No Fracture Risk for New Diabetes Drugs in Real-World Study

Miriam E. Tucker

July 17, 2019

Sodium-glucose cotransporter 2 (SGLT2) inhibitors for the treatment of type 2 diabetes are not associated with an increased fracture risk, new results from a large population-based database indicate.

"Overall, our real-world study provides further reassurance on the safety of this new class of drugs on bone health among patients with type 2 diabetes," write Devin Abrahami, a PhD candidate in pharmacoepidemiology at McGill University, Montreal, Quebec, Canada, and colleagues.

The findings, which included more than 9000 patients who took an SGLT2 inhibitor in the UK Clinical Practice Research Datalink (UKCPRD), were published online July 11 in Diabetes Care.

The association between SGLT2 inhibitors and possible increased fracture risk has been controversial.

In 2015, the US Food and Drug Administration updated its label warning for the SGLT2 inhibitor canagliflozin (Invokana, Janssen) about the risk. Publication of the Canagliflozin Cardiovascular Assessment Study (CANVAS) results in 2017, which showed a small but significant increase in fracture risk with canagliflozin vs placebo (15.4 vs 11.9/1000 patient-years; P = .02) further heightened the concern, although the risk wasn't observed in the sister CANVAS-R trial.

Three more recent observational trials also haven't identified an increased fracture risk, but those trials have had limitations such as residual confounding or restriction to a single SGLT2 inhibitor, Abrahami and colleagues say. 

SGLT2 vs DPP-4 Inhibitors: No Increased Fracture Risk

Abrahami and colleagues studied a total of 73,178 patients aged 40 years and older in the UKCPRD who initiated a glucose-lowering drug starting in 2013, the year the first SGLT2 inhibitor was introduced in the UK. Of those, 9454 patients took an SGLT2 inhibitor (1288 canagliflozin, 5539 dapagliflozin, and 2133 empagliflozin, and 494 patients took more than one SGLT2 inhibitor) and 18,410 took a dipeptidyl peptidase 4 (DPP-4) inhibitor.

Over a median follow-up of 1.9 years, there were 1973 fracture events, corresponding with an incidence of 12.88/1000 person-years.

The fracture risk was no greater among those taking an SGLT2 inhibitor compared with a DPP-4 inhibitor, at 11.0 vs 14.8/1000 person-years, respectively, and a nonsignificant hazard ratio of 0.97.

When examined by individual SGLT2 inhibitor, canagliflozin was actually associated with a decreased fracture risk (hazard ratio, 0.47), but this was not significant because of the low event number (n = 10).

"Although our stratified analysis by SGLT2 molecule revealed a protective effect for canagliflozin, this finding should be interpreted with caution given that it was based on few exposed events," Abrahami and colleagues write.

By fracture type, the only risk increase with SGLT2 inhibitors was for vertebral fractures (hazard ratio, 1.76), but that was also nonsignificant. Similarly, the association was not modified by history of fracture, osteoporosis, age, or sex. The results also remained consistent in several sensitivity analyses.

"In summary, the results of this large population-based cohort study indicate that use of SGLT2 inhibitors is not associated with an increased risk of fractures compared with use of DPP-4 inhibitors," the researchers conclude.

The study was funded by a Foundation Scheme grant from the Canadian Institutes of Health Research (CIHR). Abrahami is the recipient of a Vanier Canada Graduate Scholarship from the CIHR and a training grant from the CIHR Drug Safety and Effectiveness Training Program.

Diabetes Care. Published online July 11, 2019. Letter

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