Dataset Information

Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide.

ABSTRACT: Having demonstrated short-term weight loss with liraglutide in this group of obese adults, we now evaluate safety/tolerability (primary outcome) and long-term efficacy for sustaining weight loss (secondary outcome) over 2 years.A randomized, double-blind, placebo-controlled 20-week study with 2-year extension (sponsor unblinded at 20 weeks, participants/investigators at 1 year) in 19 European clinical research centers.A total of 564 adults (n=90-98 per group; body mass index 30-40?kg?m(-2)) enrolled, 398 entered the extension and 268 completed the 2-year trial. Participants received diet (500?kcal?deficit per day) and exercise counseling during 2-week run-in, before being randomly assigned (with a telephone or web-based system) to once-daily subcutaneous liraglutide (1.2, 1.8, 2.4 or 3.0?mg, n=90-95), placebo (n=98) or open-label orlistat (120?mg × 3, n=95). After 1 year, liraglutide/placebo recipients switched to liraglutide 2.4?mg, then 3.0?mg (based on 20-week and 1-year results, respectively). The trial ran from January 2007-April 2009 and is registered with Clinicaltrials.gov, number NCT00480909.From randomization to year 1, liraglutide 3.0?mg recipients lost 5.8?kg (95% confidence interval 3.7-8.0) more weight than those on placebo and 3.8?kg (1.6-6.0) more than those on orlistat (P?0.0001; intention-to-treat, last-observation-carried-forward). At year 2, participants on liraglutide 2.4/3.0?mg for the full 2 years (pooled group, n=184) lost 3.0?kg (1.3-4.7) more weight than those on orlistat (n=95; P<0.001). Completers on liraglutide 2.4/3.0?mg (n=92) maintained a 2-year weight loss of 7.8?kg from screening. With liraglutide 3.0?mg, 20-week body fat decreased by 15.4% and lean tissue by 2.0%. The most frequent drug-related side effects were mild to moderate, transient nausea and vomiting. With liraglutide 2.4/3.0?mg, the 2-year prevalence of prediabetes and metabolic syndrome decreased by 52 and 59%, with improvements in blood pressure and lipids.Liraglutide is well tolerated, sustains weight loss over 2 years and improves cardiovascular risk factors.

SUBMITTER: Astrup A

PROVIDER: S-EPMC3374073 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide.

Astrup A A Carraro R R Finer N N Harper A A Kunesova M M Lean M E J ME Niskanen L L Rasmussen M F MF Rissanen A A Rössner S S Savolainen M J MJ Van Gaal L L

International journal of obesity (2005) 20110816 6

<h4>Objective</h4>Having demonstrated short-term weight loss with liraglutide in this group of obese adults, we now evaluate safety/tolerability (primary outcome) and long-term efficacy for sustaining weight loss (secondary outcome) over 2 years.<h4>Design</h4>A randomized, double-blind, placebo-controlled 20-week study with 2-year extension (sponsor unblinded at 20 weeks, participants/investigators at 1 year) in 19 European clinical research centers.<h4>Subjects</h4>A total of 564 adults (n=90- ...[more]

PMID: 21844879

Similar Datasets

Project description:IntroductionMechanisms for liraglutide-induced weight loss are poorly understood.ObjectiveWe investigated the effects of liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism in obese non-diabetic individuals.DesignParticipants (N=49, 18-75 years, body mass index: 30-40 kg m(-2)) were randomized to two of three treatments: liraglutide 1.8 mg, 3.0 mg, or placebo in a double-blind, incomplete crossover trial. After 5 weeks, 24-h energy expenditure (EE) and substrate oxidation were measured in a respiratory chamber. Gastric emptying (acetaminophen absorption method), glycemic parameters and appetite were assessed during a 5-h meal test. Ad libitum energy intake during a subsequent lunch was also assessed.ResultsFive-hour gastric emptying (AUC(0-300 min)) was found to be equivalent for liraglutide 1.8 versus 3.0 mg (primary end point), and for both liraglutide doses versus placebo, as 90% confidence intervals for the estimated treatment ratios were contained within the prespecified interval (0.80-1.25). However, 1-h gastric emptying was 23% lower than placebo with liraglutide 3.0 mg (P=0.007), and a nonsignificant 13% lower than placebo with liraglutide 1.8 mg (P=0.14). Both liraglutide doses similarly reduced fasting glucose (0.5-0.6 mmol l(-1) versus placebo, P<0.0001), glucose Cmax and 1-h AUC versus placebo; only liraglutide 3.0 mg reduced iAUC(0-300 min) (by ∼26% versus placebo, P=0.02). Glucagon iAUC(0-300 min) decreased by ∼30%, and iAUC(0-60 min) for insulin and C-peptide was ∼20% lower with both liraglutide doses versus placebo. Liraglutide doses similarly increased mean postprandial satiety and fullness ratings, reduced hunger and prospective food consumption and decreased ad libitum energy intake by ∼16%. Liraglutide-associated reductions in EE were partly explained by a decrease in body weight. A relative shift toward increased fat and reduced carbohydrate oxidation was observed with liraglutide. Clinicaltrials.gov ID:NCT00978393.FundingNovo Nordisk.ConclusionGastric emptying AUC(0-300 min) was equivalent for liraglutide 1.8 and 3.0 mg, and for liraglutide versus placebo, whereas reductions in 1-h gastric emptying of 23% with liraglutide 3.0 mg and 13% with 1.8 mg versus placebo were observed. Liraglutide 3.0 mg improved postprandial glycemia to a greater extent than liraglutide 1.8 mg. Liraglutide-induced weight loss appears to be mediated by reduced appetite and energy intake rather than increased EE.

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.

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:IntroductionWe assessed the effect of the prandial state on the pharmacokinetics, safety, and tolerability of single and multiple doses of orforglipron (LY3502970), an oral, non-peptide glucagon-like peptide 1 receptor agonist (GLP-1 RA), in two studies (A and B).MethodsStudy A and study B were phase 1, randomized, crossover studies in healthy adults aged 18-65 years and 21-70 years, respectively. Participants received single (3 mg, study A) or multiple (16 mg, study B) oral doses of orforglipron under fasted and fed conditions. Blood samples were collected pre- and postdose to assess area under the concentration-time curve (AUC), maximum observed drug concentration (Cmax), time of Cmax (tmax), and half-life (t1/2) associated with terminal rate constant. AUC and Cmax were analyzed using a linear mixed-effects model. Treatment differences were presented as ratios of geometric least squares means (GLSM). Treatment-emergent adverse events (TEAEs), adverse events of special interest, and serious adverse events were assessed.ResultsStudy A included 12 participants (mean age 45.0 years; male 66.7%); study B included 34 participants (mean age 42.8 years; male 88.2%). GLSM AUC and Cmax were lower by 23.7% and 23.2% in study A, and 17.6% and 20.9% in study B, in the fed versus fasted states, respectively. In both studies, t1/2 and median tmax were comparable between fed and fasted states. The majority of TEAEs in both studies were gastrointestinal tract-related conditions. No serious adverse events or deaths were reported in either study.ConclusionThe observed pharmacokinetic differences due to the prandial state are unlikely to contribute to clinically meaningful differences in the efficacy of orforglipron. The safety profile was consistent with the known profiles of other GLP-1 RAs. Given the absence of prandial restrictions, orforglipron may emerge as a convenient oral treatment option for patients with type 2 diabetes or obesity.Trial registrationClinicalTrials.gov identifiers, NCT03929744 and NCT05110794.

Project description:BackgroundTreatment of postherpetic neuralgia (PHN) is more complicated in elderly patients, and multiple daily dosing, complex titration, and high incidences of adverse events can be limiting for many pharmacological treatment options.ObjectiveThe aim of this study was to determine whether the efficacy and tolerability of once-daily gastroretentive gabapentin (G-GR) is similar between elderly patients (≥75 years) and younger patients (<75 years).MethodsData from two phase III, placebo-controlled studies of 1,800 mg G-GR once daily with dinner in patients with PHN were integrated and analyzed by age subgroups (<75 years, n = 527; ≥75 years, n = 192). Efficacy assessments at endpoint (week 10) included baseline-adjusted change in average daily pain (ADP) and average daily sleep interference (SIS) scores, the proportion of responders (≥30 % pain reduction), and the proportion of patients feeling "Much" or "Very Much" improved on the Patient Global Impression of Change (PGIC).ResultsCompared with placebo, patients in both age subgroups treated with G-GR (placebo/G-GR) had greater reductions in mean ADP (≥75: -21.9/-34.2 %, p = 0.0348; <75: -29.9/-38.3 %, p = 0.0079) and SIS (≥75: -1.3/-2.4, p = 0.0017; <75: -1.8/-2.7, p < 0.0001), more patients were responders (≥75: 30.4/52.0 %, p = 0.0025; <75: 45.0/54.7 %, p = 0.0265), and more felt "Much" or "Very Much" improved on the PGIC (≥75: 20.7/35.0 %, p = 0.0272; <75: 33.6/44.9 %, p = 0.0077). The most common (placebo/G-GR) adverse events (AEs) were dizziness (≥75: 3.3/12.0 %; <75: 1.8/10.4 %), nausea (≥75: 1.0/5.4 %; <75: 2.9/4.2 %), and somnolence (≥75: 0/5.0 %; <75: 3.7/4.2 %). For all patients, AEs rapidly decreased to low steady levels after 4-5 weeks of treatment. The incidence of serious AEs was low and they were reported more frequently in the placebo than in the G-GR group.ConclusionsTherapy with once-daily G-GR was as effective for treating pain associated with PHN in elderly patients as it was in younger patients. G-GR was well tolerated, and the incidence of the most common AEs did not appear to be age related.

Dataset Information

Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide.

Publications

Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets