FDA warns of severe, disabling joint-pain risk with DPP-4 inhibitors

The FDA issued a safety communication Friday warning that the type 2 diabetes drugs sitagliptin, saxagliptin, linagliptin, and alogliptin may cause joint pain that can be severe and disabling, with some patients requiring hospitalisation. The agency stated that it has added a new warning about the risk to the labels of all products in the dipeptidyl peptidase-4 (DPP-4) inhibitor class.

According to the FDA, it identified 33 cases of severe arthralgia associated with the use of DPP-4 inhibitors from October 2006, when the first one was approved, to the end of 2013. The agency noted that in all cases, patients experienced "a substantial reduction in their prior level of activity," with 10 patients hospitalised due to disabling joint pain. Further, the FDA stated that in 22 cases, symptoms emerged within one month of starting treatment with a DPP-4 inhibitor. The drug was suspected as a potential cause of the pain in 20 cases and was discontinued within a month after symptoms appeared, while in eight of the remaining 13 cases, a period of 44 days to one year elapsed between symptom onset and discontinuation of the drug. Further, symptoms were relieved in the majority of patients less than a month after discontinuation of DPP-4 inhibitor therapy.

The FDA said that 28 cases occurred with sitagliptin, which Merck & Co. markets as Januvia, and as Janumet and Janumet XR when combined with metformin. Five cases were reported with saxagliptin, sold by AstraZeneca under the name Onglyza or in combination with metformin as Kombiglyze XR. Boehringer Ingelheim and Eli Lilly's linagliptin was reported in two of the cases. The companies promote the drug as Tradjenta, and also market the linagliptin-containing combination therapies Glyxambi (linagliptin/empagliflozin) and Jentadueto (linagliptin/metformin). Meanwhile, one case involved alogliptin, which Takeda sells under the Nesina brand, along with the combination drugs Kazano (alogliptin/metformin) and Oseni (alogliptin/pioglitazone).

The regulator also noted that there were two cases involving vildagliptin, which Novartis markets in Europe as Galvus and as Eucreas when combined with metformin, although the drug is not approved in the US.

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