ISSN International Journal of Innovative and Applied Research (2017) Journal home page: RESEARCH ARTICLE

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1 Journal home page: RESEARCH ARTICLE LONG-TERM DIPEPTIDYL PEPTIDASE-4 INHIBITOR USE REDUCES JOINT PAIN IN PATIENTS WITH TYPE 2 DIABETES MELLITUS: A STUDY USING THE NATIONAL HEALTH INSURANCE DATABASE. Shih-Jung Yen 1,2, Yu-Han Chang 1 and Kun-Der Lin 1,2. 1. Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan. 2. Department of Internal Medicine, Kaohsiung Medical University Hospital and Kaohsiung Medical University, Kaohsiung, Taiwan. *Corresponding Author:- Kun-Der Lin. Abstract: Introduction: The relationship between arthropathy and dipeptidyl peptidase-4 (DPP-4) inhibitors has rarely been investigated in Asian patients with type 2 diabetes mellitus (DM) treated with DPP-4 inhibitors. Materials and Methods: The Longitudinal Health Insurance Database 2000, which contains the claims data of one million beneficiaries of the National Health Insurance program, was used as the data source. A total of 19,729 patients who had received a diagnosis of type 2 DM, had received oral antidiabetic agents for at least 3 months, or were hospitalized with a diagnosis of DM without joint pain between January 1, 2009, and December 31, 2010, were recruited and followed for 1 year. Patients who received sitagliptin for at least 1 month were defined as sitagliptin users. Results: With sitagliptin use, arthralgia occurred early after the initiation of treatment when the cumulative defined daily dose (DDD) of sitagliptin was <84. The risk of joint pain did not increase significantly when sitagliptin was used for 1 year. By contrast, joint pain significantly decreased with sitagliptin use (p < 0.001). Conclusions: The cumulative DDD of nonsteroidal anti-inflammatory drugs did not increase with sitagliptin use; however, it significantly decreased within 1 year after the beginning of sitagliptin use. This may be attributable to the anti-inflammatory effect exerted by sitagliptin. Thus, Dipeptidyl Peptidase-4 Inhibitor use may reduce joint pain in patients with type 2 Diabetes Mellitus. Key Words:- Arthralgia, Diabetes Mellitus, Dipeptidyl-Peptidase IV Inhibitors. Introduction:- Some dipeptidyl peptidase-4 (DPP-4) inhibitors, such as sitagliptin, vildagliptin, and saxagliptin, have been associated with severe joint pain 1,2. Other reported musculoskeletal side effects include myalgia, muscle weakness, and muscle spasms. Symptoms have been reported from 2 days to 5 months after the initiation of DPP-4 inhibitors. In most patients, symptoms resolved within a month after discontinuing the drug 3. Some patients developed recurrent severe joint pain after restarting the same or a different DPP-4 inhibitor. If a patient develops severe and persistent joint pain while taking a DPP-4 inhibitor, the drug should be discontinued and the patient should be assessed for the resolution of symptoms. Furthermore, if symptoms resolve, a different class of diabetes medication should be prescribed. However, if symptoms do not resolve after 1 month of drug discontinuation, they are unlikely to be caused by the use of a DPP-4 inhibitor, and alternative causes of the symptoms should be investigated. To summarize the evidence on the correlation between DPP-4 inhibitors and arthralgia, we performed the National Health Insurance Database concerning this association. Materials and Methods:- Data Source:- The data for this retrospective cohort study were obtained from the Taiwan National Health Insurance Research Database (NHIRD), which was established by the Bureau of National Health Insurance of the Department of Health. Taiwan s National Health Insurance (NHI) program covers 99% of the 23 million residents of Taiwan and is contracted with 97% of Taiwanese hospitals and clinics. The Longitudinal Health Insurance Database (LHID) 62

2 2000, which was developed by the National Health Research Institute in 2000, contains the claims data of a random sample of one million beneficiaries of the NHI program. The LHID2000 contains the reimbursement claims data of the enrollees from 1996 to 2010.Study patientswe included patients aged >18 years who had received a diagnosis of type 2 diabetes mellitus (DM; International Classification of Disease, Ninth Revision, Clinical Modification [ICD-9- CM] codes 250.x0 and 250.x2), had received oral antidiabetic agents for at least 3 months, or were hospitalized with a diagnosis of diabetes between January 1, 2009, and December 31, All patients with type 2 DM were divided into 2 groups: sitagliptin users and nonsitagliptin users. Sitagliptin users were defined as those who received sitagliptin for 1 month, and we matched the comorbidities between sitagliptin users and non-sitagliptin users at a ratio of 1:3. In addition, we excluded patients with type 2 DM who were aged <18 years; had joint pain before the index date within 1 year; had received nonsteroidal anti-inflammatory drugs (NSAIDs) for joint pain for at least 1 month; had received a diagnosis of rheumatoid arthritis, systemic lupus erythematosus, osteoarthritis, gout, or chronic obstructive pulmonary disease; had received steroids; or had incomplete data. NSAIDs were defined according to the World Health Organization (WHO) Collaborating Centre for Drug Statistics Methodology, ATC/defined daily dose (DDD) index, 2016: M01A (anti-inflammatory and antirheumatic products, non-steroids). The institutional review board at the Kaohsiung Medical University Hospital approved this study (KMUHIRB- EXEMPT(II) ). Exposure assessment:- Records regarding prescribed drugs were extracted from the NHIRD. DDDs recommended by the WHO were used to quantify the usage of sitagliptin. Cumulative DDDs were calculated as the sum of the prescribed DDD of sitagliptin. Outcome measures:- The outcome of this study was new onset of joint pain (ICD-9-CM codes 719.4, 716.5, and 716.6) within 1 year. The person-years of follow-up were calculated from the index date to the date of diagnosis of new onset of joint pain, censoring caused by death during hospitalization, loss to follow-up, withdrawal from the insurance system, or the end of December 31, The follow-up period for joint pain began from the date of diagnosis to the end point of the study. Statistical Analysis:- We evaluated and compared the distribution of risk factors between sitagliptin users and nonsitagliptin users by using independent t test, chi-squared test, or Fisher's exact test. Cox proportional hazard regression analyses were conducted to determine the crude and adjusted hazard ratios (chrs and ahrs, respectively) for the risk of joint pain. Multiple Cox proportional hazard regression analysis was performed to determine the adjusted HR after adjustment for age, sex, Charlson comorbidity index (CCI) score, and comorbidities. Kaplan Meier curves were plotted to investigate the probability of new onset of joint pain, and the log-rank test or Gehan Breslow Wilcoxon test was used to evaluate differences between sitagliptin users and nonsitagliptin users. All statistical analyses were performed using SAS, Version 9.3 (SAS Institute, Inc., Cary, NC, USA). Statistical significance was set at p < Results:- The distributions of demographic characteristics, namely age, sex, CCI score, and comorbidities (such as hypertension, hyperlipidemia, ischemic heart disease, and cerebral vascular disease), did not significantly differ between the sitagliptin users and nonsitagliptin users (Table 1).Of the 2813 sitagliptin users who were followed up until the end of the study, 82 (2.9%) patients experienced an episode of joint pain. By contrast, of the 8616 nonsitagliptin users who were followed up until the end of the study, 315 (3.7%) patients experienced an episode of joint pain. Moreover, the proportions of patients who experienced joint pain did not significantly differ between sitagliptin users and non-sitagliptin users (chr = 1.05, 95% confidence interval [CI], ; ahr = 1.05, 95% CI, ; Table 2). The relationship between sitagliptin use and the risk of joint pain is shown in Table 2. We compared sitagliptin users with non-sitagliptin users and found that a DDD of <84 of sitagliptin was associated with an increasing risk of joint pain (chr = 2.42, 95% CI, ; ahr = 2.39, 95% CI, ) and a DDD of >196 of sitagliptin was associated with a decreasing risk of joint pain (chr = 0.34, 95% CI, ; ahr = 0.35, 95% CI, ). In addition, we observed the same trend in the relationship between the days of receiving sitagliptin and the risk of joint pain. The subgroup analysis indicated no differences in sex, age (<60 and 60 years), CCI score (0,1 2,and 3), and comorbidities such as hypertension (ICD-9-CM codes ), hyperlipidemia (ICD-9-CM ), 63

3 ischemic heart disease (ICD-9-CM 410,411,and 413), and cerebrovascular disease (ICD-9-CM ) between the sitagliptin users and nonsitagliptin users (Table 3). The cumulative DDD of NSAIDs received before and after starting sitagliptin for 1 year showed significant findings (p < 0.001). This indicated that the cumulative DDD of NSAIDs did not increase under sitagliptin use; however, it significantly decreased within 1 year after the beginning of sitagliptin use. This may be attributable to the anti-inflammatory effect exerted by sitagliptin 4. If DPP-IV and CD26 are proinflammatory, their inhibitors, such as sitagliptin, can potentially be anti-inflammatory and antiatherogenic because atherosclerosis is a chronic inflammation of the arterial wall. Thus, sitagliptin exerts an anti-inflammatory effect (Table 4). Table 1:- Demographic data of patients with type 2 diabetes mellitus Overall With population Sitagliptin user (N=11,252) (N=2,813) Without Sitagliptin user (N=8,439) n (%) n (%) N (%) Age Mean,SD (±) (±12.26) (±12.15) <40 y/o 610 (5.4) 160 (5.7) 450 (5.3) y/o 5174 (46.0) 1301 (46.2) 3873 (45.9) 60 y/o 5468 (48.6) 1352 (48.1) 4116 (48.8) Gender Female 5997 (53.3) 1501 (53.4) 4496 (53.3) Male 5255 (46.7) 1312 (46.6) 3943 (46.7) Charlson's index score (2.3) 66 (2.3) 188 (2.2) (43.0) 1209 (43.0) 3634 (43.1) (54.7) 1538 (54.7) 4617 (54.7) Medical disease Hypertension 7542 (67.0) 1870 (66.5) 5672 (67.2) Hyperlipidemia 7786 (69.2) 1946 (69.2) 5840 (69.2) Ischemic heart disease 1146 (10.2) 295 (10.5) 851 (10.1) Cerebral vascular disease 995 (8.8) 246 (8.7) 749 (8.9) Table 2:- Relationship between sitagliptin use and the risk of joint pain No. cases Person year Per 1,000 Person year chr (95%CI) Overall Without Sitagliptin user Ref With Sitagliptin user ( ) Cumulative DDDs < ( ) ( ) ( ) Days of taking sitagliptin ( ) ( ) ahr (95%CI) ( ) < ( ) ( ) ( ) <0.001 < ( ) < ( ) < <

4 ( ) ( ) Table 3:- Subgroup analysis Without Sitagliptin user No. cases Per 1,000 Person year With Sitagliptin user No. cases Per 1,000 Person year Table 4:- Cumulative daily defined dose of nonsteroidal anti-inflammatory drugs received before and after starting sitagliptin (index day) within 1 year by patients with type 2 diabetes mellitus NSAIDs cumulative DDDs Mean (±SD) Before index date within 1 year (±33.74) <0.001 After index date within 1 year (±29.30) With Sitagliptin user verse without Sitagliptin user ahr (95%CI) Gender Female ( ) Male ( ) Age <60 years old ( ) years old ( ) Charlson'sindex score ( ) ( ) ( ) Medical disease Hypertension No ( ) Yes ( ) Hyperlipidemia No ( ) Yes ( ) Ischemic heart disease No ( ) Yes ( ) Cerebral vascular disease No ( ) Yes ( ) Discussion:- A pooled analysis of data from 10,246 patients treated with DPP-4 inhibitors in the United States has recently been published 5. Among the reported adverse events that might be related to sitagliptin, arthralgia occurred at a frequency of 0.2 incident events per 100 patient-years in the treated patients, which was not significantly different from that in patients not exposed to DPP-4 inhibitors. The underlying mechanism for these adverse drug reactions can be explained by the wide distribution of DPP-4 in the striated muscle. Some studies have shown a reduced amount of CD26, a glycoprotein with DPP-4 enzymatic activity, in arthritis, osteoarthritis, and chronic fatigue syndrome 6-8. DPP4 inhibition also increases the levels of P substance(thus decreasing the pain threshold) and slightly increases endomorphin-2 levels 9. It might suggest that gliptins lead to musculoskeletal complaints because of an immune imbalance or through modification of pain susceptibility. From FDA Adverse Event Reporting System (FAERS) database, we identified 33 cases of severe arthralgia reported with the use of dipeptidyl peptidase-4 (DPP- 4) inhibitors from October 16, 2006, approval date of the first DPP-4 inhibitor, through December 31, Each case involved the use of one or more DPP-4 inhibitor. Sitagliptin (n=28) was the most frequently reported, followed 65

5 by saxagliptin (n=5), linagliptin (n=2), alogliptin (n=1), and vildagliptin (n=2). All 33 patients experienced arthralgia that resulted in a substantial reduction in their prior level of activity, including 10 patients who were hospitalized due to disabling joint pain. In 22 cases, symptoms appeared within 1 month of initiation of treatment with a DPP-4 inhibitor. In 20 of the 33 cases, the DPP-4 inhibitor was suspected as a possible cause of arthralgia and was discontinued within a month following the onset of symptoms. However, 8 of the remaining 13 cases reported a period of 44 days to 1 year between the onset of symptoms and discontinuation of the DPP-4 inhibitor. In 23 of the 33 cases, symptoms resolved less than 1 month after discontinuation of the drug. A cumulative DDD of <84 of sitagliptin significantly increased joint pain, indicating that joint pain may have occurred early during sitagliptin use and thus sitagliptin should be stopped immediately. Similar to this finding, taking sitagliptin for 90 days significantly increased the risk of joint pain. Because the DDD of sitagliptin is 100 mg (1 pill), the cumulative DDD should be administered for approximately 3 months if a patient has normal renal function and the drug dose need not be adjusted. The observation that symptoms appeared within 1 month of the initiation of treatment with a DPP-4 inhibitor is compatible with the information from the FAERS database. But how to explain if sitagliptin had anti-inflammatory effect but it still caused joint pain within 3 months of intiation of sitagliptin use. According to Makdissi A, all inflammatory marker decreased at 12 wk treatment of 100mg daily of sitagliptin. Thus, joint pain within 3 months of intiation of sitagliptin use may be explained as other than inflammatory effect and might suggest that gliptins lead to musculoskeletal complaints other than inflammatory effect,and might due to immune imbalance or through modification of pain susceptibility The cumulative DDD of NSAIDs received before and after starting sitagliptin for 1 year showed significant findings (p < 0.001). As shown in Table 2, the chr and ahr for the risk of joint pain after receiving sitagliptin for 224 days was <1, indicating that sitagliptin exerted a protective effect on joint pain (p < 0.001). Limitations The number of the patients receiving cumulative DDDs and taking sitagliptin for 224 days was limited; thus, the may not have adequate power. In addition, because we used only ICD-9-CM codes to define new onset of joint pain (the study outcome), the actual condition may have been overestimated or underestimated. Furthermore, we used only the LHID2000 as a data source, included only the first published DPP-4 inhibitor sitagliptin, and did not evaluate the effects of other DPP-4 inhibitors. By this method of detecting arthralgia from prescription records of NSAIDs, mild to moderate arthralgia the patients did not require pain killer could not be detected. Acknowledgment:- K.-D.L. contributed the study design and conception. S.-J.Y. drafted the manuscript and the tables. Y.-H.C. contributed the statistical analysis. Disclosure:- Nothing to disclose. Reference:- 1. Tarapués M, Cereza G, Figueras A. (2013): Association of musculoskeletal complaints and gliptin use: review of spontaneous reports. Pharmacoepidemiol Drug Saf. Oct;22(10): Chaicha-Brom T, Yasmeen T. (2013): DPP-IV inhibitor-associated arthralgias. Endocr Pract. Mar- Apr;19(2): FDA Drug Safety Communication: FDA warns that DPP-4 inhibitors for type 2 diabetes may cause severe joint pain [ ce=govdelivery] 4. Makdissi A, Ghanim H, Vora M, Green K, Abuaysheh S, Chaudhuri A, Dhindsa S, Dandona P. (2012): Sitagliptin exerts an antinflammatory action. J Clin Endocrinol Metab 97: Williams-Herman D, Engel SS, Round E, Johnson J, Golm GT, Guo H, Musser BJ, Davies MJ, Kaufman KD, Goldstein BJ. (2010): Safety and tolerability of sitagliptin in clinical studies: a pooled analysis of data from 10,246 patients with type 2 diabetes. BMC endocrine disorders 10:7. 66

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