Newly prescribed sodium-glucose cotransporter-2 (SGLT2) inhibitors are associated with higher risks of lower limb amputations, genital infections, and non-vertebral fractures compared with glucagon-like peptide-1 receptor agonists (GLP-1RA) in patients with type 2 diabetes and nondialysis-dependent chronic kidney disease (CKD) treated in routine clinical practice.
The findings are from a study of 96,128 adult patients identified using 2 US commercial insurance and Medicare databases, of whom 32,192 initiated SGLT2 inhibitors and 63,936 GLP-1RAs. Investigators propensity score matched 28,847 SGLT2 inhibitor initiators to 28,847 GLP-1RA initiators based on more than 120 baseline characteristics for analysis.
Compared with GLP-1RA initiators, SGLT2 inhibitor initiators had a significant 1.3-fold higher risk of non-vertebral fractures, a 1.7-fold higher risk of lower limb amputations, and a 3.1-fold higher risk of genital infections, Julie M. Paik, MD, ScD, MPH, of Brigham and Women’s Hospital in Boston, Massachusetts, and colleagues reported in the Clinical Journal of the American Society of Nephrology. The higher fracture risk was driven by hip and femur fractures.
The absolute risk increases for these safety outcomes were modest, the investigators noted: 2.1 more lower limb amputations, 2.5 more fractures, and 41 more genital infections per 1000 people receiving SGLT2 inhibitors vs GLP-1RAs. However, these adverse events occurred within 6 months of drug initiation.
Dr Paik’s team found similar risks of diabetic ketoacidosis, hypovolemia, hypoglycemia, and severe urinary tract infection between initiators of SGLT2 inhibitors vs GLP-1RAs. SGLT2 inhibitor users had a significant 7% lower risk of acute kidney injury.
“Our study can help inform patient-physician decision-making regarding risks and benefits before prescribing SGLT2 [inhibitors] in this population,” according to Dr Paik and colleagues.
SGLT2 inhibitors include empagliflozin, dapagliflozin, canagliflozin, and ertugliflozin. GLP-1RAs include liraglutide, dulaglutide, semaglutide, exenatide, albiglutide, and lixisenatide.
The higher risk for lower limb amputations and non-vertebral fractures was not observed with dipeptidyl peptidase-4 (DPP-4) inhibitors, the investigators reported.
The study lacked data on estimated glomerular filtration rate (eGFR) and albuminuria, so these results may not be generalizable to all patients with an eGFR less than 60 mL/min/1.73 m2 or with preserved kidney function and albuminuria.
Fu EL, D’Andrea E, Wexler DJ, Patorno E, Paik JM. Safety of sodium-glucose cotransporter-2 inhibitors in patients with CKD and type 2 diabetes: Population-based US cohort study. Clin J Am Soc Nephrol. Published online February 24, 2023. doi:10.2215/CJN.0000000000000115