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Efficacy and Tolerability of Exenatide Once Weekly Over 6 Years in Patients with Type 2 Diabetes: An Uncontrolled Open-Label Extension of the DURATION-1 Study.

ABSTRACT: Long-term treatment is necessary to slow the progression of type 2 diabetes (T2D). Here, we examined the safety and efficacy of 6 years of treatment with exenatide once weekly (QW) among patients with T2D in the DURATION-1 trial.The study enrolled patients aged ?16 years with T2D treated primarily with metformin and sulfonylureas. Following 30 weeks of randomized treatment with exenatide QW 2?mg or exenatide twice daily 10??g, patients entered an uncontrolled, open-label, open-ended study phase in which all patients received exenatide QW 2?mg. Restrictions on concomitant medication use were eased over time.Of the original 295 patients in the intent-to-treat population, 136 (46%) completed 6 years of treatment. Six-year completers had sustained significant improvements from baseline in glycated hemoglobin (HbA1c; least-squares mean [LSM] change, -1.6%), with 46.3% achieving HbA1c <7.0%, 33.1% achieving HbA1c ?6.5%, and significant improvements from baseline in fasting plasma glucose (-28?mg/dL) and body weight (-4.2?kg) at 6 years. The 78 completers who added no glucose-lowering medications had numerically greater body weight reductions than the overall cohort (6-year LSM change, -6.1?kg) with more stability over time. No unexpected adverse events were observed during 1202.4 patient-years of exposure. Most minor hypoglycemia events occurred with concomitant sulfonylurea use.Exenatide QW was associated with clinically significant, sustained improvements in glycemic control and weight in patients who continued therapy for up to 6 years, without unexpected safety findings. ClinicalTrials.gov registration: NCT00308139.

SUBMITTER: Henry RR

PROVIDER: S-EPMC5124747 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Efficacy and Tolerability of Exenatide Once Weekly Over 6 Years in Patients with Type 2 Diabetes: An Uncontrolled Open-Label Extension of the DURATION-1 Study.

Henry Robert R RR Klein Eric J EJ Han Jenny J Iqbal Nayyar N

Diabetes technology & therapeutics 20160815 11

<h4>Background</h4>Long-term treatment is necessary to slow the progression of type 2 diabetes (T2D). Here, we examined the safety and efficacy of 6 years of treatment with exenatide once weekly (QW) among patients with T2D in the DURATION-1 trial.<h4>Methods</h4>The study enrolled patients aged ≥16 years with T2D treated primarily with metformin and sulfonylureas. Following 30 weeks of randomized treatment with exenatide QW 2 mg or exenatide twice daily 10 μg, patients entered an uncontrolled, ...[more]

PMID: 27525540

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Project description: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.

Project description:This analysis assessed whether responses with exenatide once weekly plus dapagliflozin (n?=?231), exenatide once weekly alone (n?=?230), or dapagliflozin alone (n?=?233) differed in key patient subpopulations of the DURATION-8 trial. Potential treatment-by-subgroup interactions for changes in glycated haemoglobin (HbA1c) and body weight after 28?weeks were evaluated among subgroups determined by baseline HbA1c, age, sex, body mass index, type 2 diabetes duration, race, ethnicity and estimated glomerular filtration rate (eGFR). Exenatide once weekly plus dapagliflozin reduced HbA1c and body weight across all subgroups: least-squares mean reductions ranged from -8.4 to -26.1?mmol/mol (-0.77% to -2.39%) for HbA1c and from -2.07 to -4.55?kg for body weight. Potential treatment-by-subgroup interactions (P?<?.10) were found for HbA1c change by age (P?= .016) and eGFR (P?= .097). Age subgroup analysis findings were not consistent with expected mechanistic effects, with the small number of patients aged ?65?years (n?=?74 vs n?=?499 for patients aged <65?years) limiting the interpretability of the interaction term. In the exenatide once weekly plus dapagliflozin and dapagliflozin groups, but not the exenatide once weekly group, HbA1c reductions were greater among patients with eGFR ?90 vs ?60 to <90?mL/min/1.73?m2 (least-squares mean reductions of -23.6 vs -19.0?mmol/mol [-2.16% vs -1.74%], -17.3 vs -12.0?mmol/mol [-1.58% vs -1.10%], and -17.7 vs -16.9?mmol/mol [-1.62% vs -1.55%] for the respective treatments); this was consistent with the mechanism of action of dapagliflozin. A potential treatment-by-subgroup interaction was observed for change in body weight by sex (P?= .099), with greater weight loss for women vs men across all treatments (range?-2.56 to -3.98?kg vs -0.56 to -2.99?kg). In conclusion, treatment with exenatide once weekly plus dapagliflozin reduced HbA1c and body weight across all patient subgroups and was more effective than exenatide once weekly or dapagliflozin alone in all adequately sized subgroups.

Project description:BACKGROUND:Exenatide once weekly (QW) is a glucagon-like peptide-1 receptor agonist (GLP-1RA) for the treatment of type 2 diabetes. Safety and tolerability are key considerations in treatment selection. This analysis examines the safety and tolerability profile of exenatide QW, other approved GLP-1RAs (exenatide twice daily and liraglutide once daily), and a pooled population of commonly used non-GLP-1RA treatments. METHODS:Intent-to-treat populations from eight randomized Phase III trials with 24-week and 30-week comparator-controlled periods were analyzed. Data were pooled for exenatide QW, exenatide twice daily, and non-GLP-1RA comparator groups; comparisons between exenatide QW and liraglutide were analyzed separately to better match study groups. The incidence of treatment-emergent adverse events with 95% confidence intervals and exposure-adjusted incidence were calculated. Duration and recurrence were analyzed for gastrointestinal adverse events and adverse events of special interest. RESULTS:Incidences of serious adverse events did not differ between treatments. Discontinuations due to adverse events occurred numerically less frequently with exenatide QW than with other GLP-1RAs but numerically more frequently than with non-GLP-1RA comparators. The most frequent adverse events in the GLP-1RA groups were gastrointestinal and generally mild, with decreasing incidence over time. Gastrointestinal adverse event incidences appeared lower with exenatide QW versus other GLP-1RAs and greater than with non-GLP-1RA comparators. Injection site-related adverse events seemed highest with exenatide QW, but generally did not lead to withdrawal and abated over time. Hypoglycemia was infrequent overall, but occurred numerically more frequently in the non-GLP-1RA comparator group and increased with concomitant sulfonylurea use. Pancreatitis, thyroid cancer, renal failure, and gallbladder disease were rarely reported. CONCLUSION:The overall safety and tolerability profile of exenatide QW was similar to that of other GLP-1RAs, with improved gastrointestinal tolerability. The safety and tolerability profile of exenatide QW compared with non-GLP-1RA comparators was similar overall, with the exception of a lower incidence of hypoglycemia and anticipated differences in gastrointestinal and injection site-related adverse events.

Project description:AIMS:Dapagliflozin and exenatide reduce body weight by differing mechanisms. Dual therapy with these agents reduces body weight, adipose tissue volume, glycaemia and systolic blood pressure (SBP) over 24?weeks. Here, we examined these effects over 1?year in obese adults without diabetes. MATERIALS AND METHODS:Obese adults without diabetes (N?=?50; aged 18-70?years; body mass index, 30-45?kg/m2 ) were initially randomized to double-blind oral dapagliflozin 10?mg once daily plus subcutaneous long-acting exenatide 2?mg once weekly or to placebo. They entered an open-label extension from 24 to 52?weeks during which all participants received active treatment. RESULTS:Of the original 25 dapagliflozin?+?exenatide-treated and 25 placebo-treated participants, respectively, 21 (84%) and 17 (68%) entered the open-label period and 16 (64%) and 17 (68%) completed 52?weeks of treatment. At baseline, mean body weight was 104.6?kg, and 73.5% of participants had prediabetes (impaired fasting glucose or impaired glucose tolerance). Reductions with dapagliflozin?+?exenatide at 24?weeks were sustained at 52?weeks, respectively, for body weight (-4.5 and -5.7?kg), total adipose tissue volume (-3.8 and -5.3?L), proportion with prediabetes (34.8% and 35.3%), and SBP (-9.8 and -12.0?mm Hg). Effects on body weight, SBP and glycaemia at 52?weeks with placebo???dapagliflozin?+?exenatide were similar to those observed with continuation of dapagliflozin?+?exenatide. Nausea and injection-site reactions were more frequent with dapagliflozin?+?exenatide than with placebo and diminished over time. Safety and tolerability were similar to that in previous diabetes trials with these agents. No clear difference in adverse event-related withdrawals between placebo and active treatment periods was observed. CONCLUSIONS:Dapagliflozin?+?exenatide dual therapy produced sustained reductions in body weight, prediabetes and SBP over 52?weeks and was well tolerated in obese adults without diabetes.

Dataset Information

Efficacy and Tolerability of Exenatide Once Weekly Over 6 Years in Patients with Type 2 Diabetes: An Uncontrolled Open-Label Extension of the DURATION-1 Study.

Publications

Efficacy and Tolerability of Exenatide Once Weekly Over 6 Years in Patients with Type 2 Diabetes: An Uncontrolled Open-Label Extension of the DURATION-1 Study.

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