Do SGLT2 Inhibitors Really Increase Fracture Risk?

A new meta-analysis has confirmed a lack of association between all three FDA approved SGLT2 inhibitors and fracture risk. Results were published online in Diabetes, Obesity and Metabolism.¹

“Consistently, our findings and the results from one previous meta-analysis do not support the adverse effect of SGLT2 inhibitors on fracture… In addition, there was no evidence that individual SGLT2 inhibitor (e.g., canagliflozin, dapagliflozin, or empagliflozin) increased the fracture rate or had different effects,” wrote lead author Yiqing Song, MD, ScD, of Indiana University (Indianapolis, Indiana), and colleagues.

In September 2015, after reports of increased fractures with canagliflozin, the US Food and Drug Administration (FDA) issued a safety announcement. The FDA also revised the drug’s label to include a warning about fracture risk and decreased bone mineral density.² However, one past meta-analysis has found no significant association between SGLT2 inhibitor use and bone fractures,³ and studies have conflicted about their effect on bone health. 

The new meta-analysis includes more recent clinical trial data, added bone mineral density to the analysis, and used two forms of meta-analytic techniques to improve evaluation of the evidence.

In the study, researchers systematically searched PubMed, EMBASE, CENTRAL and ClinicalTrials.gov from inception to January 27, 2016 without language restriction. The search identified 38 eligible randomized controlled trials (RCTs) (10 canagliflozin, 15 dapagliflozin, and 13 empagliflozin) covering 30,384 patients. To be included, trials had to compare SGLT2 inhibitors to placebo or other anti-diabetes medication. Follow-up ranged from 24 to 160 weeks, and all included trials were industry-funded. 

Key Results:

• Fracture event rates:

♦ SGLT2 inhibitors: 1.59%

♦ Control: 1.56%

• No difference in fracture risk between SGLT2 inhibitors and control (OR 1.02, 95% CI 0.84 to 1.23)

♦ Increased fracture risk with SGLT2 inhibitor use in Asian populations (OR 2.05, 95% CI 0.86 to 4.87), though the results were not significant

♦ There was no evidence of substantial publication bias and low statistical heterogeneity (I²=22.8%)

• Similar incidence of fractures among all three SGLT2 inhibitors, none of which were linked to increased risk of fracture

♦ Canagliflozin: OR 1.15; 95% CI, 0.71 to 1.88

♦ Dapagliflozin: OR 0.68; 95% CI, 0.37 to 1.25

♦ Empagliflozin: OR 0.93; 95% CI, 0.74 to 1.18

• Two RCTS reported on bone mineral density (BMD):

♦ One of which found no significant differences in BMD with dapagliflozin over 10 weeks⁴

♦ The other found small but statistically significant decreases in BMD at the total hip with canagliflizoin over 104 weeks⁵

The authors noted that data on BMD is preliminary and more research is needed regarding the effect of SGLT2 inhibitors on bone health biomarkers. They also mentioned that longer follow-up is needed to determine long-term fracture risk of SGLT2 inhibitors.

They concluded: “[C]urrent evidence suggested that SGLT2 inhibitors were not significantly associated with an increased risk of fracture in patients with T2DM. Since lack of detailed information on bone health outcome were reported and [the] majority of RCTs were small and short term, future long term RCT and real-world data is warranted to draw more definitive conclusions regarding the bone effect of SGLT2 inhibitors.”

Take-home Points

• New meta-analysis suggests SGLT2 inhibitors are not associated with increased fracture risk.

• The findings confirm the results of one past meta-analysis.

• Results showed a similar incidence of fractures among all three SGLT2 inhibitors (canagliflozin, dapagliflozin, or empagliflozin).

• There was conflicting evidence about the effect of SGLT2 inhibitors on bone mineral density.

• Longer term trials are needed.

References:

1. Tang HL, et al. Lack of evidence for a harmful effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors on fracture risk among type 2 diabetes patients: a network and cumulative meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2016 Jul 13.

2. U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA revises label of diabetes drug canagliflozin (Invokana, Invokamet) to include updates on bone fracture risk and new information on decreased bone mineral density. 2015. Accessed August 4 2016 at: http://www.fda.gov/Drugs/DrugSafety/ucm461449.htm

3. Wu JH, et al. Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2016;4:411-419.

4. Bolinder J, et al. Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin. Diabetes Obes Metab. 2014;16:159-169.

5. Bode B, et al. Long-term efficacy and safety of canagliflozin over 104 weeks in patients aged 55-80 years with type 2 diabetes. Diabetes Obes Metab. 2015;17:294-303.