Short-term dipeptidyl peptidase-4 inhibitor use increases the risk of herpes zoster infection in Asian patients with diabetes

Transcription

1 QJM: An International Journal of Medicine, 2016, doi: /qjmed/hcv096 Advance Access Publication Date: 18 May 2015 Original paper ORIGINAL PAPER Short-term dipeptidyl peptidase-4 inhibitor use increases the risk of herpes zoster infection in Asian patients with diabetes H.-H. Chen 1,2,3, C.-L. Lin 4,5, S.-Y. Yeh 3,6 and C.-H. Kao 7,8 From the 1 Institute of Public Health and Medicine, Chung Shan Medical University, Taichung, Taiwan, 2 Division of Metabolism & Endocrinology, Changhua Christian Hospital, Changhua, Taiwan, 3 Division of Metabolism & Endocrinology, Nantou Christian Hospital, Nantou, Taiwan, 4 Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan, 5 College of Medicine, China Medical University, Taichung, Taiwan, 6 Department of Healthcare Administration, Asia University, Taichung, Taiwan, 7 Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan and 8 Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan Address correspondence to Dr C.-H. Kao, Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine, China Medical University, No. 2, Yuh-Der Road, Taichung 404, Taiwan. d10040@mail.cmuh.org.tw Summary Background: We aimed to evaluate whether patients with diabetes who use dipeptidyl peptidase (DPP)-4 inhibitors are at a higher risk of developing a herpes zoster (HZ) infection. Methods: We used a subset of the Longitudinal Health Insurance Database 2000 containing all inpatient and outpatient medical claims of 1 million people who were randomly sampled from the National Health Insurance Research Database. Patients who were newly diagnosed with Type 2 diabetes International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM 250.x0 and 250.x2) who used antidiabetic medications were divided into two cohorts based on their use of DPP-4 inhibitors between 2009 and Cox proportion hazard regression models were used to assess the effects of DPP-4 inhibitors on the incidence of HZ compared with the non-dpp-4-inhibitor-exposed cohort. Results: Patients in DPP-4-inhibitor-exposed cohort with diabetes and HZ infections revealed an incidence density of 4.20 per 1000 person-years compared with 3.50 per 1000 person-years for the non-dpp-4-inhibitor-exposed cohort (adjusted hazard ratio [HR] ¼ 1.19, 95% confidence interval [CI] ¼ ). Furthermore, high-dose DPP-4-inhibitor treatment was associated with a significantly higher risk of HZ (adjusted HR ¼ 2.46, 95% CI ¼ for a defined daily dose [DDD] 360). In addition, short-term DPP-4-inhibitor treatment was associated with a significantly higher risk of HZ (adjusted HR ¼ 2.04, 95% CI ¼ for a DDD 360 days). Conclusion: These results suggest that Asian patients with diabetes who use short-term DPP-4 inhibitors might be at a higher risk of developing HZ. Received: 8 April 2015; Revised (in revised form): 21 April 2015 VC The Author Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please journals.permissions@oup.com 91

2 92 QJM: An International Journal of Medicine, 2016, Vol. 109, No. 2 Introduction Diabetes is one of the most critical public diseases worldwide. In addition, it was one of the non-communicable diseases emphasized by the World Health Organization in According to Taiwanese health insurance data, diabetes remains among the 10 leading causes of death in Taiwan. 1 Previous studies in Taiwan 2 and the Israel study 3 have indicated that older people, those diagnosed with diabetes or immunocompromised conditions, are at a higher risk of developing herpes zoster (HZ). A possible explanation is that diabetes causes impaired cellmediated immunity. 4 In addition, incretin therapy for diabetes is one of the three major treatment options worldwide. 5 Incretin therapies include parenteral glucagon-like peptide (GLP)-1 analog injection and other oral therapies such as dipeptidyl peptidase (DPP)-4 inhibitors. Oral DPP-4 inhibitors are more popular than the parenteral GLP-1 analog injections. 1 In Taiwan, according to our local guideline after metformin treatment, we can prescribe any medications for our diabetic patients. In general, our local guideline followed American Diabetes Association Guideline. 6 Studies have indicated that DPP-4 inhibitors might affect the immune system. 7,8 Therefore, our study was intended to determine the relationships between DPP-4 inhibitors and the incidence of HZ in Asian patients with diabetes. Methods Source of data The National Health Insurance Research Database (NHIRD) is a nationwide database that contains the claims records from Taiwan s mandatory National Health Insurance (NHI) program. The NHI program was launched in 1995 and covers >99% of the Taiwanese population (23.74 million in 2009). 9 The NHIRD contains medical information such as inpatient and outpatient care, drug prescriptions, sex and date of birth, date of visit or hospitalization and diagnoses coded in the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) format. We used a subset of the NHIRD, the Longitudinal Health Insurance Database (LHID) 2000, containing all inpatient and outpatient medical claims of 1 million people who were randomly sampled from the registry for beneficiaries of the NHIRD in Because the LHID 2000 was retrieved from the NHIRD, the distribution of age, sex and average insured payroll-related amount did not differ between the LHID 2000 and the original NHIRD. Study population Patients who were newly diagnosed with Type 2 diabetes (ICD- 9-CM 250.x0 and 250.x2), who used antidiabetic medication between 2000 and 2008, were divided into two cohorts based on their use of DPP-4 inhibitors (ATC A10BH01, A10BH02, A10BH03, A10BH05 and A10BH06) between 2009 and The DPP-4- inhibitor-exposed cohort comprised patients who used DPP-4 inhibitors. The index date for each patient was the date of the first DPP-4-inhibitor treatment. Patients younger than 20 years of age or with a history of herpes (ICD-9-CM 053) before the index date were excluded. The non-dpp-4-inhibitor-exposed cohort (those who did not use DPP-4 inhibitors) was frequencymatched to the DPP-4-inhibitor-exposed cohort by sex, age (in 10-year bands), year of Type 2 diabetes diagnosis, year of beginning antidiabetic medication and index year, at a ratio of 1:3. The same exclusion criteria were also applied to the non-dpp-4- inhibitor-exposed cohort. Outcome measurement, comorbidities and measurements of DPP-4 inhibitors We identified patients who were newly diagnosed with HZ within the outpatient claims or hospitalization records from 2009 to 2011 (the study end point). All patients were followed from the index date until withdrawal from the database or the end of 2011, whichever occurred first. In addition, we incorporated the inpatient and outpatient diagnosis records to determine the baseline comorbidities: hypertension (ICD-9-CM ), hyperlipidemia (ICD-9-CM 272), obesity (ICD-9-CM 278.0), chronic kidney disease (CKD) (ICD-9-CM ) and depression (ICD-9-CM , 300.4, 311). Moreover, DPP-4-inhibitor-use records were retrieved from the ambulatory and inpatient claims data. On the basis of the total supply in days and the amount of DPP-4 inhibitors, we calculated the annual mean defined daily dose (DDD) of each DPP- 4-inhibitor type for each DPP-4-inhibitor user (ATC codes: A10BH01, A10BH02, A10BH03, A10BH05 and A10BH06). For all DPP-4-inhibitor users, the annual mean DDDs were classified into four levels based on their quartile dose, and the annual mean values of the number of days of DPP-4-inhibitor use were classified into three levels based on the tertile dose. Data availability statement All data and related metadata were deposited in an appropriate public repository. The data on the study population that were obtained from the NHIRD ( html) are maintained in the NHIRD ( The NHRI is a non-profit foundation established by the government. Ethics statement The NHIRD encrypts patient personal information to protect privacy and provides researchers with anonymous identification numbers associated with relevant claims information, including sex, date of birth, medical services received and prescriptions. Patient consent is not required to access the NHIRD. This study was approved by the Institutional Review Board (IRB) of China Medical University (CMU-REC ). The IRB specifically waived the consent requirement. Statistical analysis The baseline characteristics of the DPP-4-inhibitor-exposed and the non-dpp-4-inhibitor-exposed cohorts were compared using a chi-square test. The incidence densities of both cohorts were calculated according to age, sex and comorbidities. In addition, univariate and multivariate Cox proportion hazard regression models were used to assess the effects of DPP-4 inhibitors on the incidence of HZ compared with the non-dpp-4-inhibitorexposed cohort, denoted using hazard ratios (HRs) and 95% confidence intervals (CIs). The baseline characteristic variables that were significantly related to HZ from the initial chi-square analyses were included in the multivariate model for adjustment. A two-tailed P value of 0.05 was considered statistically significant. All statistical analyses were performed using the statistical analysis software (SAS Version 9.2 for Windows; SAS Institute, Inc., Cary, NC). Results Table 1 presents the baseline characteristics of the patients in both cohorts. Of the DPP-4-inhibitor-exposed cohort, 33.5% were

3 H.-H. Chen et al. 93 aged years, and 54.6% were men. The mean ages of the DPP-4-inhibitor-exposed and non-dpp-4-inhibitor-exposed cohorts were 57.7 (612.8) and 57.9 (612.5) years, respectively. The DPP-4inhibitor-exposed cohort was more likely to develop hypertension (68.3 vs. 64.8%, P < 0.001), hyperlipidemia (72.8 vs. 64.5%, P < 0.001), obesity (6.52 vs. 5.12%, P < 0.001) and CKD (12.5 vs. 10.6%, P < 0.001). We observed 50 events of HZ (20 in the DPP-4-inhibitorexposed cohort and 50 in the non-dpp-4-inhibitor-exposed cohort) in person-years, with incidence densities of 4.20 and 3.50 per 1000 person-years for the DPP-4-inhibitor-exposed and non-dpp-4-inhibitor-exposed cohorts, respectively (adjusted HR ¼ 1.19, 95% CI ¼ ) (Table 2). The age-specific Table 1. Demographic characteristics of study subjects among medicine Variables DPP-4 inhibitor exposure P value No Yes N ¼ N ¼ 3910 n % n % Age, years Mean (SD) a Sex 0.38 Female Male Medical history Hypertension <0.001 Hyperlipidemia <0.001 Obesity <0.001 Chronic kidney disease Depression Chi-square test, a t-test. incidence of HZ increased with age in both cohorts. In addition, the incidence of HZ was greater in the female than the male participants in both cohorts. The effects of the annual mean DDD of DPP-4 inhibitors on the incidence of HZ revealed a positive dose response relationship (Table 3). Compared with participants with no exposure to DPP-4 inhibitors, participants treated with high doses of DPP-4 inhibitors revealed a significantly higher risk of HZ (adjusted HR ¼ 2.46, 95% CI ¼ for 360 DDD). Similarly, the effects of the annual mean number of days of DPP-4 inhibitor use on the incidence of HZ revealed a positive dose response relationship (Table 4). Compared with the non-dpp-4-inhibitor-exposed cohort, the participants with long-term DPP-4 inhibitor use revealed a significantly higher incidence of HZ (adjusted HR ¼ 2.04, 95% CI ¼ for 360 days). Discussion Diabetes and HZ Several studies on Caucasian patients have reported an HZ incidence of per 1000 person-years In Taiwan, the incidence of HZ is 4.89 cases per 1000 person-years among all age groups, and diabetes is one of its independent risk factors. 2 In the same study, 20.60% of patients with HZ had diabetes, and multivariate analysis confirmed diabetes as an independent risk factor for HZ. 2 Patients with diabetes are more susceptible to infections than are those without diabetes. 13,14 The Israel study reported that the impaired cell-mediated immunity in diabetes increased the risk of HZ. 3 In Table 1, our study showed more comorbidities such as hypertension, hyperlipidemia, obesity and CKD in diabetic patients with DPP-4 inhibitor use. Although DPP-4 inhibitors could be prescribed as first to third line medication from our local guideline for diabetes treatment, most DPP-4 inhibitors were used as last line medication due to cost-effective reasons. It could partially explain the severity of diabetes between two groups. Cell-mediated immunity is critical in preventing or controlling varicella-zoster-virus-related diseases; a study reported that patients with diabetes have lower cell-mediated immunity Table 2. Comparison of incidence and HR of HZ stratified by age, sex and comorbidity according to medication DPP-4 inhibitor exposure among Type 2 DM Variables DPP-4 inhibitor exposure Crude HR b (95% CI) Adjusted HR c (95% CI) No Yes Event PY Rate a Event PY Rate a All (0.70, 1.98) 1.19 (0.70, 1.99) Age, years (0.27, 1.58) 0.71 (0.29, 1.72) (0.57, 4.06) 1.47 (0.55, 3.94) (0.84, 5.20) 1.93 (0.78, 4.80) Sex Female (0.53, 2.12) 1.09 (0.55, 2.18) Male (0.61, 2.96) 1.33 (0.60, 2.92) Comorbidity d No (0.21, 4.30) 0.92 (0.20, 4.20) Yes (0.72, 2.19) 1.28 (0.74, 2.24) PY, person-years. a Rate, incidence rate, per 1000 person-years. b Crude HR, relative hazard ratio. c Adjusted HR, multivariable analysis including age, sex, hypertension, hyperlipidemia, obesity and CKD. d Comorbidity, Only to have one of comorbidities classified as the comorbidity group.

4 94 QJM: An International Journal of Medicine, 2016, Vol. 109, No. 2 Table 3. HR and 95% CIs of HZ associated with annual mean DDD of DPP-4 inhibitor exposure Event/N to varicella zoster virus compared with healthy people. 15 Thus, cell-mediated immunity might explain the increased risk of HZ among patients with diabetes. In our study, regardless of DPP-4- inhibitor use, the proportion of women with diabetes and HZ was greater than that of men with diabetes and HZ. This finding is in agreement with the findings of other studies on diabetes and HZ. 16 Our 3-year analysis revealed an HZ incidence of 4.20 cases per 1000 person-years in the DPP-4-inhibitor-exposed cohort compared with 3.50 cases per 1000 person-years in the non-dpp-4-inhibitor-exposed cohort. These results suggest that short-term DPP-4 inhibitor use might play a possible role in the incidence of HZ in patients with diabetes. Because of short period follow-up, only an HZ incidence of 4.20 cases per 1000 person-years in the DPP-4-inhibitor-exposed cohort and this incidence was less than general data in Taiwan (4.89 cases per 1000 person-years). But the incidence in our study was still within the average from other reports ( per 1000 personyears). DPP-4 inhibitors and immunity Crude (95% CI) Adjusted HR b HR c (95% CI) Non-use of DPP-4 50/ (Reference) 1 (Reference) DPP-4 a (DDD) <130 4/ (0.30, 2.31) 0.79 (0.29, 2.20) / (0.23, 2.39) 0.74 (0.23, 2.39) / (0.42, 2.65) 1.10 (0.44, 2.77) 360 8/ (1.12, 4.97)* 2.46 (1.16, 5.19)* a The annual mean DDD dose is partitioned into three segments by quartile. b Crude HR, relative hazard ratio. c Adjusted HR, multivariable analysis including age, sex, hypertension, hyperlipidemia, obesity and CKD. *P < Table 4. HR and 95% CIs of HZ associated with annual mean the number of days of DPP-4 inhibitor exposure Event/N Crude (95% CI) Adjusted HR b HR c (95% CI) Non-use of DPP-4 50/ (Reference) 1 (Reference) DPP-4 a (days) <250 4/ (0.21, 1.64) 0.60 (0.22, 1.67) / (0.47, 2.58) 1.13 (0.48, 2.64) / (1.06, 4.13)* 2.04 (1.03, 4.04)* a The annual mean the number of days is partitioned into three segments by tertile. b Crude HR, relative hazard ratio. c Adjusted HR, multivariable analysis including age, sex, hypertension, hyperlipidemia, obesity and CKD. *P < Although DPP-4 inhibitors have been prescribed worldwide to treat diabetes, meta-analysis studies have documented an associated increased risk of all-cause infections. 7,17 A study reported a risk ratio of 1.2 (95% CI ¼ ) for nasopharyngitis and a risk ratio of 1.5 (95% CI ¼ ) for urinary tract infections in patients with diabetes who used sitagliptin or vildagliptin. 7 Another study reported a risk ratio of 1.34 (95% CI ¼ ) for all-cause infections, including viral infections in patients with diabetes who used sitagliptin. 8,17 A possible explanation is that DPP-4 inhibitors affect the immune system. Furthermore, cluster of differentiation (CD) 26 might be crucial in the association between DPP-4 inhibitors and immune regulation. CD26 is a cell surface protein with DPP-4 enzymatic activity and can be present in various cells of the immune system, such as T- lymphocytes, B-lymphocytes and macrophages. CD26 can cause T-cell activation or proliferation. An in vitro study reported that DPP-4 inhibitors can alter T-cell function, and this pathway decreases the production of cytokines such as IL-2 or interferon-c but increases transforming growthfactor-b1. 18 Moreover, few studies have reported that the DPP-4 activity of CD26 might play a role in modulating T-cell response to various external stimulations. 18,8,19 In summary, CD26 might be crucial in explaining the association between DPP-4 inhibitors and immune functions. 20 Furthermore, another study reported that 28 daily doses of sitagliptin did not alter systemic immunity, including the CD26 pathway. 21 Our analysis revealed that increased dose (360 DDD) in Table 3 and duration (360 days) in Table 4 of DPP-4-inhibitor treatment can increase HZ infection rates in Asian patients with diabetes. Limitations First, in our data bank we cannot completely collect another possible potential confounding factors including nutritional state, smoking or alcohol consumption. Second, medications such as corticosteroids or other immunosuppressants and conditions of histories of cancer, bone-marrow or organ transplantation may play a role for HZ infection. We only adjust the comorbidities and basic demorgraphic data for our metaanalysis due to a 3-year follow-up. Third, HZ illness severity (including duration) and outcome [including short-and longterm neurologic, ocular (in particular, HZ ophthalmicus) and visceral complications] could not be collected in our databank. Fourth, quality of diabetic control should be a relevant determinant of infection risk for HZ, but our data bank could not offer this data for us. Conclusion Previous studies have discussed the associations between diabetes and HZ, and several reports have confirmed the relationships between DPP-4 inhibitors and cell-mediated immunity. Our data confirmed that Asian patients with diabetes who use higher-dose or short-term DPP-4-inhibitor treatment might be at a higher risk of developing HZ infection in the future. From American Diabetes Association suggestions, 6 immunization with influenza, pneumococcal or hepatitis B vaccines is necessary to avoid further morbidities in T2DM. HZ infection was increasing in our study and HZ infection can cause more infective complications of diabetes such as pneumonia or secondary skin infection. So we suggested to consider HZ vaccination for Asian patients with diabetes who use DPP-4 inhibitors in our public health policies. Funding This study is supported in part by Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW104-TDU-B ); China Medical University Hospital, Academia Sinica Taiwan Biobank, Stroke Biosignature Project (BM ); NRPB Stroke Clinical Trial Consortium (MOST B ); Tseng-Lien Lin Foundation,

5 H.-H. Chen et al. 95 Taichung, Taiwan; Taiwan Brain Disease Foundation, Taipei, Taiwan; Katsuzo and Kiyo Aoshima Memorial Funds, Japan, and CMU under the Aim for Top University Plan of the Ministry of Education, Taiwan. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. No additional external funding received for this study. Conflict of interest: None declared. References 1. no=474&fod_list_no= Jih JS, Chen YJ, Lin MW, Chen YC, Chen TJ, Huang YL, et al. Epidemiological features and costs of herpes zoster in Taiwan: a national study 2000 to Acta Derm Venereol 2009; 89: Weitzman D, Shavit O, Stein M, Cohen R, Chodick G, Shalev V. A population based study of the epidemiology of herpes zoster and its complications. J Infect 2013; 67: Heymann AD, Chodick G, Karpati T, Kamer L, Kremer E, Green MS, et al. Diabetes as a risk factor for herpes zoster infection: results of a population-based study in Israel. Infection 2008; 36: Kendall DM, Cuddihy RM, Bergenstal RM. Clinical application of incretin-based therapy: therapeutic potential, patient selection and clinical use. Eur J Intern Med 2009; 20:S American Diabetes Association, Standards of Medical Care in Diabetes Diabetes Care 2014; 37:S Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis. JAMA 2007; 298: Richter B, Bandeira-Echtler E, Bergerhoff K, Lerch CL. Dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes mellitus. Cochrane Database Syst Rev Apr 16:CD Cheng TM. Taiwan s National Health Insurance system: high value for the dollar. In: Okma KGH, Crivelli L, ed. Six Countries, Six Reform Models: The Health Reform Experience of Israel, the Netherlands, New Zealand, Singapore, Switzerland and Taiwan. New Jersey, World Scientific, 2009, Chapman RS, Cross KR, Fleming DM. The incidence of shingles and its implication for vaccination policy. Vaccine 2003; 21: Czernichow S, Dupuy A, Flahault A, Chosidow O. Herpes zoster: incidence study among sentinel general pratictioners. Ann Dermatol Venereol 2001; 128: Chidiac C, Bruxelle J, Daures JP, Hoang-Xuan T, Morel P, Leplège A, et al. Characteristics of patient with herpes zoster on presentation to practitioners in France. Clin Infect Dis 2001; 33: Geerlings SE, Hoepelman AI. Immune dysfunction in patientswith diabetes mellitus (DM). FEMS Immunol Med Microbiol 1999; 26: Hata A, Kuniyoshi M, Ohkusa Y. Risk of herpes zoster in patients with underlying diseases: a retrospective hospitalbased cohort study. Infection 2011; 39: Okamoto S, Hata A, Sadaoka K, Yamanishi K, Mori Y. Comparison of varicella-zoster virus specific immunity of patients with diabetes mellitus and healthy individuals. J Infect Dis 2009; 200: Opstelten W, Van Essen GA, Schellevis F, Verheij TJ, Moons KG. Gender as an independent risk factor for herpes zoster: a population-based prospective study. Ann Epidemiol 2006; 16: Richter B, Bandeira-Echtler E, Bergerhoff K, Lerch C. Emerging role of dipeptidyl peptidase-4 inhibitors in the management of type 2 diabetes. Vasc Health Risk Manag 2008; 4: Aytac U, Dang NH. CD26/dipeptidyl peptidase IV: a regulator of immune function and a potential molecular target for therapy. Curr Drug Targets Immune Endocr Metabol Disord 2004; 4: Preller V, Gerber A, Togni M, Wrenger S, Schraven B, Röcken C, et al. CD26/DP IV in T cell activation and autoimmunity. Adv Exp Med Biol 2006; 575: Klemann C, Schade J, Pabst R, Leitner S, Stiller J, von Hörsten S, et al. CD26/dipeptidyl peptidase 4-deficiency alters thymic emigration patterns and leukcocyte subsets in F344-rats agedependently. Clin Exp Immunol 2009; 155: Price JD, Linder G, Li WP, Zimmermann B, Rother KI, Malek R, et al. Effects of short-term sitagliptin treatment on immune parameters in healthy individuals, a randomized placebocontrolled study. Clin Exp Immunol 2013; 174:120 8.