Sodium-glucose cotransporter-2 (SGLT-2) inhibitors were not associated with an increased risk of fracture when compared with dipeptidyl peptidase 4 (DPP-4) inhibitors or glucagon-like peptide 1 receptor agonists (GLP-1RA).

To determine the risk of fracture in new users of these antidiabetic agents, the study authors conducted a nationwide cohort study that included 137,667 Medicare beneficiaries. Study participants aged 65 years and older with type 2 diabetes and without a history of fracture were included in the analysis.

The main outcome of interest was a composite of nontraumatic pelvic fracture, hip fracture requiring surgery, or humerus, radius, or ulna fracture requiring intervention within 30 days. The incidence of falls, hypoglycemia, and syncope were designated as secondary outcomes.

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The average age of patients in the study population was 72 years and 47% were men (n=64,126). “After 3-way matching, 45,889 (73%) new SGLT-2i users were matched to new users of DPP-4i and GLP-1RA,” the study authors reported. Sixty-four percent (n=29,396) of SGLT-2 inhibitor users were reported to be on canagliflozin.

Results showed no increased risk of fracture in SGLT-2 inhibitor users when compared with those treated with DPP-4 inhibitors (hazard ratio [HR], 0.90; 95% CI, 0.73-1.11) or GLP-1RAs (HR, 1.00; 95% CI, 0.80-1.25). Subgroup analyses also showed consistent findings across a range of categories including sex, frailty, age (<75 years vs ≥75 years) and insulin use.

Compared with DPP-4 inhibitors, the risk of falls and hypoglycemia were lower in the SGLT-2 inhibitor group (HR, 0.82 [95% CI, 0.77-0.87] vs 0.75 [95% CI, 0.67-0.84], however the risk of syncope was found to be similar. No differences in these outcomes were observed when the SGLT-2 inhibitor users were compared with GLP-1RA users.

“Our results add to the evidence base evaluating the safety profile of SGLT-2i in older adults outside of [randomized controlled trials] and further characterize the risk-benefit balance of SGLT-2i in clinical practice,” the authors concluded.


Zhuo M, Hawley CE, Paik JM, et al. Association of sodium-glucose cotransporter-2 inhibitors with fracture risk in older adults with type 2 diabetes. Published online October 27, 2021. JAMA Network Open. doi:10.1001/jamanetworkopen.2021.30762

This article originally appeared on MPR