Original Article. doi: /joim.12293

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1 Original Article doi: /joim 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. Xu 1, *, Y. Bi 2, *, Z. Sun 3, *, J. Li 1, L. Guo 4, T. Yang 5,G.Wu 6, L. Shi 7, Z. Feng 8, L. Qiu 9,Q.Li 10, X. Guo 11, Z. Luo 12, J. Lu 13, Z. Shan 14, W. Yang 15,Q.Ji 16, L. Yan 17,H.Li 18,X.Yu 19,S.Li 20, Z. Zhou 21,X.Lv 22, Z. Liang 23, S. Lin 24, L. Zeng 1, J. Yan 1,L.Ji 25 & J. Weng 1 From the 1 Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou; 2 Department 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; 4 Department of Endocrinology, Beijing Hospital of the Ministry of Public Health, Beijing; 5 Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing; 6 Department of Endocrinology, the Affiliated Hospital of Guangdong Medical College, Zhanjiang; 7 Department of Endocrinology, Affiliated Hospital of Guiyang Medical College, Guizhou; 8 Department of Endocrinology, the First Affiliated Hospital, Chongqing Medical University, Chongqing; 9 Department of Endocrinology, the Affiliated Hospital of Inner Mongolia Medical University, Hohhot; 10 Department of Endocrinology, the Second Affiliated Hospital of Harbin Medical University, Harbin; 11 Department of Endocrinology, Peking University First Hospital, Beijing; 12 Department of Endocrinology, the First Affiliated Hospital of Guangxi Medical University, Nanning; 13 Department of Endocrinology, Chinese People s Liberation Army General Hospital, Beijing; 14 Department of Endocrinology, the First Affiliated Hospital of China Medical University, Shenyang; 15 Department of Endocrinology, China Japan Friendship Hospital, Beijing; 16 Department 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; 18 Department of Endocrinology, the First Affiliated Hospital of Kunming Medical University, Kunming; 19 Department of Endocrinology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan; 20 Department 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; 22 Department of Endocrinology, General Hospital of Beijing Military Region, Beijing; 23 Department of Endocrinology, First Affiliated Hospital of Shenzhen University, Shenzhen; 24 Department of Endocrinology, the First Affiliated Hospital, Shantou University Medical College, Shantou; and 25 Department 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

2 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). J Intern Med 2015; 277: Objective. Progressive b-cell dysfunction hinders the maintenance of glycaemic control in type 2 diabetes, but comparative data on b-cell-protective therapies are lacking in the early stage of type 2 diabetes. Here we evaluated the comparative glycaemic efficacy and impact on b-cell function of three antihyperglycaemic agents that have a b-cell-protective effect, exenatide, insulin and pioglitazone, in newly diagnosed patients with type 2 diabetes. Design and methods. In this 48-week, multicentre, parallel-group study, 416 patients newly diagnosed with type 2 diabetes were randomly assigned 1 : 1 : 1 to receive exenatide, insulin or pioglitazone. The primary end-point was the change in glycosylated haemoglobin (HbA1c) from. Secondary end-points included effects on weight, blood pressure, lipid profiles and b-cell function assessed by homeostasis model assessment, fasting proinsulin:insulin (PI/I), disposition index (DI) and acute insulin response (AIR). Results. At week 48, mean [95% confidence interval (CI)] HbA 1c changes from were 1.8% ( 1.55% to 2.05%) with exenatide, 1.7% ( 1.52% to 1.96%) with insulin and 1.5% ( 1.23% to 1.71%) with pioglitazone. Treatment differences were 0.20% (95% CI 0.46% to 0.06%) for exenatide versus insulin (P = 0.185), and 0.37% (95% CI 0.63% to 0.12%) for exenatide versus pioglitazone (P = 0.002). Significant improvements from in AIR, PI/I and DI were observed with all treatments, with the greatest improvements in DI, as well as weight, blood pressure and lipid profile, observed with exenatide. Conclusions. All three agents showed efficacy regarding glycaemic control and metabolic benefits; however, exenatide showed the greatest efficacy. b-cell function improved in all treatment groups; hence, early initiation of b-cell-protective therapy may halt the decline in b-cell function in type 2 diabetes. Keywords: b-cell function, exenatide, glucose, insulin, pioglitazone. Introduction Currently, one of the most challenging threats to global public health is the increasing prevalence of type 2 diabetes mellitus, a progressive disease characterized by persistent insulin resistance and declining pancreatic b-cell function [1, 2]. Achieving glycaemic control, avoidance of hypoglycaemic events and weight control are the goals of type 2 diabetes therapy, as reflected in recent management guidelines [3 5]. It is well established that improved glycaemic control reduces the risk of diabetes-related complications [6, 7]. However, long-term glycaemic control is hard to achieve because of deteriorating b-cell function [8]. Antihyperglycaemic agents that can improve b-cell function or reduce its rate of decline should help to maintain good glycaemic control by changing, or at least delaying, the natural course of the disease. Insulin, the thiazolidinedione pioglitazone and the glucagon-like peptide (GLP)-1 receptor agonist exenatide are considered to have b-cell-protective effects [9 15]. However, in the absence of comparative studies, it is still unclear whether these effects differ between agents in the early stage of type 2 diabetes. Therefore, the CONFIDENCE study (comparison of glycaemic control and b-cell function amongst newly diagnosed patients with type 2 diabetes treated with exenatide, 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, and to compare the effects on b-cell function of all three agents in previously untreated patients. Design and methods Study design and participants This 48-week, multicentre, randomized, parallelgroup clinical trial was conducted from August 2010 to August 2012 at 25 university-affiliated hospitals in 13 provinces of China. The study is registered at ClinicalTrials.gov (number NCT ). Treatment-na ıve patients, aged years, with newly diagnosed type 2 diabetes were recruited. Inclusion criteria were glycosylated haemoglobin (HbA 1c ) %, body mass index (BMI) 138 ª 2014 The Association for the Publication of the Journal of Internal Medicine

3 20 35 kg m 2 and stable body weight for 3 months. Exclusion criteria were acute or severe chronic diabetic complications or illnesses (ketoacidosis, hyperosmotic state, lactic acidosis, severe microand macro-vascular complications, and hepatic dysfunction), presence of glutamic acid decarboxylase antibodies, use of drugs affecting gastrointestinal motility, weight and glycaemia, history of pancreatitis and triglyceride (TG) levels 5 mmoll 1. The protocol was approved by the institutional review board at each site in accordance with the Declaration of Helsinki. All patients provided written informed consent before screening. Procedures To assign patients randomly in a 1 : 1 : 1 ratio to receive exenatide, insulin or pioglitazone, a randomization list was generated using Statistics Analysis System (SAS) (SAS Institute Inc., Cary, NC, USA), and patients were allocated using a secure Oracle-based interactive web response system (IWRS) (Real Data Medical Research Inc., Zhejiang, China) in accordance with the sequence from the randomization list. At, demographic and anthropomorphic data were recorded, and fasting venous blood samples were collected to measure levels of fasting plasma glucose (FPG), HbA 1c, lipids, insulin, proinsulin, amylase and lipase. To mimic the physiological state, a mixed-meal test (MMT; 162 kcal) was performed with venous blood samples collected 30 and 120 min after ingestion to determine glucose and insulin levels. On day 2, after an overnight fast, an intravenous glucose tolerance test (IVGTT) was performed using 25 g glucose, with venous blood samples taken at 0, 1, 2, 4, 6 and 10 min to measure insulin levels. Exenatide (Amylin Pharmaceuticals, Inc., San Diego, CA, USA) was injected subcutaneously at a dose of 5 lg twice daily, increasing to 10 lg twice daily after 4 weeks. Patients who frequently experienced hypoglycaemia or could not tolerate adverse events were instructed to reduce the dose to 5 lg twice daily. Premixed insulin (75% insulin lispro protamine suspension and 25% insulin lispro injection; Eli Lilly and Company, Indianapolis, IN, USA) was injected twice daily at an initial dose of 0.4 IU kg 1 daily, with 50% administered 15 min before breakfast and the remaining 50% administered 15 min before dinner. Thereafter, doses were titrated based on self-monitored blood glucose levels (Table S1). Pioglitazone (Deyuan Pharmacy, Jiangsu, China) was initially administered at 30 mg daily, increasing to 45 mg daily after 4 weeks; the dose was then maintained or adjusted to the maximum tolerated dose. Patients were followed up every 4 weeks for 12 weeks and then at 12-week intervals until week 48. At each followed-up visit, anthropomorphic data, adverse events and hypoglycaemia episodes were recorded. HbA 1c, FPG and 2-h postprandial glucose (PPG) after MMT were measured. In addition, telephone calls were scheduled at weeks 16, 20, 28, 32, 40 and 44 to collect patients information and provide guidance. All patients received diabetes information and lifestyle counselling at enrolment, with reinforcement throughout the study. All assessments were repeated at week 48, with patients instructed to stop all antihyperglycaemic therapy 2 days beforehand to avoid any acute drug effects on the collected data. HbA 1c was assessed centrally at the Diabetes Centre of the Third Affiliated Hospital of Sun Yat-sen University, and insulin and proinsulin levels were measured centrally at the Beijing North Institute of Biological Technology. The remaining biochemical variables were assessed locally at the participating centres. 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, respectively [HOMA-B = 20 9 fasting insulin (FINS)/(FPG 3.5); HOMA-IR=FINS 9 FPG/22.5] [16]. 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]. 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]. The 10-min acute insulin response (AIR) during IVGTT was calculated as the incremental area under the curve using trapezoidal estimation. The fasting proinsulin-to-insulin ratio (PI/I) was also calculated. Safety and tolerability were assessed at each visit. 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 139

4 <3.9 mmol L 1, with prompt recovery after selfadministered carbohydrate. Major hypoglycaemia was defined as an event requiring the assistance of another person to administer carbohydrate, glucagon or other resuscitative treatment. Study end-points The primary end-point was the comparison of change from in HbA 1c at 48 weeks in the three treatment groups. Secondary end-points included the proportion of patients in each group achieving HbA 1c targets of <7.0% and 6.5%, and the comparative effects on b-cell function (HOMA-B, PI/I, DI and AIR), body weight, blood pressure and lipid profiles. Safety and tolerability were also assessed. Overall, 108 patients per group were required to provide 90% power to show noninferiority of exenatide compared to insulin or pioglitazone, with a predefined margin of 0.4% for the difference in HbA 1c change from between treatments. The estimated dropout rate was 20%; thus, 405 patients were required for enrolment. Efficacy analyses were conducted in the per-protocol population, as well as in the intention-to-treat population for supporting analysis. Safety analyses were conducted in the intention-to-treat population, which included all randomly assigned patients who received at least one dose of study drug. Statistical analyses The primary end-point was analysed using mixedmodel repeated-measures analysis of covariance (ANCOVA) to estimate the change in HbA 1c, with treatment, centre and HbA 1c as covariates. Other continuous variables were similarly analysed, with treatment, centre and value of the dependent variable as covariates. Mixed-effect logistic models were used to compare the proportions of patients achieving HbA 1c <7% and 6.5% at week 48 amongst treatment groups, with centre and HbA 1c as covariates. b-cell function was compared amongst groups using ANCOVA, with treatment, centre, gender, age and BMI, TG level and b-cell function as covariates. Similar methods were used in post hoc analyses to compare the proportions of patients achieving HbA 1c <7.0% and b-cell function improvement by treatment, with calculations carried out on the study population stratified by age, gender, BMI and HbA 1c. Normally distributed and continuous variables are presented as means SE. Non-normally distributed variables (HOMA-B, HOMA-IR and PI/I) were logarithmically transformed before analysis. Data were analysed using SPSS 20.0 (IBM corporation, New York, NY, USA). Significance was defined as P < Results Of the 440 patients screened, 416 were eligible and randomly assigned to receive exenatide, insulin or pioglitazone; these patients comprised the intention-to-treat population and were evaluated for safety (Fig. 1). Baseline characteristics in this population were similar between treatment groups (Table S2). The 342 patients who completed the study (Fig. 1) were included in the per-protocol efficacy analyses. In this per-protocol population, the only difference at between groups was a lower PPG in the exenatide group (P = between groups; Table 1). The efficacy results presented here are from analyses of the per-protocol population; similar findings were obtained from analyses of the intentionto-treat population (data not shown). Glycaemic and metabolic control HbA 1c changes over the course of follow-up in those who completed the study are shown in Fig. 2a. At week 48, mean HbA 1c decreased significantly from in all treatment groups (Table 1). Differences in HbA 1c changes between treatments were as follows: 0.20% [95% confidence interval (CI) 0.46% to 0.06%] for exenatide versus insulin, and 0.37% (95% CI 0.63% to 0.12%) for exenatide versus pioglitazone; hence, exenatide was noninferior to insulin and pioglitazone. At least three-quarters of the patients in each treatment group achieved HbA 1c <7.0%, with significantly more patients assigned to exenatide achieving HbA 1c 6.5% (Fig. 3). Fasting plasma glucose and PPG levels decreased with all treatments (Fig. 2b,c). At week 48, 2 days after stopping treatment, mean reductions from were similar between treatment groups (Table 1). 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. 2d). No correlation between change in body weight and 140 ª 2014 The Association for the Publication of the Journal of Internal Medicine

5 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 ) 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 = 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) Lost to follow-up (n = 14) Discontinued intervention (n = 10) Adverse event (n = 2) Migration (n = 2) Poor compliance (n = 4) Withdrew consent (n = 2) Completed study (n = 114) Lost to follow-up (n = 10) Discontinued intervention (n = 8) Serious adverse event (n = 2) Adverse event (n = 2) Poor compliance (n = 1) Withdrew consent (n = 2) Poor glucose control (n = 1) Completed study (n = 118) Analysed for safety (intention-totreat) (n = 142) Analysed for efficacy (per protocol) (n = 110) Analysed for safety (intention-totreat) (n = 138) Analysed for efficacy (per protocol) (n = 114) Analysed for safety (intention-totreat) (n = 136) Analysed for efficacy (per protocol) (n = 118) Fig. 1 Trial profile. HbA 1c reduction was observed in any group. At week 48, mean waist circumference decreased with exenatide treatment; no significant differences from were observed with insulin or pioglitazone (Table 1). Decreases in mean systolic and diastolic blood pressures at 48 weeks were not statistically different between groups, although significant decreases in systolic and diastolic blood ª 2014 The Association for the Publication of the Journal of Internal Medicine 141

6 Table 1 Baseline characteristics and changes from at week 48 in the per-protocol population (n = 342) P-value Characteristics Exenatide Insulin Pioglitazone Overall Exenatide vs. insulin Exenatide vs. pioglitazone Insulin vs. pioglitazone n Men (%) 74 (67.3) 70 (61.4) 65 (55.1) NA NA NA Weight (kg) Baseline NA NA NA * <0.001 <0.001 < Waist (cm) Baseline NA NA NA * <0.001 <0.001 < Body mass index (kg m 2 ) Baseline NA NA NA * <0.001 <0.001 < HbA 1c (%) Baseline NA NA NA * * * Fasting plasma glucose (mmol L 1 ) Baseline NA NA NA * * * NA NA NA 2-h postprandial plasma glucose (mmol L 1 ) Baseline * * * NA NA NA Systolic blood pressure (mmhg) Baseline NA NA NA NA NA NA Diastolic blood pressure (mmhg) Baseline NA NA NA * NA NA NA Total cholesterol (mmol L 1 ) Baseline NA NA NA ª 2014 The Association for the Publication of the Journal of Internal Medicine

7 Table 1 (Continued ) P-value Characteristics Exenatide Insulin Pioglitazone Overall Exenatide vs. insulin Exenatide vs. pioglitazone Insulin vs. pioglitazone Triglycerides (mmol L 1 ) Baseline NA NA NA HDL cholesterol (mmol L 1 ) Baseline NA NA NA * < <0.001 LDL cholesterol (mmol L 1 ) Baseline NA NA NA NA NA NA Amylase (U L 1 ) Baseline NA NA NA 9 2* Lipase (U L 1 ) Baseline NA NA NA NA NA NA Lg HOMA-B Baseline NA NA NA * <0.001 < <0.001 Lg HOMA-IR Baseline NA NA NA * * <0.001 < <0.001 Matsuda index Baseline NA NA NA * * <0.001 < <0.001 Lg PI/I Baseline NA NA NA * * * NA NA NA DI Baseline NA NA NA ª 2014 The Association for the Publication of the Journal of Internal Medicine 143

8 Table 1 (Continued ) P-value Exenatide Exenatide vs. Insulin vs. Characteristics Exenatide Insulin Pioglitazone Overall vs. insulin pioglitazone pioglitazone AIR (liu ml 1 9 min) Baseline NA NA NA * * NA NA NA Variables are expressed as mean SE or n (%).*P < after therapy versus ; P < 0.05 after therapy versus. NA, not applicable; HbA 1c, glycosylated haemoglobin; HOMA-B, homeostasis model assessment of b-cell function; HOMA- IR, homeostasis model assessment of insulin resistance; PI/I, fasting proinsulin-to-insulin ratio; DI, disposition index; AIR, acute insulin response. (a) (b) (c) (d) Fig. 2 Mean changes over time in glycaemic control and weight. Antihyperglycaemic therapies were stopped 2 days before the last visit at week 48. (a) Glycosylated haemoglobin (HbA 1c ) concentrations; (b) Fasting plasma glucose (FPG); (c) 2-h postprandial glucose (PPG); and (d) change in weight. Data are presented as mean (SE). *P < between treatment groups; P < 0.05 between treatment groups. Black triangle, exenatide; black circle, insulin; black square, pioglitazone. (a) (b) P = P = Patients (%) EXE INS PIO Patients (%) EXE INS PIO Fig. 3 Proportions of patients achieving target glycosylated haemoglobin (HbA 1c ) concentrations. (a) HbA 1c <7.0%; (b) HbA 1c 6.5%. EXE, exenatide; INS, insulin; PIO, pioglitazone. 144 ª 2014 The Association for the Publication of the Journal of Internal Medicine

9 pressures were observed with exenatide (P < 0.05 vs. ), and a significant decrease in diastolic blood pressure alone was found with pioglitazone (P < 0.001) (Table 1). Exenatide treatment resulted in improvements in overall lipid profiles, with significant decreases in TG, total cholesterol and LDL cholesterol levels, and an increase in HDL cholesterol (P < 0.05 vs. for all variables). HDL cholesterol increased with pioglitazone (P < 0.001), and LDL cholesterol decreased with insulin (P < 0.05) (Table 1). Effect of treatments on b-cell function At week 48, HOMA-B (which, together with PI/I, provides an indication of b-cell function during the fasting state) increased in patients treated with insulin (P < vs. ). Improvements from were similar in all treatment groups with regard to PI/I, as well as AIR (which represents b-cell function during the stimulated state after intravenous glucose injection). DI, which provides a measure of b-cell function during the stimulated state under near-physiological conditions of food intake via the gastrointestinal system [18, 19], increased significantly in all treatment groups (P < vs. for exenatide; P < 0.05 vs. for insulin and pioglitazone). The greatest mean improvements from in DI and AIR were observed in the exenatide treatment group (Table 1 and Fig. 4). Subgroup analyses After stratified by age, gender, BMI or HbA 1c, the data showed that patients who were aged <50 years or who had a BMI kg m 2 were more likely to achieve HbA 1c <7% when treated with exenatide than with pioglitazone or insulin. In these younger patients (aged <50 years), greater improvements in b-cell function, demonstrated by greater changes in DI from to 48 weeks, were achieved with exenatide treatment than with pioglitazone or insulin (Table S3). In the 24 patients who completed the study treated with 5 lg exenatide twice daily, mean HbA 1c change was % (P < 0.001), and mean weight change was kg (P = 0.003). On the reduced dose, 20 (83%) patients achieved the HbA 1c target of <7%, and 17 (71%) achieved HbA 1c 6.5%. However, the study was underpowered to determine with any statistical significance the characteristics of patients who would benefit from the lower dose (Table S4). Safety Thirteen serious adverse events were reported (Table S5), including one cerebral infarction in each group, and one case each of pancreatitis and cholangiocellular carcinoma in the exenatide group. The most commonly observed adverse events were gastrointestinal reactions and oedema in the exenatide and pioglitazone groups, respectively (Table 2). Upper respiratory tract infections, reported most frequently in the insulin group, occurred at similar rates in the other treatment groups. Treatment-related adverse events leading to study withdrawal occurred in eight patients receiving exenatide (nausea and vomiting n = 7; rash, n = 1), two receiving insulin (allergy and weight gain, n = 1 each) and two receiving pioglitazone (arrhythmia and oedema, n = 1 each). Fig. 4 Comparison of change in b-cell function (HOMA-B, PI/I, DI and AIR) in different groups. Changes in HOMA-B and PI/I are logarithmically transformed. HOMA-B, homeostasis model assessment of b-cell function; PI/I, fasting proinsulin-to-insulin ratio; DI, disposition index; AIR, acute insulin response. Amylase levels increased in all groups with no clinical significance, whereas lipase levels after 48 weeks of treatment were similar to those at. No major hypoglycaemic episodes were reported during the study. Incidences of minor hypoglycaemia occurred in 13 of 142 (9.2%), 18 of 138 ª 2014 The Association for the Publication of the Journal of Internal Medicine 145

10 Adverse event Exenatide (n = 142) Insulin (n = 138) Pioglitazone (n = 136) Nausea 37 (26.1) 1 (0.7) 1 (0.7) Dizziness 18 (12.7) 7 (5.1) 4 (2.9) Vomiting 15 (10.6) 1 (0.7) 1 (0.7) Abdominal distension 8 (5.6) 0 1 (0.7) Appetite loss 8 (5.6) 0 0 Diarrhoea 6 (4.2) 1 (0.7) 4 (2.9) Upper respiratory tract 16 (11.3) 13 (9.4) 11 (8.1) infection Oedema (8.8) Numbness 4 (2.8) 2 (1.5) 5 (3.7) Fatigue 3 (2.1) 3 (2.2) 4 (2.9) Injection-site reaction 4 (2.8) 6 (4.4) 0 Palpitations 4 (2.8) 2 (1.5) 2 (1.5) Constipation 6 (4.2) 0 1 (0.7) Headache 3 (2.1) 2 (1.5) 2 (1.5) Blurred vision 2 (1.4) 1 (0.7) 3 (2.2) Arthralgia 0 1 (0.7) 4 (2.9) Chest tightness 2 (1.4) 0 3 (2.2) Rash 1 (0.7) 2 (1.5) 2 (1.5) Skelalgia 3 (2.1) 1 (0.7) 1 (0.7) Toothache 3 (2.1) 2 (1.5) 0 Weight gain 0 1 (0.7) 0 Allergy 0 1 (0.7) 0 Table 2 Treatment-emergent adverse events in intention-totreat (safety) population (n = 416) Data are presented as n (%) of the safety (intention-to-treat) population. (13.0%) and 5 of 136 (3.7%) patients treated with exenatide, insulin and pioglitazone, respectively. 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; 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. Discussion To our knowledge, the present study provides the only direct comparison of the impact on glycaemic control, cardiovascular disease risk factors and b-cell function of three different classes of antihyperglycaemic agents considered to have a b-cell-protective effect (exenatide, insulin and pioglitazone), during the early course of type 2 diabetes over a period of 48 weeks. Glycaemic control was maintained for the study duration with all three agents. Exenatide demonstrated noninferior glycaemic control compared to insulin and pioglitazone; hence, the primary outcome of this study was achieved. The proportions of patients who achieved HbA 1c targets were greatest with exenatide. This is consistent with a metaanalysis showing that GLP-1 receptor agonists enabled a higher proportion of patients to achieve HbA 1c <7.0% than thiazolidinediones or insulin glargine [20]. Higher proportions of patients achieved HbA 1c targets with all three agents, especially with exenatide, in this study than previously reported [21 23], probably because patients in the CONFIDENCE study were newly diagnosed and had a relatively low HbA 1c (mean 8.1%). Another possible explanation for the greater HbA 1c reduction is that Asian populations have higher 146 ª 2014 The Association for the Publication of the Journal of Internal Medicine

11 PPG levels than Caucasians [24] and exenatide had a greater effect on PPG than FPG. These findings suggest that newly diagnosed patients can achieve good glycaemic control following early treatment with these agents. 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. Exenatide treatment was associated with greater weight loss, better improvements in blood pressure and lipid profiles than the other two treatments. Given that cardiovascular complications account for 80% of the risk of mortality in type 2 diabetes and that obesity, dyslipidaemia and hypertension are well-established risk factors for cardiovascular disease, the positive metabolic effect seen with exenatide is supported its use in this patient population. This finding is consistent with previous studies. In three other trials [23, 25, 26], onceweekly exenatide showed an absolute benefit in achieving American Diabetes Association-recommended treatment goals compared to metformin, sitagliptin, pioglitazone or insulin glargine. In a retrospective analysis of patients, twicedaily exenatide was associated with a lower risk of cardiovascular disease events than other glucose-lowering therapies [27]. To our knowledge, 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. To elucidate b-cell function, 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), but also DI, to provide an indication of b-cell function modulated by insulin resistance under near-physiological conditions. Unlike HOMA-B and PI/I, DI is not based on fasting state variables alone; it is derived from the oral MMT, which is a more physiological route of glucose administration than the IVGTT. Therefore, 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. Improvements in b-cell function were observed irrespective of treatment, 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. Of note, we report here for the first time that the effects on b-cell function varied between treatments. Insulin had the greatest effects on HOMA-B and PI/I, suggestive of more improvement in basal b-cell function and attenuation of b-cell overstimulation. Although DI, the most physiologically representative index of b-cell function [18, 19], improved with all treatments, the greatest improvements were seen with exenatide. Indeed, 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, 13]. These studies showed a superior effect of exenatide in terms of b-cell function compared with insulin glargine. Although no sustained effect on b-cell function was observed after cessation of 1 year of treatment [12], after a 3-year study extension, b-cell function improvements were maintained 4 weeks after cessation of treatment with exenatide, but not insulin glargine [13]. The main differences between the studies of Bunck et al. and the CONFIDENCE study were that in the former, the investigated treatments were used as add-on therapy to metformin and the duration of diabetes in the study population was longer than 4 years. 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, insulin and pioglitazone) in terms of improving b-cell function. Longer-term evaluation of these treatments will be required to determine whether the beneficial effects we reported are maintained over time, and will ultimately delay progression of disease. The incidence of adverse events with all treatments was generally consistent with that of previous reports [21, 22, 28] and was higher with exenatide than with the other two treatments. The incidence of minor hypoglycaemia was highest with insulin (reported by 13.2% of patients); the incidence of minor hypoglycaemia of 9.2% with exenatide was higher than previously reported in Western populations [23, 25, 26], but similar to that observed in Chinese patients (12%) [29]. This difference may be due to the fact that (i) a greater proportion of patients achieved HbA 1c <7% and 6.5% than in previous studies, 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 147

12 been too high in this population. When patients who experienced hypoglycaemia whilst taking 10 lg but not 5 lg twice daily were excluded, the incidence of hypoglycaemia decreased to 4.9%, which is similar to the rate observed in the pioglitazone group. Furthermore, 83% of patients who completed this study on the reduced dose still achieved optimal glycaemic control, demonstrating the efficacy of low-dose exenatide in this population. A major strength of this study is the prospective, randomized, parallel-group design in which we compared, for the first time, the effects of monotherapy with exenatide, insulin or pioglitazone on glycaemic control and b-cell function in patients with newly diagnosed type 2 diabetes, in the absence of the confounding effects of other antidiabetic medications. A limitation of this study is the open-label design, 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. Nevertheless, to some degree, the open-label design reflects real-world clinical practice. In addition, it may be considered a study limitation that metformin, the most popular antihyperglycaemic agent, was not included as a comparator in this study. However, we did not include metformin because it is not considered to be a b-cell-preserving agent, and the noninferiority of exenatide compared to metformin in terms of glycaemic control has been shown previously in treatment-na ıve patients [23]. In conclusion, initiating b-cell-protective treatment with exenatide, insulin or pioglitazone in newly diagnosed patients with type 2 diabetes improved glycaemic control and b-cell function. Exenatide may offer the most promising option for type 2 diabetes management with regard to glycaemic efficacy, weight loss, comprehensive metabolic benefits and the potential to delay the natural course of the disease. More evidence of the efficacy of antihyperglycaemic agents is required because of recommendations for a move towards more patient-centred care [30]. 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. Authors contributions JW designed, organized and supervised the study, and co-wrote the first draft of the manuscript. LJ, JLu, WY and WX contributed to the study design. WX also contributed to assisting JW to run the study, interpret the data, and co-wrote the first draft. All authors contributed to patients followup, data collection, identification and assessments of the primary data sources for each participating study centre. 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. Conflict of interest statement LJ is an advisory board member for Eli Lilly and Co. and Bristol-Myers Squibb. JW is an advisory board member for Eli Lilly and Co. None of the other authors has any competing interests to declare. Part of this study was presented at the 72nd Scientific Sessions of the American Diabetes Association, Philadelphia, PA, USA, in June 2012 [31] and 74th Scientific Sessions of the American Diabetes Association at San Francisco, CA, USA, in June 2014, as oral presentations [32]. 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, the National Science Fund for Distinguished Young Scholars ( ), investigator-initiated trial research funds from Eli Lilly and Co. and Amylin Pharmaceuticals, Inc., and the 5010 Project of Sun Yat-sen University. The sponsors had no role in the study design, collection, analysis and interpretation of data, or writing the report. We are grateful to Professor Rury Holman, MB, ChB, FRCP from the Diabetes Trials Unit at Oxford University, Oxford, UK, for his constructive comments on the manuscript, and Professor Yuantao Hao, PhD from the School of Public Health, Sun Yat-sen University for sample size estimation and statistical analyses. We thank all the site investigators for conducting the study and the study participants. We acknowledge receiving editorial support from Samantha Santangelo, PhD of MediTech Media Asia Pacific Pte Ltd, supported by a grant from Bristol-Myers Squibb and Astra Zeneca. 148 ª 2014 The Association for the Publication of the Journal of Internal Medicine

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14 metformin-controlled, parallel-group study. Chin Med J (Engl) 2012; 125: Inzucchi SE, Bergenstal RM, Buse JB et al. 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). Diabetes Care 2012; 35: Xu W, Li J, Zeng L et al. Comparison of 24-week Treatment with Exenatide, Insulin and Pioglitazone in Newly Diagnosed and Drug-na ıve T2DM. Diabetes 2012; 61(Suppl 1): A4. 32 Xu W, Bi Y, Sun Z et al. Comparison of glycemic control and beta-cell function in newly diagnosed type 2 diabetes patients treated with exenatide, insulin or pioglitazone: a multicentre, randomized, parallel-group trial (CONFIDENCE). Diabetes 2014; 63(Suppl 1): A86. Correspondence: Jianping Weng, Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou , China. (fax: ; wjianp@mail.sysu.edu.cn). and Linong Ji, Department of Endocrinology, Peking University People s Hospital, No. 11, Xizhimen South Street, Xicheng District, Beijing , China. (fax: ; jiln@bjmu.edu.cn). Supporting Information Additional Supporting Information may be found in the online version of this article: Table S1. Titration scheme of insulin dosage for patients in insulin group. Table S2.Baseline characteristics of intention-totreat population. Table S3. Change of disposition index at week 48 with different treatments, stratified by age, gender, BMI and HbA 1c. Table S4. 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. Table S5. Serious adverse events. 150 ª 2014 The Association for the Publication of the Journal of Internal Medicine