Allergy, Asthma & Clinical Immunology

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. Background Sitagliptin is a selective dipeptidylpeptidase-4 (DPP IV, CD26, EC 3.4.14.5) inhibitor indicated for the treatment of Type II diabetes mellitus [1]. Diabetics treated with sitagliptin (JanuviaTM, Merck & Co., Inc., Whitehouse Station, N.J.) develop "upper respiratory tract infections", "cough", and "sore throat" in 5% to 6% of subjects [2]. Similar rates for these adverse events have been reported for the other DPP IV inhibitors vidagliptin [3] and saxagliptin [4]. Infections from all causes had a 34% relative risk increase (95% confidence interval 10% to 64%, P = 0.004) for sitagliptin compared to other diabetes treatments [5]. Previous studies have predicted that airway adverse events may occur with this class of drugs [6-9]. We propose that inflammatory changes may be occurring that were coded as infections in clinical studies. This is of importance in balancing the risk: benefit ratio for treatment with DPP IV inhibitors [10,11]. Two subjects who had recently started taking sitagliptin presented to our clinics with rhinorrhea, cough, dyspnea and fatigue, and requested evaluations for drug sensitivity. We challenged these index cases to determine if sitagliptin induced a reproducible syndrome. When the challenges were affirmative, we reviewed charts to identify other sitagliptin treated subjects. We identified sitagliptin intolerant and tolerant groups, and began an analysis of potential mechanism(s) and risk factors for this new drug induced syndrome. Methods The index cases were type II diabetic subjects who presented to an urban tertiary allergy center and a rural family practice clinic with upper and/or lower airway symptoms shortly after starting oral sitagliptin (25 and 100 mg per day, respectively). Chart reviews at the rural clinic identified 205 diabetics including 31 who had received sitagliptin as an adjunct to combinations of metformin, sulfonylurea and insulin. Symptoms of fatigue, anterior and posterior rhinorrhea, cough, and sensations of wheezing or dyspnea defined a "sitagliptin intolerant population". Fifteen intolerant and seventeen tolerant patients were identified and examined for potential risk factors and mechanisms of sitagliptin related complaints. Outpatient evaluations included history, review of medication related adverse events, physical examination, and, when possible, measurement of peak expiratory flow rates. Spirometry and allergy skin tests were performed at the urban clinic. Peak expiratory flow rate * Correspondence: [email protected] 2 Department of Family Medicine, Quillen College of Medicine, East Tennessee State University, McMinnville, TN, USA Full list of author information is available at the end of the article BioMed Central © 2010 Baraniuk and Jamieson; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Baraniuk and Jamieson Allergy, Asthma & Clinical Immunology 2010, 6:8 http://www.aacijournal.com/content/6/1/8 Page 2 of 9 (PEFR) and subjective impressions of anterior and posterior nasal discharge, cough, dyspnea, and fatigue symptoms scores (0 to 10 ordinal scales with 0 = none and 10 = worst in life) were assessed by the physician at the visit when sitagliptin was stopped, and by the patient for a 1 to 2 week follow-up period. Health insurance restrictions and referral opportunities precluded allergy testing for most of rural diabetics. Clinical diagnoses of allergic rhinitis and asthma were inferred from Allergic Rhinitis In Asthma (ARIA) [12] and Global Initiative for Asthma (GINA) [13] guidelines. Specific details are given in the Case Reports. The diagnosis of allergic rhinitis was made clinically using the symptom algorithm of the ARIA guidelines [12]. These rhinitis subjects had rhinitis with itch, sneezing, watery nasal and ocular discharge that was improved by nasal glucocorticoids, monteluklast, and/or antihistamine therapy during their target season(s). This rural patient population was unique because tree nursery farms were the chief agricultural industry in this naturally forested geographical area. The non-indigenous trees contributed a large additional burden to the high levels of diverse hardwood forest pollens. Community members paid careful attention to the timing of eye and nose itching, sneezing, congestion and cough symptoms in the setting of widespread commercial knowledge of pollination times for each cultivar. Allergic rhinitis was diagnosed frequently (19/31, 61%) in this group. A subsequent analysis of 330 consecutive practice patients found that 59% met allergic rhinitis criteria using the ARIA algorithm [12]. This compares to 42.5% in the 2005-2006 U.S. National Health and Nutrition Examination Survey where atopy was defined by having at least one positive result to 15 allergen tests [14]. Five patients (Cases 1, 3, 6, 7, 21) had positive skin tests to further support their diagnosis. Five patients wanted to restart the drug. Two wanted to know if sitagliptin was responsible for their symptoms, while three others tried because of its beneficial hypoglycaemic and weight effects. Each patient was counselled about the probable return of symptoms according to clinical standards of care. Patients measured PEFR and clinical symptoms after restarting the sitagliptin to assess drug effects. This amounted to a dechallenge rechallenge paradigm [15,16]. Placebo, nocebo and other related effects must be considered in reviewing the results of these open drug administrations [17-19]. Statistical differences between groups were determined by two-tailed unpaired Student's t-tests and Fisher's Exact test. Results Thirty three diabetics using sitagliptin were identified. Fifteen intolerant patients had combinations of fatigue, anterior and posterior rhinorrhea, cough, sensations of wheezing, and dyspnea. Four had obesity related restriction on spirometry. Eighteen patients were tolerant to sitagliptin and did not develop these symptoms. Significantly more of the intolerant individuals had allergic rhinitis (15/15) than the sitagliptin tolerant (6/18) group (p = 0.00005). Angiotensin converting enzyme inhibitor (ACEI) intolerance was more common in those intolerant to sitagliptin (6/13) compared to tolerant patients (1/18; p = 0.012). Overall, patients with a clinical history of allergic rhinitis had more ACEI intolerance (7/ 19) than patients without that history (0/12) (p = 0.019). The two groups were equivalent for age, gender, hemoglobin A1c, the proportions treated with metformin, sulfonylureas and insulin, sitagliptin doses, and rates of improved glucose control and weight loss on sitagliptin (p > 0.20) (Figure 1). These patients were taking multiple medications as is typical for diabetic patients. The most common were ranked as ACE inhibitors, statins, other antihypertensives and antidepressant medications. Their use was similar in both groups. Each patient's combination of medications was evaluated for cytochrome P450 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.) Case Gender Age BMI Met SU Insulin HbA1c Glucose improved Weight loss Sitaglipin Intolerant Group 1 F 55 31.1 Yes Yes No 5.9 Yes No 2 F 56 23.1 Yes Yes No 8.3/7.2 Yes Yes 3 F 55 48.1 Yes Yes No 8.9 No 20 kg 4 M 66 29.1 Yes Yes No 7.8/9.2 Yes No 5 F 71 38.0 Yes Yes No 7.8 Yes No 6 F 64 42.1 No No Yes 9.9 Yes No 7 F 60 39.3 Yes Yes No 6.2 Yes No 8 F 38 33.0 Yes Yes No 9.1 Yes Yes 9 M 69 47.7 No Yes No 7.3 Yes No 10 F 75 29.2 No Yes No 8.4 Yes No 11 M 32 37.7 Yes Yes No 8.8 Yes No 12 F 63 32.5 Yes Yes No 8.2 Yes Yes 13 M 62 19.0 Yes No No 8.1 Yes Yes 14 F 59 43.0 Yes No No 10.6 Yes No 15 F 39 39.0 Yes Yes No 10.2 Yes Yes Sitagliptin Tolerant Group 16* F 69 30.3 No Yes No 6.4 Yes Yes 17 F 61 35.7 No Yes No 7.3 Yes No 18* F 59 41.1 No No Yes 10 Yes n.d. 19 F 52 29.6 Yes No No 8.9 Yes n.d. 20 M 44 34.0 Yes No No 7.1 Yes Yes 21 F 72 23.8 Yes Yes No 7.6 Yes No 22 M 58 28.8 Yes Yes No 9.2 Yes No 23 M 77 28.8 Yes Yes No 8.4 Yes No 24 M 64 41.6 No No Yes 8.2 Yes No 25 F 48 42.7 Yes Yes No 7.6 No Yes 26 M 64 25.9 Yes Yes No 7.7 Yes No 27 F 53 35.3 No No Yes 8.6 Yes No 28 M 38 33.0 Yes No No 7.5 Yes Yes 29 M 52 38.5 Yes Yes Yes 12.0 Yes No 30 F 30 40.6 Yes Yes No 8.7 Yes No 31 M 38 35.7 No No No 6.7 Yes No 32 M 55 39.4 Yes No No 9.0 Yes Yes 33 F 51 38.5 Yes No No 9.1 Yes Yes Baraniuk and Jamieson Allergy, Asthma & Clinical Immunology 2010, 6:8 http://www.aacijournal.com/content/6/1/8 Page 3 of 9 and other drug interactions that could have caused similar patterns of symptoms. However, none were found. All sitagliptin intolerant subjects had seasonal or perennial allergic rhinitis treated with intermittent antihistamines and nasal steroid sprays (Figure 2). Those with mild intermittent asthma generally had been prescribed montelukast, an inhaled glucocorticoid or inhaled albuterol which were used on an ad hoc basis. The median time for onset of sitagliptin related symptoms was 3 weeks (range 1 to 8 weeks) except for Cases 10 and 15. Case 10 began taking sitagliptin during ragweed season while taking montelukast and had no adverse symptoms. However, during the next ragweed season she developed intolerable rhinitis symptoms despite the montelukast. Symptoms resolved within a week of stopping sitagliptin even though the ragweed season continued unabated. Case 15 began having symptoms during the local grass season. Symptoms persisted for months into the winter and resolved within a week of stopping sitagliptin. Anterior and/or posterior rhinorrhea, fatigue, cough and the sensation of wheezing or dyspnea developed in all eleven intolerant patients, with the following exceptions. Fatigue may have been related to concomitant ischemic heart disease in Cases 6, 12 and 13. Obesity related airflow restriction was present in Cases 3, 9, 10 and 12. Case 5 had no wheeze or dyspnea, while Case 8 had no cough, wheezing or dyspnea. Case 11 did not have symptoms 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). Sitagliptin – Related Symptoms Discontinuing Sitagliptin Sitagliptin Challenge Case AR AR Rx ACE intol. Weeks of Tx Before Symptoms Cough Ant./Post. Rhinorrhea Wheeze/ Dyspnea Fatigue Weeks to Resolution % PEFR Symptoms % PEFR Sitagliptin Intolerant Group 1 Yes Yes Yes n.d. Yes Yes Yes Yes 1 week 38% Positive 30% 2 Yes Yes Yes n.d. Yes Yes Yes Yes 1 week 49% Positive 19% 3 Yes Yes Yes 7 weeks Yes Yes Yes Yes n.d. Restriction Positive n.d. 4 Yes nil nil 8 weeks Yes Yes Yes Yes 1 week n.d. Positive 11% 5 Yes Yes nil 1 week Yes Yes Yes Yes 1 week 33% INS+ICS 0% 6 Yes Yes Yes 2 weeks Yes Yes Yes Yes 1 week 31% n.d. n.d. 7 Yes nil nil n.d. Yes Yes Yes Yes 1 week 17% n.d. n.d. 8 Yes Yes No Rx 2 weeks nil Yes nil Yes 1 week n.d. n.d. n.d. 9 Yes Yes nil 4 weeks Yes Yes Yes Yes 1 week Restriction n.d. n.d. 10 Yes Yes nil 54 weeks Yes Yes nil Yes 1 week Restriction n.d. n.d 11 Yes Yes nil 2 weeks nil Yes nil nil 1 week 80% pred Positive n.d. 12 Yes Yes Yes 1 week Yes Yes Yes Yes 1 week Restriction n.d. n.d. 13 Yes Yes No Rx n.d. Yes Yes Yes heart 1 week 0% n.d. n.d. 14 Yes Yes nil n.d. Yes Yes nil Yes 1 week 73% n.d. n.d. 15 Yes Yes Yes 24 weeks Yes Yes Yes nil 1 week 80% pred n.d. n.d. Sitagliptin Tolerant Group 16* Yes Yes nil 12 weeks Spring Spring Spring Spring 2 weeks 74% pred n.d. n.d. 17 Yes Yes nil 8 weeks nil Viral nil nil 8 weeks n.d. n.d. n.d. 18* Yes Yes Yes nil nil nil nil nil nil n.d. n.d. n.d. 19 Yes Yes nil nil nil nil nil nil nil n.d. n.d. n.d. 20 Yes nil nil nil nil nil nil nil nil n.d. n.d. n.d. 21 Yes nil nil nil nil nil nil nil nil n.d. n.d. n.d. 22 nil nil nil nil nil nil nil nil nil 95% pred n.d. n.d. 23 nil nil nil nil nil nil nil nil nil 107% pred n.d. n.d. 24 nil nil nil nil nil nil nil nil nil n.d. n.d. n.d. 25 nil nil nil nil nil nil nil nil nil n.d. n.d. n.d. 26 nil nil nil nil nil nil nil nil nil n.d. n.d. n.d. 27 nil nil nil nil nil nil nil nil nil n.d. n.d. n.d. 28 nil nil nil nil nil nil nil nil nil n.d. n.d. n.d. 29 nil nil nil nil nil nil nil nil nil n.d. n.d. n.d. 30 nil nil nil nil nil nil nil nil nil n.d. n.d. n.d. 31 nil nil nil nil nil nil nil nil nil n.d. n.d. n.d. 32 nil nil nil nil nil nil nil nil nil Restriction n.d. n.d. 33 nil nil nil nil nil nil nil nil nil n.d. n.d. n.d.