Canagliflozin may not increase fracture risk in patients at low risk for fractures

Although canagliflozin has been linked to decreased bone mineral density, patients with type 2 diabetes who initiated the drug had similar risk of a first fracture as those who started a glucagon-like peptide-1 receptor agonist.


New use of canagliflozin, a sodium-glucose cotransporter-2 inhibitor, was not associated with an increased risk for fracture compared with new use of glucagon-like peptide-1 (GLP-1) receptor agonists in a recent study of about 160,000 propensity score-matched patients with type 2 diabetes and a relatively low fracture risk despite its association with decreased bone density.

Researchers used two U.S. commercial health care databases to identify 79,964 patients who, between March 29, 2013, and Oct. 1, 2015, initiated use of canagliflozin, which has been linked to decreased bone mineral density. After matching these patients to 79,964 patients who initiated treatment with a GLP-1 receptor agonist, they compared the estimated risk for nonvertebral fracture between groups. The mean age of the cohorts was 55 years; 48% of patients were women. The average baseline HbA1c level was 8.7%, and 27% of patients were prescribed insulin.

Results were published Jan. 1 by Annals of Internal Medicine.

After a mean follow-up of 34 weeks, the rate of the primary outcome (a composite endpoint of humerus, forearm, pelvis, or hip fracture requiring intervention) was similar between groups. The canagliflozin group had 2.2 events per 1,000 person-years, compared to 2.3 events per 1,000 person-years in the GLP-1 receptor agonist group (overall hazard ratio [HR], 0.98; 95% CI, 0.75 to 1.26). Risk for fractures at other sites (e.g., pelvis, hip, humerus, radius, ulna, carpal, metacarpal, metatarsal, ankle) were also similar for the canagliflozin group and the GLP-1 receptor agonist group (14.5 vs. 16.1 events per 1,000 person-years, respectively; overall HR, 0.92 [95% CI, 0.83 to 1.02]).

The authors noted limitations, such as a lack of access to information on diabetes severity (including duration), risk factors for fracture (e.g., body mass index, smoking), and other confounders (e.g., race, physical fitness). They added that they excluded patients with a previous fracture and that most of the study participants did not have osteoporosis, so the findings may not be generalizable to older patients or those with a higher baseline risk of fracture.

While the results are encouraging for patients at low risk for fracture, further research is needed to determine whether they apply to patients with high fracture risk due to factors such as advanced age, very low bone mineral density, prior fracture, or frailty, an accompanying editorial noted.

“In the meantime, although these data may reassure health care providers that prescribing canagliflozin will not increase fracture risk in their patients with diabetes, caution may still be appropriate when using this agent in older patients who have high fracture risk, with particular attention given to hydration status and fall risk,” the editorialists wrote.