No Increased Risk of Fracture with SGLT2 Inhibitors in Diabetic Kidney Disease, Study Finds

A new analysis leveraging data from more than 75,000 patients with diabetic kidney disease provides evidence that could put concern over the risk of fracture with SGLT2 inhibitors in these patients to rest.

Conducted by investigators from the Institute for Clinical and Evaluative Sciences (ICES) in London, Ontario, Canada, the study compared fracture incidence among 38,994 new users of SGLT2 inhibitors and 37,449 new users of DPP-4 inhibitors from linked administrative databases and concluded there was no significant difference in fracture incidence with the agents in weighted analyses assessing risk at 185 and 365 days.

“This study reassures patients and doctors that SGLT2 inhibitors are not associated with an increased risk of fracture in patients with chronic kidney disease,” said Andrea Cowan, MD, of the London Health Sciences Centre in Ontario, Canada, in a statement from the American Society of Nephrology.

Few agents have received the amount of acclaim and attention as SGLT2 inhibitors in recent years as trials have confirmed their cardiorenal benefits both in and out of diabetes. With these revelations, uptake of these agents has increased markedly in recent years. However, some early trials reported a potential increase in fracture risk with these agents and, while this has been the subject of multiple studies in recent years, some concerns remain around subgroups of patients with diabetes, including those with chronic kidney disease.

With this in mind, investigators hoped to estimate the risk of fracture using SGLT2 inhibitors versus DPP-4 inhibitors in real-world settings. To do so, Cowan and a team of colleagues designed the current study as a population-based cohort study of adults aged 66 years or older with type 2 diabetes and CKD who received a new prescription for SGLT2 inhibitors or DPP-4 inhibitors between July 1, 2015, and September 30, 2019, from a set of 8 linked administrative health databases with data from patients in Ontario, Canada.

The investigators’ initial search yielded an unweighted population of 144,694 patients, with 105,700 new users of DPP-4 inhibitors and 38,994 new users of SGLT2 inhibitors. Using inverse probability of treatment weighting, investigators created cohorts of 37,449 new users of DPP-4 inhibitors and 38,994 new users of SGLT 2 inhibitors for inclusion in their final analyses.

The primary outcome of interest for the analyses was a hospital encounter for a fragility fixture within 180 days of new prescription for either agent. For the purpose of fragility fractures included fractures of the hip, spine, shoulder, upper arm, forearm, wrist, or pelvis. Investigators planned to assess hospitalizations for fragility features at 365 days and site of fracture as secondary outcomes. Additionally, prespecified subgroup analyses were planned to estimate effect by eGFR category.

Among the 76,443 patients included in the study cohort, a total of 342 fractures occurred at 180 days and 689 fractures at 365 days. Upon analysis, results indicated there was no significant difference in fracture risk observed for new users of SGLT2 inhibitors compared with new users of DPP-4 inhibitors at 180 days (HR, 0.95 [95% CI, 0.79-1.13]) and 365 days (HR, 0.88 [95% CI, 0.88-1.00]). In subgroup analyses, results suggested eGFR did not significantly alter the association between SGLT2 inhibitors versus DDP-4 inhibitors and fracture outcomes at 180 (P for interaction=.37) and 365 days (P for interaction=.53), with no evidence of a higher fracture risk with SGLT2 inhibitors in all eGFR categories.

In an editorial, Mirela Dobre, MD, PhD, a nephrologist in the Division of Nephrology and Hypertension at Case Western Reserve University, detailed the breadth of evidence examining the potential risk of fracture with SGLT2 inhibitors, but noted limitations within the research conducted by Cowan and colleagues and called for further research to determine the real-world risk of fracture with these agents in patient subgroups.

“Deciphering the mechanisms of SGLT2i influence on bone metabolism and fracture risk in individuals with CKD will help design interventions to reduce these devastating consequences. The report by Cowan et al. adds to the growing body of evidence related to the safety of SGLT2is; however, it should encourage continued basic and clinical studies to determine with more certainty their potential risk of fractures, especially in individuals with advanced CKD,” Dobre wrote.

This study, “Fracture Risk of Sodium-Glucose Cotransporter-2 Inhibitors in Chronic Kidney Disease,” was published in the Clinical Journal of the American Society of Nephrology.