Reassuring Data on Fracture Risk With Canagliflozin

December 31, 2018

By Megan Brooks

NEW YORK (Reuters Health) - Treatment with the sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin does not increase the risk for fracture in patients with type 2 diabetes at relatively low risk for fracture, according to results of a large observational study online today in Annals of Internal Medicine.

"Our results should be reassuring to both patients and physicians. Less than 1% of patients prescribed canagliflozin had a fracture, and the rate of fracture was similar to patients taking another class of diabetes medications (i.e., glucagon like peptide-1 agonists)," Dr. Michael Fralick of Brigham and Women's Hospital and Harvard Medical School in Boston told Reuters Health by email.

SGLT2 inhibitors promote glycosuria, resulting in possible effects on calcium, phosphate, and vitamin D homeostasis. Canagliflozin is associated with decreased bone mineral density and a potential increase in fracture risk.

"One recent clinical trial of about 4,000 patients demonstrated an increased risk of fracture with canagliflozin while a second clinical trial of about 6,000 patients did not. Our study included approximately 200,000 adults with type 2 diabetes mellitus and found that canagliflozin was not associated with an increased risk of fracture," said Dr. Fralick, who led the study.

The researchers used two U.S. commercial health care databases to estimate the risk for nonvertebral fracture among new users of canagliflozin. A total of 79,964 patients with type 2 diabetes who initiated canagliflozin were propensity score-matched to a like number who initiated a GLP-1 agonist. Participants had a mean age of 55 years, 48% were female, average baseline hemoglobin A1c level was 8.7%, and about a quarter were using insulin.

The rate of the primary outcome – a composite end point of humerus, forearm, pelvis, or hip fracture requiring intervention – was similar for canagliflozin and GLP-1 agonists (2.2 and 2.3 events per 1000 person-years), with an overall hazard ratio of 0.98 (95% confidence interval. 0.75 to 1.26), the researchers report.

There was also no difference in the rate of pelvic, hip, humerus, radius, ulna, carpal, metacarpal, metatarsal, or ankle fracture canagliflozin and GLP-1 agonists (14.5 and 16.1 events per 1000 person-years), for an overall hazard ratio of 0.92 (95% CI, 0.83 to 1.02).

In an editorial, Dr. William Leslie from University of Manitoba in Winnipeg, Canada and Dr. John Schousboe from University of Minnesota in Minneapolis note that the upper limit of the overall 95% CI for both databases was 1.26, "which would exclude a large or moderate increase (but not necessarily a small increase) in fracture risk."

They also note that despite the large number of participants from two databases, drug exposure was only 34 weeks on average and the population had low fracture risk. "Although this study adds to the accumulating evidence that there is probably little if any risk associated with canagliflozin use among patients with diabetes who have low fracture risk, further investigations are needed to determine whether these results apply to persons with both diabetes and high fracture risk due to advanced age, very low bone mineral density, prior fracture, frailty, or a combination of these factors," write Drs. Leslie and Schousboe.

"In the meantime, although these data may reassure health care providers that prescribing canagliflozin will not increase fracture risk in their patients with diabetes, caution may still be appropriate when using this agent in older patients who have high fracture risk, with particular attention given to hydration status and fall risk," they conclude.

The study had no commercial funding.


Ann Intern Med 2018.

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