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Exenatide once weekly: sustained improvement in glycemic control and cardiometabolic measures through 3 years.

ABSTRACT: BACKGROUND:Type 2 diabetes mellitus is a progressive metabolic disease necessitating therapies with sustained efficacy and safety over time. Exenatide once weekly (ExQW), an extended-release formulation of the glucagon-like peptide-1 receptor agonist exenatide, has demonstrated improvements in glycemic and cardiometabolic measures from 30 weeks to 2 years of treatment. Here, the efficacy and safety of treatment with ExQW for 3 years are described. METHODS:Patients were initially randomized to receive either ExQW (2 mg) or exenatide twice daily for 30 weeks. Following the initial 30 weeks, all patients were treated with ExQW in an open-label extension. Analyses of primary glycemic endpoints, beta-cell function, and cardiometabolic measures were assessed for patients who completed 3 years of ExQW treatment and for the intention-to-treat population. Safety and tolerability analyses were provided for the intention-to-treat population. RESULTS:Sixty-six percent of the intention-to-treat population (n = 295) completed 3 years of treatment (n = 194). At 3 years, a significant reduction in hemoglobin A(1c) (least squares mean ± standard error) of -1.6% ± 0.08% was observed, with 55% and 33% of patients achieving hemoglobin A(1c) targets of <7% and ?6.5%, respectively. Consistent with a sustained reduction in hemoglobin A(1c), improvements in beta-cell function were also observed. Body weight was significantly reduced by -2.3 ± 0.6 kg. Reductions in blood pressure, total cholesterol, low-density lipoprotein cholesterol, and triglycerides were also observed. Adverse events reported most frequently during both controlled and uncontrolled periods included diarrhea, nausea, and vomiting of mostly mild intensity. The incidence of these adverse events decreased over time. Incidence of minor hypoglycemia was low and no major hypoglycemia was observed. CONCLUSION:ExQW produced clinically meaningful improvements in glycemic control that were durable through 3 years of treatment. Significant improvements in cardiometabolic measurements were also observed. ExQW was well-tolerated during long-term treatment and no new adverse events were noted. TRIAL REGISTRATION:ClinicalTrials.gov NCT00308139.

SUBMITTER: Macconell L

PROVIDER: S-EPMC3555554 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Exenatide once weekly: sustained improvement in glycemic control and cardiometabolic measures through 3 years.

Macconell Leigh L Pencek Richard R Li Yan Y Maggs David D Porter Lisa L

Diabetes, metabolic syndrome and obesity : targets and therapy 20130121

<h4>Background</h4>Type 2 diabetes mellitus is a progressive metabolic disease necessitating therapies with sustained efficacy and safety over time. Exenatide once weekly (ExQW), an extended-release formulation of the glucagon-like peptide-1 receptor agonist exenatide, has demonstrated improvements in glycemic and cardiometabolic measures from 30 weeks to 2 years of treatment. Here, the efficacy and safety of treatment with ExQW for 3 years are described.<h4>Methods</h4>Patients were initially r ...[more]

PMID: 23358123

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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:BackgroundTo determine whether there were racial differences in short-term cardiometabolic responses to once-weekly exenatide (EQW) in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL).MethodsEXSCEL enrolled 14,752 patients with type 2 diabetes (hemoglobin A1c (HbA1c) 6.5-10.0% [48-86 mmol/mol]) with or without cardiovascular disease who were randomized double-blind to EQW or placebo. Background glucose-lowering/other cardiovascular therapies were unaltered for 6 months post-randomization unless clinically essential, facilitating comparison of EQW-associated effects in 14,665 evaluable participants self-identifying as White (n = 11,113), Asian (n = 1444), Black (n = 870), or Other Race (n = 1,238. Placebo-adjusted 6 month absolute changes in cardiometabolic variables were assessed using generalized linear models.ResultsMean 6-month placebo-adjusted HbA1c reductions were similar in the four groups (range 0.54-0.67% [5.9 to 7.3 mmol/mol], P = 0.11 for race×treatment interaction), with no significant difference in Asians (reference) versus other groups after covariate adjustment (all P ≥ 0.10). Six-month placebo-adjusted mean changes in systolic (-1.8 to 0.0 mmHg) and diastolic (0.2 to 1.2 mmHg) blood pressure, serum LDL (- 0.06 to 0.02 mmol/L) and HDL (0.00 to 0.01 mmol/L) cholesterol, and serum triglycerides (-0.1 to 0.0 mmol/L) were similar in the racial groups (P ≥ 0.19 for race×treatment interaction and all P ≥ 0.13 for comparisons of Asians with other races). Resting pulse rate increased more in Asians (4 beats/min) than in other groups (≤ 3 beats/min, P = 0.016 for race×treatment interaction and all P ≤ 0.050 for comparisons of Asians with other races).ConclusionsShort-term cardiometabolic responses to EQW were similar in the main racial groups in EXSCEL, apart from a greater pulse rate increase in Asians.Trial registration https://clinicaltrials.gov NCT01144338.

Project description:BackgroundOverweight or obesity contributes to the development of type 2 diabetes mellitus (T2DM) and increases cardiovascular risk. Exenatide, a glucagon-like peptide-1 receptor agonist, significantly reduces glycated hemoglobin (A1C) and body weight and improves cardiovascular risk markers in patients with T2DM. As weight loss alone has been shown to reduce A1C and cardiovascular risk markers, this analysis explored whether weight loss contributed importantly to clinical responses to exenatide once weekly.MethodsA pooled analysis from eight studies of exenatide once weekly was conducted. Patients were distributed into quartiles from greatest weight loss (Quartile 1) to least loss or gain (Quartile 4). Parameters evaluated for each quartile included A1C, fasting plasma glucose (FPG), blood pressure (BP), heart rate, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol, triglycerides, and the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST).ResultsThe median changes from baseline in body weight in Quartiles 1-4 were -6.0, -3.0, -1.0, and +1.0 kg, respectively. All quartiles had reductions in A1C (median changes -1.6, -1.4, -1.1, and -1.2%, respectively) and FPG (-41, -40, -31, and -25 mg/dL, respectively), with the greatest decreases in Quartiles 1 and 2. Most cardiovascular risk markers (except diastolic BP) and liver enzymes improved in Quartiles 1 through 3 and were relatively unchanged in Quartile 4. Higher rates of gastrointestinal adverse events and hypoglycemia were observed in Quartile 1 compared with Quartiles 2 through 4.ConclusionsExenatide once weekly improved glycemic parameters independent of weight change, although the magnitude of improvement increased with increasing weight loss. The greatest trend of improvement in glycemic parameters, cardiovascular risk factors including systolic BP, LDL-C, total cholesterol, and triglycerides, and in liver enzymes, was seen in the patient quartiles with the greatest reductions in body weight.

Project description: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.This analysis included 675 Intent-to-Treat patients with T2DM [baseline (mean ± SD) HbA1c, 8.1?±?1.2%; fasting blood glucose (FBG), 166?±?48 mg/dl; weight, 94.3?±?19.4 kg; systolic/diastolic blood pressure (SBP/DBP), 129?±?15/78 ± 9 mm?Hg; total cholesterol, 178.5?±?41.9 mg/dl; low-density lipoprotein (LDL), 100.1?±?35.0 mg/dl; high-density lipoprotein (HDL), 44.5?±?11.6 mg/dl; triglycerides, 155.6?±?3.3 mg/dl; alanine aminotransferase (ALT), 32.1?±?19.5 U/l] treated with diet and exercise alone or in combination with metformin, sulfonylurea, and/or thiazolidinedione who received 52 weeks of ExQW in four clinical trials.At 52 weeks, ExQW significantly improved HbA1c [mean (SE) change from baseline, -1.3 (0.05)%], FBG [-36.3 (2.02) mg/dl], body weight [-2.6 (0.19) kg], SBP/DBP [-3.6 (0.56) mm?Hg/-1.2 (0.34) mm?Hg], total cholesterol, -4.4 (1.33) mg/dl; LDL, -2.6 (1.08) mg/dl; HDL, 1.1 (0.31) mg/dl; triglycerides, -7 (1.6)%], and ALT [-4.3 (0.71) IU/l] concentrations, with greater improvements in patients with elevated analyte levels at baseline. Improvements were observed across a range of background antihyperglycaemia therapies. Of patients completing 52 weeks, 19% achieved the composite American Diabetes Association goal (HbA1c < 7.0%, BP < 130/80 mm?Hg, LDL?<?100 mg/dl), compared to 1% at baseline. Nearly half (48%) achieved HbA1c < 7.0% without weight gain or major/minor hypoglycaemia. Nausea was the most frequent adverse event and was predominantly mild. Hypoglycaemia was infrequent, and more common with a sulfonylurea.With 52 weeks of ExQW, patients experienced sustained improvements in glycaemic control and CV risk factors, with an increased likelihood of achieving both a clinically relevant composite outcome (HbA1c?<?7% without weight gain or increased risk of hypoglycaemia) and a composite of key therapeutic goals (HbA1c?<?7%, BP < 130/80 mm?Hg, LDL?<?100 mg/dl).

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.

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Exenatide once weekly: sustained improvement in glycemic control and cardiometabolic measures through 3 years.

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Exenatide once weekly: sustained improvement in glycemic control and cardiometabolic measures through 3 years.

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