Summary Safety Review - SGLT2 Inhibitors (canagliflozin, dapagliflozin, empagliflozin) - Assessing the Potential Risk of Bone-Related Side Effects

November 14, 2016

Product

Sodium-glucose cotransporter-2 (SGLT2) inhibitors: Invokana (canagliflozin), Forxiga (dapagliflozin), Jardiance (empagliflozin)

Potential Safety Issue

Loss of bone minerals with a risk of brittle or broken bones

Key Messages

• SGLT2 inhibitors are drugs used to treat adults with type 2 diabetes.
• This safety review was triggered following international reports about the increased risk of losing bone minerals or suffering broken bones in patients taking canagliflozin.
• Health Canada's safety review found a link between bone-related side effects and the use of canagliflozin. Health Canada is working with the manufacturer to update the safety information of canagliflozin to reflect these risks. For dapagliflozin, these risks were only identified in patients who had kidney problems and this is already explained in the safety information. No evidence of bone-related side effects was found to date with the use of empagliflozin.

Overview

The minerals stored within the bones help provide strength. Bones that have fewer minerals (less bone mineral density) are more likely to become brittle and break (fracture). A safety review was carried out by Health Canada to evaluate the risk of bone-related side effects of using SGLT2 inhibitors. The review was triggered by a notice about international reports of bone-related side effects experienced in patients taking the SGLT2 inhibitor canagliflozin.

Use in Canada

• SGLT2 inhibitors are drugs designed to lower blood sugar in adults with type 2 diabetes by helping remove excess sugar from the body through the urine.
• SGLT2 inhibitors are used along with diet and exercise either alone or in combination with other specific agents that control blood sugar.
• Three SGLT2 inhibitors are currently available in Canada: Invokana (canagliflozin), Forxiga (dapagliflozin) and Jardiance (empagliflozin). Drugs of this type have been available in Canada since 2014.

Safety Review Findings

• At the time of the review Health Canada had not received any Canadian reports of loss of bone mineral density or broken bones related to the use of SGLT2 inhibitors.
• Recent medical studies have found an increased risk of losing bone mineral density and an increased risk of bone fracture occurring as early as 12 weeks of being on treatment with canagliflozin, but these side effects are still rare. An increased risk of bone fracture associated with the use of dapagliflozin was also noted in patients with kidney problems (moderate renal impairment). No evidence of bone-related side effects was found to date with the use of empagliflozin.
• Based on how SGLT2 inhibitors work in the body, they may affect the way the body takes in minerals to strengthen the bones. The evidence from scientific literature showed that this may contribute to the side effects.
• At the time of the review, the product safety information for canagliflozin and dapagliflozin already included some information on the risk of bone fracture.

Conclusions and Actions

• Health Canada's safety review concluded that the evidence supported a link between the risks of bone fracture and loss of bone mineral density with the use of canagliflozin. With use of dapagliflozin, these risks were only identified in patients who had kidney problems.No evidence of bone-related side effects was found to date with the use of empagliflozin.
• Health Canada is working with the manufacturer to update the safety information for canagliflozin to reflect these risks. The dapagliflozin product safety information already mentions the risks, so no updates were recommended from this review.
• Health Canada will mention the update in the Health Product InfoWatch, to inform physicians about the potential risk of bone-related side effects in patients treated with canagliflozin, and to consider factors that contribute to the fracture risk.
• Health Canada will continue to monitor safety information involving SGLT2 inhibitors, as it does for all health products on the Canadian market, to identify and assess potential harms. Health Canada will take appropriate and timely action if and when any new health risks are identified.

Additional Information

The analysis that was carried out for this safety review took into consideration information from scientific and medical literature, Canadian and international adverse reaction reports as well as what is known about the use of these drugs and their associated risks in Canada and internationally.

For additional information, contact the Marketed Health Products Directorate.