Summary Safety Review - Dipeptidylpeptidase-4 inhibitors - Assessing the potential risk of a skin reaction (bullous pemphigoid)

January 25, 2018

Product

DPP-4 inhibitors (gliptins): alogliptin, saxagliptin, sitagliptin, and linagliptin

Potential Safety Issue

Skin reaction (bullous pemphigoid)

Key Messages

  • DPP-4 inhibitors, known as gliptins, are prescription drugs authorized for sale in Canada to treat type 2 diabetes in adults.
  • Health Canada reviewed the risk of a skin reaction known as bullous pemphigoid with the use of DPP-4 inhibitors because of international reports in patients treated with these products. These reports were part of safety information submitted by the manufacturers of these products.
  • Health Canada’s review concluded that there may be a link between any of the DPP-4 inhibitors and the risk of bullous pemphigoid. Health Canada has asked that manufacturers update the product safety information for all DPP-4 inhibitors to include warnings for this risk.
  • Patients taking DPP-4 inhibitors should contact their healthcare provider if they experience blisters or a breakdown of the skin which could be signs of bullous pemphigoid.

Overview

Health Canada reviewed the risk of a skin reaction known as bullous pemphigoid with the use of DPP-4 inhibitors because of international reports of this reaction with the use of these products. These cases were identified as part of information submitted by the manufacturers of these products. Bullous pemphigoid is a rare disease involving an abnormal response from the body’s immune system which results in a skin reaction. The disease may cause blisters commonly seen on a person’s abdomen, arms or legs. If it is not treated, patients may have problems with their body fluids (e.g., dehydration, electrolyte imbalance) or skin infections, or they may die from the body’s response to infection (i.e., death due to sepsis).

Use in Canada

  • DPP-4 inhibitors, also known as gliptins, are prescription drugs authorized for sale in Canada to treat type 2 diabetes in adults. They are used along with an appropriate diet and exercise to control blood sugar. In some cases, they are used with another anti-diabetic drug.
  • There are currently four different gliptins on the Canadian market: sitagliptin, saxagliptin, linagliptin and alogliptin. These drugs are also available in products that combine them with other drugs that treat type 2 diabetes.
  • In 2008, sitagliptin became the first gliptin sold in Canada. There were around 5.7 million prescriptions for DPP-4 inhibitors in 2016.

Safety Review Findings

  • At the time of the review, Health Canada had not received Canadian reports of bullous pemphigoid related to the use of DPP-4 inhibitors since their marketing in Canada.
  • While Health Canada was carrying out the safety review, the safety information for two of the four DPP-4 inhibitors (sitagliptin and linagliptin) was updated with warnings regarding the potential risk of bullous pemphigoid. Therefore, international reports for sitagliptin and linagliptin were not further assessed.
  • A total of 24 serious international reports of potential bullous pemphigoid with the use of alogliptin (16) or saxagliptin (8) were identified by manufacturers and from a search in the Canada Vigilance database. All 24 reports were considered to show a possible link between the skin reaction and the drug. Other factors such as older age, the presence of other medical conditions, and the use of certain drugs linked to this skin reaction were observed and could have also played a role. Of the 24 reports, three deaths were reported, one of which was considered to be possibly linked to bullous pemphigoid from using the DPP-4 inhibitor.
  • A search in the World Health Organization’s Adverse Drug Reaction Database found that, internationally, cases of bullous pemphigoid have been reported more often than expected with the use of DPP-4 inhibitors available in Canada.
  • Health Canada reviewed 16 publications regarding DPP-4 inhibitors and the potential risk of bullous pemphigoid. Three publications showed a potential link between bullous pemphigoid and the use of any of the DPP-4 inhibitors. The remaining publications referred to patient reports in association with specific DPP-4 inhibitors.

Conclusions and Actions

  • Health Canada’s review concluded that there may be a link between the use of DPP-4 inhibitors and the risk of bullous pemphigoid. Health Canada has asked that manufacturers update the product safety information for all DPP-4 inhibitors to contain warnings for this risk.
  • In addition, Health Canada will publish a notice in the Health Product InfoWatch to inform Canadians and healthcare professionals of this new safety information.
  • Health Canada encourages consumers and healthcare professionals to report any side effects related to the use of these and any other health products.
  • Health Canada will continue to monitor safety information involving DPP-4 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 contributed to this safety review included scientific and medical literature, Canadian and international information, and what is known about the use of these drugs both in Canada and internationally.

For additional information, contact the Marketed Health Products Directorate.

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