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A double-blind, placebo-controlled, randomised trial to assess the effect of liraglutide on ectopic fat accumulation in South Asian type 2 diabetes patients.

ABSTRACT: BACKGROUND:South Asians have a high risk to develop type 2 diabetes, which may be related to substantial ectopic fat deposition. Since glucagon-like peptide-1 analogues can reduce ectopic fat accumulation, the aim of the present study was to assess the effect of treatment with liraglutide for 26 weeks on ectopic fat deposition and HbA1c in South Asian patients with type 2 diabetes. METHODS:In a placebo-controlled trial, 47 South Asian patients with type 2 diabetes were randomly assigned to treatment with liraglutide (1.8 mg/day) or placebo added to standard care. At baseline and after 26 weeks of treatment we assessed abdominal subcutaneous, visceral, epicardial and paracardial adipose tissue volume using MRI. Furthermore, myocardial and hepatic triglyceride content were examined with proton magnetic resonance spectroscopy. RESULTS:In the intention-to-treat analysis, liraglutide decreased body weight compared to placebo (-?3.9?±?3.6 kg vs -?0.6?±?2.2 kg; mean change from baseline (liraglutide vs placebo): -?3.5 kg; 95% CI [-?5.3, -?1.8]) without significant effects on the different adipose tissue compartments. HbA1c was decreased in both groups without between group differences. In the per-protocol analysis, liraglutide did decrease visceral adipose tissue volume compared to placebo (-?23?±?27 cm2 vs -?2?±?17 cm2; mean change from baseline (liraglutide vs placebo): -?17 cm2; 95% CI [-?32, -?3]). Furthermore, HbA1c was decreased by liraglutide compared to placebo (-?1.0?±?0.8% (-?10.5?±?9.1 mmol/mol)) vs (-?0.6?±?0.8% (-?6.1?±?8.8 mmol/mol)), with a between group difference (mean change from baseline (liraglutide vs placebo): -?0.6% (-?6.5 mmol/mol); 95% CI [-?1.1, -?0.1 (-?11.5, -?1.5)]). Interestingly, the decrease of visceral adipose tissue volume was associated with the reduction of HbA1c (?: 0.165 mmol/mol (0.015%) per 1 cm2 decrease of visceral adipose tissue volume; 95% CI [0.062, 0.267 (0.006, 0.024%)]). CONCLUSIONS:While the intention-to-treat analysis did not show effects of liraglutide on ectopic fat and HbA1c, per-protocol analysis showed that liraglutide decreases visceral adipose tissue volume, which was associated with improved glycaemic control in South Asians. Trial registration NCT02660047 (clinicaltrials.gov). Registered 21 January 2016.

SUBMITTER: van Eyk HJ

PROVIDER: S-EPMC6615254 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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A double-blind, placebo-controlled, randomised trial to assess the effect of liraglutide on ectopic fat accumulation in South Asian type 2 diabetes patients.

van Eyk Huub J HJ Paiman Elisabeth H M EHM Bizino Maurice B MB de Heer Paul P Geelhoed-Duijvestijn Petronella H PH Kharagjitsingh Aan V AV Smit Johannes W A JWA Lamb Hildo J HJ Rensen Patrick C N PCN Jazet Ingrid M IM

Cardiovascular diabetology 20190709 1

<h4>Background</h4>South Asians have a high risk to develop type 2 diabetes, which may be related to substantial ectopic fat deposition. Since glucagon-like peptide-1 analogues can reduce ectopic fat accumulation, the aim of the present study was to assess the effect of treatment with liraglutide for 26 weeks on ectopic fat deposition and HbA1c in South Asian patients with type 2 diabetes.<h4>Methods</h4>In a placebo-controlled trial, 47 South Asian patients with type 2 diabetes were randomly as ...[more]

PMID: 31288820

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Project description:BackgroundThe glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide may be beneficial in the regression of diabetic cardiomyopathy. South Asian ethnic groups in particular are at risk of developing type 2 diabetes.PurposeTo assess the effects of liraglutide on left ventricular (LV) diastolic and systolic function in South Asian type 2 diabetes patients.Study typeProspective, double-blind, randomized, placebo-controlled trial.PopulationForty-seven type 2 diabetes patients of South Asian ancestry living in the Netherlands, with or without ischemic heart disease, who were randomly assigned to 26-week treatment with liraglutide (1.8 mg/day) or placebo.Field strength/sequence3T (balanced steady-state free precession cine MRI, 2D and 4D velocity-encoded MRI, 1 H-MRS, T1 mapping).AssessmentPrimary endpoints were changes in LV diastolic function (early deceleration peak [Edec], ratio of early and late peak filling rate [E/A], estimated LV filling pressure [E/Ea]) and LV systolic function (ejection fraction). Secondary endpoints were changes in aortic stiffness (aortic pulse wave velocity [PWV]), myocardial steatosis (myocardial triglyceride content), and diffuse fibrosis (extracellular volume [ECV]).Statistical testsData were analyzed according to intention-to-treat. Between-group differences were reported as mean (95% confidence interval [CI]) and were assessed using analysis of covariance (ANCOVA).ResultsLiraglutide (n = 22) compared with placebo (n = 25) did not change Edec (+0.2 mL/s2 × 10-3 (-0.3;0.6)), E/A (-0.09 (-0.23;0.05)), E/Ea (+0.1 (-1.2;1.3)) and ejection fraction (0% (-3;2)), but decreased stroke volume (-9 mL (-14;-5)) and increased heart rate (+10 bpm (4;15)). Aortic PWV (+0.5 m/s (-0.6;1.6)), myocardial triglyceride content (+0.21% (-0.09;0.51)), and ECV (-0.2% (-1.4;1.0)) were unaltered.Data conclusionLiraglutide did not affect LV diastolic and systolic function, aortic stiffness, myocardial triglyceride content, or extracellular volume in Dutch South Asian type 2 diabetes patients with or without coronary artery disease.Level of evidence1 Technical Efficacy Stage: 4 J. Magn. Reson. Imaging 2020;51:1679-1688.

Project description:AIMS/HYPOTHESIS:The aim of this work was to assess the effect of liraglutide on ectopic fat accumulation in individuals with type 2 diabetes mellitus. METHODS:This study is a pre-specified subanalysis of the MAGNetic resonance Assessment of VICTOza efficacy in the Regression of cardiovascular dysfunction In type 2 diAbetes mellitus (MAGNA VICTORIA) study, with primary endpoints being the effects of liraglutide on left ventricular diastolic and systolic function. The MAGNA VICTORIA study was a single-centre, parallel-group trial in 50 individuals with type 2 diabetes mellitus (BMI >25 kg/m2) who were randomly assigned (1:1, stratified for sex and insulin use) to receive liraglutide 1.8 mg once daily or placebo for 26 weeks, added to standard care. Participants, study personnel and outcome assessors were blinded to treatment allocation. The secondary endpoints of visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (SAT) and epicardial fat were measured with MRI. Hepatic triacylglycerol content (HTGC) and myocardial triacylglycerol content (MTGC) were quantified with proton MR spectroscopy. Between-group differences (change from baseline) were tested for significance using ANCOVA. Mean differences with 95% CIs were reported. RESULTS:The trial was completed in 2016. Twenty-four participants were randomised to receive liraglutide and 26 to receive placebo. One patient in the liraglutide group withdrew consent before having received the study drug and was not included in the intention-to-treat analysis. Liraglutide (n = 23) vs placebo (n = 26) significantly reduced body weight (liraglutide 98.4 ± 13.8 kg to 94.3 ± 14.9 kg; placebo 94.5 ± 13.1 kg to 93.9 ± 13.2 kg; estimated treatment effect -4.5 [95% CI -6.4, -2.6] kg). HbA1c declined in both groups without a significant treatment effect of liraglutide vs placebo (liraglutide 66.7 ± 11.5 mmol/mol to 55.0 ± 13.2 mmol/mol [8.4 ± 1.1% to 7.3 ± 1.2%]; placebo 64.7 ± 10.2 mmol/mol to 56.9 ± 6.9 mmol/mol [8.2 ± 1.0% to 7.5 ± 0.7%]; estimated treatment effect -2.9 [95% CI -8.1, 2.3] mmol/mol or -0.3 [95% CI -0.8, 0.2]%). VAT did not change significantly between groups (liraglutide 207 ± 87 cm2 to 203 ± 88 cm2; placebo 204 ± 63 cm2 to 200 ± 55 cm2; estimated treatment effect -7 [95% CI -24, 10] cm2), while SAT was reduced by a significantly greater extent with liraglutide than with placebo (liraglutide 361 ± 142 cm2 to 339 ± 131 cm2; placebo 329 ± 107 cm2 to 333 ± 125 cm2; estimated treatment effect -29 [95% CI -51, -8] cm2). Epicardial fat did not change significantly between groups (liraglutide 8.9 ± 4.3 cm2 to 9.1 ± 4.7 cm2; placebo 9.6 ± 4.1 cm2 to 9.6 ± 4.6 cm2; estimated treatment effect 0.2 [95% CI -1.5, 1.8] cm2). Change in HTGC was not different between groups (liraglutide 18.1 ± 11.2% to 12.0 ± 7.7%; placebo 18.4 ± 9.4% to 14.7 ± 10.0%; estimated treatment effect -2.1 [95% CI -5.3, 1.0]%). MTGC was not different after treatment with liraglutide (1.5 ± 0.6% to 1.2 ± 0.6%) vs placebo (1.3 ± 0.5% to 1.2 ± 0.6%), with an estimated treatment effect of -0.1 (95% CI -0.4, 0.2)%. There were no adjudicated serious adverse events. CONCLUSIONS/INTERPRETATION:Compared with placebo, liraglutide-treated participants lost significantly more body weight. Liraglutide primarily reduced subcutaneous fat but not visceral, hepatic, myocardial or epicardial fat. Future larger studies are needed to confirm the results of this secondary endpoint study. TRIAL REGISTRATION:ClinicalTrials.gov NCT01761318. FUNDING:This study was funded by Novo Nordisk A/S (Bagsvaerd, Denmark).

Project description:BackgroundGlucagon-like peptide-1 receptor (GLP-1R) activation may improve myocardial performance in the context of ischaemia, independent of glycaemic control, in individuals with and without type 2 diabetes mellitus.MethodsThe LIONESS trial was a single-centre randomised double-blind placebo-controlled crossover study to determine whether prolonged GLP-1R activation could improve exercise haemodynamics in chronic stable angina patients. Eligibility criteria comprised angiographic evidence of obstructive coronary artery disease (CAD) and an abnormal baseline exercise tolerance test (ETT) demonstrating > 0.1 mV of planar or downsloping ST-segment depression (STD). Those randomised to active agent started with a 1-week run-in phase of 0.6 mg liraglutide daily, an established injectable GLP-1R agonist, followed by 1 week of 1.2 mg liraglutide, after which patients performed a week 2 ETT. Patients then self-administered 1.8 mg liraglutide for a week before completing a week 3 ETT. The placebo arm received visually and temporally matched daily saline injections. Participants then crossed over to a 3-week course of saline injections interspersed with a week 5 ETT and week 6 ETT and vice versa. Co-primary endpoints were rate pressure product (RPP) at 0.1 mV STD and magnitude of STD at peak exercise.ResultsTwenty-two patients (21 without diabetes) were randomised. There was no significant difference between saline versus liraglutide in the co-primary endpoints of RPP achieved at 0.1 mV STD (saline vs. liraglutide 1.2 mg p = 0.097; saline vs. liraglutide 1.8 mg p = 0.48) or the degree of STD at peak exercise (saline vs. liraglutide 1.2 mg p = 0.68; saline vs. liraglutide 1.8 mg p = 0.57). Liraglutide did not cause symptomatic hypoglycaemia, renal dysfunction, acute pancreatitis or provoke early withdrawal from the trial. Liraglutide significantly reduced weight (baseline 88.75 ± 16.5 kg vs. after liraglutide 87.78 ± 16.9 kg; p = 0.0008) and improved the lipid profile (mean total cholesterol: at baseline 3.97 ± 0.88 vs. after liraglutide 3.56 ± 0.71 mmol/L; p < 0.0001).ConclusionLiraglutide did not enhance exercise tolerance or haemodynamics compared with saline placebo during serial treadmill testing in patients with established obstructive CAD. It did, however, significantly reduce weight and improve the lipid profile. Trial Registration ClinicalTrials.gov Identifier NCT02315001. Retrospectively registered on 11th December 2014.

Project description:IntroductionOrlistat is an inhibitor of pancreatic lipase and is used as an anti-obesity drug in many countries. However, there are no data available regarding the effects of orlistat on visceral fat accumulation in Japanese subjects. Therefore, this comparative, placebo-controlled, double-blind, randomized study aimed to evaluate the efficacy and safety of orlistat in Japanese participants with excessive visceral fat accumulation and without dyslipidemia, diabetes mellitus, and hypertension ("metabolic diseases").MethodsThe study population included Japanese participants with excessive visceral fat accumulation (waist circumference ≥ 85 cm in males and ≥ 90 cm in females, which corresponds to a visceral fat area of 100 cm2) and without metabolic diseases. Following a 12-week observation term, participants were randomized to the orlistat 60 mg group (n = 100) or placebo group (n = 100). Both drugs were administered orally three times daily for 24 weeks. Participants were also counseled to improve their diet and to maintain exercise throughout the study. Visceral fat area, subcutaneous fat area, waist circumference, body weight, body mass index, adverse reactions, laboratory tests, and blood pressure were regularly assessed.ResultsVisceral fat area, waist circumference, and body weight were significantly reduced in the orlistat group (mean ± standard error, - 13.50 ± 1.52%, - 2.51 ± 0.25%, and - 2.79 ± 0.30%, respectively) compared to the placebo group (- 5.45 ± 1.50%, - 1.55 ± 0.26%, and - 1.22 ± 0.28%, respectively) at the last assessment. The main adverse reactions were defecation-related symptoms including oily spotting and flatus with discharge, resulting from the pharmacological effects of orlistat. Most adverse reactions were mild, and none were serious or severe.ConclusionOrlistat administration reduced visceral fat area, waist circumference, and body weight in Japanese participants with excessive visceral fat and without metabolic diseases. In addition, safety was confirmed with a tolerable profile. Orlistat may be useful to reduce excessive visceral fat accumulation when used in combination with diet and exercise.Trial registrationJapan Pharmaceutical Information Center identifier, JapicCTI-184005.FundingTaisho Pharmaceutical Co., Ltd.

Project description:BackgroundRecombinant human growth hormone (rhGH) reduces visceral adipose tissue (VAT) volume in HIV-infected patients but can worsen glucose homeostasis and lipoatrophy. We aimed to determine if adding rosiglitazone to rhGH would abrogate the adverse effects of rhGH on insulin sensitivity (SI) and subcutaneous adipose tissue (SAT) volume.Methodology/principal findingsRandomized, double-blind, placebo-controlled, multicenter trial using a 2×2 factorial design in which HIV-infected subjects with abdominal obesity and insulin resistance were randomized to rhGH 3 mg daily, rosiglitazone 4 mg twice daily, combination rhGH + rosiglitazone, or double placebo (control) for 12 weeks. The primary endpoint was change in SI by frequently sampled intravenous glucose tolerance test from entry to week 12. Body composition was assessed by whole body magnetic resonance imaging (MRI) and dual Xray absorptiometry (DEXA). Seventy-seven subjects were randomized of whom 72 initiated study drugs. Change in SI from entry to week 12 differed across the 4 arms by 1-way ANCOVA (P = 0.02); by pair-wise comparisons, only rhGH (decreasing SI; P = 0.03) differed significantly from control. Changes from entry to week 12 in fasting glucose and glucose area under the curve on 2-hour oral glucose tolerance test differed across arms (1-way ANCOVA P = 0.004), increasing in the rhGH arm relative to control. VAT decreased significantly in the rhGH arms (-17.5% in rhGH/rosiglitazone and -22.7% in rhGH) but not in the rosiglitazone alone (-2.5%) or control arms (-1.9%). SAT did not change significantly in any arm. DEXA results were consistent with the MRI data. There was no significant rhGH x rosiglitazone interaction for any body composition parameter.Conclusions/significanceThe addition of rosiglitazone abrogated the adverse effects of rhGH on insulin sensitivity and glucose tolerance while not significantly modifying the lowering effect of rhGH on VAT.Trial registrationClinicaltrials.gov NCT00130286.

Project description:Obesity is increasingly associated with COPD, but little is known about the prevalence of ectopic fat accumulation in COPD and whether this can possibly be associated with poor clinical outcomes and comorbidities. The Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) substudy tested the hypothesis that COPD is associated with increased ectopic fat accumulation and that this would be associated with COPD-related outcomes and comorbidities.Computed tomography (CT) images of the thorax obtained in ECLIPSE were used to quantify ectopic fat accumulation at L2-L3 (eg, cross-sectional area [CSA] of visceral adipose tissue [VAT] and muscle tissue [MT] attenuation, a reflection of muscle fat infiltration) and CSA of MT. A dose-response relationship between CSA of VAT, MT attenuation and CSA of MT and COPD-related outcomes (6-minute walking distance [6MWD], exacerbation rate, quality of life, and forced expiratory volume in 1 second [FEV1] decline) was addressed with the Cochran-Armitage trend test. Regression models were used to investigate possible relationships between CT body composition indices and comorbidities.From the entire ECLIPSE cohort, we identified 585 subjects with valid CT images at L2-L3 to assess body composition. CSA of VAT was increased (P<0.0001) and MT attenuation was reduced (indicating more muscle fat accumulation) in patients with COPD (P<0.002). Progressively increasing CSA of VAT was not associated with adverse clinical outcomes. The probability of exhibiting low 6MWD and accelerated FEV1 decline increased with progressively decreasing MT attenuation and CSA of MT. In COPD, the probability of having diabetes (P=0.024) and gastroesophageal reflux (P=0.0048) at baseline increased in parallel with VAT accumulation, while the predicted MT attenuation increased the probability of cardiovascular comorbidities (P=0.042). Body composition parameters did not correlate with coronary artery scores or with survival.Ectopic fat accumulation is increased in COPD, and this was associated with relevant clinical outcomes and comorbidities.

Dataset Information

A double-blind, placebo-controlled, randomised trial to assess the effect of liraglutide on ectopic fat accumulation in South Asian type 2 diabetes patients.

Publications

A double-blind, placebo-controlled, randomised trial to assess the effect of liraglutide on ectopic fat accumulation in South Asian type 2 diabetes patients.

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