In a search of the FDA Adverse Event Reporting System (FAERS) database, we identified 33 cases of severe arthralgia reported with the use of dipeptidyl peptidase-4 (DPP-4) inhibitors from October 16, 2006, approval date of the first DPP-4 inhibitor, through December 31, 2013. Each case involved the use of one or more DPP-4 inhibitor. Sitagliptin (n=28) was the most frequently reported, followed by saxagliptin (n=5), linagliptin (n=2), alogliptin (n=1), and vildagliptin (n=2); vildagliptin is not marketed in the United States. In five cases, the patient experienced severe arthralgia with two different DPP-4 inhibitors. All 33 patients experienced arthralgia that resulted in a substantial reduction in their prior level of activity, including 10 patients who were hospitalized due to disabling joint pain. In 22 cases, symptoms appeared within 1 month of initiation of treatment with a DPP-4 inhibitor. In 20 of the 33 cases, the DPP-4 inhibitor was suspected as a possible cause of arthralgia and was discontinued within a month following the onset of symptoms. However, 8 of the remaining 13 cases reported a period of 44 days to 1 year between the onset of symptoms and discontinuation of the DPP-4 inhibitor. In 23 of the 33 cases, symptoms resolved less than 1 month after discontinuation of the drug.
Reports of eight of the 33 cases documented a positive rechallenge. In these eight cases, individuals discontinued treatment, experienced a resolution of symptoms, restarted therapy with a DPP-4 inhibitor (a different member of the class in six of the eight cases), experienced the reappearance of the arthralgia, and subsequently, experienced resolution of the symptoms when DPP-4 inhibitor therapy was again discontinued. Twenty-one of the 33 patients were treated for arthritis with drug therapies that included corticosteroids, nonsteroidal anti-inflammatory drugs, methotrexate, and immune-modulating drugs.
We reviewed the clinical details in the FAERS cases to determine whether the severe joint pain could have been caused by an autoimmune condition rather than the DPP-4 inhibitors. Ten of the 33 cases reported fever and chills, rash, and swelling, which are suggestive of an immunological reaction. Of the 13 cases with available results of laboratory assays for systemic autoimmune disorders, 8 reported a negative or normal test result. Five cases reported positive test results: antinuclear antibody (n=2), erythrocyte sedimentation rate (n=1), C-reactive protein (n=1), and antinuclear cytoplasmic antibody (n=1). However, none of these tests are specific for a particular autoimmune condition that can cause severe joint pain.
We also searched the medical literature and identified seven case reports,1-4 two of which were also identified in the FAERS database.3, 4 All seven reports described patients who developed arthralgia after starting therapy with either sitagliptin (n=6) or vildagliptin (n=1). In six cases, patients had partial or complete resolution of symptoms within 6 weeks of discontinuing the drug. Only one case reported the pain to be disabling, and none reported the need for hospitalization.