Rhinorrhea, cough and fatigue in patients taking sitagliptin

Abstract

Sitagliptin is a dipeptidyl peptidase-4 (DPP IV, CD26) inhibitor indicated for treatment of Type II diabetes as a second line therapy after metformin. We report fifteen sitagliptin intolerant patients who developed anterior and posterior rhinorrhea, cough, dyspnea, and fatigue. Symptoms typically developed within 1 to 8 weeks of starting, and resolved within 1 week of stopping the drug. Peak expiratory flow rates increased 34% in 8 patients who stopped sitagliptin. Similar changes were found in 4 out of 5 persons who had confirmatory readministration. Chart review identified 17 patients who tolerated sitagliptin and had no symptomatic changes. The sitagliptin intolerant group had higher rates of clinically diagnosed allergic rhinitis (15/15 vs. 6/18; p = 0.00005), Fisher's Exact test) and angiotensin converting enzyme inhibitor - induced cough (6/13 vs. 1/18; p = 0.012). Nasal and inhaled glucocorticoids may control the underlying allergic inflammation and abrogate this new sitagliptin - induced pharmacological syndrome. Potential mucosal and central nervous system mechanisms include disruption of neuropeptides and/or cytokines that rely on DPP IV for activation or inactivation, and T cell dysfunction.

Figure 1

Demographics, treatments and responses for the sitagliptin intolerant and tolerant groups. Treatments were metformin (Met), sulfonylureas (SU) and insulin. (* Cases 16 and 18 were treated with chronic low dose methotrexate for rheumatoid arthritis. ^† Case 7 died of a pulmonary embolism, and Case 24 had a sudden unexplained death. n.d., not determined.)

Figure 2

Sitagliptin adverse events. The presence of allergic rhinitis (AR) and its treatment (AR Rx), ACE inhibitor intolerance (ACE intol.), duration of sitagliptin treatment before symptoms began, the nature of the symptoms, and effects of discontinuation and subsequent challenge are shown. PEFR values are shown as % change after stopping sitagliptin, or normalized % of predicted (% pred) for tolerant subjects. Five subjects had restrictive patterns on spirometry that may have been related to obesity. Their PEFRs were not reported. Effective use of intranasal and inhaled corticosteroids (INS+ICS) prevented the return of symptoms for Case 5. Cases 16 and 18 used chronic methotrexate for rheumatoid arthritis (*). Case 23 developed a rash with sitagliptin which recurred on rechallenge. Case 9 now requires hemodialysis for hypertensive renal failure. Case 25 developed non Hodgkins lymphoma. Case 7 died from a pulmonary embolism. Case 24 had a sudden unexpected death. (nil, no complaints; n.d., not determined).

Figure 3

Case 1. Increased dyspnea was noted while on sitagliptin (week 0). Peak flows increased rapidly within several days of stopping the drug. Restarting sitagliptin after 2 1/2 weeks led to a progressive, 30% decline in PEFR. PEFR again returned to her usual after stopping the drug (weeks 5 and 6).