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Effect of exenatide QW or placebo, both added to titrated insulin glargine, in uncontrolled type 2 diabetes: The DURATION-7 randomized study.

ABSTRACT: AIMS:To compare the efficacy and safety of adding the glucagon-like peptide-1 receptor agonist exenatide once weekly (QW) 2 mg or placebo among patients with type 2 diabetes who were inadequately controlled despite titrated insulin glargine (IG) ± metformin. METHODS:This multicentre, double-blind study (ClinicalTrials.gov identifier: NCT02229383) randomized (1:1) patients with persistent hyperglycaemia after an 8-week titration phase (glycated haemoglobin [HbA1c] 7.0%-10.5% [53-91 mmol/mol]) to exenatide QW or placebo. The primary endpoint was HbA1c change from baseline to week 28. Secondary endpoints included body weight, 2-hour postprandial glucose, and mean daily IG dose. RESULTS:Of 464 randomized patients (mean: age, 58 years; HbA1c, 8.5% [69 mmol/mol]; diabetes duration, 11.3 years), 91% completed 28 weeks. Exenatide QW + IG vs placebo + IG significantly reduced HbA1c (least-squares mean difference, -0.73% [-8.0 mmol/mol]; 95% confidence interval, -0.93%, -0.53% [-10.2, -5.8 mmol/mol]; P < .001; final HbA1c, 7.55% [59 mmol/mol] and 8.24% [67 mmol/mol], respectively); body weight (-1.50 kg; -2.17, -0.84; P < .001); and 2-hour postprandial glucose (-1.52 mmol/L [-27.5 mg/dL]; -2.15, -0.90 [-38.7, -16.2]; P < .001). Significantly more exenatide QW + IG-treated patients vs placebo + IG-treated patients reached HbA1c <7.0% (<53 mmol/mol) (32.5% vs 7.4%; P < .001); daily IG dose increased by 2 and 4 units, respectively. Gastrointestinal and injection-site adverse events were more frequent with exenatide QW + IG (15.1% and 7.8%, respectively) than with placebo + IG (10.8% and 3.0%, respectively); hypoglycaemia incidence was similar between the exenatide QW + IG (29.7%) and placebo + IG (29.0%) groups, with no major hypoglycaemic events. CONCLUSIONS:Among patients with inadequate glycaemic control, exenatide QW significantly improved glucose control and decreased body weight, without increased hypoglycaemia or unexpected safety findings.

SUBMITTER: Guja C

PROVIDER: S-EPMC6032936 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Effect of exenatide QW or placebo, both added to titrated insulin glargine, in uncontrolled type 2 diabetes: The DURATION-7 randomized study.

Guja Cristian C Frías Juan P JP Somogyi Aniko A Jabbour Serge S Wang Hui H Hardy Elise E Rosenstock Julio J

Diabetes, obesity & metabolism 20180325 7

<h4>Aims</h4>To compare the efficacy and safety of adding the glucagon-like peptide-1 receptor agonist exenatide once weekly (QW) 2 mg or placebo among patients with type 2 diabetes who were inadequately controlled despite titrated insulin glargine (IG) ± metformin.<h4>Methods</h4>This multicentre, double-blind study (ClinicalTrials.gov identifier: NCT02229383) randomized (1:1) patients with persistent hyperglycaemia after an 8-week titration phase (glycated haemoglobin [HbA1c] 7.0%-10.5% [53-91 ...[more]

PMID: 29473704

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Project description:ImportanceThe effects of tirzepatide, a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, as an addition to insulin glargine for treatment of type 2 diabetes have not been described.ObjectiveTo assess the efficacy and safety of tirzepatide added to insulin glargine in patients with type 2 diabetes with inadequate glycemic control.Design, setting, and participantsRandomized phase 3 clinical trial conducted at 45 medical research centers and hospitals in 8 countries (enrollment from August 30, 2019, to March 20, 2020; follow-up completed January 13, 2021) in 475 adults with type 2 diabetes and inadequate glycemic control while treated with once-daily insulin glargine with or without metformin.InterventionsPatients were randomized in a 1:1:1:1 ratio to receive once-weekly subcutaneous injections of 5-mg (n = 116), 10-mg (n = 119), or 15-mg (n = 120) tirzepatide or volume-matched placebo (n = 120) over 40 weeks. Tirzepatide was initiated at 2.5 mg/week and escalated by 2.5 mg every 4 weeks until the assigned dose was achieved.Main outcomes and measuresThe primary end point was mean change from baseline in glycated hemoglobin A1c (HbA1c) at week 40. The 5 key secondary end points included mean change in body weight and percentage of patients achieving prespecified HbA1c levels.ResultsAmong 475 randomized participants (211 [44%] women; mean [SD] age, 60.6 [9.9] years; mean [SD] HbA1c, 8.31% [0.85%]), 451 (94.9%) completed the trial. Treatment was prematurely discontinued by 10% of participants in the 5-mg tirzepatide group, 12% in the 10-mg tirzepatide group, 18% in the 15-mg tirzepatide group, and 3% in the placebo group. At week 40, mean HbA1c change from baseline was -2.40% with 10-mg tirzepatide and -2.34% with 15-mg tirzepatide vs -0.86% with placebo (10 mg: difference vs placebo, -1.53% [97.5% CI, -1.80% to -1.27%]; 15 mg: difference vs placebo, -1.47% [97.5% CI, -1.75% to -1.20%]; P < .001 for both). Mean HbA1c change from baseline was -2.11% with 5-mg tirzepatide (difference vs placebo, -1.24% [95% CI, -1.48% to -1.01%]; P < .001]). Mean body weight change from baseline was -5.4 kg with 5-mg tirzepatide, -7.5 kg with 10-mg tirzepatide, -8.8 kg with 15-mg tirzepatide and 1.6 kg with placebo (5 mg: difference, -7.1 kg [95% CI, -8.7 to -5.4]; 10 mg: difference, -9.1 kg [95% CI, -10.7 to -7.5]; 15 mg: difference, -10.5 kg [95% CI, -12.1 to -8.8]; P < .001 for all). Higher percentages of patients treated with tirzepatide vs those treated with placebo had HbA1c less than 7% (85%-90% vs 34%; P < .001 for all). The most common treatment-emergent adverse events in the tirzepatide groups vs placebo group were diarrhea (12%-21% vs 10%) and nausea (13%-18% vs 3%).Conclusions and relevanceAmong patients with type 2 diabetes and inadequate glycemic control despite treatment with insulin glargine, the addition of subcutaneous tirzepatide, compared with placebo, to titrated insulin glargine resulted in statistically significant improvements in glycemic control after 40 weeks.Trial registrationClinicalTrials.gov Identifier: NCT04039503.

Project description:IntroductionGlucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for treatment of type 2 diabetes mellitus; however, there have been concerns that GLP-1RA treatment may be associated with an increased incidence of pancreatitis. This study aimed to evaluate the incidence of pancreatitis in a pooled population of type 2 diabetes trials from the clinical development program of the GLP-1RA exenatide as well as to describe patient-level data for all reported cases.MethodsThe primary analysis examined pooled data among patients with type 2 diabetes from the controlled arms of 35 trials (ranging from 4 to 234 weeks' duration) in the integrated clinical databases for exenatide twice daily, once weekly, and once-weekly suspension, excluding comparator arms with other incretin-based therapies. The exposure-adjusted incidence rate (EAIR) of pancreatitis was calculated for exenatide and non-exenatide (non-incretin-based therapy or placebo) treatment groups. Patient-level data were described for all pancreatitis incidences.ResultsThe primary analysis included 5596 patients who received exenatide and 4462 in the non-exenatide group. The mean duration of study medication exposure for the exenatide and non-exenatide treatment groups was 57.0 and 47.9 weeks, respectively. Pancreatitis was diagnosed in 14 patients (exenatide, n = 8; non-exenatide, n = 6), of whom 13 recovered with or without sequelae. The pancreatitis EAIR was 0.1195 events per 100 patient-years [95% confidence interval (CI), 0.0516-0.2154] in the exenatide group versus 0.1276 events per 100 patient-years (95% CI 0.0468-0.2482) in the non-exenatide treatment group. The EAIR ratio for the exenatide versus non-exenatide treatment group was 0.761 (95% CI 0.231-2.510).ConclusionIn this pooled analysis of 10,058 patients among studies comparing exenatide with other glucose-lowering medications or placebo, pancreatitis was rare. The EAIRs of pancreatitis were low and similar between exenatide and non-exenatide treatment groups. No evidence of an association between exenatide and pancreatitis was observed.FundingBristol-Myers Squibb and AstraZeneca. Plain language summary available for this article.

Project description:INTRODUCTION:Increasing the frequency of blood glucose monitoring aids the evaluation of glycemic variability and blood glucose control by antidiabetic drugs. It remains unclear, however, whether GLP-1 receptor agonists or basal insulin has a better effect on glycemic variability in type 2 diabetes mellitus (T2DM) patients who are inadequately controlled by metformin. We used a continuous glucose monitoring system (CGMS) to compare patients on a GLP-1 receptor agonist with patients on basal insulin in terms of glycemic variability. METHODS:This prospective randomized study assigned T2DM patients treated with metformin (N = 39) to either exenatide treatment or insulin glargine treatment for 16 weeks. Glycemic variability was assessed using a CGMS; hemoglobin A1c (HbA1c), β-cell function, weight, body mass index (BMI), and waist circumference were also evaluated. RESULTS:Mean blood glucose level, continuous overlapping net glycemic action, mean amplitude of glycemic excursions, percentage of the time that the blood glucose value was > 10.0 mmol/L, and highest blood glucose level (P < 0.01-0.05) significantly decreased in both groups. Standard deviation of the mean glucose value, largest amplitude of glycemic excursions, and waist circumference significantly decreased for those treated with exenatide (P < 0.05), while no changes were observed with insulin glargine treatment. Percentage of the time that the blood glucose value was > 7.8 mmol/L decreased after insulin glargine use (P < 0.05) but not with the exenatide intervention. Similar decreases in fasting blood glucose and HbA1c and increases in the 1/homeostasis model assessment of insulin resistance, disposition index 30, and disposition index 120 were observed in both groups (P < 0.01-0.05). Reductions in weight and BMI were greater with exenatide than with insulin glargine treatment (P < 0.05). CONCLUSIONS:In overweight and obese patients with T2DM inadequately controlled by metformin, exenatide and insulin glargine have similar efficacies in terms of glycemic variability, HbA1c alleviation, and β-cell function, but exenatide has a greater effect on body weight and BMI.

Dataset Information

Effect of exenatide QW or placebo, both added to titrated insulin glargine, in uncontrolled type 2 diabetes: The DURATION-7 randomized study.

Publications

Effect of exenatide QW or placebo, both added to titrated insulin glargine, in uncontrolled type 2 diabetes: The DURATION-7 randomized study.

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