DPP-4 inhibitors in diabetics and severe joint pain

The FDA just came out with a warning about DPP-4 inhibitors causing severe joint pain (see http://www.fda.gov/Drugs/DrugSafety/ucm459579 ). They reviewed their FDA Adverse Event Reporting System (FAERS) database and the medical literature and identified cases of severe joint pain associated with the use of DPP-4 inhibitors, with symptoms starting 1 day to years after starting the DPP-4 inhibitor, and relief of symptoms usually within a month of stopping the med. 

results:
--they identified 33 such cases, all resulting in "substantial reduction in their prior level of activity", and 10 of whom were hospitalized
--in 22 cases, the joint symptoms developed within one month of starting the med
--in 23, the symptoms resolved within a month of stopping the med
--8 had recurrent symptoms on rechallenge with DPP-4 inhibitor (6 of them with a different DPP-4 inhibitor)
--10 of the cases suggested an immunological reaction with fever, chills, rash and swelling.  
--8 of 13 who had immunological testing had normal results, 2 with positive ANA, 1 with increased ESR, 1 with increased CRP, and 1 with antinuclear cytoplasmic antibody (ie, nonspecific)

As a result, the FDA is adding this "Warning and Precaution" to the drugs.

DPP-4 inhibitors (dipeptidyl peptidase-4 inhibitors, which include sitagliptin, saxagliptin, linagliptin, and alogliptin) are newer agents used in the treatment of diabetes, and data on their efficacy in diabetes is based on their effect on HgbA1C levels (which is pretty minimal at that!!  see blog from june 2015  http://gmodestmedblogs.blogspot.com/2015/06/dpp-4-inhibitors-and-cardiovascular.html  which notes that A1c improves only a little, and there is no cardiac protection, a primary clinical endpoint​, even after 3 years in almost 15K people with average age of 66). So, from my perspective these meds are expensive and minimally useful adjuncts to therapy at best, and not surprisingly lead to adverse effects (by blocking DPP-4, they effectively block a ubiquitous enzyme on the surface of most cells and deactivate a variety of bioactive peptides).

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