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Keywords:

  • body weight;
  • cardiovascular disease;
  • exenatide;
  • glycaemic control

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Appendix

Aim:  The ability of the incretin mimetic exenatide to improve glycaemic control and reduce body weight was assessed over 82 weeks in patients with type 2 diabetes failing to achieve glycaemic control with maximally effective doses of metformin.

Methods:  In this interim 82-week analysis, 150 (total cohort) of an eligible population of 183 patients opted to continue exenatide treatment in an uncontrolled open-label extension of a 30-week double-blind, placebo-controlled trial. Of these, 92 patients (completer cohort) achieved 82 weeks of exenatide therapy. Patients continued metformin throughout the study.

Results:  At the end of the placebo-controlled trial, exenatide resulted in an haemoglobin A1c (HbA1c) reduction from baseline of −1.0 ± 0.1% (mean ± SE) (exenatide treatment arms), with durable HbA1c reductions after 82 weeks of −1.3 ± 0.1%. The percent of patients who achieved HbA1c≤7% at weeks 30 and 82 was 46 and 59% respectively. After 30 weeks, exenatide caused a reduction in weight from baseline of −3.0 ± 0.6 kg, with a progressive reduction in weight of −5.3 ± 0.8 kg after 82 weeks. In addition, exenatide treatment produced clinically significant improvements in cardiovascular risk factors after 82 weeks. The most frequent adverse event after 30 and 82 weeks of exenatide was nausea, which was generally of mild-or-moderate intensity. It decreased in incidence after initiation in the controlled trial and the uncontrolled open-label extension. Hypoglycaemia was rare, with no severe events.

Conclusion:  Exenatide was generally well tolerated, producing a durable reduction in HbA1c and a progressive reduction in weight over 82 weeks in patients with type 2 diabetes failing to achieve glycaemic control with metformin.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Appendix

Type 2 diabetes is characterized by hyperglycaemia, which occurs through a failure of pancreatic β-cells to secrete sufficient insulin, often with a background of insulin resistance [1]. The United Kingdom Prospective Diabetes Study (UKPDS) has demonstrated that the loss of β-cell function and the capacity to secrete insulin are progressive in nature over the course of the disease and may explain why therapies such as diet, metformin, sulphonylureas (SU) and insulin become less effective over time [2,3]. The goal of antidiabetic therapies is to improve glycaemic control and thus reduce the incidence of microvascular and macrovascular complications. However, efforts to achieve glycaemic control are often inadequate, as evidenced by glycosylated haemoglobin A1c (HbA1c) values over 8% in many patients [4,5]. Potential barriers to the intensification of therapy include undesirable side effects such as hypoglycaemia, oedema and weight gain that may reduce patient compliance [6,7].

Patients with type 2 diabetes are often prescribed metformin, a common antidiabetic drug that reduces hepatic glucose output and as a secondary mode of action, reduces insulin resistance in peripheral tissues. Metformin can be used as monotherapy, or in combination with other oral antidiabetic drugs, or insulin. Metformin has the advantages of causing slight weight loss or not causing excessive weight gain [8], and not being a hypoglycaemia-inducing agent. Often patients who fail to attain glycaemic control with metformin are faced with a choice of other treatment options that may elicit undesirable side effects and the likelihood of an ultimate loss of glycaemic control [2,3,7–11].

The 39-amino acid peptide exenatide is an incretin mimetic with glucoregulatory actions similar to the incretin hormone GLP-1 [12–21]. These effects include glucose-dependent enhancement of insulin secretion, suppression of inappropriately high glucagon secretion, slowing of gastric emptying and reduction of food intake [14,17,22,23]. Furthermore, exenatide treatment results in the restoration of 1st phase and 2nd phase insulin secretion [24]. In addition, exenatide and GLP-1 have been reported to promote β-cell proliferation and neogenesis from precursor cells in vitro and in vivo in animal models, thus transforming non-insulin-producing cells into insulin secretory cells [17].

An earlier study reported that a patient population with type 2 diabetes failing to achieve glycaemic control with metformin had improved glycaemic control and reduction of body weight when treated with exenatide and metformin for 30 weeks in a placebo-controlled trial [25]. This 82-week interim analysis evaluates the population of patients who completed the 30-week placebo-controlled trial and opted to enroll in an uncontrolled open-label extension, continuing treatment with exenatide and metformin.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Appendix

Study Patients

Patients were required to have type 2 diabetes and have completed the earlier 30-week placebo-controlled study with metformin and exenatide treatment [25]. General inclusion criteria required patients to have been treated with ≥1500 mg/day metformin for 3 months prior to screening, and have HbA1c 7.1 to 11.0%, fasting plasma glucose (FPG) concentration <240 mg/dl, body mass index (BMI) 27–45 kg/m2 and be 16–75 years old. Patients must also have had stable weight (±10%) for 3 months prior to screening. Female patients were surgically sterile, postmenopausal or using contraceptives prior to screening, continuing for the duration of the study. Exclusion criteria prohibited the use of meglitinides, SUs, thiazolidinediones, α-glucosidase inhibitors, weight loss drugs, exogenous insulin therapy, drugs affecting gastrointestinal motility, corticosteroids, transplantation medicines, investigational drugs or comorbid conditions of a clinically significant nature for 3 months prior to screening.

Ethics

A common clinical protocol was approved for each of the 54 sites in this study by an Institutional Review Board and in accordance with the principles described in the Declaration of Helsinki, including all amendments through the 1996 South Africa revision [26]. All patients provided written informed consent prior to participation.

Study Design

This was a long-term multicentre, uncontrolled open-label extension of the prior 30-week study designed after consultation with the United States Food and Drug Administration, such that all patients received exposure to exenatide for 82 weeks (figure 1) [25]. The purpose was to evaluate long-term glycaemic control, as assessed by HbA1c, body weight, and blood lipids, as well as evaluate safety and tolerability in patients treated with metformin and subcutaneous (SC) twice daily (BID) 10 µg exenatide injection.

image

Figure 1. Patient disposition flow chart, describing patient entry into the placebo-controlled 30-week trial, and the subsequent uncontrolled open-label extension study. *Patients who received 5μg or 10μg exenatide in the placebo-controlled trial.**10% of patients withdrew due to adverse events or loss of glucose control. For full disposition listings see Table 1.

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The patients in this interim analysis received 5 µg or 10 µg exenatide BID (SC) for 30 weeks in the placebo-controlled trial [25]. At the start of the uncontrolled open-label extension study, patients all received 5 µg exenatide BID for 4 weeks, followed by 10 µg exenatide BID for the duration of the study. Patients in the placebo group from the placebo-controlled trial were not included in this interim analysis as they had not received exposure to exenatide for 82 weeks. All patients continued to receive their current regimen of metformin treatment and were instructed to fast overnight prior to a study site visit. Exenatide was self-administered into the abdomen (SC) within 15 min prior to meal consumption in the morning and evening. Patients did not take part in a diet and exercise regimen as part of the trial protocol.

Endpoints

The primary objectives of this interim analysis were to evaluate the changes from baseline to each visit in HbA1c and body weight in the population who completed 82 weeks of exenatide treatment (30 weeks in the placebo-controlled trial and 52 weeks in the uncontrolled open-label extension), referred to as the 82-week completer cohort. In addition, the proportion of patients with baseline HbA1c >7% who achieved HbA1c≤7% was calculated, and changes in body weight were stratified by baseline BMI < or ≥30 kg/m2.

Safety endpoints included adverse events occurring upon or after receiving the first exenatide dose, clinical laboratory tests, physical examination, 12-lead ECG and vital signs. All safety analyses were performed using the 82-week total cohort (n = 150), defined as all patient's who received at least one injection of exenatide starting from the beginning of the uncontrolled open-label extension study and who enrolled with timing such that they could achieve 82 weeks of exenatide treatment. For an adverse event to be described as hypoglycaemia, the patient had to have experienced symptoms consistent with hypoglycaemia, with or without an accompanying glucose measurement. But if blood glucose measurement was available, the value had to be <60 mg/dl (3.33 mmol/l). Hypoglycaemia was further characterized as being mild-or-moderate or severe. Severe hypoglycaemia was defined as an episode that required the assistance of another person for treatment.

Statistical Analysis

For the 82-week completer cohort, missing week 82 results were imputed from scheduled or unscheduled postbaseline visits using the last observation carried forward (LOCF) method. Observed data were used for all other time points. For the 82-week total cohort, missing results at all postbaseline time points were imputed from scheduled or unscheduled postbaseline visits using the LOCF method. Results are given as mean ± SE with 95% confidence intervals unless otherwise indicated. For the nausea subgroup analysis, patients were grouped into one of four categories based on whether nausea was reported during weeks 0–8, and whether it occurred for more than 7 days during weeks 8–82. Descriptive statistics were provided for these subgroups for changes in HbA1c and weight. Additional information on statistical methods can be found in the publications of the 30-week placebo-controlled trial [25].

Conversion Factors and Assays

From conventional units to SI units multiply by the following conversion factors. For FPG: 0.0555 (mg/dl to mmol/l). For total cholesterol, low-density lipoprotein (LDL)-cholesterol and high-density lipoprotein (HDL)-cholesterol: 0.0259 (mg/dl to mmol/l). For triglycerides: 0.0113 (mg/dl to mmol/l). For apolipoprotein B (Apo B): 0.01 (mg/dl to g/l). Plasma analytes were quantified by Quintiles Laboratories (Smyrna, GA, USA) or Esoterix Endocrinology (Calabasas Hills, CA, USA) using standard methods as previously described [25].

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Appendix

Patient Demographics and Disposition

Patient disposition is presented in table 1 for the 82-week total cohort who completed the placebo-controlled trial and entered the uncontrolled open-label extension study. Patient demographics are presented for the 82-week completer cohort, who received 82 weeks of exenatide treatment. Demographics at the start of the placebo-controlled trial and the uncontrolled open-label extension study were similar.

Table 1.  Patient disposition (82-week total cohort, n = 150) and baseline demographics (82-week completer cohort, n = 92) for the 82-week clinical trial
 82-week total cohort
  • BMI, body mass index; FPG, fasting plasma glucose; HbA1c, haemoglobin A1c.

  • *

    Administrative withdrawals were primarily due to study site closure.

  • Mean ± SD unless otherwise indicated. Percentages may not add up to 100 due to rounding.

Disposition
 Total cohort, n150
 Completed, n92 (61%)
 Withdrew, n58 (39%)
  Withdrawal of consent11%
  Loss of glucose control3%
  Adverse event7%
  Investigator decision3%
  Protocol violation3%
  Lost to follow-up7%
  Administrative*6%
 82-week completer cohort
Demographics
  Sex, Male/Female (%)69/31
  Age (years)54 ± 10
  Race, Caucasian/Black/Asian/Hispanic (%)86/9/4/1
  HbA1c (%)8.1 ± 1.0
  Weight (kg)102 ± 21
  BMI (kg/m2)34 ± 6
  FPG (mg/dl)169 ± 42
  Duration of diabetes (years)5 ± 5

HbA1c and FPG

After 30 weeks of exenatide treatment in the placebo-controlled trial, the 82-week completer cohort had significant reductions in HbA1c from baseline of−1.0 ± 0.1%. The reductions in HbA1c were sustained to week 82 with changes from baseline of −1.3 ± 0.1% (95% CI: −1.5 to −1.0%, p < 0.05) (figure 2A). For the total cohort, changes from baseline to weeks 30 and 82 were −0.7 ± 0.1% (95% CI: −0.8 to −0.5%, p < 0.05) and −0.8 ± 0.1% (95% CI: −1.0 to −0.6%, p < 0.05) respectively. The durable improvement in glycaemic control was reflected in the increased proportion of patients in the 82-week completer cohort who achieved HbA1c≤7% at week 30 (46%), and week 82 (59%). After 30 weeks of exenatide treatment, the completer cohort had reduced FPG from baseline by −23 ± 4 mg/lL. At week 82, reductions from baseline in the 82-week completer cohort were −31 ± 4 mg/dl.

image

Figure 2. Change in haemoglobin A1c (HbA1c) (a) and body weight (b) from baseline with exenatide and metformin treatment over 82 weeks for the 82-week completer cohort (n = 92) and the 82-week total cohort (n = 150) (Mean ± SE).

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Body Weight

After 30 weeks of exenatide treatment, the 82-week completer cohort exhibited a reduction in body weight from baseline of −3.0 ± 0.6 kg. Reduction in body weight after 82 weeks was progressive with a change from baseline of −5.3 ± 0.8 kg (95% CI: −7.0 to−3.7 kg, p < 0.05) (figure 2B). The change from baseline to weeks 30 and 82 for the total cohort was−2.3 ± 0.4 kg (95% CI: −3.1 to −1.5 kg, p < 0.05) and−4.3 ± 0.6 kg (95% CI: −5.5 to −3.2 kg, p < 0.05) respectively. Reduction in body weight after 82 weeks of exenatide treatment in the completer cohort was further analysed after stratification by baseline (BMI < 30 kg/m2 or ≥30 kg/m2). Greater reductions were seen for the group with baseline BMI ≥30 kg/m2, in which weight reduction was −6.9 ± 1.1 kg, compared with −2.3 ± 0.8 kg for the group with baseline BMI < 30 kg/m2 (figure 3).

image

Figure 3. Change in body weight from baseline stratified by baseline BMI < or ≥30 kg/m2 at weeks 30 and 82 for the 82-week completer cohort (n = 92) and the 82-week total cohort (n = 150) (Mean ± SE).

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Cardiovascular Risk Factors

Lipid profiles improved after 82 weeks of exenatide treatment with reductions from baseline for Apo B (−5.2 mg/dl) and triglycerides (−73 mg/dl) and increased HDL-cholesterol (+4.5 mg/dl). Total cholesterol (−7.3 mg/dl) and LDL-cholesterol (−4.4 mg/dl) were also reduced from baseline values. Furthermore, the ratios of LDL-cholesterol/HDL-cholesterol (−0.37), total cholesterol/HDL-cholesterol (−0.73) and endpoint/baseline triglycerides (+0.74) also significantly improved. Similarly, after 82 weeks of exenatide treatment, both systolic (−6.3 mmHg) and diastolic (− 4.1 mmHg) blood pressures were significantly reduced (table 2).

Table 2.  Lipid and blood pressure changes from baseline for the 82-week completer cohort (n = 92)
 Mean baselineChange from baseline (%)Change from baseline (Mean ± SE)95% confidence interval
  1. Apo B, apolipoprotein B; HDL, high-density lipoprotein; LDL, low-density lipoprotein.

Blood lipids
 Total cholesterol (mg/dl)196−3.7−7.3 ± 4.2−16 to +0.92
 LDL-cholesterol (mg/dl)119−3.7−4.4 ± 4.1−13 to +3.7
 HDL-cholesterol (mg/dl)40+11.3+4.5 ± 1.1+2.3 to +6.6
 Apo B (mg/dl)96−5.4−5.2 ± 2.5−10 to −0.22
 Triglycerides (mg/dl)277−26.4−73 ± 17−107 to −39
 Endpoint/Baseline triglycerides ratio+0.74 ± 0.11+0.66 to +0.82
 Total cholesterol/HDL-cholesterol ratio5.2−0.73 ± 0.14−1.0 to −0.45
 LDL-cholesterol/HDL-cholesterol ratio3.1−0.37 ± 0.10−0.57 to −0.17
Sitting blood pressure
 Systolic (mmHg)129−4.9−6.3 ± 1.6−9.4 to −3.1
 Diastolic (mmHg)79−5.2−4.1 ± 1.0−6.1 to −2.2

Analysis of lipids and blood pressure by body weight loss quartiles in patients treated with exenatide for 82 weeks showed improvements in clinically significant cardiovascular risk factors in the 1st weight loss quartile (patients who lost the most weight). Notable mean changes from baseline were seen with triglycerides (−139 mg/dl), total cholesterol (−9.3 mg/dl), Apo B (−6.2 mg/dl), and HDL-cholesterol (+7.1 mg/dl). Improvements in both systolic (−11.2 mmHg) and diastolic (−4.6 mmHg) blood pressures were also seen in the 1st weight loss quartile. These improvements in clinically significant cardiovascular risk factors were also observed in the 2nd and 3rd weight loss quartiles (table 3).

Table 3.  Analysis of lipid and blood pressure changes by weight loss quartiles for the 82-week completer cohort (n = 92, n = 23 for each quartile)
 Quartile analysis (Mean ± SE)   
  1. HDL, high-density lipoprotein; LDL, low-density lipoprotein.

  2. 1st weight loss quartile is defined as patients who lost the most weight.

Blood lipids1st2nd3rd4th
Weight loss (kg)−16 ± 1.7−5.6 ± 0.2−2.4 ± 0.2+2.3 ± 0.7
Total cholesterol (mg/dl)−9.3 ± 7.5−5.5 ± 6.4−2.3 ± 8.9−12.3 ± 10.3
LDL-cholesterol (mg/dl)−2.0 ± 7.1+2.9 ± 6.4−2.5 ± 9.1−16.0 ± 9.9
HDL-cholesterol (mg/dl)+7.1 ± 1.4+6.3 ± 1.5+3.3 ± 1.7+1.3 ± 3.4
Apo B (mg/dl)−6.2 ± 4.6−4.7 ± 4.1−0.2 ± 6.2−9.5 ± 4.8
Triglycerides (mg/dl)−139 ± 41.6−90.7 ± 29.9−23.9 ± 26.0−38.2 ± 32.8
Total cholesterol/HDL-cholesterol Ratio−1.1 ± 0.30−0.8 ± 0.20−0.4 ± 0.29−0.6 ± 0.33
LDL-cholesterol/HDL-cholesterol Ratio−0.5 ± 0.20−0.3 ± 0.16−0.3 ± 0.20−0.5 ± 0.24
Sitting blood pressure
 Systolic (mmHg)−11.2 ± 2.7−9.6 ± 2.6−6.2 ± 3.0+2.0 ± 3.8
 Diastolic (mmHg)−4.6 ± 1.9−6.7 ± 1.9−6.5 ± 1.7+1.3 ± 2.0

Clinical Laboratory Findings and Safety

There was no evidence of pulmonary, hepatic, renal, or cardiovascular toxicity, or idiosyncratic side effects attributable to exenatide use. There were no adverse trends in physical examination findings, vital sign measurements, heart rate or blood pressure. In the total cohort, 39% of patients withdrew from the study (table 1). The majority of the patients who withdrew were lost to follow-up (7%), withdrew due to administrative reasons (mostly study site closure (6%), withdrew consent (11%), violated protocol (3%) or were withdrawn by the investigator (3%). Other causes of withdrawal were adverse events (7%, of which 3% was due to nausea) and loss of glucose control (3%). The most frequent adverse events were nausea and upper respiratory tract infection, which were generally mild-or-moderate in intensity (table 4). The incidence of nausea peaked during the initiation phases of the 30-week placebo-controlled trial, when one arm of the trial titrated from 5 to 10 µg exenatide (weeks 4–8), and the uncontrolled open-label extension (weeks 30–34) when all patients were titrated from 5 to 10 µg exenatide. The incidence of hypoglycaemic episodes was consistent with the 30-week placebo-controlled trial, with no reported cases of severe hypoglycaemia.

Table 4.  Most frequent adverse events with an overall incidence ≥5% by 10-week intervals up to 82 weeks in the 82-week total cohort (n = 150)
 Placebo-controlled trials (weeks 0–30)Uncontrolled open-label extension (weeks 30–82)
 0–1010–2020–3030–4040–5050–6060–7070–82
Nausea (%)3018153324181514
Upper respiratory599103874
tract infection (%)
Diarrhoea (%)95353774
Vomiting (%)65355231
Dizziness (%)62146542

The incidence of nausea declined over the course of the trial (data on file), but the reduction in body weight was progressive (figure 2B). Pearson correlation analysis, which was used to evaluate the nausea-by-weight correlations for the 82-week completer cohort, showed that reductions in body weight with exenatide treatment were unlikely to be driven by the direct effect of nausea (r = −0.071).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Appendix

In the recently published randomised, placebo-controlled phase of this clinical trial involving 30 weeks of exenatide treatment in patients with type 2 diabetes inadequately controlled with metformin, HbA1c and body weight were reduced by −0.8% and −2.8 kg (10 µg exenatide treatment arm) respectively [25]. Similar reductions in HbA1c were reported in 30-week, placebo-controlled clinical trials when patients were treated with exenatide adjunctive to a SU [27], or a SU and metformin [28]. In this interim analysis of 92 patients who completed the 30-week controlled trial, enrolled in the uncontrolled open-label extension and were treated with exenatide and metformin for a total of 82 weeks, HbA1c reduction from baseline was sustained at −1.3 ± 0.1%. Moreover, body weight was progressively reduced over 82 weeks of exenatide treatment, such that weight loss from baseline was −5.3 ± 0.8 kg. The durable reduction in HbA1c and progressive loss of body weight with exenatide over 82 weeks is in contrast to treatment with insulin and oral agents, such as SUs reported by the UKPDS over the same period, where effects on lowering HbA1c were reversed and body weight typically increased [2,3].

The durable improvement in glycaemic control resulting from exenatide treatment, as measured by HbA1c, may in part be explained by improved insulin secretion only in the presence of hyperglycaemia, suppression of glucagon secretion and slowing of gastric emptying, resulting in significantly reduced postprandial plasma glucose (PPG) excursions and also in FPG, albeit to a lesser degree relative to the PPG effect [12]. In standardized meal tolerance tests carried out in the placebo-controlled trial, after 4 weeks of treatment, exenatide reduced PPG from baseline by 34% (measured as PPG geometric mean area under the curve 15–180 min), a pattern that was sustained at week 30 [25]. Epidemiological studies have demonstrated that reducing postprandial hyperglycaemia by lowering PPG may reduce the risk and severity of microvascular and macrovascular complications, and the risk of cardiovascular mortality [29]. Although both FPG and PPG contribute to the increase of HbA1c seen in patients with diabetes, the primary mode of action of most agents is the reduction of overall hyperglycaemia by reducing FPG. Agents that function in this manner include SUs, metformin and thiazolidinediones [7]. These agents have only slight effects on PPG. Furthermore, another group of agents specifically target PPG (repaglinide, nateglinide and acarbose), although in practice they have demonstrated only marginal improvements in PPG [30–32]. However, exenatide treatment caused significant reductions in PPG and also resulted in modest reductions in FPG.

In direct contrast to the weight gain ordinarily seen with glycaemic improvement achieved by other therapies [4,7,10,11,33], exenatide was associated with reductions in body weight that did not appear to plateau by week 82. These progressive reductions in body weight are consistent with the known ability of exenatide to reduce food intake and are especially noteworthy, given that the reduction in body weight was achieved in the absence of a diet and exercise regimen as part of the trial protocol [7,16,22,34–36].

Insulin resistance contributes to hyperglycaemia and dyslipidaemia, leading to cardiovascular complications such as heart attack and stroke, which are the major causes of death in patients with type 2 diabetes [37]. Oral agents that reduce insulin resistance are associated with improvements in dyslipidaemia. For example, metformin when used as a monotherapy or in combination with a SU is associated with improvements in hyperglycaemia and is also correlated with decreased plasma triglyceride and LDL-cholesterol concentrations, and reduced risk of heart attack and stroke [7,34]. However, metformin and SU combination therapy produces body weight gain, negating the slight weight loss effects of metformin monotherapy [7,34]. Recently, the thiazolidinediones, rosiglitazone and pioglitazone have been investigated as add-on therapies to metformin. Metformin and rosiglitazone have been reported to cause small increases in LDL-cholesterol and HDL-cholesterol concentrations, but no change in triglyceride concentration or total cholesterol/HDL-cholesterol ratio. The neutral effects on dyslipidaemia may be confounded by the increased body weight associated with rosiglitazone use, even in combination therapy with metformin [38,39]. In contrast, metformin and pioglitazone have been reported to cause increases in both LDL-cholesterol and HDL-cholesterol, and reductions in triglycerides and total cholesterol/HDL-cholesterol ratio [40]. In this study, we report that exenatide and metformin treatment for 82 weeks was associated with improvements in clinically meaningful cardiovascular risk factors, such as reductions in Apo B, and triglyceride concentrations, coupled with increased HDL-cholesterol concentration and improved total cholesterol/HDL-cholesterol, LDL-cholesterol/HDL-cholesterol and endpoint/baseline triglyceride ratios. In addition, both systolic and diastolic blood pressures were reduced over the course of the study. Furthermore, analysis by body weight loss quartiles demonstrated that the greatest improvement in cardiovascular risk factors was associated with the patients who experienced the greatest weight reduction. Overall, exenatide in combination with metformin appears to further improve clinically meaningful cardiovascular risk factors.

The type and the frequency of treatment-emergent adverse events encountered in the controlled trial and the uncontrolled open-label extension were similar. The most common adverse event associated with exenatide treatment was nausea, which was generally of mild-or-moderate intensity. Nausea was most common during treatment initiation and dose-escalation in both the 30-week placebo-controlled trial and the uncontrolled open-label extension, but declined with time [41]. However, reductions in body weight were progressive over 82 weeks, indicating that weight loss was not due to nausea. Subgroup analyses indicate that the greatest body weight reduction was observed among patients with nausea during the first 8 weeks, but with nausea for less than 7 days during the period of 8–82 weeks of the trial. Similarly, patients who experienced nausea during the first 8 weeks, but had nausea for more than 7 days in the period of 8–82 weeks of the trial, had similar changes in body weight (−8.4 kg vs. −7.5 kg). Moreover, reductions in HbA1c and body weight were similar in groups reporting various incidence of nausea. The rate of hypoglycaemia during the study was low and always of mild-or-moderate intensity during the 82 weeks of exenatide and metformin treatment, an observation that is consistent with the known mode of action of exenatide in which insulin secretion is stimulated in a glucose-dependent manner [14].

The 82-week completer cohort measured long-term effects of exenatide treatment, however, there are limitations to this type of analysis, such as potential bias in the uncontrolled open-label extension, the lack of a comparator group and the possibility of self-selection. To address this issue, HbA1c and body weight effects were analysed in the 82-week total cohort of patients who were treated with exenatide during the 30-week placebo-controlled trial and who then entered, but did not necessarily complete the uncontrolled open-label extension. The reductions from baseline to 82 weeks for HbA1c and body weight in the 82-week total cohort were consistent with those observed in the 82-week completer cohort. Furthermore, it is significant that the reduction in HbA1c was sustained between weeks 30 and 82 in the 82-week total cohort. Although these data are suggestive of minimal self-selection bias, one cannot rule out the possibility of self-selection in this type of uncontrolled open-label extension.

In conclusion, exenatide treatment in combination with metformin resulted in durable improvements in glycaemic control, progressive reductions in body weight and improvements in clinically meaningful cardiovascular risk factors over 82 weeks in patients with type 2 diabetes. The most common adverse event was mild-or-moderate nausea. Furthermore, hypoglycaemia was rare, with no severe cases. Exenatide is the first FDA-approved incretin mimetic and represents a novel treatment option for patients with type 2 diabetes failing oral therapy.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Appendix

The data were analysed by all authors, who also contributed to and reviewed the final manuscript. The authors to thank the Exenatide-112E Clinical Study Group for their excellent assistance in the conduct, reporting and quality control of the study, and all patients who volunteered to participate. The following are gratefully acknowledged for their valuable contributions to the conduct, reporting, quality control of the study and to the development of the manuscript: Maria Aisporna, Arvinder Dhillon, Mark Fineman, Eling Gaines, Robert Halstead, Jenny Han, John Holcombe, Jennifer Johnson, Orville Kolterman, Susanna Mac, Amanda Montoya Varns, James Ruggles, Cinde Scroggins, Larry Shen, Kristin Taylor, Michael Trautmann, Matthew Wintle, Liping Xie. Supported by Amylin Pharmaceuticals, San Diego, CA and Eli Lilly and Company, Indianapolis, IN.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Appendix
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Appendix

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Appendix

Principal investigators in the Exenatide-112E Clinical Study Group were Ahmann A, Albery R, Albu J, Beasey M, Blonde L, Bock A, Canadas R, Casner p, Cathcart H, Cavanaugh J, Chandiok S, Cohen J, Cohen L, Collins G, Conway M, Corder C, Cyrus J, Davis L, de la Garza C, DeFronzo R, Duckor S, Farrell J, Farnsworth K, Fishman N, Gaman W, Gavin L, Geary B, Gee D, Goldstein B, Harrison B, Harvey W, Herring C, Heuer M, Holloway R, Horowitz B, Klein E, Klonoff D, Kopin J, LaCava E, Landgarten S, Littlejohn T, Miller J, Miller S, Mills R, McIlwain H McInroy R, Mendelson A, Moretto T, Mudaliar S, Myers L Norwood p, Osei K, Pullman J, Raad G, Radparvar A, Ratner R, Riff D, Robinson J, Rood R, Saponaro J, Schactman B Schumacher D, Schwartz S, Shapiro J, Shapiro W, Shockey G, Strauss M, Snyder J, Sullivan J, Taber L, Troupin B, Ward W, Weerasinghe M, Weinstein R, Weiss D, Weiss R, Weissman p, Whitehouse F, Williams K, Wofford M, Wysham C, Zayed A, Zigrang W.