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Placebo-controlled randomised trial with liraglutide on magnetic resonance endpoints in individuals with type 2 diabetes: a pre-specified secondary study on ectopic fat accumulation.

ABSTRACT: 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).

SUBMITTER: Bizino MB

PROVIDER: S-EPMC6890592 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Placebo-controlled randomised trial with liraglutide on magnetic resonance endpoints in individuals with type 2 diabetes: a pre-specified secondary study on ectopic fat accumulation.

Bizino Maurice B MB Jazet Ingrid M IM de Heer Paul P van Eyk Huub J HJ Dekkers Ilona A IA Rensen Patrick C N PCN Paiman Elisabeth H M EHM Lamb Hildebrandus J HJ Smit Johannes W JW

Diabetologia 20191105 1

<h4>Aims/hypothesis</h4>The aim of this work was to assess the effect of liraglutide on ectopic fat accumulation in individuals with type 2 diabetes mellitus.<h4>Methods</h4>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 ...[more]

PMID: 31690988

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Project description: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.

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.

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:Background & aimsMaternal hyperglycemia during pregnancy is an important risk factor for childhood adiposity. Maternal dietary glycemic index during pregnancy directly influences maternal and fetal glucose concentrations. We examined the associations of maternal early-pregnancy dietary glycemic index with offspring general, abdominal and ectopic fat accumulation among normal weight and overweight or obese pregnant women and their offspring.MethodsIn a population-based cohort study among 2488 Dutch pregnant women and their children, we assessed maternal dietary glycemic index by food frequency questionnaire at median 13.4 (95% range 10.7; 21.1) weeks gestation. Dietary glycemic index was used continuously and categorized into low (≤55), normal (56-69) and high (≥70) glycemic index diet. We measured offspring BMI, total fat mass and android/gynoid fat mass ratio by DXA, and visceral fat mass and liver fat fraction by MRI at 10 years.ResultsNo associations of maternal early-pregnancy dietary glycemic index with offspring adiposity were present among normal weight women and their children. Among overweight and obese women and their children, 1-Standard Deviation Score (SDS) increase in maternal early-pregnancy dietary glycemic index was associated with higher childhood BMI (0.10 SDS, 95% Confidence Interval (CI) 0.01; 0.19), total fat mass index (0.13 SDS, 95% CI 0.05; 0.22), visceral fat mass index (0.19 SDS, 95% CI 0.07; 0.32) and tended to be associated with a higher android/gynoid fat mass ratio (0.09 SDS, 95% CI -0.01; 0.19) and higher risk of childhood overweight (Odds Ratio (OR) 1.20, 95% CI 0.97; 1.48). Overweight and obese women consuming an early-pregnancy low-glycemic index diet, as compared to an early-pregnancy normal-glycemic index diet, had children with lower BMI, total fat mass index, visceral fat mass index and android/gynoid fat mass ratio at 10 years (p-values<0.05). No women consumed a high-glycemic index diet. No associations were explained by maternal socio-economic, lifestyle and dietary characteristics, birth or childhood characteristics. No associations with liver fat fraction were present.ConclusionsIn overweight or obese women and their children, a higher maternal early-pregnancy dietary glycemic index is associated with childhood general, abdominal and visceral fat accumulation, but not with liver fat. Intervention studies among overweight and obese pregnant women may need to target the dietary glycemic index to prevent childhood adiposity.

Project description:BackgroundPolycystic ovary syndrome's (PCOS) main feature is hyperandrogenism, which is linked to a higher risk of metabolic disorders. Gene expression analyses in adipose tissue and skeletal muscle reveal dysregulated metabolic pathways in women with PCOS, but these differences do not necessarily lead to changes in protein levels and biological function.MethodsTo advance our understanding of the molecular alterations in PCOS, we performed global proteomic and phosphorylation site analysis using tandem mass spectrometry, and analyzed gene expression and methylation. Adipose tissue and skeletal muscle were collected at baseline from 10 women with and without PCOS, and in women with PCOS after 5 weeks of treatment with electrical stimulation.ResultsPerilipin-1, a protein that typically coats the surface of lipid droplets in adipocytes, was increased whereas proteins involved in muscle contraction and type I muscle fiber function were downregulated in PCOS muscle. Proteins in the thick and thin filaments had many altered phosphorylation sites, indicating differences in protein activity and function. A mouse model was used to corroborate that androgen exposure leads to a shift in muscle fiber type in controls but not in skeletal muscle-specific androgen receptor knockout mice. The upregulated proteins in muscle post treatment were enriched in pathways involved in extracellular matrix organization and wound healing, which may reflect a protective adaptation to repeated contractions and tissue damage due to needling. A similar, albeit less pronounced, upregulation in extracellular matrix organization pathways was also seen in adipose tissue.ConclusionsOur results suggest that hyperandrogenic women with PCOS have higher levels of extra-myocellular lipids and fewer oxidative insulin-sensitive type I muscle fibers. These could be key factors leading to insulin resistance in PCOS muscle while electric stimulation-induced tissue remodeling may be protective.FundingSwedish Research Council (2020-02485, 2022-00550, 2020-01463), Novo Nordisk Foundation (NNF22OC0072904), and IngaBritt and Arne Lundberg Foundation. Clinical trial number NTC01457209.

Dataset Information

Placebo-controlled randomised trial with liraglutide on magnetic resonance endpoints in individuals with type 2 diabetes: a pre-specified secondary study on ectopic fat accumulation.

Publications

Placebo-controlled randomised trial with liraglutide on magnetic resonance endpoints in individuals with type 2 diabetes: a pre-specified secondary study on ectopic fat accumulation.

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