Some clinical trials have linked sodium-glucose cotransporter-2 (SGLT2) inhibitors to a higher risk for skeletal fractures. In contrast to this research, a new study finds that SGLT2 inhibitors pose no greater fracture risk in patients with chronic kidney disease (CKD) compared with dipeptidyl peptidase-4 (DPP-4) inhibitors, diabetes drugs with no known association with fracture risk.
Investigators compared 37,449 new users of a DPP-4 inhibitor and 38,994 new users of an SGLT2 inhibitor aged 66 years or older from Ontario, Canada. A total of 342 skeletal fractures occurred within 180 days and 689 fractures within 365 days. Fracture risk at 180 days and 365 days after drug initiation did not differ significantly between the DPP4-inhibitor and SGLT2 inhibitor groups (0.46% vs 0.44% and 0.96% vs 0.84%, respectively), Andrea Cowan, MD, of Western University, London, Canada, and colleagues reported in the Clinical Journal of the American Society of Nephrology. Fracture risk also did not vary by kidney function (estimated glomerular filtration rate more than 30 mL/min/1.73 m2). Users of these diabetes medications had comparable risks for falls, hypotension, and hypoglycemia.
Patients with CKD are vulnerable to fractures due to CKD mineral bone disorder. Dr Cowan’s team noted that in short-term studies, the SGLT2 inhibitors dapagliflozin and canagliflozin (but not empagliflozin) have been associated with hyperphosphatemia, secondary hyperparathyroidism, and increased bone turnover. Most SGLT2 inhibitor prescriptions in this population-based cohort were for empagliflozin. The investigators could not assess fracture risk by individual medication. Another limitation of the study is the 1-year time frame. Fracture risk due to SGLT2 inhibitor use may take longer than a year to manifest.
“This study re-assures patients and doctors that SGLT-2 inhibitors are not associated with an increased risk of fracture in patients with chronic kidney disease,” Dr Cowan stated in a news release from the American Society of Nephrology.
The authors said that, to their knowledge, their study is the first of its kind to specifically examine fracture risk in patients with CKD. Another study strength was the use of outpatient laboratory values that are more accurate in identifying individuals with CKD compared with administrative data codes. With regard to study limitations, the investigators said that to preserve statistical power, they were unable to stratify their analysis by SGLT2 inhibitor type.
In an accompanying editorial, Mirela Dobre, MD, MPH, of Case Western Reserve University in Cleveland, Ohio, encouraged continued research.
“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 (eGFR less than 30 ml/min per 1.73 m2).”
Dr Dobre noted that if a risk is identified, interventions may include phosphate binders, active vitamin D, and a low-phosphate diet rich in fruits and vegetables.
Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
Cowan A, Jeyakumar N, Kang Y, Dixon SN, et al. Fracture risk of sodium-glucose cotransporter-2 inhibitors in chronic kidney disease. Clin J Am Soc Nephrol. Published May 26, 2022. doi:10.2215/CJN.16171221
New research questions previous link between diabetes drugs and bone fractures [news release]. American Society of Nephrology; May 26, 2022.
Dobre M. Safety of SGLT2 inhibitors in CKD: Walking the fine line. Clin J Am Soc Nephrol. 17:774–776. Published May 26, 2022. doi:10.2215/CJN.04900422