Three-year efficacy and safety of exenatide once weekly: A pooled analysis of three trials

    Three-year efficacy and safety of exenatide once weekly: A pooled analysis of three trials Michael E. Trautmann, Luc Van Gaal, Jenny Han, Elise Hardy PII: DOI: Reference:

S1056-8727(17)30035-1 doi: 10.1016/j.jdiacomp.2017.06.004 JDC 7042

To appear in:

Journal of Diabetes and Its Complications

Received date: Revised date: Accepted date:

10 January 2017 31 March 2017 8 June 2017

Please cite this article as: Trautmann, M.E., Van Gaal, L., Han, J. & Hardy, E., Threeyear efficacy and safety of exenatide once weekly: A pooled analysis of three trials, Journal of Diabetes and Its Complications (2017), doi: 10.1016/j.jdiacomp.2017.06.004

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Three-year efficacy and safety of exenatide once weekly: A pooled analysis of

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three trials

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Michael E. Trautmanna,*, Luc Van Gaalb, Jenny Hanc, Elise Hardyd Diabetes Research, Fueerbarg 16a, D-22393, Hamburg, Germany

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Antwerp University Hospital, Antwerp, Belgium

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Pharmapace, 10509 Vista Sorrento Parkway, Suite 303, San Diego, CA, USA 92121

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AstraZeneca, Gaithersburg, MD, USA

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* Corresponding author at: Diabetes Research, Fueerbarg 16a, D-22393 Hamburg, Germany.

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Tel.: +49 40 60097132; fax: +49 40 60097135.

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E-mail address: [email protected] (M.E. Trautmann).

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Running Head: Long-term use of exenatide once weekly in type 2 diabetes

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ABSTRACT

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Aims: To evaluate the 3-year efficacy and safety of exenatide once weekly (QW) for type 2

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diabetes (T2D) in a large clinical population.

Methods: This post hoc analysis of three DURATION studies examined pooled efficacy and

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adverse events with exenatide QW from the 2.5- to 3-year completer populations; insulin

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glargine (glargine) was a reference (DURATION-3). Patients randomized to exenatide QW during the controlled study periods continued controlled treatment (DURATION-3) or single-

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arm treatment (DURATION-1; DURATION-2) with exenatide QW for the study duration. Results: In the exenatide QW group (N=329), reductions from baseline in HbA1c, fasting

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glucose, and body weight were maintained from weeks 4 to 156 (HbA1c: −1.1±1.3%; fasting

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glucose: −1.7±2.7 mmol/L; body weight: −2.4±5.6 kg; P<0.05). Glycemic efficacy with exenatide QW and glargine was similar (HbA1c reduction: −0.8±1.0%; N=158); body weight

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increased with glargine (+2.0±4.9 kg). Variable reductions in systolic blood pressure and low-

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density lipoprotein cholesterol occurred with exenatide QW. At week 156, 48.3% and 30.7% of exenatide QW recipients achieved HbA1c goals of <7.0% and ≤6.5%, respectively. No new safety or tolerability issues were identified. Conclusions: Exenatide QW improved glycemic outcomes and was well tolerated in patients with T2D for up to 156 weeks. Keywords: Exenatide, GLP-1, Glucagon-like peptide-1 receptor agonist, Type 2 diabetes

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1. Introduction

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Generally, patients with type 2 diabetes (T2D) do not experience reversal of their disease

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and require continuous long-term monitoring and treatment to prevent or minimize macrovascular and microvascular complications (American Diabetes Association, 2017c).

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Clinical experience indicates that most patients will eventually require multiple glucose-lowering medications to maintain glycemic control as the disease progresses, and it is important that the

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medications chosen continue to provide efficacy without worsened or new adverse events (AEs).

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Data from extension studies provide information on the clinical outcomes of patients who choose to receive a given treatment for the long term and reflect the course of patients choosing to

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receive treatment in practice.

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Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a class of glucose-lowering agents that have been shown to reduce glycated hemoglobin (HbA1c), fasting glucose (FG), and

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postprandial glucose, along with reductions in body weight and improvements in some

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cardiovascular risk factors, in short-term (6-month) studies (Kayaniyil, et al., 2016; Shaefer, et al., 2015). Exenatide, the first GLP-1RA developed and available for clinical use (Keating, 2005), is available in a short-acting formulation for twice-daily (BID) administration and a longacting formulation administered once weekly (QW) using a single-dose tray or a single-use, dual-chamber pen (AstraZeneca Pharmaceuticals LP, 2015a, 2015b). The efficacy and safety of exenatide QW, an extended-release formulation of exenatide dispersed in biodegradable poly-(D,L-lactide-co-glycolide) polymer microspheres for gradual, long-term exenatide release (DeYoung, et al., 2011), has been investigated in the DURATION phase 3 clinical trial program (DURATION-1–6) in patients with T2D (Bergenstal, et al., 2010; 3

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Blevins, et al., 2011; Buse, et al., 2013; Diamant, et al., 2010; Drucker, et al., 2008; RussellJones, et al., 2012). These studies showed that 24–30 weeks of exenatide QW treatment resulted

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in significant reductions from baseline in HbA1c (1.3–1.9%), fasting plasma or serum glucose (1.8–2.3 mmol/L), and body weight (2.0–3.7 kg). To provide longer-term efficacy and safety

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information, DURATION-1 was extended for up to 7 years, but the overall population was small at the 7-year follow-up (N=122) (Wysham, et al., 2016). However, DURATION-2 had 2.5 years

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of extension data available, and DURATION-3 included a prospective controlled extension for a

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total study duration of 3 years (Diamant, et al., 2014). It was hypothesized that pooling data from all three studies would increase the likelihood of observing patterns of response in efficacy

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and/or safety endpoints.

This analysis investigated efficacy and safety outcomes in the available pooled long-term

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data from the DURATION-1, -2, and -3 extension studies in patients with T2D receiving

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exenatide QW. Insulin comparator data from the same time period obtained in DURATION-3

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were included for reference.

2. Materials and methods 2.1. Study designs and patient population This post hoc analysis examined efficacy and safety data obtained from patients in the DURATION-1, -2, and -3 extension studies. Full details of the study designs and results for the overall patient populations have been published previously (Supplementary Table 1) (Bergenstal, et al., 2010; Buse, et al., 2010; Diamant, et al., 2014; Diamant, et al., 2012; Diamant, et al., 2010; Drucker, et al., 2008; MacConell, et al., 2013; Taylor, et al., 2011; Wysham, et al., 2011). Briefly, participants in the studies were aged ≥18 years (16 years in DURATION-1), with T2D 4

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weight-loss medications were not permitted. Physicians were permitted but not encouraged to adjust concomitant glucose-lowering therapies. Each primary study was approved by the

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appropriate ethical review board and conducted in accordance with the Declaration of Helsinki.

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2.2. Statistical analyses

The primary analysis population for efficacy and safety was the 2.5- to 3-year completer

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population, which included patients randomized to exenatide QW or insulin glargine in the three studies who received treatment for ≥130 weeks. The exenatide QW population did not include

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patients who switched to exenatide QW in the extension studies. The intention-to-treat (ITT)

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population, defined as patients who were randomized to exenatide QW or insulin glargine and had any treatment exposure during the three primary studies, was used to evaluate study

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withdrawals. Results with exenatide QW from the three trials were pooled. No direct statistical

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comparisons were analyzed for between-treatment differences with exenatide QW and insulin glargine because pooled data for exenatide QW included patients who were not enrolled in DURATION-3.

Efficacy outcomes were determined from baseline to week 156 (analysis endpoint, with last observation carried forward for 2.5-year completers), including assessments at weeks 4, 6, 10, 14, 18, 22, 26, 30, 36, 44, 52, 60, 68, 76, 84, 104, 132, and 156. Efficacy endpoints were summarized descriptively, and n, mean, standard deviation, and standard error were calculated. Nominal P values were calculated for changes over time versus baseline (on a per-patient basis) using paired t tests. Efficacy outcomes investigated were: HbA1c; achievement of usual and 5

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cholesterol [LDL-C], triglycerides [TG]); the composite endpoint of HbA1c goal achievement, no major/minor hypoglycemia, and no weight gain; and the composite outcome of HbA1c goal

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achievement (<7.0%), systolic BP (SBP) <130 mmHg, no major/minor hypoglycemia, and no weight gain. Minor hypoglycemia was defined as patients reporting symptoms consistent with

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hypoglycemia and a plasma glucose concentration <3.0 mmol/L; major hypoglycemia was

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defined as loss of consciousness, seizure, or coma that resolved after glucagon or glucose administration, or required third-party assistance to resolve, and a glucose concentration

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<3.0 mmol/L.

AEs reported during the 156-week period were assessed for frequency, incidence, and

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exposure-adjusted event and incidence rates in the completer (continuous exposure) population.

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Endpoints investigated were: AEs with an incidence of >5% in either treatment group; serious AEs (SAEs); hypoglycemic events (with and without concomitant sulfonylurea therapy); and

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AEs of special interest (thyroid neoplasms, pancreatitis, acute renal failure, and cardiac disorders). AEs were classified by investigators using standard Medical Dictionary for Regulatory Activities terminology (www.meddra.org). 3. Results 3.1. Patients Among patients randomized to exenatide QW, 148, 160, and 233 patients comprised the ITT populations in DURATION-1, -2, and -3, respectively; among patients randomized to insulin glargine in DURATION-3, 223 patients comprised the ITT population (Bergenstal, et al., 6

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2010; Diamant, et al., 2010; Drucker, et al., 2008). Of these, 128 (86%), 119 (74%), and 194 (83%) patients in the exenatide QW groups, respectively, and 196 (88%) in the insulin glargine

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group entered the extension phases (Buse, et al., 2010; Diamant, et al., 2012; Wysham, et al., 2011). Among ITT patients randomized to exenatide QW, 100 (68%), 76 (48%), and 153 (66%)

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completed 2.5–3 years of treatment in DURATION-1, -2, and -3, respectively; 158 patients (71%) in the insulin glargine group completed treatment (Supplementary Table 1). In the pooled

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ITT population of exenatide QW-treated patients, the most common reasons for withdrawal

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during the core study phase were patient’s decision (6.3%), AEs (6.1%), and loss to follow-up (2.0%). During the extension phase, the most common reasons for withdrawal in the exenatide

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QW group were patient’s decision (10.0%), AEs (3.0%), and loss to follow-up (2.2%). Patient demographics and clinical characteristics were generally similar between the

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pooled exenatide QW (n=329) and insulin glargine (n=158) groups in the completer population

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(Table 1). However, exenatide QW-treated patients had a higher mean body weight and were more likely to be white than insulin-treated patients. A large proportion of patients in both

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groups received concomitant glucose-lowering therapy (Table 1), with some differences between treatment groups. 3.2. Efficacy 3.2.1. Long-term effects on glycemic endpoints and cardiovascular risk markers In the pooled completer population, 2.5–3 years of exenatide QW treatment resulted in improvements from baseline in clinically important parameters like HbA1c and FG (both P<0.001) (Table 2). Changes in TC (P<0.05), LDL-C (P<0.05), HDL-C (P<0.001), and body weight (P<0.001) were also reported (Table 2). Compared with baseline, small numerical 7

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decreases in mean SBP (P=0.15), mean diastolic BP (DBP) (P=0.21), and mean TG levels (P=0.65) were observed with exenatide QW at week 156. Patients receiving insulin glargine for

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2.5–3 years had improvements from baseline in HbA1c (P<0.001), FG (P<0.001), DBP (P<0.05), TC (P<0.05), and LDL-C (P<0.05), and weight gain of 2.0 kg (P<0.001) (Table 2). Compared

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with baseline, small numerical increases in mean SBP (P=0.21) and mean HDL-C levels (P=0.11), and a numerical decrease in mean TG levels (P=0.16), were observed with insulin

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glargine at week 156.

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3.2.2. Effects on glycemic endpoints and cardiovascular risk markers over time Glycemic endpoints improved from baseline to week 156 in both treatment groups.

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Reductions in HbA1c from baseline were consistent throughout the extension period for both

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exenatide QW and insulin glargine (Fig. 1A); specifically, reductions from baseline (P<0.001) occurred from week 4 to study end among exenatide QW-treated patients, and from week 10 to

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study end in insulin glargine-treated patients. Also, a reduction from baseline was consistently

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observed in FG in both groups, from week 6 to study end (P<0.001) (Fig. 1B). Overall, small decreases in BP were observed in both groups from baseline beginning at week 4. SBP reductions from baseline were noted in the exenatide QW group from weeks 4–104 (P<0.05) (Fig. 1C), with a trend towards DBP reductions from baseline in both groups from week 30 in exenatide QW recipients and week 10 in insulin glargine recipients. At week 156, DBP reduction was −0.6 ± 9.3 mmHg in exenatide QW recipients and −2.1 ± 9.5 mmHg (P<0.05) in insulin glargine recipients. Exenatide QW-treated patients had consistent body weight loss from week 4 onwards (P<0.001), whereas weight gain was observed in the insulin glargine group from week 18 (P<0.001) (Fig. 1D). 8

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Exenatide QW treatment was associated with an improvement in lipid profile relative to baseline (Fig. 2). Variable LDL-C reductions from baseline occurred over time in exenatide QW-

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treated patients (range, −0.01 to −0.15 mmol/L) (Fig. 2A), with a final reduction of −0.13 ± 0.73 mmol/L at week 156. The exenatide QW group also had an HDL-C increase from baseline from

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week 52 onwards (P<0.05) (Fig. 2B), with a final increase of 0.08 ± 0.20 mmol/L. Improvements in TC were observed throughout the study in both treatment groups (Fig. 2C); final reductions

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were −0.11 ± 0.93 mmol/L with exenatide QW and −0.15 ± 0.86 mmol/L with insulin glargine.

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Reductions from baseline in TGs also occurred during the course of the study in both treatment groups (Fig. 2D), with final reductions of −0.05 ± 1.79 mmol/L with exenatide QW and −0.14 ±

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1.19 mmol/L with insulin glargine.

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3.2.3. Glycemic goal achievement

Compared with baseline, treatment with exenatide QW and insulin glargine resulted in an

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increase in the proportion of patients achieving glycemic goals (Supplementary Fig. 1). At baseline, 96.0% and 99.4% of exenatide QW-treated patients, and 96.2% and 99.4% of insulin

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glargine-treated patients, had an HbA1c of ≥7.0% and >6.5%, respectively. At week 156, 48.3% and 30.7% of exenatide QW-treated patients had an HbA1c of <7.0% and ≤6.5%, respectively. In the insulin glargine group, 37.3% and 16.5% of patients had an HbA1c of <7.0% and ≤6.5%, respectively, at week 156. Among exenatide QW-treated patients, 28.9% achieved the composite endpoint of HbA1c <7.0%, no major/minor hypoglycemia, and no weight gain at week 156, while 7.0% of insulin glargine-treated patients achieved this composite endpoint (Supplementary Fig. 1). The composite endpoint of HbA1c <7.0%, SBP <130 mmHg, no major/minor hypoglycemia, and no weight gain was achieved by 15.8% of exenatide QW-treated patients compared with 9

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3.2% of insulin glargine-treated patients at week 156. Moreover, 19.8% of exenatide QW recipients achieved the composite endpoint of HbA1c ≤6.5%, no major/minor hypoglycemia, and

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no weight gain, while 3.2% of insulin glargine recipients achieved this endpoint. 3.3. Safety

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3.3.1. General AEs

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In the ITT population, withdrawal rates due to AEs were low in both the exenatide QW and insulin glargine treatment groups (9.1% and 1.8%, respectively). Most discontinuations due

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to AEs occurred during the first year of treatment (Supplementary Fig. 2).

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Among the 2.5- to 3-year completer population, AEs occurred in 91.2% and 81.0% of patients receiving exenatide QW and insulin glargine, respectively (Table 3). SAEs occurred in

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14.9% and 16.5% of patients in the exenatide QW and insulin glargine groups, respectively. Among insulin glargine-treated patients, only one specific SAE (cholecystitis) was observed in

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≥1% of patients (2 of 158 patients [1.3%]), whereas no specific SAE occurred in ≥1% of

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exenatide QW-treated patients. The most common AEs observed with exenatide QW were diarrhea, pharyngitis, nausea, upper respiratory tract infection, and headache (Table 3). Nausea, vomiting, and diarrhea occurred in <11.0%, <3.0%, and <8.0% of patients during any 2-week period from weeks 0−30 or any 24- to 26-week period from weeks 30−104 (Supplementary Fig. 3). Generally, gastrointestinal AEs tended to decrease over time with exposure. Injection-site pruritus occurred in 8.2% of exenatide QW recipients and no patients receiving insulin glargine (Table 3).

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3.3.2. Hypoglycemia

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In both treatment groups in the 2.5- to 3-year completer population, patients receiving

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concomitant sulfonylurea therapy during long-term treatment had more hypoglycemic episodes (major + minor hypoglycemia) than those who were not. Among patients receiving

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sulfonylureas, hypoglycemia occurred in 32.6% of exenatide QW recipients and 70.2% of insulin glargine recipients, whereas hypoglycemia incidence among patients not taking sulfonylureas

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was 10.0% and 45.9%, respectively. Hypoglycemic events occurred in <7.0% of patients in the

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exenatide QW group during any 2-week period from weeks 0−30 or any 24- to 26-week period from weeks 30−104 (Supplementary Fig. 4). The exposure-adjusted event rate (EAER) per 1000

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patient-years among patients receiving sulfonylureas was 679.3 and 1612.1 in the exenatide QW and insulin glargine groups, respectively. Patients not receiving sulfonylureas in the exenatide

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QW and insulin glargine groups had EAERs per 1000 patient-years of 111.7 and 614.6,

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respectively.

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3.3.3. AEs of special interest

Most AEs of special interest occurred at a frequency of <1% in patients receiving exenatide QW among the 2.5- to 3-year completer population. Pancreatitis occurred in 0.3% and 0.6% of exenatide QW and insulin glargine recipients, respectively, and acute renal failure in 0.6% and 0.0% of patients, respectively. One exenatide QW-treated patient (0.3%) developed a malignant thyroid neoplasm, which the study investigator deemed unrelated to study medication. Onset occurred during the study extension (after 588 days of treatment); the thyroid nodule was categorized as mild in severity and did not lead to hospitalization or study withdrawal.

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4. Discussion

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The most recent guidelines from the American Diabetes Association (ADA) for the

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management of microvascular and macrovascular diabetes complications are directed at reducing stress and the importance of controlling hyperglycemia, maintaining weight control, achieving

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optimal BP targets, and controlling dyslipidemia and hypertriglyceridemia in patients with diabetes (American Diabetes Association, 2017a, 2017b). While these clinical goals are

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undeniably important, data on the effects of specific glucose-lowering therapies on these

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endpoints in a representative population for >1 year are uncommon, as long-term extensions may eventually be limited to few patients (Wysham, et al., 2015; Wysham, et al., 2016). Although

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many patients discontinue therapy during trial extensions, data from these self-selected populations apply to real-world patients receiving life-long therapy to prevent complications of

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diabetes, since real-world patients also select a therapy that they can adhere to. Additionally, it is

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possible that new AEs may arise over longer-term therapy, and it is important to examine the available data for AE patterns. This analysis examined the clinical outcomes mentioned by the

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ADA in the 2.5- to 3-year exenatide QW treatment population along with AEs reported with long-term exenatide treatment. Pooling data from three separate exenatide QW trials provided the largest population of patients treated for up to 3 years to date. Results of the current analysis confirmed continued efficacy and safety of exenatide QW over the study period, with reductions from baseline in HbA1c and FG from weeks 4–156. Although these reductions persisted at each time point compared with baseline, a slight upward trend in HbA1c and FG levels was observed between weeks 52 and 156, which could indicate disease progression over time. Approximately 48% and 30% of the population achieved HbA1c 12

ACCEPTED MANUSCRIPT goals of <7.0% and ≤6.5%, respectively. Weight reductions were observed at week 4 and maintained throughout the 156-week analysis period. Additionally, reductions in LDL-C were

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observed at weeks 14–22 and maintained at week 156, although there was an upward trend in reductions from weeks 26–84. A small HDL-C increase occurred after 52 weeks, which was

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maintained at most subsequent assessments and at week 156 (+0.08 ± 0.20 mmol/L). Reductions from baseline in SBP and DBP at week 156 were small. These results could potentially be

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affected by continued changes in background BP medication over time.

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Changes in weight within each treatment group were consistent throughout the study. Treatment with exenatide showed a reduction in body weight (−2.4 ± 5.6 kg) over the 156-week

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study period, while insulin glargine-treated patients experienced weight gain (+2.0 ± 4.9 kg). It is well known that obesity contributes to progression of diabetes complications and can be a risk

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factor for cardiovascular events in patients with T2D (Van Gaal & Scheen, 2015; Van Gaal, et

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al., 2006). Weight loss is important in the management of diabetes and remains a challenge with most conventional therapies (Cefalu, et al., 2015; Van Gaal & Scheen, 2015). Results of the

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present analysis are consistent with previous reports that indicate the weight-loss potential of GLP-1RAs (Ryan & Acosta, 2015). However, a fixed dose of exenatide was used in these studies, whereas the insulin glargine dose was adjusted over the DURATION-3 study period to achieve HbA1c goal. In this pooled analysis, long-term exenatide QW treatment appeared to be well tolerated, with a safety profile generally typical of that seen with GLP-1RAs at earlier time points (Consoli & Formoso, 2015; Trujillo & Nuffer, 2014). No new SAE patterns were observed; most AEs of special interest were sporadic, and no AE of special interest was seen in >1% of patients. 13

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Overall, the safety profile was comparable to that observed in the head-to-head comparison of exenatide QW and insulin glargine (DURATION-3) at 3 years’ follow-up (Diamant, et al.,

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2014). In this pooled analysis, hypoglycemia rates were low among exenatide QW-treated patients, consistent with the short-term DURATION studies that demonstrated no episodes of

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major hypoglycemia and low rates of minor hypoglycemia with exenatide (Bergenstal, et al., 2010; Blevins, et al., 2011; Buse, et al., 2013; Diamant, et al., 2010; Drucker, et al., 2008;

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Russell-Jones, et al., 2012). The proportion of exenatide QW-treated patients who withdrew due

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to AEs was ~10%, and most study withdrawals occurred during the first year of treatment. Results of this analysis were comparable to those observed in a smaller population with

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exenatide QW in the 6-year follow-up of DURATION-1 (n=136) (Henry, et al., 2016). After 6 years, sustained reductions from baseline were observed in HbA1c, FG, and body weight, along

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with improvements in some cardiovascular risk markers, including TC, LDL-C, HDL-C,

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LDL/HDL ratio, and TGs. Safety and tolerability findings of the current analysis were also comparable to those of DURATION-1 at the 6-year follow-up, which found no new long-term

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safety concerns.

While long-term data regarding the efficacy and safety of other GLP-1RAs are generally lacking, some 2- to 3-year data are available for liraglutide, dulaglutide, and albiglutide. Data from the HARMONY study program showed that 3 years of treatment with albiglutide resulted in superior HbA1c and FG reductions from baseline versus placebo, sitagliptin, and sulfonylurea therapy in patients with T2D (Matthews, et al., 2014). Two-year data for liraglutide and dulaglutide showed that efficacy and safety were generally maintained over the long term; however, a trend toward lesser HbA1c reductions was observed at later time points (Garber, et al., 14

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2011; Nauck, et al., 2013; Weinstock, et al., 2015). Similar trends in HbA1c and FG levels were

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observed in the present analysis with exenatide treatment from weeks 52–156.

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Lesser reductions in glycemic measures over time could indicate disease progression with long-term GLP-1RA treatment in some patients, regardless of the type or duration of therapy.

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The EUREXA study comparing exenatide BID with glimepiride in patients with T2D uncontrolled on metformin (N=977) reported that the median time to inadequate HbA1c control

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was 180 weeks with exenatide BID versus 142.1 weeks with glimepiride (P=0.032) (Gallwitz, et

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al., 2012). FG concentrations in the exenatide group were significantly lower from baseline at 1 (P=0.048), 2 (P=0.004), and 3 years (P<0.0001) of treatment. In an analysis of patient-level data

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from DURATION-3 up to week 156, the proportion of patients maintaining HbA1c <7.0% was greater with exenatide QW compared with insulin glargine (Trautmann, et al., 2016). Findings

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indicative of disease progression may reflect β-cell failure in patients with T2D on long-term

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GLP-1RA treatment. However, a 3-year extension study with exenatide BID in metformintreated patients with T2D reported improvement in β-cell function with exenatide compared with

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insulin glargine; the number of patients who completed the study was relatively small (n=36), and these results need to be interpreted with caution (Bunck, et al., 2011). A key limitation of the current analysis is the lack of detailed information on concomitant therapies used during the three extension studies. This information could be particularly important since continuous use of concomitant therapies like statins or irregular use of BPlowering drugs might be the reason for the specific patterns observed in the changes in cardiovascular risk parameters during the study. While rescue medications for glucose control were not prespecified, some patients may have used more oral medication and a low percentage 15

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may have added insulin, as observed in extension trials of DURATION-1 and -3. Among patients treated for 6 years in DURATION-1, 57% added no new glucose-lowering medications,

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and oral medications such as metformin and sulfonylureas were more commonly added than insulin (fast-acting, up to 2.9% of patients; intermediate-acting, 0.7%; long-acting, 8.8%)

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(Henry, et al., 2016). It would be reasonable to assume similar or lesser changes in medication use at earlier time points in DURATION-2. Three-year data from DURATION-3 showed that,

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among exenatide QW-treated patients, 20% of patients increased the dose of oral glucose-

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lowering therapy, 12% added other oral glucose-lowering therapies, and 2% added insulin (Diamant, et al., 2014). Improvements in glucose control persisted with these minimal changes in

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concomitant medications.

Other limitations include those inherent in post hoc analyses and the open-label nature of

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the original studies, particularly the withdrawal of patients over time. Furthermore, the patient

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population was still too small to detect rare AEs. In addition, differences in the design of the primary trials, such as geographic location and permitted background therapies, may have

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affected results. The lack of a head-to-head comparator group in the extension of two of the three original DURATION studies prevented comparisons between exenatide QW and a comparator, which would assist in choice of long-term therapy. Only one of the three studies included an insulin glargine arm, which did not allow for statistical comparisons between the pooled exenatide QW group and the insulin glargine reference group. Since T2D is a chronic disease requiring long-term treatment, effective and sustained disease control is crucial to avoid acute and long-term complications that result in a substantial burden for the patient, their family and friends, and the healthcare system (American Diabetes 16

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Association, 2017c). A classic study by Gaede and colleagues reported that, after a mean of 13.3 years of treatment for T2D, the absolute risk of death was reduced by 20% from any cause

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among patients who received intensive, target-driven (HbA1c <6.5%, fasting TC <4.5 mmol/L, fasting TG <1.7 mmol/L, SBP <130 mmHg, and DBP <80 mmHg) therapy versus those who

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received conventional therapy, with a 13% absolute risk reduction for death due to cardiovascular causes (Gaede, et al., 2008). These findings stress the importance of an intensive,

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target-driven and individualized approach to treating patients with T2D. Positive findings from

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the LEADER trial also support the possibility that control of multiple risk factors might reduce the complications of diabetes over time in these patients. The LEADER trial, which included

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9340 patients at higher risk of cardiovascular events treated with liraglutide or placebo over a 2year period, reported fewer deaths from cardiovascular causes, lower frequency of nonfatal

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myocardial infarction and stroke, and lower rate of death from any cause among liraglutide-

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compared with placebo-treated patients (Marso, et al., 2016). Also, liraglutide treatment showed a significant reduction in the cardiovascular risk factors of body weight, SBP, DBP, and heart

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rate, along with decreased incidence of microvascular complications (P=0.02), compared with placebo. Another cardiovascular outcomes study, the Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial, investigated the addition of lixisenatide or placebo to conventional therapy for a median of 25 months among 6068 patients with T2D and a recent acute coronary syndrome (Pfeffer, et al., 2015). In this trial, investigators found a neutral effect of lixisenatide on cardiovascular events, with no significant differences between treatment groups in the rate of hospitalization for heart failure or rate of death. The EXenatide Study of Cardiovascular Event Lowering (EXSCEL; NCT01144338), a randomized, placebo-controlled trial of approximately 7.5 years’ duration, (Holman, et al., 2016) is currently underway and will 17

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provide important additional information on the long-term effects of exenatide QW on T2D

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complications, including cardiovascular and microvascular complications, and general safety.

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5. Conclusions

In this pooled analysis of patients with T2D receiving over 3 years of exenatide QW

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treatment, glycemic and weight outcomes continued to improve versus baseline and exenatide

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QW treatment was well tolerated. Exenatide QW is an option for long-term treatment to achieve glycemic goals and to improve control of some cardiovascular risk factors associated with

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diabetes complications.

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Acknowledgments

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Sheridan Henness, PhD, of inScience Communications, and Andrea Bothwell, on behalf of

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inScience Communications, provided medical writing support, which was funded by AstraZeneca.

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Conflict of Interest Disclosures: M.E.T. is a consultant for companies developing new diabetes

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medications. He is a former employee and current stockholder of Eli Lilly. L.V.G. is/has been a member of the advisory board and speakers bureau for AstraZeneca, Boehringer Ingelheim, Eli

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Lilly, Janssen, Merck Sharp and Dohme, Novo Nordisk, Sanofi, and Servier. J.H. is a consultant for AstraZeneca. E.H. is an employee of AstraZeneca.

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Funding/Support: The analysis was supported by AstraZeneca.

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pioglitazone to once-weekly exenatide. Diabet Med, 28(6), 705–714. doi: 10.1111/j.1464-5491.2011.03301.x Wysham, C. H., MacConell, L. A., Maggs, D. G., Zhou, M., Griffin, P. S., & Trautmann, M. E. (2015). Five-year efficacy and safety data of exenatide once weekly: long-term results from the DURATION-1 randomized clinical trial. Mayo Clin Proc, 90(3), 356–365. doi: 10.1016/j.mayocp.2015.01.008 Wysham, C. H., Philis-Tsimikas, A., Klein, E. J., Öhman, P., Iqbal, N., Han, J., et al. (2016). DURATION-1 extension in patients with T2D: Efficacy and tolerability of exenatide once weekly (QW) over 7 years [abstract]. Paper presented at the American Diabetes 25

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Association, June 10–14, 2016, New Oreans, LA, USA.

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Figure Legends

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Fig. 1. Mean ± standard error changes from baseline over time among the 2.5- to 3-year

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completer population of patients treated with exenatide QW or insulin glargine for (A) HbA1c; (B) FG; (C) SBP; and (D) body weight. *P<0.001 vs baseline; †P<0.05 vs baseline. ExQW,

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QW, once weekly; SBP, systolic blood pressure.

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exenatide once weekly; FG, fasting glucose; HbA1c, glycated hemoglobin; IG, insulin glargine;

Fig. 2. Time course of the effect of exenatide QW and insulin glargine on lipid levels among the

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2.5- to 3-year completer population. Mean ± standard error changes from baseline in (A) LDL-C; (B) HDL-C; (C) TC; and (D) TGs. *P<0.001 vs baseline; †P<0.05 vs baseline. ExQW, exenatide

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once weekly; HDL-C, high-density lipoprotein cholesterol; IG, insulin glargine; LDL-C, low-

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density lipoprotein cholesterol; TC, total cholesterol; TG, triglycerides; QW, once weekly.

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Table 1. Demographic and baseline characteristics of patients treated with exenatide QW compared with insulin glargine: pooled data from DURATION-1, -2, and -3 for completer and

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Insulin glargine

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Characteristica Exenatide QW 2.5–3.0-year completer population N 329 Age, y 55.8 ± 8.9 Male, n (%) 179 (54.4) Race, n (%) White 240 (72.9) Hispanic 47 (14.3) Asian 25 (7.6) Black 17 (5.2) Weight, kg 93.7 ± 19.0 BMI, kg/m2 33.0 ± 5.2 HbA1c, % 8.3 ± 1.1 FG, mmol/Lb 9.3 ± 2.6 Duration of diabetes, y 7.5 ± 5.9 HbA1c ≥7.0%, n (%) 316 (96.0) HbA1c >6.5%, n (%) 327 (99.4) Concomitant therapies, n (%) Diet and exercise only 13 (4.0) Metformin 216 (65.7) TZD 2 (0.6) Metformin + SFU 79 (24.0) SFU ± TZD 8 (2.4) Metformin + TZD ± SFU 10 (3.0) ITT population

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ITT populations.

N Age, y Male, n (%) Race, n (%) White Hispanic Asian Black Weight, kg BMI, kg/m2 HbA1c, % FG, mmol/Lc Duration of diabetes, y Concomitant therapies, n (%) Diet and exercise only Metformin

158 57.9 ± 8.7 87 (55.1) 135 (85.4) 15 (9.5) 7 (4.4) 1 (0.6) 90.3 ± 16.2 32.4 ± 4.9 8.3 ± 1.0 9.8 ± 2.6 8.1 ± 6.3 152 (96.2) 157 (99.4) 0 (0.0) 111 (70.3) 0 (0.0) 47 (29.7) 0 (0.0) 0 (0.0)

541 55.2 ± 10.1 291 (53.8)

223 57.8 ± 9.1 123 (55.2)

366 (67.7) 94 (17.4) 50 (9.2) 30 (5.5) 93.4 ± 19.5 32.9 ± 5.3 8.4 ± 1.1 9.4 ± 2.7 7.2 ± 5.6

189 (84.8) 19 (8.5) 14 (6.3) 1 (0.4) 90.6 ± 16.3 32.3 ± 4.8 8.3 ± 1.0 9.8 ± 2.7 7.8 ± 6.0

21 (3.9) 378 (69.9)

0 (0.0) 156 (70.0)

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Characteristica Exenatide QW Insulin glargine TZD 3 (0.6) 0 (0.0) Metformin + SFU 114 (21.1) 67 (30.0) SFU ± TZD 11 (2.0) 0 (0.0) Metformin + TZD ± SFU 14 (2.6) 0 (0.0) BMI, body mass index; FG, fasting plasma or serum glucose; HbA1c, glycated hemoglobin; ITT, intention-to-treat; QW, once weekly; SFU, sulfonylurea; TZD, thiazolidinedione. Data are shown as mean ± standard deviation unless otherwise noted.

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Exenatide QW: n=319; insulin glargine: n=146.

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Exenatide QW: n=522; insulin glargine: n=206.

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Table 2. Mean outcome changes from baseline at 156 weeks in the 2.5- to 3-year completer population. Parametera

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Exenatide QW Insulin glargine (n=329) (n=158) * HbA1c, % −1.1 ± 1.3 −0.8 ± 1.0* FG, mmol/L −1.7 ± 2.7* −2.8 ± 3.2* * Body weight, kg −2.4 ± 5.6 2.0 ± 4.9* SBP, mmHg −1.3 ± 16.5 1.5 ± 15.1 DBP, mmHg −0.6 ± 9.3 −2.1 ± 9.5† † LDL-C, mmol/L −0.13 ± 0.73 −0.12 ± 0.72† * HDL-C, mmol/L 0.08 ± 0.20 0.03 ± 0.22 TC, mmol/L −0.11 ± 0.93† −0.15 ± 0.86† TGs, mmol/L −0.05 ± 1.79 −0.14 ± 1.19 DBP, diastolic blood pressure; FG, fasting plasma or serum glucose; HbA1c, glycated hemoglobin; HDLC, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; QW, once weekly;

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SBP, systolic blood pressure; TC, total cholesterol; TGs, triglycerides. Data are shown as mean ± standard deviation.

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*P<0.001, †P<0.05 vs. baseline

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Table 3. AEs occurring in >5% of patients in the completer population treated with exenatide QW.

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All AEs All serious AEs Gastrointestinal disorders Constipation 30 (9.1) Diarrhea 79 (24.0) Dyspepsia 27 (8.2) Gastroesophageal reflux disease 25 (7.6) Nausea 73 (22.2) Vomiting 35 (10.6) General disorders and administration site conditions Fatigue 23 (7.0) Injection-site pruritus 27 (8.2) Infections and infestations Bronchitis 26 (7.9) Gastroenteritis 23 (7.0) Gastroenteritis viral 23 (7.0) Influenza 25 (7.6) Nasopharyngitis 78 (23.7) Sinusitis 25 (7.6) Upper respiratory tract infection 62 (18.8) Urinary tract infection 40 (12.2) Musculoskeletal and connective tissue disorders Arthralgia 37 (11.2) Back pain 28 (8.5) Muscle spasms 17 (5.2) Musculoskeletal pain 32 (9.7) Pain in extremity 27 (8.2) Nervous system disorders Dizziness 17 (5.2) Headache 47 (14.3) Respiratory, thoracic, and mediastinal disorders Cough 26 (7.9) Oropharyngeal pain 25 (7.6) Vascular disorders Hypertension 33 (10.0) AEs, adverse events; QW, once weekly.

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Insulin glargine (n=158) 128 (81.0) 26 (16.5)

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Exenatide QW (n=329) 300 (91.2) 49 (14.9)

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Patients, n (%)

5 (3.2) 13 (8.2) 8 (5.1) 2 (1.3) 4 (2.5) 5 (3.2) 2 (1.3) 0 (0.0) 15 (9.5) 9 (5.7) 3 (1.9) 8 (5.1) 49 (31.0) 5 (3.2) 10 (6.3) 9 (5.7) 8 (5.1) 12 (7.6) 9 (5.7) 11 (7.0) 3 (1.9) 7 (4.4) 19 (12.0) 10 (6.3) 8 (5.1) 15 (9.5)

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Figure 1

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Figure 2

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Highlights

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 Type 2 diabetes patients require long-term treatment for glycemic control.

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 Extension data from 3 studies of exenatide QW were pooled to assess long-term efficacy and safety.

Reductions in HbA1c, fasting glucose, and weight were maintained from weeks 4–156.

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

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 No new safety or tolerability issues for exenatide QW were identified over time.

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