Fracture Risk and Sodium-Glucose Transport Inhibitors

Did the FDA make a mistake by labeling SGLT2 inhibitors as a fracture risk?

In recent years, there have been controversial warnings for the use of SGLT-2 Inhibitors that suggest an increased risk of fracture when placed on one SGLT2 inhibitor, canagliflozin. In 2015, the US FDA added a warning on canagliflozin, indicating that patients on canagliflozin must use caution because of a fracture risk associated with the diabetes medication. This conclusion came from previous data published in the Canagliflozin Cardiovascular Assessment Study, otherwise known as CANVAS. The data of CANVAS suggested that there was an increased risk of fracture in those who were on the medication when compared to that of the placebo group (15.4 vs. 11.9 per 1000 patient-years; P = .02). CANVAS had a sister trial known as CANVAS-Renal, or CANVAS-R, that did not show an increase in fracture risk. Recent observational trials seemed to confirm the increased risk of fracture, although, as noted by Devin Abrahami, a PhD candidate in pharmacoepidemiology at McGill University and his colleagues, there were limitations and these trials may not have captured the full scope of the SGLT2 Inhibitor class.

To help dispel the fears of fracture risk, Abrahami and his colleagues analyzed the data of 73,178 patients from a previous trial in the United Kingdom, called the UK Clinical Practice Research Datalink (UKCPRD). The patients were 40 years and older who started diabetes therapy in 2013 and had a mean followup of 1.9 years. The year 2013 was chosen because that is when SGLT2 was approved in the UK. Of the participants, 9,454 participants had been taking an SGLT2 inhibitor. There were two cohorts for this study, the first group were those on an SGLT2 inhibitor (1288 canagliflozin, 5539 dapagliflozin,  2133 empagliflozin, and 494 patients took more than one SGLT2 inhibitor) and the second group were those on a Dipeptidyl Peptidase 4 (DPP-4) inhibitor (18,410 of whom were taking one).

The results of Abrahami’s research showed that 1,973 fracture events took place (12.88/1,000 person-years). There was no significant difference when comparing the SGLT2 inhibitor participants and the DPP4 Inhibitor participants (11.0 vs. 14.8/1000 person-years, respectively, HR of 0.97). Upon further analysis, Abrahami notes that when the SGLT2 inhibitors were compared to one another, canagliflozin had a hazard ratio of 0.47 and was associated with having a lower fracture risk. Due to the population size and event rate that was observed, the results of canagliflozin proved insignificant. Although it was not significant, it is important to note that future studies with larger population sizes can focus on SGLT2 fracture risk and compare each medication to each other. SGLT2 inhibitors showed an increase in vertebral fracture (HR 1.76), but the resulting data also proved not significant.

Though SGLT2 medications have been associated with increased fracture risk, Abrahami and his colleagues, through the analysis of the UK participants, have shown that is not the case. When SGLT2 inhibitors and DPP4 inhibitors were compared using the data of UKCPRD, the significance could not be proven and was shown to be lower in canagliflozin. In future studies, a large scale, randomized trial should be performed by the FDA, to once and for all, confirm or deny whether SGLT2 inhibitors cause fractures.

Practice Pearls:

• The FDA issued warnings in 2017, indicating that patients who were currently taking canagliflozin, an SGLT2 inhibitor, were at an increased risk of developing a fracture.
• Abrahami and his colleagues analyzed data from the UKCPRD trial to prove whether there was an increased fracture rate with the use of SGLT2 inhibitors when compared to DPP4 inhibitors, which have not been associated with fracture. 
• The results of the trial could not establish significance between SGLT2 inhibitors and fractures. It is important to note that future trials should be considered to solidify the claim further.

Abrahami, Devin, et al. “Sodium-Glucose Cotransporter 2 Inhibitors and the Risk of Fractures Among Patients With Type 2 Diabetes.” Diabetes Care, 2019, p. dc190849., DOI:10.2337/dc19-0849.

Tucker, Miriam. “No Fracture Risk for New Diabetes Drugs in Real-World Study.” Medscape, 17 July 2019, www.medscape.com/viewarticle/915709.

Usif Darwish, PharmD Candidate, Florida A&M University, College of Pharmacy & Pharmaceutical Sciences