Summary Safety Review - Dipeptidylpeptidase-4 (DPP-4) inhibitors - Assessing the risk of joint pain (arthralgia)
A Summary Safety Review complements other safety related information to help Canadians make informed decisions about their use of health products. Each summary outlines what was assessed in Health Canada’s review, what was found and what action was taken by Health Canada, if any.
Dipeptidylpeptidase-4 (DPP-4) inhibitors
Potential Safety Issue
Severe joint pain (arthralgia)
Use in Canada
- DPP-4 inhibitors 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 11 products marketed in Canada that contain a DPP-4 inhibitor: Nesina (alogliptin), Kazano (alogliptin-metformin), Osenia (alogliptin-pioglitazone), Trajenta (linagliptin), Jentadueto (linagliptin-metformin), Glyxambia (linagliptin-empagliflozin), Onglyza (saxagliptin), Komboglyze (saxagliptin-metformin), Qterna (saxagliptin-dapagliflozin), Januvia (sitagliptin), and Janumet/Janumet XR (sitagliptin-metformin).
Safety Review Findings
- At the time of the review, Health Canada received 10 Canadian reportsb of severe joint pain associated with the use of a DPP-4 inhibitor (saxagliptin, sitagliptin or linagliptin). Health Canada also received another 20 international reports from the manufacturers regarding severe joint pain with the use of any DPP-4 inhibitor.
- The reports provided evidence that the use of DPP-4 inhibitors contributed to severe (disabling or incapacitating) joint pain. Of all the reports, 17 noted that the patient developed joint pain within the first 30 days of taking the DPP-4 inhibitor. The majority of patients either improved or recovered from their joint pain after the treatment was stopped.
- Some of the cases have also reported medical conditions that may have contributed to the joint pain including gout, pre-existing rheumatoid arthritis, Crohn's disease and obesity.
- This safety review also considered information from the United States Food and Drug Administration which included 33 reports of severe joint pain with the use of DPP-4 inhibitors. Two other publications have noted reports of joint pain with the use of these drugs. 1, 2, 3
- At the time of the review, the Canadian safety information for saxagliptin-containing products had a warning for the risk of severe and disabling joint pain. This warning was not included in the safety information of the other DPP-4 inhibitor-containing products marketed in Canada.
Conclusions and actions
- Health Canada's review of the available information concluded there is a potential link between the use of DPP-4 inhibitors and the development of severe joint pain.
- Health Canada is working with manufacturers to update the product safety information for all DPP-4 inhibitors to inform healthcare professionals and patients about the risk of developing joint pain when DPP-4 inhibitors are used.
- 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.
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.
- FDA Drug Safety Communication: FDA warns that DPP-4 inhibitors for type 2 diabetes may cause severe joint pain. August 28, 2015. Accessed February 28, 2017. http://www.fda.gov/Drugs/DrugSafety/ucm459579.htm.
- Tarapues M, Cereza G, and Figueras A. (2013), Association of musculoskeletal complaints and gliptin use: Review of spontaneous reports. Pharmacoepidemiol Drug Saf;22:1115-1118.
- Mascolo A, Rafaniello C, Sportiello L, et al., (2016), Dipeptidyl peptidase (DPP)-4 inhibitor-induced Arthritis/Arthralgia: A review of clinical cases. Drug Saf 39(5): 401-407.
- The products Oseni, Glyxambi and Qtern were not yet marketed in Canada at the time of the safety review.
- Canadian reports can be accessed through the Canada Vigilance Online Database.