The US Food and Drug Administration (FDA) is warning that the type 2 diabetes medicines sitagliptin, saxagliptin, linagliptin, and alogliptin may cause joint pain that can be severe and disabling.
The FDA has added a new Warning and Precaution about this risk to the labels of all medicines in this drug class, dipeptidyl peptidase-4 (DPP-4) inhibitors.
Health care professionals should consider DPP-4 inhibitors as a possible cause of severe joint pain and discontinue the drug if appropriate.
In a search of the FDA Adverse Event Reporting System (FAERS) database, the FDA identified 33 cases of severe arthralgia reported with the use of DPP-4 inhibitors from October 16, 2006 through December 31, 2013. Each case involved the use of 1 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 5 cases, the patient experienced severe arthralgia with 2 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 hospitalised 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 1 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 8 of the 33 cases documented a positive re-challenge. In these 8 cases, individuals discontinued treatment, experienced a resolution of symptoms, restarted therapy with a DPP-4 inhibitor (a different member of the class in 6 of the 8 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.
The FDA 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.
The FDA also searched the medical literature and identified 7 case reports — 2 of which were also identified in the FAERS database. All 7 reports described patients who developed arthralgia after starting therapy with either sitagliptin (n = 6) or vildagliptin (n = 1). In 6 cases, patients had partial or complete resolution of symptoms within 6 weeks of discontinuing the drug. Only 1 case reported the pain to be disabling, and none reported the need for hospitalisation.
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