Jenny Han

Interim analysis of the effects of exenatide treatment on A1C, weight and cardiovascular risk factors over 82 weeks in 314 overweight patients with type 2 diabetes

Aim:  Exenatide, an incretin mimetic for the adjunct treatment of type 2 diabetes (DM2), reduced A1C and weight in 30‐week placebo‐controlled trials. This analysis examined the effects of exenatide on glycaemic control and weight over an 82‐week period in patients with DM2 unable to achieve adequate glycaemic control with sulphonylurea (SU) and/or metformin (MET).

Cardiovascular safety of exenatide BID: an integrated analysis from controlled clinical trials in participants with type 2 diabetes

It is important for patients that treatments for diabetes not increase cardiovascular (CV) risk. The objective of this analysis was to examine retrospectively the CV safety of exenatide BID, a GLP-1 receptor agonist approved for treating hyperglycemia in patients with type 2 diabetes not adequately controlled with diet and exercise. Individual participant data was pooled to assess the relative risk (RR) of CV events with exenatide BID versus a pooled comparator (PC) group treated with either placebo or insulin from 12 controlled, randomized, clinical trials ranging from 12-52 weeks. Mean baseline values for HbA1c (8.33-8.38%), BMI (31.3-31.5 kg/m2), and duration of diabetes (8 y) were similar between groups. Trials included patients with histories of microvascular and/or macrovascular disease. Customized primary major adverse CV events (MACE) included stroke, myocardial infarction, cardiac mortality, acute coronary syndrome, and revascularization procedures. The Primary MACE RR (0.7; 95% CI 0.38, 1.31), calculated by the Mantel-Haenszel method (stratified by study), suggested that exenatide use (vs. PC) did not increase CV risk; this result was consistent across multiple analytic methods. Because the trials were not designed to assess CV outcomes, events were identified retrospectively from a list of preferred terms by physicians blinded to treatment. Other limitations included the low number of CV events, the short duration of trials (≤1 y), and a single active comparator (insulin). The results of these analyses are consistent with those of a recent retrospective analysis of a large insurance database that found that patients treated with exenatide twice daily were less likely to have a CV event than were patients treated with other glucose-lowering therapies.Keywords: GLP-1 receptor agonist, diabetes, cardiovascular safety

Relationship of baseline HbA1c and efficacy of current glucose-lowering therapies: a meta-analysis of randomized clinical trials.

Diabet. Med. 27, 309–317 (2010)

Exenatide once weekly treatment maintained improvements in glycemic control and weight loss over 2 years

BackgroundThe once-weekly (QW) formulation of the glucagon-like peptide-1 receptor agonist exenatide has been demonstrated to improve A1C, fasting plasma glucose (FPG), body weight, serum lipid profiles, and blood pressure in patients with type 2 diabetes through 52 weeks of treatment. In this report, we describe the 2-year results of the open-label, open-ended extension to the DURATION-1 trial of exenatide QW for type 2 diabetes.MethodsA 2-stage protocol was used: patients received either exenatide QW (2 mg) or exenatide twice daily for 30 weeks (5 μg for the first 4 weeks and 10 μg thereafter), followed by 1.5 years of treatment with exenatide QW (2 mg), for a total of 2 years (104 weeks) of exenatide treatment. Of the 295 (intent-to-treat [ITT]) patients who entered the trial, 73% (n = 216) completed 2 years of treatment (completer population). Baseline characteristics (mean ± SE) for these patients were: A1C, 8.2 ± 0.1%; FPG, 168.4 ± 43.0 mg/dL; body weight, 101.1 ± 18.7 kg; and diabetes duration, 7 ± 5 years.ResultsIn the completer population, significant improvements (LS mean ± SE [95% CI]) were maintained after 2 years of treatment in A1C (-1.71 ± 0.08% [-1.86 to -1.55%]), FPG (-40.1 ± 2.9 mg/dL [-45.7 to -34.5 mg/dL]), and body weight (-2.61 ± 0.52 kg [-3.64 to -1.58 kg]) compared with baseline. The percentages of patients who achieved an A1C of <7.0% and ≤6.5% at 2 years were 60% and 39%, respectively. A significant reduction in systolic blood pressure (SBP; -3.0 ± 1.0 mmHg [-4.9 to -1.1 mmHg]) was maintained through 2 years of treatment. Serum lipid profiles were also significantly improved, including triglycerides (geometric LS mean change from baseline, -15 ± 2.7% [-21% to -10%]), total cholesterol (-8.6 ± 2.8 mg/dL [-14.0 to -3.1 mg/dL]), and low-density lipoproteins (-4.5 ± 2.2 mg/dL [-8.9 to -0.01 mg/dL]). Changes in A1C, body weight, FPG, SBP, and lipids in the ITT population were similar to those seen in the completer population. Nausea (predominantly mild in intensity) was the most common adverse event, although the frequency and intensity of nausea decreased over time. No severe hypoglycemia was observed.ConclusionsExenatide QW was well tolerated during the 2-year treatment period. This study demonstrated sustained glucose control and weight loss throughout 2 years of treatment with exenatide QW.Trial RegistrationClinicalTrials.gov NCT00308139

Safety and tolerability of exenatide twice daily in patients with type 2 diabetes: integrated analysis of 5594 patients from 19 placebo-controlled and comparator-controlled clinical trials

Background Exenatide twice daily is a first-in-class glucagon-like peptide receptor agonist approved for the treatment of type 2 diabetes. The objective of this analysis was to evaluate the safety profile of exenatide twice daily and to compare its profile with that of a pooled comparator (placebo and insulin) in patients with type 2 diabetes. Methods Data from 19 completed, randomized, controlled clinical trials of exenatide twice daily (5 μg and 10 μg) were pooled and analyzed; the pooled data included 5594 intent-to-treat patients who were followed for 12–52 weeks. Incidence rates, exposure-adjusted incidence rates, and 95% confidence intervals around risk differences between groups were calculated. Results Baseline demographics and exposure time were comparable between groups (exenatide, N = 3261; pooled comparator, N = 2333; mean exposure time 166–171 days). Transient, mild- to-moderate nausea was the most frequent adverse event with exenatide (36.9% versus 8.3% in the pooled comparator). The incidence of hypoglycemia (minor or major) with concomitant sulfonylurea (exenatide 26.5%, pooled comparator 20.7%) was higher than that without sulfonylurea (exenatide 3.1%, pooled comparator 2.7%) in all groups. Serious adverse events, discontinuations due to serious adverse events, and deaths were reported with similar frequency in the exenatide and pooled comparator groups. Composite exposure-adjusted incidence rates were not statistically different between groups for pancreatitis, renal impairment, or major adverse cardiac events; there was a difference in incidence rates for benign thyroid neoplasm (0.3% versus 0%). Conclusion Overall, this analysis, representing over 1500 patient-years of exposure, demonstrated that exenatide twice daily was safe and generally well tolerated in patients with type 2 diabetes. The incidence of most adverse events, including serious adverse events, was similar in both exenatide-treated and comparator-treated patients. The most distinct differences between groups were in gastrointestinal-related adverse events, which is consistent with other therapies within the glucagon-like peptide class.

Efficacy, Safety, and Tolerability of Exenatide Once Weekly in Patients With Type 2 Diabetes Mellitus: An Integrated Analysis of the DURATION Trials

Abstract Background and Aim: Exenatide is a glucagon-like peptide-1 receptor agonist demonstrated to improve glycemic control with low hypoglycemia risk in patients with type 2 diabetes mellitus. The Diabetes Therapy Utilization: Researching Changes in A1C, Weight, and Other Factors Through Intervention With Exenatide Once Weekly (DURATION) program comprised 6 randomized, comparator-controlled, 24- to 30-week trials of exenatide once weekly (EQW), an extended-release formulation. This post hoc analysis pooled data from patients taking EQW across 6 trials to assess efficacy and safety in a large, varied patient population. Materials and Methods: The intent-to-treat (ITT) population contained 1379 patients (baseline mean ± standard deviation glycated hemoglobin [HbA1c] levels of 8.4% ± 1.1%) who were treated with EQW over the course of 24 to 30 weeks. Changes from baseline in efficacy parameters for the ITT population and a completer population (1195 patients with ≥ 22 weeks of exposure) were evaluated. Results: The ITT population experienced significant reductions from baseline (least-squares mean [95% CI]) in HbA1c levels (−1.4% [−1.5% to −1.4%]), fasting blood glucose levels (−36 mg/dL [−38.4 mg/dL to −33.8 mg/dL]), and body weight (−2.5 kg [−2.8 kg to −2.3 kg]) after 24 to 30 weeks of EQW treatment. Reductions in HbA1c and fasting blood glucose levels were observed across baseline HbA1c, level strata; patients with higher baseline HbA1c levels experienced greater reductions. Treatment with EQW was associated with modest, significant reductions in blood pressure (systolic blood pressure, −2.8 mm Hg [−3.5 mm Hg to −2.1 mm Hg]; diastolic blood pressure, −0.8 mm Hg [−1.2 mm Hg to −0.4 mm Hg]), and fasting lipid levels (total cholesterol, −6.5 mg/dL [−8.2 mg/dL to −4.7 mg/dL]; low-density lipoprotein cholesterol, −3.9 mg/dL [5.3 mg/dL to −2.5 mg/dL]; and triglyceride [geometric least-squares mean percent change (95% CI)], −6% [−8% to −4%] levels). Similar reductions were observed in the completer population. Exenatide once weekly was generally well tolerated. Transient, mild-to-moderate gastrointestinal treatment-emergent adverse events and injection-site treatment-emergent adverse events were reported most frequently, but were seldom treatment limiting. No major hypoglycemic events were observed; minor hypoglycemic events occurred infrequently in patients not using a sulfonylurea. Conclusion: This post hoc analysis of > 1300 patients demonstrated that EQW was associated with significant reductions in HbA1c levels, body weight, blood pressure, and fasting lipid levels, with minimal hypoglycemia risk. Consistent with established safety profiles, EQW therapy was generally well tolerated., Trial registration: www.ClinicalTrials.gov identifiers: NCT00308139, NCT00637273, NCT00641056, NCT00676338, NCT00877890, NCT01029886

Exenatide at therapeutic and supratherapeutic concentrations does not prolong the QTc interval in healthy subjects

Aims Exenatide has been demonstrated to improve glycaemic control in patients with type 2 diabetes, with no effect on heart rate corrected QT (QTc) at therapeutic concentrations. This randomized, placebo- and positive-controlled, crossover, thorough QT study evaluated the effects of therapeutic and supratherapeutic exenatide concentrations on QTc. Methods Intravenous infusion was employed to achieve steady-state supratherapeutic concentrations in healthy subjects within a reasonable duration (i.e. days). Subjects received exenatide, placebo and moxifloxacin, with ECGs recorded pre-therapy and during treatment. Intravenous exenatide was expected to increase heart rate to a greater extent than subcutaneous twice daily or once weekly formulations. To assure proper heart rate correction, a wide range of baseline heart rates was assessed and prospectively defined methodology was applied to determine the optimal QT correction. Results Targeted steady-state plasma exenatide concentrations were exceeded (geometric mean ± SEM 253 ± 8.5 pg ml−1, 399 ± 11.9 pg ml−1 and 627 ± 21.2 pg ml−1). QTcP, a population-based method, was identified as the most appropriate heart rate correction and was prespecified for primary analysis. The upper bound of the two-sided 90% confidence interval for placebo-corrected, baseline-adjusted QTcP (ΔΔQTcP) was <10 ms at all time points and exenatide concentrations. The mean of three measures assessed at the highest steady-state plasma exenatide concentration of ∼500 pg ml−1 (ΔΔQTcPavg) was −1.13 [−2.11, −0.15). No correlation was observed between ΔΔQTcP and exenatide concentration. Assay sensitivity was confirmed with moxifloxacin. Conclusions These results demonstrated that exenatide, at supratherapeutic concentrations, does not prolong QTc and provide an example of methodology for QT assessment of drugs with an inherent heart rate effect.

Comparison of safety and tolerability with continuous (exenatide once weekly) or intermittent (exenatide twice daily) GLP‐1 receptor agonism in patients with type 2 diabetes

Exenatide is a glucagon‐like peptide‐1 receptor agonist shown to improve glycaemic control in patients with type 2 diabetes (T2DM). Intermittent exenatide exposure is achieved with the twice‐daily formulation (ExBID), while the once‐weekly formulation (ExQW) provides continuous exenatide exposure. This integrated, retrospective analysis compared safety and tolerability of ExQW vs. ExBID in patients with T2DM.

Exenatide is Non-inferior to Insulin in Reducing HbA1c: An Integrated Analysis of 1423 Patients with Type 2 Diabetes

Abstract Objective: The objective was to compare the treatment effects between exenatide and insulin, which are 2 injectable peptide hormone-based therapy options for the treatment of type 2 diabetes mellitus. Methods: Data from 4 randomized, open-label, comparator-controlled clinical trials in 1423 patients with type 2 diabetes followed for 16 to 52 weeks were pooled and analyzed. Results: At 26 weeks, glycemic control with exenatide (−1.2% HbA1c) was non-inferior to insulin (−1.1%; exenatide vs insulin; P = 0.09). In a tertile analysis of HbA1c reduction from baseline, exenatide induced similar reductions compared with insulin, with the greatest reductions observed in the tertile with the highest baseline HbA1c (9%−12.7%). Exenatide treatment induced weight loss (−2 kg) and reduced systolic blood pressure (SBP) from baseline (SBP, −4.9 mm Hg, exenatide vs insulin; P < 0.0001). In contrast, insulin treatment increased body weight (1.8 kg) and decreased SBP by −0.4 mm Hg. Overall, about 3-fold more exenatide-treated patients (70%) experienced weight loss compared with those treated with insulin (21%). Occurrence of nocturnal mild-to-moderate hypoglycemia was lower with exenatide (15%) treatment than with insulin (29%; difference, −14; [95% CI, −18, −9.8]). Effects of exenatide on HbA1c and weight were sustained at 52 weeks. Conclusion: These findings indicate that exenatide is non-inferior to insulin for glycemic control. Further studies are warranted to explore the effects of exenatide on blood pressure and body weight, and the potential for long-term effects on cardiovascular outcomes.

Exenatide once weekly improved glycaemic control, cardiometabolic risk factors and a composite index of an HbA1c < 7%, without weight gain or hypoglycaemia, over 52 weeks.

Type 2 diabetes mellitus (T2DM) is often associated with cardiovascular (CV) risk factors such as obesity, hypertension and dyslipidemia. The objective of this analysis was to evaluate potential effects of exenatide once weekly (ExQW), a GLP‐1 receptor agonist, on glycaemic control and CV risk factors.