Some SGLT2 inhibitors increase risk of loss of bone mineral density and fracture

A Health Canada safety review has revealed a link between the use of certain sodium-glucose cotransporter-2 (SGLT2) inhibitors and the development of reduced bone mineral density and bone fracture. Three SGLT2 inhibitors are marketed for the treatment of type 2 diabetes in Canada: canagliflozin (Invokana, Invokamet), dapagliflozin (Forxiga, Xigduo) and empagliflozin (Jardiance, Synjardy).(1)The safety review was initiated following international reports of an increased risk of reduced bone mineral density and increased fracture risk in patients taking canagliflozin. At the time of the review, Health Canada had not received any Canadian reports of loss of bone mineral density or fracture related to SGLT2 inhibitors.(1)Recent studies have found an increased risk of reduced bone mineral density and fracture occurring as early as 12 weeks after starting treatment with canagliflozin. However, Health Canada stresses that these side effects are rare. Dapagliflozin has also been associated with an increased risk of bone fracture, but only when used in patients with moderate renal impairment (eGFR 30–60 mL/min/1.73m2). To date, empagliflozin does not appear to be associated with any increased risk of bone-related side effects.(1)Canadian product information for canagliflozin and dapagliflozin already includes some information on the risk of bone fracture. Health Canada is working with the manufacturer to update the safety information for canagliflozin to note the increased risk of reduced bone mineral density and bone fracture.(1)In September 2015, the US Food and Drug Administration (FDA) also strengthened the warning about the increased risk of bone fractures with canagliflozin. New information about decreased bone mineral density with canagliflozin was also added.(2,3) The FDA is advising healthcare professionals to consider factors that contribute to fracture risk before starting a patient on canagliflozin.(3)The cause of increased fracture risk with canagliflozin is unknown.(4) It has been speculated that it could be related to increases in parathyroid hormone levels and decreases in 1,25-dihydroxyvitamin D levels.(5) Other possibilities include an increased risk of falls because most patients are older, and many have a prior history or increased risk of cardiovascular disease, lower baseline estimated glomerular filtration rate and higher baseline diuretic use.(4)ReferencesHealth Canada. Summary safety review - SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin) - assessing the potential risk of bone-related side effects. November 14, 2016. www.hc-sc.gc.ca/dhp-mps/medeff/reviews-examens/sglt2-3-eng.php (accessed November 15, 2016).U.S. Food and Drug Administration. Invokana and Invokamet (canagliflozin): Drug Safety Communication - new information on bone fracture risk and decreased bone mineral density. September 10, 2015. www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalproducts/ucm461876.htm (accessed November 15, 2016).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. September 10, 2015. www.fda.gov/Drugs/DrugSafety/ucm461449.htm (accessed November 15, 2016).Watts NB, Bilezikian JP, Usiskin K, et al. Effects of canagliflozin on fracture risk in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab 2016;101:157-66.Mannucci E, Monami M. Bone fractures with sodium-glucose co-transporter-2 inhibitors: how real is the risk? Drug Saf 2016 Nov 8. [Epub ahead of print].

Some SGLT2 inhibitors increase risk of loss of bone mineral density and fracture

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