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Original Article

doi: 10.1111/joim.12293

Comparison of the effects on glycaemic control and b-cell
function in newly diagnosed type 2 diabetes patients of
treatment with exenatide, insulin or pioglitazone: a
multicentre randomized parallel-group trial (the
CONFIDENCE study)
W. Xu1,*, Y. Bi2,*, Z. Sun3,*, J. Li1, L. Guo4, T. Yang5, G. Wu6, L. Shi7, Z. Feng8, L. Qiu9, Q. Li10, X. Guo11, Z. Luo12,
J. Lu13, Z. Shan14, W. Yang15, Q. Ji16, L. Yan17, H. Li18, X. Yu19, S. Li20, Z. Zhou21, X. Lv22, Z. Liang23, S. Lin24, L. Zeng1,
J. Yan1, L. Ji25 & J. Weng1
From the 1Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, the Third Affiliated Hospital
of Sun Yat-sen University, Guangzhou; 2Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School;
3
Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, Medical School, Southeast University, Nanjing; 4Department of
Endocrinology, Beijing Hospital of the Ministry of Public Health, Beijing; 5Department of Endocrinology, the First Affiliated Hospital of
Nanjing Medical University, Nanjing; 6Department of Endocrinology, the Affiliated Hospital of Guangdong Medical College, Zhanjiang;
7
Department of Endocrinology, Affiliated Hospital of Guiyang Medical College, Guizhou; 8Department of Endocrinology, the First Affiliated
Hospital, Chongqing Medical University, Chongqing; 9Department of Endocrinology, the Affiliated Hospital of Inner Mongolia Medical
University, Hohhot; 10Department of Endocrinology, the Second Affiliated Hospital of Harbin Medical University, Harbin; 11Department of
Endocrinology, Peking University First Hospital, Beijing; 12Department of Endocrinology, the First Affiliated Hospital of Guangxi Medical
University, Nanning; 13Department of Endocrinology, Chinese People’s Liberation Army General Hospital, Beijing; 14Department of
Endocrinology, the First Affiliated Hospital of China Medical University, Shenyang; 15Department of Endocrinology, China–Japan Friendship
Hospital, Beijing; 16Department of Endocrinology and Metabolism, Xijing Hospital affiliated to the Fourth Military Medical University, Xi’an;
17
Department of Endocrinology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou; 18Department of Endocrinology, the
First Affiliated Hospital of Kunming Medical University, Kunming; 19Department of Endocrinology, Tongji Hospital, Tongji Medical College of
Huazhong University of Science and Technology, Wuhan; 20Department of Endocrinology, Qingyuan People’s Hospital, Qingyuan;
21
Diabetes Centre, Institute of Metabolism and Endocrinology, the Second Xiangya Hospital and Key Laboratory of Diabetes Immunology,
Ministry of Education, Central South University, Changsha; 22Department of Endocrinology, General Hospital of Beijing Military Region,
Beijing; 23Department of Endocrinology, First Affiliated Hospital of Shenzhen University, Shenzhen; 24Department of Endocrinology, the First
Affiliated Hospital, Shantou University Medical College, Shantou; and 25Department of Endocrinology, Peking University People’s Hospital,
Beijing, China

Abstract. Xu W, Bi Y, Sun Z, Li J, Guo L, Yang T, Wu
G, Shi L, Feng Z, Qiu L, Li Q, Guo X, Luo Z, Lu J,
Shan Z, Yang W, Ji Q, Yan L, Li H, Yu X, Li S, Zhou
Z, Lv X, Liang Z, Lin S, Zeng L, Yan J, Ji L, Weng J
(The Third Affiliated Hospital of Sun Yat-sen
University, Guangzhou; Drum Tower Hospital
Affiliated to Nanjing University Medical School,
Nanjing; Zhongda Hospital, Institute of Diabetes,
Medical School, Southeast University, Nanjing;
Beijing Hospital of the Ministry of Public Health,
Beijing; The First Affiliated Hospital of Nanjing
Medical University, Nanjing; The Affiliated Hospital
of Guangdong Medical College, Zhanjiang;
Affiliated Hospital of Guiyang Medical College,
Guizhou; The First Affiliated Hospital, Chongqing
Medical University, Chongqing; The Affiliated
Hospital of Inner Mongolia Medical University,
Hohhot; The Second Affiliated Hospital of Harbin
Medical University, Harbin; Peking University First
Hospital, Beijing; The First Affiliated Hospital of
*These authors contributed equally.

Guangxi Medical University, Nanning; Chinese
People’s Liberation Army General Hospital,
Beijing; The First Affiliated Hospital of China
Medical University, Shenyang; China–Japan
Friendship Hospital, Beijing; Xijing Hospital
affiliated to the Fourth Military Medical
University, Xi’an; Sun Yat-sen Memorial Hospital
of Sun Yat-sen University, Guangzhou; The First
Affiliated Hospital of Kunming Medical University,
Kunming; Tongji Hospital, Tongji Medical College
of Huazhong University of Science and Technology,
Wuhan; Qingyuan People’s Hospital, Qingyuan;
Diabetes Centre, Institute of Metabolism and
Endocrinology, the Second Xiangya Hospital and
Key Laboratory of Diabetes Immunology, Ministry
of Education, Central South University, Changsha;
General Hospital of Beijing Military Region, Beijing;
First Affiliated Hospital of Shenzhen University,
Shenzhen; The First Affiliated Hospital, Shantou
University Medical College, Shantou; and Peking
University People’s Hospital, Beijing; China).
Comparison of the effects on glycaemic control

ª 2014 The Association for the Publication of the Journal of Internal Medicine

137

06%) for exenatide versus insulin (P = 0. However. J Intern Med 2015. fast- Introduction Currently. In this 48-week. Objective. aged 30–70 years. At week 48.63% to 0. long-term glycaemic control is hard to achieve because of deteriorating b-cell function [8]. a progressive disease characterized by persistent insulin resistance and declining pancreatic b-cell function [1. but comparative data on b-cell-protective therapies are lacking in the early stage of type 2 diabetes.46% to 0. exenatide. Treatment-na€ıve patients. Results. PI/I and DI were observed with all treatments. blood pressure and lipid profile. insulin or pioglitazone. 7]. parallel-group study. Antihyperglycaemic agents that can improve b-cell function or reduce its rate of decline should help to maintain good glycaemic control by changing. hence. However. multicentre.71%) with pioglitazone. Keywords: b-cell function. Design and methods. Insulin.96%) with insulin and 1. Treatment differences were 0. parallelgroup clinical trial was conducted from August 2010 to August 2012 at 25 university-affiliated hospitals in 13 provinces of China.8% ( 1.W. Exenatide versus insulin or pioglitazone in early type 2 diabetes and b-cell function in newly diagnosed type 2 diabetes patients of treatment with exenatide. and 0.55% to 2. and to compare the effects on b-cell function of all three agents in previously untreated patients. one of the most challenging threats to global public health is the increasing prevalence of type 2 diabetes mellitus. Here we evaluated the comparative glycaemic efficacy and impact on b-cell function of three antihyperglycaemic agents that have a b-cell-protective effect. The study is registered at ClinicalTrials. pioglitazone. Significant improvements from baseline in AIR. observed with exenatide. insulin or pioglitazone: a multicentre randomized parallel-group trial (the CONFIDENCE study). blood pressure. exenatide showed the greatest efficacy. disposition index (DI) and acute insulin response (AIR). in the absence of comparative studies. The primary end-point was the change in glycosylated haemoglobin (HbA1c) from baseline. 277: 137–150. insulin and pioglitazone. with newly diagnosed type 2 diabetes were recruited. as reflected in recent management guidelines [3–5].12%) for exenatide versus pioglitazone (P = 0. insulin or pioglitazone: a multicentre randomized parallel-group study) was conducted to test the hypothesis that exenatide provides noninferior glycaemic control to insulin and pioglitazone. multicentre.0%. 416 patients newly diagnosed with type 2 diabetes were randomly assigned 1 : 1 : 1 to receive exenatide. Inclusion criteria were glycosylated haemoglobin (HbA1c) 7. b-cell function improved in all treatment groups. glucose. Conclusions. the natural course of the disease.0–10.5% ( 1. avoidance of hypoglycaemic events and weight control are the goals of type 2 diabetes therapy. Secondary end-points included effects on weight. lipid profiles and b-cell function assessed by homeostasis model assessment. effects differ between agents in the early stage of type 2 diabetes. the thiazolidinedione pioglitazone and the glucagon-like peptide (GLP)-1 receptor agonist exenatide are considered to have b-cell-protective effects [9–15].185). it is still unclear whether these 138 ª 2014 The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine. or at least delaying. however.gov (number NCT01147627). Progressive b-cell dysfunction hinders the maintenance of glycaemic control in type 2 diabetes. the CONFIDENCE study (comparison of glycaemic control and b-cell function amongst newly diagnosed patients with type 2 diabetes treated with exenatide.52% to 1. 1. Achieving glycaemic control. randomized.37% (95% CI 0. It is well established that improved glycaemic control reduces the risk of diabetes-related complications [6. 277. mean [95% confidence interval (CI)] HbA1c changes from baseline were 1.002).05%) with exenatide. 137–150 ing proinsulin:insulin (PI/I). 2015. body mass index (BMI) . All three agents showed efficacy regarding glycaemic control and metabolic benefits. early initiation of b-cell-protective therapy may halt the decline in b-cell function in type 2 diabetes. Therefore.7% ( 1.23% to 1. Design and methods Study design and participants This 48-week. with the greatest improvements in DI. in newly diagnosed patients with type 2 diabetes. 2]. as well as weight. exenatide. Xu et al.20% (95% CI 0. insulin.

The 10-min acute insulin response (AIR) during IVGTT was calculated as the incremental area under the curve using trapezoidal estimation. after an overnight fast.. CA. 1. At each followed-up visit.. Insulin sensitivity during the MMT was calculated from the Matsuda index [10 000/square root of (FPG [mg dL 1] 9 FINS) 9 (mean glucose [mg dL 1] 9 mean insulin during MMT)] [17].5). severe microand macro-vascular complications. 6 and 10 min to measure insulin levels. The fasting proinsulin-to-insulin ratio (PI/I) was also calculated. HbA1c. respectively [HOMA-B = 20 9 fasting insulin (FINS)/(FPG–3. and insulin and proinsulin levels were measured centrally at the Beijing North Institute of Biological Technology. with patients instructed to stop all antihyperglycaemic therapy 2 days beforehand to avoid any acute drug effects on the collected data. HOMA-IR=FINS 9 FPG/22. USA) was injected twice daily at an initial dose of 0. increasing to 10 lg twice daily after 4 weeks. The remaining biochemical variables were assessed locally at the participating centres. amylase and lipase. history of pancreatitis and triglyceride (TG) levels ≥5 mmol L 1. NC. 137–150 139 . All baseline assessments were repeated at week 48.4 IU kg 1 daily. Patients were followed up every 4 weeks for 12 weeks and then at 12-week intervals until week 48. presence of glutamic acid decarboxylase antibodies. The protocol was approved by the institutional review board at each site in accordance with the Declaration of Helsinki. Several indices were used in this study to comprehensively evaluate b-cell function: the homoeostasis model assessment of b-cell function (HOMA-B) and the homoeostasis model assessment of insulin resistance (HOMA-IR) were used to estimate basal b-cell function and insulin resistance. lipids. the dose was then maintained or adjusted to the maximum tolerated dose. Eli Lilly and Company. with reinforcement throughout the study. anthropomorphic data. 28. Pioglitazone (Deyuan Pharmacy. adverse events and hypoglycaemia episodes were recorded. hyperosmotic state. Exenatide versus insulin or pioglitazone in early type 2 diabetes 20–35 kg m 2 and stable body weight for ≥3 months. Indianapolis. Inc. and fasting venous blood samples were collected to measure levels of fasting plasma glucose (FPG). 2015. FPG and 2-h postprandial glucose (PPG) after MMT were measured. a mixed-meal test (MMT. and hepatic dysfunction). doses were titrated based on self-monitored blood glucose levels (Table S1). increasing to 45 mg daily after 4 weeks. Cary. Jiangsu. Zhejiang. China) was initially administered at 30 mg daily. proinsulin. insulin. USA). demographic and anthropomorphic data were recorded. 20. To mimic the physiological state. an intravenous glucose tolerance test (IVGTT) was performed using 25 g glucose. HbA1c. weight and glycaemia.W. and patients were allocated using a secure Oracle-based interactive web response system (IWRS) (Real Data Medical Research Inc. HbA1c was assessed centrally at the Diabetes Centre of the Third Affiliated Hospital of Sun Yat-sen University. All patients provided written informed consent before screening. On day 2. Exclusion criteria were acute or severe chronic diabetic complications or illnesses (ketoacidosis. 40 and 44 to collect patients’ information and provide guidance. Patients who frequently experienced hypoglycaemia or could not tolerate adverse events were instructed to reduce the dose to 5 lg twice daily. China) in accordance with the sequence from the randomization list. In addition. All patients received diabetes information and lifestyle counselling at enrolment. San Diego. with 50% administered 15 min before breakfast and the remaining 50% administered 15 min before dinner. use of drugs affecting gastrointestinal motility. 162 kcal) was performed with venous blood samples collected 30 and 120 min after ingestion to determine glucose and insulin levels. Safety and tolerability were assessed at each visit. Xu et al. 4. Premixed insulin (75% insulin lispro protamine suspension and 25% insulin lispro injection. At baseline. with venous blood samples taken at 0. Minor hypoglycaemia was defined as symptoms confirmed by a blood glucose concentration ª 2014 The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine. USA) was injected subcutaneously at a dose of 5 lg twice daily. The disposition index (DI) was calculated as the insulinogenic index [MMT 0–30 min increments in insulin and glucose concentrations (mg dL 1) ratio] 9 Matsuda index [18]. insulin or pioglitazone. a randomization list was generated using Statistics Analysis System (SAS) (SAS Institute Inc.5] [16]. lactic acidosis.. Exenatide (Amylin Pharmaceuticals. 277. Procedures To assign patients randomly in a 1 : 1 : 1 ratio to receive exenatide. telephone calls were scheduled at weeks 16. 2. 32. IN. Thereafter.

Significance was defined as P < 0. Differences in HbA1c changes between treatments were as follows: 0. 416 were eligible and randomly assigned to receive exenatide. TG level and b-cell function as covariates. Similar methods were used in post hoc analyses to compare the proportions of patients achieving HbA1c <7. 108 patients per group were required to provide 90% power to show noninferiority of exenatide compared to insulin or pioglitazone.5% at week 48 amongst treatment groups. body weight. centre. with treatment.5%. similar findings were obtained from analyses of the intentionto-treat population (data not shown). In this per-protocol population. with centre and baseline HbA1c as covariates. 137–150 Normally distributed and continuous variables are presented as means SE. 1). 2d). At week 48. age and baseline BMI.63% to 0. Data were analysed using SPSS 20. with treatment. exenatide was noninferior to insulin and pioglitazone.0 (IBM corporation. thus. NY. The 342 patients who completed the study (Fig. these patients comprised the intention-to-treat population and were evaluated for safety (Fig. 3). DI and AIR). mean HbA1c decreased significantly from baseline in all treatment groups (Table 1). Fasting plasma glucose and PPG levels decreased with all treatments (Fig. insulin or pioglitazone. blood pressure and lipid profiles. 2a. At least three-quarters of the patients in each treatment group achieved HbA1c<7.37% (95% CI 0. Major hypoglycaemia was defined as an event requiring the assistance of another person to administer carbohydrate. with prompt recovery after selfadministered carbohydrate. New York. USA).20% [95% confidence interval (CI) 0. with treatment. with significantly more patients assigned to exenatide achieving HbA1c ≤6.12%) for exenatide versus pioglitazone. 140 ª 2014 The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine. mean reductions from baseline were similar between treatment groups (Table 1). PI/I. Table 1). glucagon or other resuscitative treatment. Mixed-effect logistic models were used to compare the proportions of patients achieving HbA1c <7% and ≤6.034 between groups. At week 48.05. The efficacy results presented here are from analyses of the per-protocol population.4% for the difference in HbA1c change from baseline between treatments. Results Of the 440 patients screened. Study end-points The primary end-point was the comparison of change from baseline in HbA1c at 48 weeks in the three treatment groups. No correlation between change in body weight and . HOMA-IR and PI/I) were logarithmically transformed before analysis. Non-normally distributed variables (HOMA-B. Overall. Baseline characteristics in this population were similar between treatment groups (Table S2). Statistical analyses The primary end-point was analysed using mixedmodel repeated-measures analysis of covariance (ANCOVA) to estimate the change in HbA1c. Mean weight change was significantly different between the exenatide group and the insulin and pioglitazone groups from weeks 4 and 8 until the end of the study (Table 1 and Fig.5% (Fig. Other continuous variables were similarly analysed. Glycaemic and metabolic control HbA1c changes over the course of follow-up in those who completed the study are shown in Fig.0% and b-cell function improvement by treatment. centre and baseline HbA1c as covariates. hence. Safety and tolerability were also assessed. as well as in the intention-to-treat population for supporting analysis. and the comparative effects on b-cell function (HOMA-B. which included all randomly assigned patients who received at least one dose of study drug.0%. b-cell function was compared amongst groups using ANCOVA. Exenatide versus insulin or pioglitazone in early type 2 diabetes <3. baseline BMI and baseline HbA1c. the only difference at baseline between groups was a lower PPG in the exenatide group (P = 0. Xu et al.c).W.46% to 0. 2015. with a predefined margin of 0.0% and ≤6.9 mmol L 1. The estimated dropout rate was 20%. Secondary end-points included the proportion of patients in each group achieving HbA1c targets of <7. 405 patients were required for enrolment. Safety analyses were conducted in the intention-to-treat population. 1) were included in the per-protocol efficacy analyses. and 0. gender. 2b. 277.06%] for exenatide versus insulin. 2 days after stopping treatment. centre and baseline value of the dependent variable as covariates. with calculations carried out on the study population stratified by age. gender. Efficacy analyses were conducted in the per-protocol population.

no significant differences from baseline were observed with insulin or piog- litazone (Table 1). At week 48. mean waist circumference decreased with exenatide treatment. 137–150 141 . 2015. HbA1c reduction was observed in any group. 1 Trial profile. although significant decreases in systolic and diastolic blood ª 2014 The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine. 277.W. Xu et al. Exenatide versus insulin or pioglitazone in early type 2 diabetes Assessed for eligibility (n = 440) Excluded (n = 24) • Did not meet inclusion criteria (n = 24 ) – HbA1c >10% (n = 2) – HbA1c <7% (n = 22) Randomly assigned (n = 416) Allocated to exenatide (n = 142) • Received allocated intervention (n = 142 ) Lost to follow-up (n = 13) Discontinued intervention (n = 19) • • • • • Serious adverse event (n = 3) Adverse event (n = 8) Migration (n = 4) Poor compliance (n = 2) Withdrew consent (n = 2) Completed study (n = 110) Allocated to insulin (n = 138) • Received allocated intervention (n = 138) Allocated to pioglitazone (n = 136) • Received allocated intervention (n = 136) Lost to follow-up (n = 14) Discontinued intervention (n = 10) Lost to follow-up (n = 10) Discontinued intervention (n = 8) • • • • • Serious adverse event (n = 2) Adverse event (n = 2) Migration (n = 2) Poor compliance (n = 4) Withdrew consent (n = 2) • Adverse event (n = 2) • Poor compliance (n = 1) • Withdrew consent (n = 2) • Poor glucose control (n = 1) Completed study (n = 118) Completed study (n = 114) Analysed for safety (intention-totreat) (n = 142) Analysed for safety (intention-totreat) (n = 138) Analysed for safety (intention-totreat) (n = 136) Analysed for efficacy (per protocol) (n = 110) Analysed for efficacy (per protocol) (n = 114) Analysed for efficacy (per protocol) (n = 118) Fig. Decreases in mean systolic and diastolic blood pressures at 48 weeks were not statistically different between groups.

4) 65 (55.406 NA NA NA 5.484 NA NA NA Change from 1.8  0.1 8.5  0.9 3.001 <0.1  0.3 3.020 1.1 0.754 0.3† 3.1 0.6* 89.1  0.1  0.5  0. Exenatide versus insulin or pioglitazone in early type 2 diabetes Table 1 Baseline characteristics and changes from baseline at week 48 in the per-protocol population (n = 342) P-value Characteristics n Exenatide Insulin 110 Men (%) 114 74 (67.127 NA NA NA 79  1 80  1 0. 137–150 .002 0.928 baseline 2-h postprandial plasma glucose (mmol L Baseline Change from 13.2  0.1 0.8 0.001 0.1) Weight (kg) Baseline Change from 71.2  0.001 0.171 Pioglitazone Overall 118 70 (61.4  0.342 0.0  0.1 5.2 9.019 0.7  0.7  0.2* 0.001 baseline Body mass index (kg m Baseline 2 ) 25.444 NA NA NA Change from 1.0  0.191 baseline Total cholesterol (mmol L Baseline Change from 1 ) 5.002 0.4 <0.3 25.317 Change from baseline HbA1c (%) baseline Fasting plasma glucose (mmol L 1 ) Baseline 8.3  0.001 <0.273 NA NA NA <0.034 0.0 1.3) Exenatide Exenatide vs. 2015.353 NA NA NA baseline Systolic blood pressure (mmHg) Baseline Change from 126  1 41 † baseline Diastolic blood pressure (mmHg) Baseline Change from 80  1 31 † 11 3  1* 0.8  0.0  0.4  0.9  0.9  0.185 0.5  0.1 † 0.030 0.6  1.1 <0.7  1.8  0.8  1.001 0.3 1.4* baseline Waist (cm) Baseline Change from 90.9  0.2 9.2* 1.1* 0.W.9  0.8 89.8  0.5 <0.6  0.1  0.001 <0.1† Baseline 8.4  0. 277.0  0.001 <0.2 0.742 NA NA NA 01 11 0. Insulin vs.1 69.3 0.1 8.1 0.0  0.403 0  0. Xu et al.4* 3.001 25. insulin pioglitazone pioglitazone 0.1 0.6  0.055 NA NA NA 125  1 125  1 0.4  0.1  0.4* 14.491 NA NA NA 0  0.000 0.3* 2.3* 0.5  0.8  0.1* 1.085 NA NA NA <0.2  0.4 0.2  0.1 baseline 142 ª 2014 The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine.3 1 ) 14.1* 1.1* 0.8  0.129 NA NA NA 0.187 NA NA NA 0.168 NA NA NA 70.3 3. vs.

000 <0.5  0.4  0.3  0.2 ) 2. 277.110 NA NA NA baseline Lg PI/I baseline DI Baseline 0.03 0.1 3.7  0.5  0.0  0.6  0.6  0.14† 0.2  0.001 <0.1  0.02 0.20  0.02* <0.715 NA NA NA Change from 0.4  0.W.946 NA NA NA Change from 29  8 13  8 17  9 0.5  0.395 0.5  0.42* 0.001 1.4  0.0  0.02 0.1 Baseline Exenatide Insulin baseline HDL cholesterol (mmol L 1 ) 1.6  0.2  0.2  0.14 0.9  0.1 Change from Exenatide vs.03  0.7  0.000 baseline ª 2014 The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine.03 <0.000 0.2  0.9  0.009 <0.033 1.14  0.438 baseline Lipase (U L 1 ) Baseline 71  8 68  8 68  9 0.30 4.289 NA NA NA baseline 1 Amylase (U L ) 50  2 Baseline Change from 9  2* 48  2 5  2† 53  2 5  2† 0.005 0.698 0.001 1.08 0.03 0.2  0.3  0.1† 0.4  0.03 0.38* <0.1 3.308 NA NA NA 0.6  0.05* baseline Lg HOMA-IR Baseline 0.5  0.025 0.02  0.1 2. insulin pioglitazone pioglitazone 0.03 Change from baseline LDL cholesterol (mmol L 1 ) Baseline 3.4  0.04 0.7  0.1 0. vs.1 0.973 NA NA NA Change from 1.39† 0.03 1.03 0.176 NA NA NA 1.088 NA NA NA 0.02  0.3  0.767 NA NA NA Change from 0.5  0.23  0.16  0.03 0.07* 0.001 Pioglitazone Overall 1.14† 0.050 NA NA NA 0.03 Baseline † 0.45 3.008 1.000 <0.23 0.584 NA NA NA 0.4  0.001 baseline Matsuda index Baseline 4.033 1.4  0.634 <0.1† 0.03* 0.2  0.02 Change from 0.03 1.03 0.03* <0. Xu et al.1  0.118 0.027 0.001 baseline Lg HOMA-B Baseline Change from 1.6  0.2  0.08  0.07* 0. Insulin vs.001 NA NA NA <0.03  0.22 4. 137–150 143 .084 0.43  0.001 Baseline 0.078 Change from 3.3  0.030 0.02 0. 2015.001 0.02 0.001 NA NA NA <0.10* 0.15 0.1 0.001 0.1 0. Exenatide versus insulin or pioglitazone in early type 2 diabetes Table 1 (Continued ) P-value Characteristics Exenatide Triglycerides (mmol L 1 † 0.

003 (b) 85 75 50 Fig. insulin pioglitazone pioglitazone 0. 137–150 INS PIO Fig. exenatide.027 75 Patients (%) Patients (%) 144 80 75. insulin. †P < 0. 3 Proportions of patients achieving target glycosylated haemoglobin (HbA1c) concentrations.05 between treatment groups. AIR. black circle. (a) HbA1c <7.3 80 77. vs.9  8.507 NA NA NA Pioglitazone Overall 10. homeostasis model assessment of insulin resistance. (c) 2-h postprandial glucose (PPG). pioglitazone. HbA1c. Data are presented as mean (SE). Antihyperglycaemic therapies were stopped 2 days before the last visit at week 48. INS.4  10. black square.3 57.W.5 65 65 60 55 55 PIO 76. .05 after therapy versus baseline. exenatide.0 baseline Variables are expressed as mean  SE or n (%).4 70 EXE P = 0. †P < 0. homeostasis model assessment of b-cell function. Xu et al.922 NA NA NA 0. 50 61. *P < 0.001 after therapy versus baseline. PIO. (b) Fasting plasma glucose (FPG). not applicable. glycosylated haemoglobin. PI/I. EXE.0 14. 2 Mean changes over time in glycaemic control and weight. 277.001 between treatment groups. HOMA-B. insulin. fasting proinsulin-to-insulin ratio. HOMAIR. Exenatide versus insulin or pioglitazone in early type 2 diabetes Table 1 (Continued ) P-value Characteristics AIR (lIU mL 1 Baseline Change from Exenatide Insulin Exenatide Exenatide vs. 2015.9 70 60 INS P = 0. (a) (b) (c) (a) 85 (d) 84. acute insulin response. NA.1* † 30.4  10.*P < 0.0 42. (a) Glycosylated haemoglobin (HbA1c) concentrations. DI.6  6.0* 9 min) 11. Insulin vs.0%. disposition index.5%. pioglitazone.9 EXE ª 2014 The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine.7  5. (b) HbA1c ≤6. and (d) change in weight. Black triangle.0 31.4  5.

9  0. Effect of treatments on b-cell function At week 48. demonstrated by greater changes in DI from baseline to 48 weeks. occurred at similar rates in the other treatment groups. and an increase in HDL cholesterol (P < 0.05 vs. as well as AIR (which represents b-cell function during the stimulated state after intravenous glucose injection). Amylase levels increased in all groups with no clinical significance. baseline for all variables). n = 1). Exenatide versus insulin or pioglitazone in early type 2 diabetes pressures were observed with exenatide (P < 0. gender.05 vs.001 vs. Treatment-related adverse events leading to study withdrawal occurred in eight patients receiving exenatide (nausea and vomiting n = 7. respectively (Table 2). n = 1 each). Improvements from baseline were similar in all treatment groups with regard to PI/I. whereas lipase levels after 48 weeks of treatment were similar to those at baseline. were achieved with exenatide treatment than with pioglitazone or insulin (Table S3). and mean weight change was 2. 4). acute insulin response. 137–150 145 . In the 24 patients who completed the study treated with 5 lg exenatide twice daily. PI/I. provides an indication of b-cell function during the fasting state) increased in patients treated with insulin (P < 0.001 vs. baseline BMI or baseline HbA1c. increased significantly in all treatment groups (P < 0. 277. The greatest mean improvements from baseline in DI and AIR were observed in the exenatide treatment group (Table 1 and Fig. HOMA-B (which. baseline for insulin and pioglitazone). fasting proinsulin-to-insulin ratio. Subgroup analyses After stratified by age. PI/I. including one cerebral infarction in each group. DI and AIR) in different groups. P < 0. reported most frequently in the insulin group.5  0. On the reduced dose.001) (Table 1). 4 Comparison of change in b-cell function (HOMA-B.W. two receiving insulin (allergy and weight gain. baseline for exenatide. 19]. Xu et al. AIR. HOMA-B.5%. No major hypoglycaemic episodes were reported during the study. total cholesterol and LDL cholesterol levels.2%). However. mean HbA1c change was 1. the data showed that patients who were aged <50 years or who had a baseline BMI 24–28 kg m 2 were more likely to achieve HbA1c <7% when treated with exenatide than with pioglitazone or insulin. together with PI/I. baseline). disposition index. The most commonly observed adverse events were gastrointestinal reactions and oedema in the exenatide and pioglitazone groups. Upper respiratory tract infections. Exenatide treatment resulted in improvements in overall lipid profiles.003). greater improvements in b-cell function. 18 of 138 ª 2014 The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine. the study was underpowered to determine with any statistical significance the characteristics of patients who would benefit from the lower dose (Table S4). homeostasis model assessment of b-cell function. rash. In these younger patients (aged <50 years). HDL cholesterol increased with pioglitazone (P < 0. 20 (83%) patients achieved the HbA1c target of <7%.05 vs. and 17 (71%) achieved HbA1c ≤6. and LDL cholesterol decreased with insulin (P < 0. baseline).8 kg (P = 0. 2015. Fig.001).001). DI. with significant decreases in TG. Safety Thirteen serious adverse events were reported (Table S5). which provides a measure of b-cell function during the stimulated state under near-physiological conditions of food intake via the gastrointestinal system [18.3% (P < 0. DI. Incidences of minor hypoglycaemia occurred in 13 of 142 (9. n = 1 each) and two receiving pioglitazone (arrhythmia and oedema.05) (Table 1). and one case each of pancreatitis and cholangiocellular carcinoma in the exenatide group. and a significant decrease in diastolic blood pressure alone was found with pioglitazone (P < 0. Changes in HOMA-B and PI/I are logarithmically transformed.

4) 0 3 (2.3) 1 (0.1%). respectively.W.0%) and 5 of 136 (3.7) 2 (1.7) 1 (0.2) Rash 1 (0.0% than thiazolidinediones or insulin glargine [20].9) Vomiting 15 (10.7) Abdominal distension 8 (5.1) 2 (1.1) 3 (2.1) 4 (2.7) 7 (5.9) Injection-site reaction 4 (2.5) 5 (3. the present study provides the only direct comparison of the impact on glycaemic control.7) Toothache 3 (2.1) 1 (0.9) 13 (9. insulin and 146 ª 2014 The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine.6) 0 1 (0. 2015.4) 0 Palpitations 4 (2.1) 1 (0.6) 0 0 Diarrhoea Upper respiratory tract 6 (4.1) Table 2 Treatment-emergent adverse events in intention-totreat (safety) population (n = 416) infection Oedema 0 0 12 (8.6) 1 (0.7%) patients treated with exenatide.7) 1 (0. Exenatide demonstrated noninferior glycaemic control compared to insulin and pioglitazone. This is consistent with a metaanalysis showing that GLP-1 receptor agonists enabled a higher proportion of patients to achieve HbA1c <7.7) 0 Data are presented as n (%) of the safety (intention-to-treat) population.9) Chest tightness 2 (1. cardiovascular disease risk factors and b-cell function of three different classes of antihyperglycaemic agents considered to have a b-cell-protective effect (exenatide.5) 2 (1.7) 1 (0.2) 16 (11.2) 4 (2.1) 2 (1. during the early course of type 2 diabetes over a period of 48 weeks. Exenatide versus insulin or pioglitazone in early type 2 diabetes Exenatide Insulin Pioglitazone Adverse event (n = 142) (n = 138) (n = 136) Nausea 37 (26. especially with exenatide.5) 0 Weight gain 0 1 (0.7) Dizziness 18 (12. (13.7) Headache 3 (2.5) 2 (1.5) Skelalgia 3 (2.8) 6 (4. 277.5) Constipation 6 (4.2) Arthralgia 0 1 (0. The proportions of patients who achieved HbA1c targets were greatest with exenatide. Discussion To our knowledge. Another possible explanation for the greater HbA1c reduction is that Asian populations have higher . hence.7) Fatigue 3 (2.5) Blurred vision 2 (1.7) 4 (2.8) 2 (1.5) 2 (1.2) 0 1 (0.4) 1 (0.8) Numbness 4 (2. 137–150 pioglitazone). probably because patients in the CONFIDENCE study were newly diagnosed and had a relatively low baseline HbA1c (mean 8. the primary outcome of this study was achieved. Xu et al. Exenatide was reduced from 10 lg twice daily to 5 lg twice daily in 29 patients who experienced frequent hypoglycaemic episodes or could not tolerate adverse events.7) 3 (2. Glycaemic control was maintained for the study duration with all three agents. in this study than previously reported [21–23]. the dose was reduced in six of these patients because of frequent episodes of confirmed hypoglycaemia (with no further hypoglycaemia reported after exenatide dose reduction) and in nine patients because of frequent hypoglycaemia symptoms without blood glucose confirmation.4) 11 (8.7) Appetite loss 8 (5.7) 0 Allergy 0 1 (0. insulin and pioglitazone.7) 4 (2.8) 2 (1. Higher proportions of patients achieved HbA1c targets with all three agents.

pioglitazone or insulin glargine. suggestive of more improvement in basal b-cell function and attenuation of b-cell overstimulation. twicedaily exenatide was associated with a lower risk of cardiovascular disease events than other glucose-lowering therapies [27]. Insulin had the greatest effects on HOMA-B and PI/I. dyslipidaemia and hypertension are well-established risk factors for cardiovascular disease. the most ‘physiologically representative’ index of b-cell function [18. These findings suggest that newly diagnosed patients can achieve good glycaemic control following early treatment with these agents. 26]. we evaluated not only HOMA-B and PI/I (which represent the fasting state) and AIR (which represents the stimulated state after intravenous glucose intake). 19]. 277. 28] and was higher with exenatide than with the other two treatments. 26]. Unlike HOMA-B and PI/I. but also DI. The CONFIDENCE study provides supporting evidence for initiating early b-cell-protective treatment in treatment-na€ıve patients with newly diagnosed type 2 diabetes and suggests that exenatide may offer the greatest benefits of the three agents (exenatide. DI is not based on fasting state variables alone. In three other trials [23. these data are in agreement with those of previous studies by Bunck and colleagues comparing b-cell function with insulin glargine versus exenatide over a period of either 1 or 3 years [12. DI provides a more comprehensive assessment of b-cell function by taking into account intestinal incretin hormone’s action and the interaction between changes in insulin sensitivity and insulin secretion. b-cell function improvements were maintained 4 weeks after cessation of treatment with exenatide.W. indicating that early initiation of b-cell-protective treatment is likely to contribute to halting the decline of b-cell function in type 2 diabetes. Indeed. onceweekly exenatide showed an absolute benefit in achieving American Diabetes Association-recommended treatment goals compared to metformin. Exenatide versus insulin or pioglitazone in early type 2 diabetes PPG levels than Caucasians [24] and exenatide had a greater effect on PPG than FPG. Subgroup analyses in the present study to identify patient characteristics that are associated with greater benefits from these interventions indicated that younger (<50 years) patients may experience greater benefits with exenatide than with insulin or pioglitazone in terms of glycaemic control. 2015. Improvements in b-cell function were observed irrespective of treatment. The incidence of adverse events with all treatments was generally consistent with that of previous reports [21. better improvements in blood pressure and lipid profiles than the other two treatments. sitagliptin. and the CONFIDENCE study were that in the former. Although DI. the greatest improvements were seen with exenatide. CONFIDENCE is the first comparative study with different classes of antihyperglycaemic agents to investigate b-cell function in such detail in treatment-na€ıve patients with early disease.5% than in previous studies. Longer-term evaluation of these treatments will be required to determine whether the beneficial effects we reported are maintained over time.2% of patients). 25. the investigated treatments were used as ‘add-on’ therapy to metformin and the baseline duration of diabetes in the study population was longer than 4 years. we report here for the first time that the effects on b-cell function varied between treatments. it is derived from the oral MMT. This finding is consistent with previous studies. To elucidate b-cell function. The incidence of minor hypoglycaemia was highest with insulin (reported by 13. These studies showed a superior effect of exenatide in terms of b-cell function compared with insulin glargine. This difference may be due to the fact that (i) a greater proportion of patients achieved HbA1c <7% and ≤6. Given that cardiovascular complications account for 80% of the risk of mortality in type 2 diabetes and that obesity. to provide an indication of b-cell function modulated by insulin resistance under near-physiological conditions. Therefore. To our knowledge.2% with exenatide was higher than previously reported in Western populations [23. Xu et al. but similar to that observed in Chinese patients (12%) [29]. 13]. Although no sustained effect on b-cell function was observed after cessation of 1 year of treatment [12]. the positive metabolic effect seen with exenatide is supported its use in this patient population. but not insulin glargine [13]. which is a more physiological route of glucose administration than the IVGTT. 137–150 147 . 22. 25. In a retrospective analysis of 383 525 patients. after a 3-year study extension. which may have increased the risk of hypoglycaemia and (ii) the exenatide dose may have ª 2014 The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine. the incidence of minor hypoglycaemia of 9. insulin and pioglitazone) in terms of improving b-cell function. improved with all treatments. and will ultimately delay progression of disease. Of note. The main differences between the studies of Bunck et al. Exenatide treatment was associated with greater weight loss.

However. JW is an advisory board member for Eli Lilly and Co. organized and supervised the study. USA. was not included as a comparator in this study. to some degree. Exenatide may offer the most promising option for type 2 diabetes management with regard to glycaemic efficacy. insulin or pioglitazone on glycaemic control and b-cell function in patients with newly diagnosed type 2 diabetes. for the first time. and the noninferiority of exenatide compared to metformin in terms of glycaemic control has been shown previously in treatment-na€ıve patients [23]. PhD of MediTech Media Asia Pacific Pte Ltd. 137–150 Authors’ contributions JW designed. for his constructive comments on the manuscript. demonstrating the efficacy of low-dose exenatide in this population. 148 ª 2014 The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine. Nevertheless. LJ. Oxford. Exenatide versus insulin or pioglitazone in early type 2 diabetes been too high in this population. and co-wrote the first draft of the manuscript. In addition. the open-label design reflects real-world clinical practice. UK. in the absence of the confounding effects of other antidiabetic medications. and co-wrote the first draft.9%. the most popular antihyperglycaemic agent. the National Science Fund for Distinguished Young Scholars (81025005). The findings from the CONFIDENCE study on the use of these three classes of antidiabetic agents in type 2 diabetes can therefore be useful to inform clinicians’ and patients’ shared decisions regarding the treatment of early-stage type 2 diabetes. identification and assessments of the primary data sources for each participating study centre. When patients who experienced hypoglycaemia whilst taking 10 lg but not 5 lg twice daily were excluded. . MB. analysis and interpretation of data. A limitation of this study is the open-label design. We thank all the site investigators for conducting the study and the study participants. More evidence of the efficacy of antihyperglycaemic agents is required because of recommendations for a move towards more patient-centred care [30]. CA. USA. and Amylin Pharmaceuticals.W. as oral presentations [32]. PA. A major strength of this study is the prospective. We are grateful to Professor Rury Holman. Acknowledgements This investigator-initiated study was funded by the Key Projects of Clinical Disciplines of Hospitals Affiliated to Ministry of Health from Ministry of Health of the People’s Republic of China. supported by a grant from Bristol-Myers Squibb and Astra Zeneca. investigator-initiated trial research funds from Eli Lilly and Co. randomized. collection. or writing the report. WX also contributed to assisting JW to run the study. it may be considered a study limitation that metformin. Conflict of interest statement LJ is an advisory board member for Eli Lilly and Co. ChB. Furthermore.. and Professor Yuantao Hao. the effects of monotherapy with exenatide. comprehensive metabolic benefits and the potential to delay the natural course of the disease. and Bristol-Myers Squibb. The sponsors had no role in the study design. parallel-group design in which we compared. interpret the data. Part of this study was presented at the 72nd Scientific Sessions of the American Diabetes Association. which is similar to the rate observed in the pioglitazone group. JW had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. we did not include metformin because it is not considered to be a b-cell-preserving agent. in June 2012 [31] and 74th Scientific Sessions of the American Diabetes Association at San Francisco. weight loss. FRCP from the Diabetes Trials Unit at Oxford University. 277. and the 5010 Project of Sun Yat-sen University. We acknowledge receiving editorial support from Samantha Santangelo. initiating b-cell-protective treatment with exenatide. Xu et al. None of the other authors has any competing interests to declare. Philadelphia. 2015. All authors contributed to patients’ followup. WY and WX contributed to the study design. PhD from the School of Public Health. 83% of patients who completed this study on the reduced dose still achieved optimal glycaemic control. which could have introduced bias due to (i) increased patient expectations of injected treatment or concern about injection and hence reduced adherence to therapy or (ii) increased vigilance by the investigators with regard to injected treatment. in June 2014. insulin or pioglitazone in newly diagnosed patients with type 2 diabetes improved glycaemic control and b-cell function. the incidence of hypoglycaemia decreased to 4. In conclusion. JLu. data collection. Inc. Sun Yat-sen University for sample size estimation and statistical analyses.

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(fax: +862085252107. stratified by age. Exenatide versus insulin or pioglitazone in early type 2 diabetes metformin-controlled. e-mail: wjianp@mail. No. 150 ª 2014 The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine. 30 Inzucchi SE. Xizhimen South Street.Baseline characteristics of intention-totreat population. Xicheng District. Table S5. Diabetes 2012. No.sysu. Diabetes Care 2012. Change of disposition index at week 48 with different treatments.cn). 2015. Buse JB et al. Bergenstal RM. Table S3. 31 Xu W. Insulin and Pioglitazone in Newly Diagnosed and Drug-na€ıve T2DM. Li J. Baseline characteristics and outcomes in patients who completed the 48-week study on a reduced dose of 5 µg exenatide twice daily compared with those on 10 µg exenatide twice daily. Serious adverse events. Department of Endocrinology. 137–150 Supporting Information Additional Supporting Information may be found in the online version of this article: Table S1. insulin or pioglitazone: a multicentre. Chin Med J (Engl) 2012. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Guangdong Provincial Key Laboratory of Diabetology. parallel-group study. (fax: +86-1088324775. 61(Suppl 1): A4. randomized. Titration scheme of insulin dosage for patients in insulin group. Table S2. 277. parallel-group trial (CONFIDENCE). Zeng L et al. 125: 2677–81. Xu et al. . Comparison of 24-week Treatment with Exenatide. 63(Suppl 1): A86. Bi Y.W. Peking University People’s Hospital. gender. baseline BMI and baseline HbA1c. Guangzhou 510630. China. Comparison of glycemic control and beta-cell function in newly diagnosed type 2 diabetes patients treated with exenatide. Sun Z et al. and Linong Ji. 11. The Third Affiliated Hospital of Sun Yat-sen University. 600 Tianhe Road. Beijing 100044.cn).edu.edu. Diabetes 2014. China. Department of Endocrinology and Metabolism. Table S4. e-mail: jiln@bjmu. 35: 1364– 79. 32 Xu W. Correspondence: Jianping Weng.