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

Abstract

Aim To examine whether sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors are associated with a higher risk of lower‐extremity amputation than dipeptidyl‐peptidase‐4 (DPP‐4) inhibitors and sulphonylureas. Methods We conducted a retrospective cohort study, using the MarketScan Commercial Claims and Encounters Database (2013‐2015), to compare the incidence of lower‐extremity amputation (LEA) between initiators of SGLT2 inhibitors and initiators of two second‐line drugs, DPP‐4 inhibitors and sulphonylureas (SUs). We estimated crude incidence rates (IRs) and adjusted hazard ratios (aHR), with 95% confidence intervals (CIs), before and after propensity‐score weighting. We additionally conducted sensitivity analyses using a comparator group of all non‐metformin, non‐SGLT2 inhibitor glucose‐lowering drugs, as previous studies used this approach. Results In a cohort of 328 150 individuals aged 18 to 64 years, the IR of LEA ranged from 1.5 to 2.4 per 1000 person‐years. In as‐treated analysis, the estimated hazard of LEA was increased among SGLT2 inhibitor initiators compared to DPP‐4 inhibitor initiators (aHR 1.69, 95% CI 1.20‐2.38), but not compared to SU initiators (aHR 1.02, 95% CI 0.67‐1.55) or non‐metformin, non‐SGLT2 inhibitor initiators (aHR 1.02, 95% CI 0.54‐1.93). Results were consistent in intention‐to‐treat analysis and across a number of sensitivity analyses. Conclusions Among commercially insured patients in the United States, our results suggest that initiation of SGLT2 inhibitors may increase the risk of LEA compared to initiation of DPP‐4 inhibitors. Contrasting results when comparing SGLT2 inhibitor initiators to DPP‐4 inhibitor and SU initiators highlight the importance of choosing appropriate comparator drugs when addressing comparative effectiveness and safety questions that can inform clinical decision‐making.

Use of sodium glucose cotransporter 2 inhibitors and risk of major cardiovascular events and heart failure: Scandinavian register based cohort study

“…The results are in line with a relatively consistent body of literature supporting an increased risk of diabetic ketoacidosis with SGLT2 inhibitors 116 22 23 27 Further, the estimate for lower limb amputation in our study was inconclusive (hazard ratio 1.26 (95% confidence interval 0.88 to 1.81)), adding to the uncertainty regarding this potential adverse event, with some data supporting an association2 16 24 28 and other data not in support 13 28 29…”

“…16 22 23 27 Further, the estimate for lower limb amputation in our study was inconclusive (hazard ratio 1.26 (95% confidence interval 0.88 to 1.81)), adding to the uncertainty regarding this potential adverse event, with some data supporting an association2 16 24 28 and other data not in support 13 28 29…”

Canagliflozin and Amputation Risk: Evidence So Far

“…27 In another cohort study, the estimated hazard of lower limb amputation was increased among SGLT2i initiators compared with DPP-4i but not compared with sulfonylurea initiators or non-metformin, non-SGLT2i initiators. 28 In a real-world analysis of 4 observational US databases (OBSERVE-4D) including over 700 000 patients, there was no increased risk for amputation among patients treated with canagliflozin compared with other SGLT2i or any other glucose-lowering agent. 29…”

Canagliflozin should be prescribed with caution to individuals with type 2 diabetes and high risk of amputation

“…Multiple observational studies have been conducted on the association between amputation and use of SGLT2 inhibitors, using databases from electronic health records or those maintained for administrative purposes. By our count, six studies have been published that used the Truven MarketScan health claims database from the USA, solely or in part, with varying results: three reported similar risk for amputation with canagliflozin compared with non-SGLT2-inhibitor glucoselowering agents [16][17][18]; two reported a lower amputation risk among those using SGLT2 inhibitors (where canagliflozin therapy comprised 70% of SGLT2 inhibitor use) compared with sulfonylurea agents, but not dipeptidyl peptidase 4 (DPP-4) inhibitors [19,20]; and one reported a higher amputation risk for SGLT2 inhibitors compared with DPP-4 inhibitors, but not compared with sulfonylurea agents or non-metformin, non-SGLT2-inhibitor glucose-lowering agents [21]. Reconciling the different results reported from research using the Truven database appears to be needed, but is beyond the scope of this commentary.…”