabetes using sodium-glucose co-transporter 2 inhibitors

“…Another study using US data [ 11 ] and including both patients using insulin at baseline and patients with a history of amputation yielded similar results, with an HR estimate of 1.69 (95% CI 1.20–2.38). In contrast, two other cohort studies with a median follow-up of approximately 1 year [ 12 , 13 ] report no difference in LEA risk between users of SGLT2i and users of DPP-4i (HR estimates around 0.88). Both studies include patients treated with insulin at baseline (21–27.5% of the study cohort) and exclude patients with a history of amputation.…”

“…Previous observational studies comparing DPP-4i and SGLT2i provide conflicting results [ 8 , 10 – 13 ]. The differences in findings might be due to differences in study populations, methodological approach, inclusion/exclusion of patients with history of amputation or use of insulin at baseline, duration of follow-up, statistical analysis used, and type of SGLT2i prescribed.…”

“…Both studies include patients treated with insulin at baseline (21–27.5% of the study cohort) and exclude patients with a history of amputation. The study by Yu et al [ 13 ] is the only study to evaluate risk of LEA in which most patients (approximately 60%) use empagliflozin or dapagliflozin; in all other studies, canagliflozin is by far the most commonly prescribed SGLT2i [ 11 , 12 ].…”

“…peptide-1 receptor agonists (GLP-1RA). However, studies using dipeptidyl peptidase-4 inhibitors (DPP-4i) as a comparator showed conflicting findings [8,[10][11][12][13]. These conflicting results could be due to differences in study design and exclusion criteria, such as the exclusion of patients at higher risk of amputation (e.g.…”

“…For example, a cohort study by Ueda et al [ 9 ] showed a more than twofold increased risk of LEA (median follow-up of 0.7 years) in patients using empagliflozin or dapagliflozin, compared with patients using glucagon-like peptide-1 receptor agonists (GLP-1RA). However, studies using dipeptidyl peptidase-4 inhibitors (DPP-4i) as a comparator showed conflicting findings [ 8 , 10 – 13 ]. These conflicting results could be due to differences in study design and exclusion criteria, such as the exclusion of patients at higher risk of amputation (e.g.…”