Sodium-glucose cotransporter 2 inhibitors and fracture risk in patients with type 2 diabetes mellitus: a meta-analysis of randomized controlled trials

Abstract

Background: Patients with type 2 diabetes mellitus (T2DM) have an increased risk of fracture compared with those without T2DM. Some oral glucose-lowering agents may increase the incidence of fracture. Whether sodium-glucose co-transporter 2 inhibitors (SGLT2is) are associated with increased risk of fracture remains unclear. Methods: We retrieved articles from PubMed, Embase, Cochrane Library database, and other sources up to 24 October 2019. We included randomized controlled trials (RCTs) that reported fractures and analyzed the fracture incidence of SGLT2i, canagliflozin, dapagliflozin, and empagliflozin. Subgroup analysis was also performed based on baseline characteristics. Results: A total of 78 RCTs with 85,122 patients were included in our analysis. The overall SGLT2i fracture incidence was 2.56% versus 2.77% in the control group [odds ratio (OR), 1.03; 95% confidence interval (CI) (0.95, 1.12); p = 0.49]. Compared with the control treatment, treatment with canagliflozin led to a higher rate of fractures [OR, 1.17; 95% CI (1.00, 1.37); p = 0.05], but no significant difference was observed when compared with dapagliflozin [OR, 1.02; 95% CI (0.90, 1.15); p = 0.79] or empagliflozin [OR, 0.89; 95% CI (0.73, 1.10); p = 0.30]. Subgroup analysis showed that, in a follow-up of less than 52 weeks, SGLT2i decreased the incidence of fracture by 29% [OR, 0.71; 95% CI (0.55, 0.93); p = 0.01], but this benefit was lost when the follow-up extended to more than 52 weeks [OR, 1.08; 95% CI (0.98, 1.18); p = 0.12]. Conclusion: Canagliflozin seems to increase the risk of fracture, while other SGLT2is do not result in a higher incidence of fracture.

Association of Sodium-Glucose Cotransporter–2 Inhibitors With Fracture Risk in Older Adults With Type 2 Diabetes

“…47 This increased fracture risk was not observed in the following Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy trial and other large RCTs, 2,[4][5][6]17 nor was an association observed in subsequent meta-analyses. 48,49 A disproportionality and Bayesian analysis of Food and Drug Administration safety reporting data from 2004 to 2019 also showed no difference in fracture event reports for patients taking SGLT-2i vs SGLT-2i plus other diabetes agents. 50 Thus, cohort studies to assess the effect of SGLT-2i on fracture in routine practice are warranted.…”

Effects of Anti-Diabetic Drugs on Fracture Risk: A Systematic Review and Network Meta-Analysis

“…A systematic review suggested that canagliflozin is linked to an increased fracture rate ( 33 ), a conclusion that is similar with our results. One study suggested that SGLT2 inhibitors have neutral effects on fracture risk ( 34 ). In a clinical trial, SGLT2 inhibitors exhibited better benefits than other anti-diabetic drugs in T2DM patients suffering from chronic kidney disease ( 10 ).…”

Effects of empagliflozin on markers of calcium and phosphate homeostasis in patients with type 2 diabetes – Data from a randomized, placebo-controlled study

“…A recent meta-analysis suggested only canagliflozin but none of the other SGLT2 inhibitors to increase fracture risk ( Lou et al, 2020 ) – suggesting compound specific differences.…”