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Impact of dose-escalation schemes and drug discontinuation on weight loss outcomes with liraglutide 3.0?mg: A model-based approach.

ABSTRACT: AIMS:To investigate the impact on weight loss of the treatment changes in overweight or obese people that may be needed in case of gastrointestinal (GI) tolerability issues during escalation of the glucagon-like peptide-1 analogue liraglutide. MATERIALS AND METHODS:The individual longitudinal body weight data from the main trial periods of three phase II/III trials in overweight or obese patients (56-week treatment with once-daily liraglutide 1.2, 1.8, 2.4 or 3.0?mg or placebo, n = 4952) were analysed using a non-linear mixed-effect modelling approach. Individual pharmacokinetic profiles were derived based on published pharmacokinetic models. Baseline body weight, baseline glycated haemoglobin (HbA1c), age, gender, diabetes status (no diabetes, prediabetes or type 2 diabetes), race and trial region were investigated as covariates. As a form of external validation, the model was used to predict the weight regain after treatment cessation at week 56 (data not included in model development). RESULTS:A pharmacokinetic/pharmacodynamic model provided an adequate description of the weight loss trajectories for all studied doses. Gender and diabetes status were identified as the most influential covariates, and an underlying seasonal weight fluctuation was identified. Slower than that recommended, one-week dose-escalation algorithms led up to 2 weeks slower initial weight loss but similar long-term weight loss trajectories. CONCLUSIONS:The relationship between liraglutide systemic exposure and weight loss was successfully established in overweight or obese people. The model could predict the time course of weight regain after treatment cessation and suggests that GI tolerability can be mitigated by slower escalation with only minor impact on the weight loss trajectory.

SUBMITTER: Papathanasiou T

PROVIDER: S-EPMC7317899 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Impact of dose-escalation schemes and drug discontinuation on weight loss outcomes with liraglutide 3.0 mg: A model-based approach.

Papathanasiou Theodoros T Strathe Anders A Agersø Henrik H Lund Trine Meldgaard TM Overgaard Rune Viig RV

Diabetes, obesity & metabolism 20200219 6

<h4>Aims</h4>To investigate the impact on weight loss of the treatment changes in overweight or obese people that may be needed in case of gastrointestinal (GI) tolerability issues during escalation of the glucagon-like peptide-1 analogue liraglutide.<h4>Materials and methods</h4>The individual longitudinal body weight data from the main trial periods of three phase II/III trials in overweight or obese patients (56-week treatment with once-daily liraglutide 1.2, 1.8, 2.4 or 3.0 mg or placebo, n ...[more]

PMID: 32009288

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Project description:IntroductionData from randomized controlled trials show that liraglutide 3.0 mg, in combination with diet and exercise, is associated with greater weight loss than diet and exercise alone in patients with obesity. In practice, the utilization of weight loss drugs is influenced by various factors, including the cost of treatment. We conducted a retrospective, observational study to assess the effectiveness of liraglutide 3.0 mg and patients' persistence on treatment, in a real-world setting.MethodsData were extracted from de-identified electronic medical records from an obesity management clinic in Switzerland. Changes in body weight and blood pressure were evaluated in the full cohort (N = 277, 19% of whom had undergone bariatric surgery) and subgroups who were persistent on liraglutide 3.0 mg for at least 4 months (n = 236), 7 months (n = 159), or 12 months (n = 71).ResultsMedian persistence on liraglutide was 6.8 months. Median maximum dose received was 1.5 mg, and 13.7% of patients reached the maintenance dose of 3.0 mg. Mean 7-month weight change from baseline in the full cohort was -4.1 kg (95% confidence interval: -5.0, -3.2; p < 0.001; -4.2%). Weight change was -4.4 kg (-4.7%) in the ≥4-month persistence subgroup at 4 months, -5.1 kg (-5.3%) in the ≥7-month persistence subgroup at 7 months, and -7.5 kg (-7.1%) in the ≥12-month persistence subgroup at 12 months (all p < 0.001). In the full cohort, 40% and 14% of patients lost ≥5% and >10% of body weight at 7 months, respectively. Weight loss did not differ significantly according to history of bariatric surgery (p = 0.94). Diastolic blood pressure decreased (from 87.0 to 83.9 mm Hg at 7 months; p = 0.018), with no significant changes in systolic blood pressure. Approximately two-thirds of patients did not have health insurance that could cover the cost of liraglutide.ConclusionIn a real-world setting with low insurance coverage and with most patients not reaching the recommended maintenance dose of 3.0 mg, the use of liraglutide, in combination with diet and exercise, was associated with clinically meaningful weight loss.

Project description:Abstract The objective of the SCALE IBT trial (NCT02963935) was to compare the weight loss of liraglutide 3.0 mg, a medication approved by the Food and Drug Administration for chronic weight management, to placebo, both in combination with 56 weeks of intensive behavior therapy (IBT) (i.e. reduced calorie intake, increased physical activity [max target: 250 mins/week], and 23 counseling sessions). The primary outcomes of the study were assessed in the intention-to-treat sample, regardless of individuals’ medication adherence. The weight loss estimated in the primary analysis, regardless of drug adherence, was 7.5% versus 4.0% for liraglutide 3.0 mg and placebo, respectively, reflecting a treatment difference favoring liraglutide 3.0 mg of 3.5% (95% CI: 1.6%; 5.3%; p=0.0003). In this pre-specified secondary analysis, we sought to determine the expected effect of liraglutide 3.0 mg on weight loss, as compared to placebo, if all randomized individuals had adhered to study drug for 56 weeks. A total of 282 individuals with obesity (BMI ≥30 kg/m2) were randomized in a 1:1 ratio to 56 weeks of IBT combined with daily injections of either liraglutide 3.0 mg or placebo. The weight loss, based on the assumption that all individuals adhered to the medication, was estimated using two different approaches. The first approach (mixed model repeated measures; MMRM) estimated the weight loss that would have been achieved if all individuals adhered to the trial drug by utilizing information from individuals still on drug after the point of a given individual’s discontinuation to provide a (counter-factual) weight change as if the individual in question had not discontinued the drug. The second (covariate) approach used a regression model to calculate the weight change of individuals with full adherence to trial drug by including adherence as a moderator of the effect of treatment condition on weight change. The MMRM approach yielded a weight loss difference of 4.6% (95% CI: 2.6%; 6.5%; p<0.0001), and the covariate approach yielded a weight loss difference of 4.6% (95% CI: 2.8%; 6.5%; p<0.0001), with both estimates favoring liraglutide 3.0 mg. As such, there was good agreement between the two statistical approaches for estimating the effect of liraglutide 3.0 mg versus placebo for individuals who adhere to trial product for 56 weeks. The estimated placebo-subtracted weight loss for liraglutide at week 56 of approximately 4.6% in medication-adherent individuals therefore indicates that underlying assumptions are robust. We believe this finding is an important supplement to the study’s primary outcome and can inform practitioners’ expectations when prescribing liraglutide 3.0 mg in combination with IBT for 56 weeks. Supported by Novo Nordisk.

Project description:AimsLiraglutide, a GLP-1 receptor agonist, regulates appetite via receptors in the brain. Because of concerns regarding the potential of centrally-acting anti-obesity medications to affect mental health, pooled neuropsychiatric safety data from all phase 2 and 3a randomized, double-blind trials with liraglutide 3.0?mg were evaluated post hoc.MethodsData from the liraglutide weight-management programme were pooled. Across trials, individuals with a body mass index ?30 or ?27?kg/m2 with weight-related comorbidities were randomized to once-daily subcutaneous liraglutide 3.0?mg (n?=?3384) or placebo (n?=?1941), both with a 500?kcal/d deficit diet, plus exercise. Adverse events related to neuropsychiatric safety were collected in all trials. Additionally, in the phase 3a trials, validated mental-health questionnaires were prospectively and systematically administered.ResultsIn the pooled analysis of 5325 randomized and exposed individuals, rates of depression (2.1 vs 2.1 events/100 person-years) and anxiety (1.9 vs 1.7 events/100 person-years) through adverse event reporting were similarly low in liraglutide and placebo groups. Nine (0.3%) individuals receiving liraglutide and 2 (0.1%) receiving placebo reported adverse events of suicidal ideation or behaviour. In phase 3a trials, mean baseline Patient Health Questionnaire-9 scores of 2.8?±?3.0 vs 2.9?±?3.1 for liraglutide vs placebo improved to 1.8?±?2.7 vs 1.9?±?2.7, respectively, at treatment end; 34/3291 individuals (1.0%) receiving liraglutide 3.0?mg vs 19/1843 (1.0%) receiving placebo reported suicidal ideation on the Columbia-Suicide Severity Rating Scale.ConclusionsResults of this exploratory pooled analysis provide no cause for concern regarding the neuropsychiatric safety of treatment with liraglutide 3.0?mg in patients similar to those included in the examined trials. Although there was a small numerical imbalance in suicidal ideation with liraglutide through adverse event reporting, no between-treatment imbalances in suicidal ideation/behaviour or depression were noted through prospective questionnaire assessments.

Project description:ImportanceMetabolic surgery leads to weight loss and improved health, but these outcomes are highly variable. Poor weight loss is associated with lower circulating levels of glucagon-like peptide-1 (GLP-1).ObjectiveTo assess the efficacy and safety of the GLP-1 receptor agonist, liraglutide, 3.0 mg, on percentage body weight reduction in patients with poor weight loss and suboptimal GLP-1 response after metabolic surgery.Design, setting, and participantsThe Evaluation of Liraglutide 3.0 mg in Patients With Poor Weight Loss and a Suboptimal Glucagon-Like Peptide-1 Response (BARI-OPTIMISE) randomized placebo-controlled trial recruited adult patients at least 1 year after metabolic surgery who had experienced 20% or less body weight loss from the day of surgery and a suboptimal nutrient-stimulated GLP-1 response from 2 hospitals in London, United Kingdom, between October 2018 and November 2019. Key exclusion criteria were type 1 diabetes; severe concomitant psychiatric, gastrointestinal, cardiac, kidney or metabolic disease; and use of insulin, GLP-1 receptor analogues, and medication that can affect weight. The study period was 24 weeks followed by a 4-week follow-up period. Last participant follow-up was completed in June 2020. All participants and clinical study personnel were blinded to treatment allocation. Of 154 assessed for eligibility, 70 met trial criteria and were included in the study, and 57 completed follow-up.InterventionsLiraglutide, 3.0 mg, once daily or placebo as an adjunct to lifestyle intervention with a 500-kcal daily energy deficit for 24 weeks, on a 1:1 allocation by computer-generated randomization sequence, stratified by surgery type (Roux-en-Y gastric bypass [RYGB] or sleeve gastrectomy [SG]) and type 2 diabetes status.Main outcome and measuresThe primary outcome was change in percentage body weight from baseline to the end of the 24-week study period based on an intention-to-treat analysis. Participant safety was assessed through monitoring of biochemical parameters, including kidney and liver function, physical examination, and assessment for adverse events.ResultsA total of 70 participants (mean [SD] age, 47.6 [10.7] years; 52 [74%] female) with a poor weight loss response following RYGB or SG were randomized to receive 3.0-mg liraglutide (n = 35) or placebo (n = 35). All participants received at least 1 dose of the trial drug. Eight participants discontinued treatment (4 per group), and 2 in the 3.0-mg liraglutide group and 1 in the placebo group were lost to follow-up. Due to COVID-19 restrictions, 3 participants in the 3.0-mg liraglutide group and 7 in the placebo group were unable to attend their final in-person assessment. Estimated change in mean (SD) percentage body weight from baseline to week 24 was -8.82 (4.94) with liraglutide, 3.0 mg (n = 31), vs -0.54 (3.32) with placebo (n = 26). The mean difference in percentage body weight change for liraglutide, 3.0 mg, vs placebo was -8.03 (95% CI, -10.39 to -5.66; P < .001). Adverse events, predominantly gastrointestinal, were more frequent with liraglutide, 3.0 mg (28 events [80%]), than placebo (20 events [57%]). There were no serious adverse events and no treatment-related deaths.Conclusion and relevanceThese findings support the use of adjuvant liraglutide, 3.0 mg, for weight management in patients with poor weight loss and suboptimal GLP-1 response after metabolic surgery.Trial registrationClinicalTrials.gov Identifier: NCT03341429.

Dataset Information

Impact of dose-escalation schemes and drug discontinuation on weight loss outcomes with liraglutide 3.0?mg: A model-based approach.

Publications

Impact of dose-escalation schemes and drug discontinuation on weight loss outcomes with liraglutide 3.0 mg: A model-based approach.

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