Sodium-glucose cotransporter-2 (SGLT2) inhibitors with proven cardiorenal benefits are used in the treatment of diabetic kidney disease; however, their use has been associated with a higher risk of skeletal fracture in some clinical trials.¹ In a recent population-based cohort study involving over 140,000 Canadian adult patients, published in Clinical Journal of the America Society of Nephrology (CJASN), it was found that new users of SGLT2 inhibitors were not associated with an increased risk of fracture compared with new users of dipeptidyl peptidase 4 (DPP-4) inhibitors at 180 or 365 days, regardless of their estimated glomerular filtration rate (eGFR) of 30-90mL/min/1.73m².¹ This study provided a real-world assurance for clinicians to safely prescribe SGLT2 inhibitors to their chronic kidney disease (CKD) patients, without a higher risk of fracture.¹

SGLT2 inhibitors are effective hypoglycemic agent in the management of type 2 diabetes (T2D), resulting in the possibility of lowering the risk of serious cardiovascular (CV) complications, kidney disease and death.^2,3 As such, SGLT2 inhibitors are recommended in all diabetic kidney disease patients with eGFR ≥30mL/min/1.73m².¹ However, some large trials such as the CANVAS trial (n=10,142) reported the use of SGLT2 inhibitors having a higher risk of fracture compared with placebo.¹ The possible mechanism of SGLT2 inhibitor-induced fracture included an increased risk of falls through hypoglycemia, a decrease in bone quality through weight loss, to name a few.¹ Because of their predisposition to the metabolic derangements of CKD mineral bone disorder, CKD patients have a two- to five-fold higher risk of fracture compared with the general population.¹ As such, it is imperative to ensure that SGLT2 inhibitors do not pose a higher fracture risk to CKD patients.¹

The population-based cohort study compared the incidence rates of fracture in adults ≥66 years old, who were prescribed SGLT2 inhibitors (canagliflozin, empagliflozin, or dapagliflozin) vs. those prescribed DPP-4 inhibitors (saxagliptin, sitagliptin, or linagliptin) which have no known fracture risk.¹ The analysis included 38,994 new users of an SGLT2 inhibitor and 37,449 new users of a DPP-4 inhibitor, and excluded individuals who had severely decreased kidney function.¹ The primary outcome involved hospital encounters (hospitalization or emergency department visit) for a fragility fracture (hip, spine, shoulder/ upper arm, forearm/wrist, and pelvis) within 180 days of a new user receiving an SGLT2 inhibitor or a DPP-4 inhibitor.¹ The secondary outcomes were the hospital encounters for fragility fracture at 365 days and site of fracture.¹

The analysis revealed a total of 342 fractures at 180 days and 689 fractures at 365 days.1 New use of SGLT2 inhibitor was not associated with an increased risk of fracture at 180 days vs. new use of DPP-4 inhibitor (weighted HR=0.95; 95% CI: 0.79-1.13).1 Investigators of this study observed no difference in fracture site between the user groups, and no substantial difference in the 180-day risk of hospital encounters with falls (weighted HR= 0.98; 95% CI: 0.91-1.05), hypoglycemia (weighted HR=0.91; 95% CI: 0.68-1.22), or hypotension (weighted HR=0.98; 95% CI: 0.65-1.47).¹ On the other hand, there was a modestly significant lower risk of fracture in new SGLT2 inhibitor users vs. DPP-4 inhibitor users at 365 days (HR=0.88; 95% CI: 0.77-1.00).¹ In a sub-analysis of different eGFR categories, there was no apparent evidence of a higher risk of fracture with SGLT2 inhibitor vs. DDP-4 inhibitor.¹

In short, the population-based cohort study showed no difference in fracture risk between individuals prescribed an SGLT2 inhibitor and those prescribed a DPP-4 inhibitor, suggesting that SGLT2 inhibitor was not associated with an increased risk of fracture.¹ The findings of this study helped remove the shade cast on the SGLT2 inhibitor treatment in CKD patients with high fracture risk.¹