The Impact of Different Antidiabetic Drugs on Fracture Risk in Patients With Type 2 Diabetes Mellitus: A Systematic Review and Network Meta-analysis of Randomized Controlled Trials With a Focus on SGLT2 Inhibitors

Diabetes affects about 537 million people around the world, and most of them have type 2 diabetes mellitus (T2DM). This number is projected to increase to 783 million by 2045.1 People with diabetes have a much higher risk of heart failure (HF),2 which is 2 to 4 times more than normal. The American Diabetes Association (ADA)3,4 recommends that people with T2DM who have HF or chronic kidney disease (CKD) or who are at high risk of these conditions should use sodium-glucose co-transporter 2 (SGLT2) inhibitors to prevent harmful outcomes. This new approach to treating T2DM is based on the results of several important clinical trials, such as EMPA-REG OUTCOME, CANVAS, LEADER, and SUSTAIN-6,5, 6, 7, 8, 9 which showed the benefits of these drugs. However, in 2016, the US Food and Drug Administration (FDA) warned that canagliflozin, one of the SGLT2 inhibitors, may increase the risk of fracture.10 This was after the CANVAS trial found more fractures in people who took this drug. Some researchers suggested that these drugs may affect how calcium and phosphate are used in the body, which may lead to compromised bone integrity and increase fractures risk.11 But later studies did not find the same problem. The CREDENCE trial in 2019 showed no difference in fracture risk between people who took canagliflozin or a placebo.12 The same was true for the EMPA-REG and DECLARE–TIMI 58 trials, which tested empagliflozin and dapagliflozin, respectively.13 Another trial, VERTIS-MET, even found that ertugliflozin, another SGLT2 inhibitor, reduced the risk of fractures.14 There are many different drugs for diabetes, but there has not been a study that compared them all together and looked at their effects on fracture risk.15, 16, 17 This is important because the new guidelines suggest using SGLT2 inhibitors more often, but their skeletal safety profile remains to be clearly established. To answer this question, we used a statistical method called Frequentist meta-analysis, which can combine data from different studies and compare different treatments. We reviewed all the clinical trials that reported fracture events in people with diabetes who used different drugs. Our goal was to evaluate the safety of these drugs for the bones. Our study may help doctors and patients make better decisions about diabetes treatment in the future.