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Pancreatic beta cell function following liraglutide-augmented weight loss in individuals with prediabetes: analysis of a randomised, placebo-controlled study.

ABSTRACT: AIMS/HYPOTHESIS:Liraglutide can modulate insulin secretion by directly stimulating beta cells or indirectly through weight loss and enhanced insulin sensitivity. Recently, we showed that liraglutide treatment in overweight individuals with prediabetes (impaired fasting glucose and/or impaired glucose tolerance) led to greater weight loss (-7.7% vs -3.9%) and improvement in insulin resistance compared with placebo. The current study evaluates the effects on beta cell function of weight loss augmented by liraglutide compared with weight loss alone. METHODS:This was a parallel, randomised study conducted in a single academic centre. Both participants and study administrators were blinded to treatment assignment. Individuals who were 40-70 years old, overweight (BMI 27-40 kg/m(2)) and with prediabetes were randomised (via a computerised system) to receive liraglutide (n?=?35) or matching placebo (n?=?33), and 49 participants were analysed. All were instructed to follow an energy-restricted diet. Primary outcome was insulin secretory function, which was evaluated in response to graded infusions of glucose and day-long mixed meals. RESULTS:Liraglutide treatment (n?=?24) significantly (p???0.03) increased the insulin secretion rate (% mean change [95% CI]; 21% [12, 31] vs -4% [-11, 3]) and pancreatic beta cell sensitivity to intravenous glucose (229% [161, 276] vs -0.5% (-15, 14]), and decreased insulin clearance rate (-3.5% [-11, 4] vs 8.2 [0.2, 16]) as compared with placebo (n?=?25). The liraglutide-treated group also had significantly (p???0.03) lower day-long glucose (-8.2% [-11, -6] vs -0.1 [-3, 2]) and NEFA concentrations (-14 [-20, -8] vs -2.1 [-10, 6]) following mixed meals, whereas day-long insulin concentrations did not significantly differ as compared with placebo. In a multivariate regression analysis, weight loss was associated with a decrease in insulin secretion rate and day-long glucose and insulin concentrations in the placebo group (p???0.05), but there was no association with weight loss in the liraglutide group. The most common side effect of liraglutide was nausea. CONCLUSIONS/INTERPRETATION:A direct stimulatory effect on beta cell function was the predominant change in liraglutide-augmented weight loss. These changes appear to be independent of weight loss. TRIAL REGISTRATION:ClinicalTrials.gov NCT01784965 FUNDING: The study was funded by the ADA.

SUBMITTER: Kim SH

PROVIDER: S-EPMC5072364 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Pancreatic beta cell function following liraglutide-augmented weight loss in individuals with prediabetes: analysis of a randomised, placebo-controlled study.

Kim Sun H SH Liu Alice A Ariel Danit D Abbasi Fahim F Lamendola Cindy C Grove Kaylene K Tomasso Vanessa V Reaven Gerald G

Diabetologia 20131211 3

<h4>Aims/hypothesis</h4>Liraglutide can modulate insulin secretion by directly stimulating beta cells or indirectly through weight loss and enhanced insulin sensitivity. Recently, we showed that liraglutide treatment in overweight individuals with prediabetes (impaired fasting glucose and/or impaired glucose tolerance) led to greater weight loss (-7.7% vs -3.9%) and improvement in insulin resistance compared with placebo. The current study evaluates the effects on beta cell function of weight lo ...[more]

PMID: 24326527

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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: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.

Project description:AIMS/HYPOTHESIS:The aim of this study was to evaluate the effect of sitagliptin on glucose tolerance, plasma lipids, energy expenditure and metabolism of brown adipose tissue (BAT), white adipose tissue (WAT) and skeletal muscle in overweight individuals with prediabetes (impaired glucose tolerance and/or impaired fasting glucose). METHODS:We performed a randomised, double-blinded, placebo-controlled trial in 30 overweight, Europid men (age 45.9?±?6.2 years; BMI 28.8?±?2.3 kg/m2) with prediabetes in the Leiden University Medical Center and the Alrijne Hospital between March 2015 and September 2016. Participants were initially randomly allocated to receive sitagliptin (100 mg/day) (n?=?15) or placebo (n?=?15) for 12 weeks, using a randomisation list that was set up by an unblinded pharmacist. All people involved in the study as well as participants were blinded to group assignment. Two participants withdrew from the study prior to completion (both in the sitagliptin group) and were subsequently replaced with two new participants that were allocated to the same treatment. Before and after treatment, fasting venous blood samples and skeletal muscle biopsies were obtained, OGTT was performed and body composition, resting energy expenditure and [18F] fluorodeoxyglucose ([18F]FDG) uptake by metabolic tissues were assessed. The primary study endpoint was the effect of sitagliptin on BAT volume and activity. RESULTS:One participant from the sitagliptin group was excluded from analysis, due to a distribution error, leaving 29 participants for further analysis. Sitagliptin, but not placebo, lowered glucose excursion (-40%; p?<?0.003) during OGTT, accompanied by an improved insulinogenic index (+38%; p?<?0.003) and oral disposition index (+44%; p?<?0.003). In addition, sitagliptin lowered serum concentrations of triacylglycerol (-29%) and very large (-46%), large (-35%) and medium-sized (-24%) VLDL particles (all p?<?0.05). Body weight, body composition and energy expenditure did not change. In skeletal muscle, sitagliptin increased mRNA expression of PGC1? (also known as PPARGC1B) (+117%; p?<?0.05), a main controller of mitochondrial oxidative energy metabolism. Although the primary endpoint of change in BAT volume and activity was not met, sitagliptin increased [18F] FDG uptake in subcutaneous WAT (sWAT; +53%; p?<?0.05). Reported side effects were mild and transient and not necessarily related to the treatment. CONCLUSIONS/INTERPRETATION:Twelve weeks of sitagliptin in overweight, Europid men with prediabetes improves glucose tolerance and lipid metabolism, as related to increased [18F] FDG uptake by sWAT, rather than BAT, and upregulation of the mitochondrial gene PGC1? in skeletal muscle. Studies on the effect of sitagliptin on preventing or delaying the progression of prediabetes into type 2 diabetes are warranted. TRIAL REGISTRATION:ClinicalTrials.gov NCT02294084. FUNDING:This study was funded by Merck Sharp & Dohme Corp, Dutch Heart Foundation, Dutch Diabetes Research Foundation, Ministry of Economic Affairs and the University of Granada.

Project description:BackgroundConversional bariatric surgery inherently has less weight loss (WL) compared to primary procedures. Adjunctive use of the GLP-1 analog, liraglutide with conversional Roux-en-Y Gastric Bypass (cRYGB) may maximize the WL benefits of surgery.Material and methodsThis single-center randomized double-blind placebo-controlled trial included 80 patients randomized into two groups; the liraglutide group (40 patients) who received daily injections of liraglutide, and the placebo group (40 patients) who received normal saline starting at 6 weeks from cRYGB and continued for 6 months. After discontinuing the drugs at 6 months and unblinding, the patient were followed up to 12 months. The endpoints were percentage of total weight loss (%TWL) and percentage of excess weight loss (%EWL), and changes in the metabolic biomarkers, and complications within 30 and 90 days according to the global outcome benchmark (GOB) stratification.ResultsIn total, 38 patients in the liraglutide group and 31 in the placebo group completed the 24 weeks. Liraglutide group experienced better WL with a significantly higher mean %TWL at 1 month (10.27±1.39 vs. 8.41±2.08), at 6 weeks (12.65±1.77 vs. 10.47±2.23), at 6 months (18.29 ±1.74 vs. 15.58 ±1.65), and at 12 months 24.15±2.35 versus 22.70±2.13 (all P <0.001). For %EWL, this was also significantly higher in the liraglutide group at all time points. A %TWL of greater than 20% at 6 months of treatment was recorded in six (15.8%) patients in the liraglutide group and none in the placebo group ( P =0.029). Both groups had comparable changes in metabolic biomarkers. Adverse events were recorded in 11 (27.5%) patients in the liraglutide, with no adverse events in the placebo group ( P <0.001). Both groups had Clavien-Dindo scores I and II (5.0 and 2.5%), and GOB values indicated that 90.0 and 97.5% were low-risk patients.ConclusionAdjunctive use of liraglutide with cRYGB gives significantly higher WL and resolution of associated medical problems.

Dataset Information

Pancreatic beta cell function following liraglutide-augmented weight loss in individuals with prediabetes: analysis of a randomised, placebo-controlled study.

Publications

Pancreatic beta cell function following liraglutide-augmented weight loss in individuals with prediabetes: analysis of a randomised, placebo-controlled study.

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