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Real-World Effectiveness of Sitagliptin as Add-On Therapy in Patients With Type 2 Diabetes Mellitus a

a

Tse-Ying Chen MD & Ching-Jung Hsieh MD a

Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan Published online: 28 May 2015.

Click for updates To cite this article: Tse-Ying Chen MD & Ching-Jung Hsieh MD (2014) Real-World Effectiveness of Sitagliptin as Add-On Therapy in Patients With Type 2 Diabetes Mellitus, Postgraduate Medicine, 126:3, 205-215 To link to this article: http://dx.doi.org/10.3810/pgm.2014.05.2768

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C L I N I C A L F O C U S : D I A B E T E S A N D C O N C O M I TA N T D I S O R D E R S

Real-World Effectiveness of Sitagliptin as Add-On Therapy in Patients With Type 2 Diabetes Mellitus

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DOI: 10.3810/pgm.2014.05.2768

Tse-Ying Chen, MD 1 Ching-Jung Hsieh, MD 1 Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 1

Abstract

Aims: To assess the effectiveness of sitagliptin in glycemic control in a clinical practice. Methods: This was a retrospective medical chart review study conducted in a single hospital. A total of 3081 patients with diabetes mellitus who were prescribed sitagliptin were selected, including 2729 continuous sitagliptin users (defined as continuous usage $ 24 weeks) and 352 subjects who used sitagliptin for , 24 weeks. An additional 12-month observation period was monitored after initiating sitagliptin to extract clinical information at 3, 6, 9, and 12 months through patient medical chart review. Results: In the 2729 continuous users, a baseline glycated hemoglobin (HbA1c) level of 9.0% was reduced to 8.1%, 8.1%, 8.1%, and 8.2% at 3, 6, 9, and 12 months, respectively, representing a 0.9% HbA1c level reduction at 3, 6, and 9 months and a 0.8% HbA1c level reduction at 12 months. With a goal of HbA1c value of , 7.0%, 9.1% of the patients were under control at baseline; after initiating sitagliptin, 22.7% of the patients achieved the HbA1c level goal at 3 months, 23.6% at 6 months, 20.8% at 9 months, and 20.4% at 12 months. The proportion of patients attaining the goal of HbA1c level , 7.0% at least doubled at different time points after treatment with sitagliptin. Conclusions: In this single-hospital retrospective chart analysis, a meaningful clinical improvement in glycemic control before and after sitagliptin treatment commenced, including HbA1c level reduction and the HbA1c goal attainment rate, was observed. The results reflect the actual clinical practice in a large hospital in Taiwan, and supplement data from randomized controlled trials. Keywords: type 2 diabetes mellitus; sitagliptin; oral antidiabetic drugs; dipeptidyl peptidase IV inhibitor

Introduction

Correspondence: Ching-Jung Hsieh, MD, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, 123 Ta-Pei Road, Niao-Sung District, Kaohsiung City 83305, Taiwan. Tel: 886-7-7317123, x 8302 Fax: 886-7-7322402 E-mail: [email protected]

The number of individuals affected by type 2 diabetes mellitus (T2DM) is continuing to increase globally, including in Asia.1 The International Diabetes Federation has estimated that 8.5% of Taiwanese were affected by diabetes mellitus (DM) in 2011, and the percentage will increase to 8.9% by 2030.2 This increased prevalence will contribute to a significant increase in T2DM–related complications, such as cardiovascular disease, renal insufficiency, blindness, neuropathy, and diabetic foot. Adequate treatment options to prevent DM-related complications play an important role in T2DM management. Currently there are 5 major classes of oral antidiabetic drugs (OADs) with different mechanisms of action (MOAs) approved for clinical use: biguanides, sulfonylureas (SUs), thiazolidinediones (TZD; glitazone), alpha-glucosidase inhibitors (AGI), and dipeptidyl peptidase IV (DPP-4) inhibitors. Metformin, a biguanide, has been shown to reduce the risk of cardiovascular morbidity and mortality compared with other OADs.3

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Tse-Ying Chen and Ching-Jung Hsieh

Based on the clinical guidelines, for T2DM management, metformin is recommended as the first-line drug of choice if not contraindicated.4,5 Type 2 diabetes mellitus is a progressive disease and it is difficult to control with a single OAD long-term. Turner et al6 reported a 50% failure rate after 3 years and up to a 75% failure rate after 9 years of using a single OAD. Therefore, adding a second or even a third OAD with different MOAs is inevitable in most patients with T2DM as the disease progresses. The SUs are the most popular OAD used in combination with metformin, according to a review by Inzucchi.7 A similar result was reported in a Taiwanese study.8 However, SUs, which directly stimulate pancreatic β-cells for insulin secretion and lead to reduction in the blood glucose level, may yield hypoglycemia, which has become one of the most worrisome adverse events in the management of T2DM.7 In addition, early-generation SUs and glibenclamide have been shown to increase the relative risk of mortality in observational studies.3,7,9,10 Thiazolidinedione, another OAD that improves insulin resistance, may also be related to an increased risk of cardiovascular events3,11 and bladder cancer.9,12,13 The well-known adverse effects of AGIs are gastrointestinal, especially flatulence and diarrhea.7 Hence, there is still a need for more efficacious and safer treatment options for T2DM. In 2006, sitagliptin was the first in the class of DPP-4 inhibitors to be approved and made commercially available in the United States. The MOA for sitagliptin involves enhancement of the incretin axis via an increase in concentration of endogenous glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, active form, both of which result in glucose-dependent insulin stimulation and glucagon inhibition.14–16 When compared with other established OADs in several randomized controlled trials,17–22 sitagliptin was not inferior to metformin, SUs, TZDs, or AGIs for the efficacy endpoints. Williams-Herman et  al23 analyzed $ 10 000 subjects in clinical trials and concluded that sitagliptin was well tolerated for # 2 years of treatment duration. In elderly patients, a vulnerable patient group, sitagliptin has also been demonstrated to have clinically significant efficacy, good safety, and an acceptable tolerability profile.24 There is increasing scientific and clinical interest in the effectiveness of sitagliptin in the broader population, especially in nonclinical trial settings. Sitagliptin was licensed by the Taiwan Food and Drug Administration and marketed in 2008, and obtained reimbursement status from the Bureau of National Health Insurance in April 2009. In our hospital, which is located 206

in southern Taiwan, approximately 20 000 patients with DM regularly seek medical care at the Metabolism and Endocrinology Clinic and other specialty outpatient clinics. Sitagliptin was listed in the hospital formulary shortly after approval in 2008 and used in patients who failed to achieve adequate glycemic control, in combination with other OADs. The clinical information in the hospital electronic medical record system was retrievable and made the evaluation of glycemic control status and the effectiveness of sitagliptin possible. A significant number of the clinical medical records were reviewed to evaluate the overall treatment and to explore the clinical characteristics of sitagliptin users within a heterogeneous population. The results generated from this clinical setting complement the results of clinical trials, thereby helping clinicians make effective treatment choices.

Materials and Methods Study Design

This was a single-center, hospital-based, retrospective chart review analysis. There was no investigational or interventional medication provided. The variables were solely collected from the subjects’ medical charts.

Case Identification The case identification period, or index period, was defined as the time between January 1, 2009, and September 30, 2010. Subjects who were diagnosed with DM, as documented by International Classification of Diseases, ninth revision, codes 250.0, 250.1, 250.2, 250.3, 250.4, 250.5, and 250.6, and prescription records of OAD codes during the index period were extracted from the hospital outpatient electronic database. In general, all eligible patients were enrolled to minimize any potential bias in the sampling process. Patients meeting the diagnostic inclusion criteria were further classified in the category of sitagliptin users, which was composed of patients who were prescribed sitagliptin as an add-on treatment to their prior regimen during the index period. After electronic database selection, a subsequent manual chart review based on the selection criteria was performed to generate the predefined continuous sitagliptin-user cohort (ie, sitagliptin use $ 24 weeks). The inclusion criteria required the following: a stable dose of all OAD regimens, with “stable dose” defined as $ 3 months with no therapy or dose change prior to the addition of sitagliptin; a minimum core data set in the medical records; and outpatient status. The exclusion criteria included the following: type 1 DM; treatment with insulin on a regular basis; DM that resulted from other causes (eg, surgery, pharmaceutical products, malnutrition, infections,

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Effectiveness of Sitagliptin in Patients With T2DM

and other conditions); and participation in a clinical trial or other clinical study during the index period. We also selected as controls 2091 age- and sex-matched patients with T2DM but not using sitagliptin during the index period.

Case Observation Period

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The observational period for each patient was 12 months, commencing with sitagliptin initiation. Among the continuous sitagliptin-user cohort, glycated hemoglobin (HbA1c) data from baseline to different time points (3 and 6 months) were collected, analyzed, and compared. The 9- and 12-month time points were also collected and analyzed for exploratory purposes.

Ethical Review This study proposal was approved by the institutional review board of our institution and conducted accordingly. It also followed the guidelines outlined in the Declaration of Helsinki. This study was also registered in ClinicalTrials.gov as NCT01316835.

Statistical Analysis Statistical Methods

Data management and analysis were performed using SAS 9.3. The patient characteristics were summarized and tabulated. Data are presented as the mean ± standard deviation for continuous variables; the number and proportion are shown for categorical variables. For statistical analysis, Student’s t test or the Χ 2 test was used to determine the differences between groups. The mean changes in HbA1c level from baseline at different time points were also computed using paired t tests. In addition, overall and subgroup analyses of the goal attainment rate at different time points were also conducted. All tests were 2-sided and performed at the 5% level of significance.

Power/Sample Size As this was a retrospective study and no hypothesis testing was applied to the power calculation, there was no predetermination of sample size. In general, all eligible patients were enrolled to minimize any potential bias in the sampling process.

Results

A total of 4081 patients who were prescribed sitagliptin during the index period were extracted from the hospital outpatient electronic medical chart database. After excluding 476 subjects who had prior insulin use before adding

sitagliptin, 264 subjects who had no baseline HbA1c level determinations, 181 subjects who had no OAD treatment before sitagliptin was prescribed, 60 subjects who had sitagliptin-alone use during the index period, and 19 subjects who used sitagliptin after the index period, we were left with a total of 3081 patients who met the selection criteria of sitagliptin users. Further stratifying the sitagliptin users, 2729 subjects were shown to be compliant with sitagliptin treatment $ 24 weeks (ie, continuous sitagliptin users), whereas 352 subjects used sitagliptin , 24 weeks. The predefined sitagliptin compliance rate was # 88.4%. The selection algorithm is shown in Figure 1. The baseline sitagliptin-user characteristics are shown in Table 1. The mean age was 64.0 ± 11.4 years. The mean body mass index (BMI) was 26.5 ± 4.2 kg/m2, with a mean weight of 69.1 ± 13.0 kg. The percentage of patients who were female was 49.5%. The average baseline HbA1c level was 9.0% ±  1.7%. There were no statistically significant differences in age, gender, weight, BMI, and baseline HbA1c level between both groups of sitagliptin users (treatment duration , 24 and $ 24 weeks). The group of sitagliptin users (treatment duration $ 24 weeks) showed a reduction in HbA1c level that was not inferior to that of the group of sitagliptin nonusers (0.9 ± 0.1 vs 1.0 ± 0.2; P = 0.44; Table 2). Within the sitagliptin-user cohort, only 9.8% of subjects were taking a single therapeutic class of OADs, whereas 90.2% were taking $ 2 therapeutic classes. Two therapeutic classes are the most common OAD regimen, found in 48.8% of patients; 3 therapeutic classes were used in 36.2% of patients; and 4 therapeutic classes were used in 5.3% of patients. The 2729 subjects comprised the predefined continuous sitagliptin-user cohort, and the serial percent change in HbA1c level was analyzed at different time points (3, 6, 9, and 12 months), as shown in Table 3. The baseline mean HbA1c level (9.0% ± 1.7%) decreased to 8.1% ± 1.5% at 3 months and 8.1% ± 1.5% at 6 months; specifically, the mean HbA1c level changes from baseline were –0.96% ± 0.04% at 3 months and –0.96% ± 0.04% at 6 months. The 9- and 12-month data are shown in Figure 2A and Table 3 for those patients who continued sitagliptin. Because the index period was from January 1, 2009, to September 30, 2010, and period for starting sitagliptin as the add-on therapy was from January 1, 2009, to March 30, 2010, there was a 25% reduction in cases from month 9 to month 12. Effective HbA1c level reduction was observed 3 months after beginning treatment with sitagliptin. The HbA1c level reduction was sustained for 12 months, at which time the study concluded

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Figure 1.  Disposition of subjects.

Abbreviations: HbA1c, glycated hemoglobin; OAD, oral antidiabetic drug.

(3, 6, 9, and 12 months compared with baseline, all P , 0.01; no statistically significant difference between 3, 6, 9, and 12 months). Based on the results of clinical studies that have shown that the baseline HbA1c level will influence the reduction in HbA1c level, we have further divided the patients into a low HbA1c level at baseline (, 8.0%) subgroup and a high HbA1c level at baseline ($ 8.0%) subgroup. The reduction in HbA1c level was significantly higher in the high baseline

group compared with the low baseline group, confirming the results from previous clinical studies (Figure 2B and Table 3). According to the American Diabetes Association (ADA) and the European Association of the Study for Diabetes recommendations and other international DM guidelines, the DM control goal is an HbA1c level , 7.0%.4,5 Only 9.1% of study participants had a baseline HbA1c level of , 7%

Table 1.  Baseline Characteristics of Sitagliptin Users Sitagliptin Users

Duration $ 24 Wks

Duration , 24 Wks

Total

N Age, y ± SD Gender: female, n (%) Weight, kg BMI, kg/m2 HbA1c level, % HbA1c $ 8.0% HbA1c , 8.0% Classes of OADs used (mean class)a Single class Double classes Triple classes Quadruple classes 3 H comorbidities 1 H (DM only) 2 H (+ either HTN or hyperlipidemia) DM + HTN DM + hyperlipidemia 3 H (+ both HTN and hyperlipidemia)

2729 63.9 ± 11.4 1352 (49.5%) 69.2 ± 13.1 26.6 ± 4.2

352 64.9 ± 11.3 174 (49.4%) 67.8 ± 12.9 26.3 ± 4.2

3081 64.0 ± 11.4 1526 (49.5%) 69.1 ± 13.0 26.5 ± 4.2

1932 (70.8%) 797 (29.2%)

235 (66.8%) 117 (33.2%)

2167 (70.3%) 914 (29.7%)

2.40 ± 0.73 239 (8.8%) 1322 (48.4%) 1015 (37.2%) 153 (5.6%)

2.17 ± 0.75 62 (17.6%) 180 (51.1%) 99 (28.1%) 11 (3.1%)

2.37 ± 0.73 301 (9.8%) 1502 (48.8%) 1114 (36.2%) 164 (5.3%)

124 (4.5%) 801 (29.4%) 453 (16.6%) 348 (12.8%) 1804 (66.1%)

22 (6.3%) 108 (30.7%) 78 (22.2%) 30 (8.5%) 222 (63.1%)

146 (4.7%) 909 (29.5%) 531 (17.2%) 378 (12.3%) 2026 (65.8%)

OAD classes were classified as metformin, SU, TZD, and AGI. Among them, SU included both sulfonylureas and SU-like insulin secretagogue glinides.

a

Abbreviations: AGI, alpha-glucosidase inhibitor; BMI, body mass index; DM, diabetes mellitus; H, high; HTN, hypertension; OAD, oral antidiabetic drug; SD, standard deviation; SU, sulfonylurea; TZD, thiazolidinedione.

208

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Effectiveness of Sitagliptin in Patients With T2DM

Table 2.  Comparison of the Change of HbA1c Level After 6 Months of Treatment Between Sitagliptin Users and Sitagliptin Nonusers

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N Age (y ± SD) Gender: female, n (%) HbA1c level, % HbA1c M0 HbA1c M6 Classes of OADs used Sita+1/double therapies Sita+2/triple therapies Sita+3/quadruple therapies Sita+4 3 H comorbidities 1H (DM only) 2H (+ either HTN or hyperlipidemia) 3H (+ both HTN and hyperlipidemia)

Sitagliptin Users

Sitagliptin Nonusers

P

2729 63.9 ± 11.4 1352 (49.5%)

2091 64.4 ± 13.1 1004 (48%)

NS NS NS

9.0 ± 1.7 8.1 ± 1.5a

9.2 ± 1.4 8.2 ± 1.8a

NS NS

245 (9.0%) 1368 (50.1%) 942 (34.5%) 174 (6.4%)

184 (9.8%) 1056 (52.5%) 740 (37.7%)

NS NS NS

124 (4.5%) 801 (29.4%) 1804 (66.1%)

502 (24.0%) 970 (46.4%) 619 (29.6%)

, 0.001 0.04 , 0.001

P , 0.01 by paired t test from baseline.

a

Abbreviations: DM, diabetes mellitus; H, high; HbA1c, glycated hemoglobin; HTN, hypertension; NS, not significant; OAD, oral antidiabetic drug; sita, sitagliptin; SD, standard deviation.

before sitagliptin therapy was started. After initiating sitagliptin, the proportion of patients achieving the goal of HbA1c level , 7.0% at 3 months was 22.7%, and 23.6% at 6 months, resulting in a 2.6-fold increase in goal attainment at 6 months compared with baseline. The goal attainment rates at 9 and 12 months were 20.8% and 20.4%, respectively. After 6 months, the data demonstrated a sustained

goal attainment rate in . 20% of the patients studied for the full 12-month period. In the current study, sitagliptin intervention doubled the goal attainment rate throughout the treatment duration of 12 months. When separating patients according to the baseline HbA1c level into 2 subgroups (low baseline, , 8.0% [n = 798]; and high baseline, $ 8.0% [n = 1931]), the high

Table 3.  The Serial HbA1c Level of Glycemic Control, the Mean HbA1c Level Change From Baseline and Goal Attainment Rate by Quarter Among 2729 Continuous Sitagliptin-User Patients, Including Low and High HbA1c Level at Baseline Subgroups Time Point

Month 0

Month 3

Month 6

Month 9a

Month 12b

All patients HbA1c level ± SD, % Mean HbA1c change from baseline Goal attainment rate, n (%) N

9.0 ± 1.7 NA 249 (9.1%) (n = 2729)

8.1 ± 1.5c –0.96 ± 0.04c 325 (22.7%) (n = 1435)

8.1 ± 1.5c –0.96 ± 0.04c 317 (23.6%) (n = 1342)

8.1 ± 1.5c –0.92 ± 0.05c 221 (20.8%) (n = 1064)

8.2 ± 1.5c –0.93 ± 0.06c 156 (20.4%) (n = 765)

Low HbA1c level at baseline (, 8.0%) subgroup HbA1c ± SD (%) Mean HbA1c change from baseline Goal attainment rate, n (%) n

7.2 ± 0.6 NA 249 (31.2%) (n = 797)

7.0 ± 0.9c –0.19 ± 0.05c 197 (53.0%) (n = 372)

7.1 ± 1.0 –0.10 ± 0.06 168 (48.4%) (n = 347)

7.3 ± 1.0 0.01 ± 0.06 123 (44.2%) (n = 278)

7.3 ± 1.0 0.07 ± 0.08 81 (43.1%) (n = 188)

8.4 ± 1.5c –1.24 ± 0.05c 128 (12.0%) (n = 1063) , 0.001 , 0.001

8.4 ± 1.5c –1.26 ± 0.05c 149 (15.0%) (n = 995) , 0.001 , 0.001

8.4 ± 1.5c –1.25 ± 0.06c 98 (12.5%) (n = 786) , 0.001 , 0.001

8.6 ± 1.6c –1.26 ± 0.07c 75 (13.0%) (n = 577) , 0.001 , 0.001

High HbA1c level at baseline ($ 8.0%) subgroup 9.7 ± 1.5 HbA1c ± SD (%) Mean HbA1c change from baseline NA Goal attainment rate, n (%) 0 (0%) n (n = 1932) P valued for mean change from baseline between low vs high subgroups P valuee for goal attainment rate between low vs high subgroups Only for patients using sitagliptin over 9 months.

a

b c

Only for patients using sitagliptin over 12 months.

P , 0.01 by paired t test from baseline. By Student’s t test.

d e

By Χ 2 test.

Abbreviations: HbA1c, glycated hemoglobin; NA, not available; SD, standard deviation. © Postgraduate Medicine, Volume 126, Issue 3, May 2014, ISSN – 0032-5481, e-ISSN – 1941-9260 209 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.

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Figure 2.  Glycemic control over time by baseline HbA1c levels (P , 0.01, based on paired t test to measure mean change from baseline). (A) Overall glycemic control over time (n = 2729) and (B) Glycemic control over time by baseline HbA1c subgroups (low HbA1c level at baseline , 8% vs high HbA1c level at baseline $ 8%).

Abbreviation:  HbA1c, glycated hemoglobin.

HbA1c level at baseline subgroup had a goal attainment range of 12.0% to 15.0% at different time points, whereas the low baseline subgroup fluctuated between 43.1% and 53.0%. When compared with the baseline goal attainment rate of 31.2%, the low baseline HbA1c level subgroup demonstrated a statistically significant increase in goal attainment at all time points (P , 0.001), as detailed in Table 2. The absolute increase in the HbA1c goal attainment rate in the low HbA1c level at baseline subgroup was 21.8% at 3 months and 17.2% at 6 months. Similarly, at 9 and 12 months the 210

absolute increase in the HbA1c goal attainment rate was still . 10%. Table 4 shows the HbA1c level responses based on sitagliptin added to the concurrent use of OADs. Sitagliptin added to metformin has more HbA1c−level-lowering ability than TZDs and SUs (−1.03 ± 0.11, −0.90 ± 0.14, −0.83 ± 0.24, respectively, P = 0.03). However, there are no apparent differences if sitagliptin is added to double therapy (any 2 pairings of metformin, TZDs, and SUs). Sitagliptin added to triple therapy (metformin, SUs, and TZDs) reduced HbA1c level signifi-

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Effectiveness of Sitagliptin in Patients With T2DM

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Table 4.  The HbA1c Responses Based on the Type of Concurrent Use of OADs Mean Number of OHA

Case Number, n (%)

Change of HbA1c Level at Month 6

Sita + 1 Sita + Met Sita + TZD Sita + SU

245 (9.0%) 96 (39.2%) 12 (4.9%) 137 (55.9%)

Sita + 2 Sita + Met + SU Sita + SU + TZD Sita + Met + TZD

1368 (50.1%) 1203 (87.9%) 68 (5.0%) 97 (7.1%)

Sita + 3 Sita + Met + SU + TZD Sita + Met + SU + AGI Sita + TZD + SU + AGI

942 (34.5%) 617 (65.5%) 194 (20.6%) 131 (13.9%)

Sita + 4 Sita + Met + SU + TZD + AGI

174 (6.4%)

–0.91 ± 0.16 –1.03 ± 0.11 –0.90 ± 0.14 –0.83 ± 0.24 P = 0.03 –1.10 ± 0.06 –1.12 ± 0.11 –1.00 ± 0.08 –0.98 ± 0.06 NS –0.78 ± 0.08 –0.81 ± 0.07 –0.74 ± 0.06 –0.70 ± 0.11 P = 0.01 –0.91 ± 0.22

*OAD classes were classified as metformin, SU, TZD, and AGI. Among them, SU included both sulfonylureas and SU-like insulin secretagogue glinides. Abbreviations: AGI, alpha-glucosidase inhibitor; HbA1c, glycated hemoglobin; Met, metformin; NS, not significant; OAD, oral antidiabetic drug; OHA, oral hypoglycemic agent; sita, sitagliptin; SU, sulfonylurea; TZD, thiazolidinedione; SU#, sulfonylurea and meglitinide.

cantly (P = 0.001). We categorized the HbA1c level response in 3 ranges (Table 5): decreasing HbA1c level of $ 1, $ 0.5 but , 1, and , 0.5. There is a high initial HbA1c level and higher dose of sitagliptin with a better response (P , 0.001 and 0.008, respectively), but these findings are not related to age, gender, BMI, duration of DM, or comorbidities.

Discussion

Unlike prospective randomized controlled clinical trials, this study was a retrospective analysis of actual clinical practice

involving patients treated by DM specialists and other nonspecialist physicians in a single large hospital in Taiwan. We utilized a systemic, rational, comprehensive process to retrieve data from the medical charts. The results reflected the observations in an actual clinical practice setting. All eligible patients had been diagnosed with T2DM and were started on sitagliptin during the index period. Based on a predefined sitagliptin compliance criterion (continuous use $ 24 weeks), there was a high compliance rate of 88.4% in the current study. In a pooled safety analysis of data from

Table 5.  Comparisons of Clinical Characteristics Between the Different Responders With Sitagliptin Therapy Sitagliptin Users

Good Responders (Change in HbA1c level $ 1; n = 608)

Fair Responders (Change in HbA1c level $ 0.5 but , 1; n = 230)

Poor Responders (Change in HbA1c level , 0.5; n = 504)

P valuea

Initial HbA1c level, %

9.8 ± 1.6 62.3 ± 11.2 297 (48.8%) 26.4 ± 4.3 8.3 ± 4.4 2.40 ± 0.71

8.5 ± 1.2 63.8 ± 10.9 111 (48.3%) 26.4 ± 3.5 8.7 ± 4.3 2.45 ± 0.71

8.3 ± 1.5 63.4 ± 11.7 260 (51.6%) 26.7 ± 4.1 8.7 ± 4.8 2.42 ± 0.72

, 0.001 0.118 0.582 0.640 0.242 0.718

82.1 ± 25.6 392 (64.5%)

76.1 ± 28.0 146 (63.5%)

81.9 ± 255 331 (65.7%)

0.008 0.960

71 (11.7%) 14 (2.3%) 1 (0.2%) 82 (13.5%)

39 (17.0%) 6 (2.6%) 2 (0.9%) 30 (13.0%)

71 (14.1%) 18 (3.6%) 4 (0.8%) 67 (13.3%)

0.268 0.623 0.345 0.902

Age, y ± SD Gender: female, n (%) BMI, kg/m2 Duration of T2DM, y Mean classes of OADs before add-on Mean dose of sitagliptin, mg/day 3H (+ both HTN and hyperlipidemia), n (%) Ischemic heart disease, n (%) Congestive heart failure, n (%) Myocardial infarction, n (%) Stroke, n (%)

HbA1c level data available both at baseline and month 6.

a

Abbreviations: BMI, body mass index; T2DM, type 2 diabetes mellitus; HTN, hypertension; OAD, oral antidiabetic drug; SD, standard deviation. © Postgraduate Medicine, Volume 126, Issue 3, May 2014, ISSN – 0032-5481, e-ISSN – 1941-9260 211 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.

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Tse-Ying Chen and Ching-Jung Hsieh

10 246 patients with DM, Williams-Herman et al23 reported that sitagliptin was well tolerated in clinical trials # 2 years in duration and the adverse event profile of sitagliptin users in the pooled safety analysis was comparable with that of non-sitagliptin users. Our study showed a high patient compliance rate, which was partially explained by a good safety and tolerability profile. The limitation of the study was that for the 11.6% of patients who discontinued sitagliptin in # 24 weeks, there were no documented reasons for discontinuation or adverse events recorded in the medical charts. Similarly to McIntosh et al25 in their meta-analysis, we also found that sitagliptin added to any single OAD is not inferior to double, triple, or higher combinations of other OADs. Sitagliptin added to metformin seems have more apparent glucose levels reduction than when it is combined with SU and TZD. With sitagliptin as the centered drug, the other OADs with different MOAs, including metformin, SUs, TZDs, and AGIs, could be added or changed, and the dosages could be increased or decreased in clinical practice. Therefore, the HbA1c level reductions observed in this study provided just an overall view before and after sitagliptin was initiated, although there may have been multiple confounding factors influencing the results, which we could not control for in the current analysis. When compared with the findings of randomized controlled trials, the baseline HbA1c level improved from 9.0%  ± 1.7% to 8.1% ± 1.5% at 6 months in the 2729 continuous sitagliptin users (P , 0.01), which resulted in a mean change of −0.96% ± 0.04% (P , 0.01). The HbA1c level reduction of approximately 1% appeared better in our study than in other clinical trial results that reported 0.6% to 0.8% reductions in HbA1c level. One possibility for the disparate results is the ethnic issue, which is probably a discrepancy in the efficacy of sitagliptin. Nonaka et al26 reported a randomized placebo-controlled Japanese study that found that sitagliptin monotherapy of 12 weeks’ duration had good efficacy, with an HbA1c level difference of 1.05% and a good safety profile. Mohan et al27 reported that sitagliptin reduced the mean HbA 1c level by 1.0% from a mean baseline of 8.7% after 18 weeks of treatment in 530 Chinese, Indian, and Korean patients in an Asian population study. The different effects of incretin-based therapy in different ethnic groups have been suggested to be due to the differences in the pathophysiology of T2DM between Caucasians and Asians. The DPP-4 inhibitors are considered more efficacious in HbA1c level reduction in the Asian population than in the Western population. Our study enrolled patients with DM from a single center in southern 212

Taiwan; 100% of the patients were Taiwanese. Therefore, a 1% reduction in HbA1c level 24 weeks after sitagliptin treatment is not surprising. In addition, a significant and large proportion of patients were treated with triple and quadruple therapies. In the high HbA1c level at baseline subgroup ($ 8.0%) with a mean HbA1c level of 9.70% ± 1.5%, the reduction in HbA1c level approached 1.26% ± 0.05% at 6 months. Thus, sitagliptin results in a greater HbA1c level reduction in patients with a high HbA1c level at baseline than in patients with a low HbA1c level at baseline. A commonly accepted hypothesis is that a single OAD can provide a greater reduction in HbA1c level in patients with a high HbA1c level at baseline compared with patients with a low HbA1c level at baseline. It was also found in a study of Korean patients with T2DM.28 In a subgroup analysis from a randomized controlled trial that enrolled 1250 patients with DM who were not well-controlled, Reasner et al29 concluded that the high baseline subgroup had an average HbA1c level of 11.4%, the metformin plus sitagliptin regimen resulted in a 3.3% reduction in HbA1c level after 18 weeks of treatment, whereas the low baseline subgroup had an average HbA1c level of 8.4% and the metformin plus sitagliptin regimen generated a 1.5% reduction in HbA1c level. In an open-label randomized study involving elderly patients in Taiwan, Chien et al30 reported that 24 weeks of sitagliptin produced a reduction in the HbA1c level of 1.3% from a baseline average HbA1c level of 9.5% (least square mean change) compared with the control group. The effectiveness of sitagliptin in patients with a high HbA1c level at baseline consistently resulted in better HbA1c level reduction than in the patients with a low HbA1c level at baseline. However, in our low HbA1c level at baseline (, 8.0%) subgroup, the HbA1c condition was shown to be flat, ranging from 7.0% to 7.3%, without significant change; that is, in our data analysis sitagliptin was seemingly ineffective for this group. We tried to determine the possible causes in this study setting, and we decided it was probably because in regular practice for low HbA1c level at baseline patients, the physicians added sitagliptin and often discontinued part of the OADs or decreased the dosages of the original OADs to avoid some adverse effects. Unlike the HbA1c level $ 8.0% group, for which including sitagliptin is more likely to be a pure add-on, for patients with HbA1c level , 8.0%, the other therapeutic classes of OADs were sometimes decreased or discontinued. For this patient subgroup, when sitagliptin was added to the OAD regimens, SU use was discontinued or its dose was decreased at the same time to avoid potentially hypoglycemic

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Effectiveness of Sitagliptin in Patients With T2DM

symptoms. This type of regimen adjustment was not uncommon, and it might dilute the real efficacy of sitagliptin in the relatively low HbA1c level at baseline subgroup in our study. In the manual chart review processes, we found it was very complicated and often impossible to categorize the repeated adjusting or changing prescription patterns due to the many available choices. So we could not clarify why the low HbA1c level at baseline patients did not benefit from adding sitagliptin. As a result, the approaches that clinicians took to adjusting the OAD regimen were interesting. Besides the adverse effects of the original OAD regimen, such as hypoglycemia or weight gain, many other reasons might also be considered, such as the durability of OADs7,10 or the potential benefits (other than glucose-lowering) of DPP-4 inhibitors in patients with DM, including cardiovascular, neurological, and renal protection, which is yet to be confirmed in outcomes trials.31,32 In the current study, the reduction in HbA1c level was apparent after 3 months of treatment, and persisted for 12 months. Williams-Herman et al33 maintain that DPP-4 inhibitors are a novel class of OADs with potentially good durability, especially in combination with metformin. At the 2-year follow-up, sitagliptin continued to improve the homeostatic model assessment of β-cell function, thus likely demonstrating good drug durability.33 In actual practice, although the OAD regimens were continuously adjusted or changed, the current study found that sitagliptin was effective and sustainable for 1 year, both early at 3 months and even later at 12-month follow-up. Goal attainment is of importance to minimize the risk of long-term consequences associated with T2DM. An abundance of evidence suggests that many of the long-term complications of the disease result from poor glycemic control. According to the results of the United Kingdom Prospective Diabetes Study,34 each 1% reduction in HbA1c level in patients with T2DM is associated with a 37% decrease in the risk of microvascular complications and a 21% decrease in the risk of any endpoint or death related to DM. The latest ADA HbA1c goal recommendation for the general diabetic population is , 7.0%.4,5 For frail patients, a patient-centered approach is the key; that is, a less stringent target such as 8% is also acceptable and reasonable depending on patient characteristics.5 Our retrospective study found that just before and 24 weeks after sitagliptin was prescribed, the goal (HbA1c level  , 7.0% with a baseline of 9.1%) attainment rate improved to 22.7% at 3 months and 23.6% at 6 months, and thereafter was sustained to 12 months (20.8% at 9 months

and 20.4% at 12 months). There was a crude 2.6-fold difference at 6 months, compared with the baseline goal attainment rate. The average goal attainment rate after sitagliptin was prescribed at least doubled at different time points throughout the study period; however, other possible causes should be addressed as well in actual practice. In Taiwan, Yu et al reported on the results of a national survey of DM health promotion institutes. These institutes disclosed trends of ABC control in 2 nationwide surveys in 2006 and 2011 and found that regarding T2DM control, the HbA1c goal attainment rate of 32.4% in 2006 improved to a rate of 34.5% in 2011 (P , 0.001).35 That is, there was an improvement of individual and overall attainment of DM goals during these 5 years in Taiwan. The authors anticipate that these improvements will translate into reductions of macro- and microvascular complications, in part due to the recent implementation of several DM patient care models and initiatives. These programs were designed to increase disease awareness and medication compliance, to instruct patients on how to implement a good diet and exercise plan, and to provide methods to manage the adverse effects of OADs. Sitagliptin has demonstrated its 2 principal advantages of less frequent hypoglycemic episodes and weight neutrality in several clinical trials,15–19 and provided physicians with a good option for better glycemic control in patients with T2DM, without the concerns about the potential adverse effects typically experienced with other classes of OADs. Based on our study results, DPP-4 inhibitors, such as sitagliptin, which were launched in Taiwan during the period of these 2 nationwide surveys, might also serve as a factor to improve overall DM control. The safety profile and tolerability of these new class DPP-4 inhibitors appear to be better than those of the conventional and older treatments, and enable clinicians to be less concerned about intensively controlling their patients to achieve the treatment goal. The longer a patient has been diagnosed with T2DM, maintaining glycemic control becomes more difficult, especially with monotherapy. Adding additional classes of oral agents, glucagon-like peptide-1 receptor agonists, or insulin to the oral monotherapy is usually required. In addition, the efficacy, safety, tolerability, and drug durability are always considered in clinicians’ prescription behaviors. As seen in this report, the DPP-4 inhibitor sitagliptin provides clinicians with a treatment option to add to the original OAD regimen.

Limitations

There were several limitations to this study. First, there were many confounding factors in this retrospective, uncontrolled

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Tse-Ying Chen and Ching-Jung Hsieh

study. In an actual clinical setting, it is difficult to exclude or avoid confounding factors; however, the data retrieved from the systematic review of the medical charts were informative because they reflected actual cases. The results can complement randomized controlled trial data, which would exclude the great majority of the patients analyzed in the current study. Second, it cannot be denied that the improvement in the study cohort resulted from other causes, such as increased disease awareness, enhancement of diet and exercise control, and dosage and regimen adjustment of other OADs. Third, the study did not collect data beyond 12 months, so it cannot confirm whether or not the treatment’s effectiveness continued. We need more studies to observe the long-term effectiveness of adding sitagliptin to the existing oral hypoglycemic agent regimen. Fourth, although Chang Gung Memorial Hospital is the largest medical center in south Taiwan, with . 12 000 patients with T2DM, the findings of this study cannot be generalized to other patients with DM.

Conclusion

This retrospective chart review study has provided an overview of the effectiveness in a large hospital before and after treatment with sitagliptin. Glycemic control in the patients with DM improved significantly, and a clinically meaningful HbA1c level reduction was observed, as well as an improvement in the goal attainment rate, with sustained effects # 1 year and high treatment compliance with sitagliptin. This study has used a retrospective medical chart review and can provide useful data for clinicians and health care professionals involved in the treatment of patients with T2DM.

Conflict of Interest Statement

Tse-Ying Chen, MD, and Ching-Jung Hsieh, MD, have no conflicts of interest to declare.

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Real-world effectiveness of sitagliptin as add-on therapy in patients with type 2 diabetes mellitus.

To assess the effectiveness of sitagliptin in glycemic control in a clinical practice...
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