Risk of limb amputation and bone fractures with sodium glucose cotransporter-2 inhibitors: a network meta-analysis and meta-regression.

Background: Sodium glucose cotransporter-2 inhibitors (SGLT2is) have gained immense attention for a variety of indications. Limb amputations (LA) and fractures were reported in clinical trials. This network meta-analysis and meta-regression were carried out to quantify the risks of these events.
Research Design and Methods: Randomized clinical trials evaluating SGLT2is and reporting patients developing LA/fracture were included. Odds ratios (OR) with 95% confidence intervals (95% CI) were the effect estimates. Sub-group analyses and meta-regression analysis were carried out.
Results: Ninety articles were included (LA: 36 studies; 96522 participants and fracture: 66 studies; 102,862 participants). An increased risk of LA (OR: 1.2; 95% CI: 1.1, 1.3) was observed. Amongst SGLT2is, canagliflozin was associated with increased risk of LA (OR: 1.6, 95% CI: 1.1, 2.4) while dapagliflozin with fracture (OR: 1.1, 95% CI: 1, 1.2). Sub-group analysis revealed increased risk of LA with an OR of 1.3 among those in the age group of > 40 to < 65, body-mass index of > 30 kg/m ² , HbA1c category of > 7%, duration of diabetes of > 10 years, type 2 diabetes, and an OR of 1.2 for SGLT2is administration of > 6 months.
Conclusions: SGLT2is were observed with an increased risk of LA. High- risk categories were identified for which precautions should be recommended in the standard treatment guidelines.
Protocol Registration: Open Science Framework (https://osf.io/5fwyk).