Abstract
Aims/hypothesisThe aim of this work was to assess the effect of liraglutide on ectopic fat accumulation in individuals with type 2 diabetes mellitus.MethodsThis 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.ResultsThe 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/interpretationCompared 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 registrationClinicalTrials.gov NCT01761318.FundingThis study was funded by Novo Nordisk A/S (Bagsvaerd, Denmark).
Highlights
Insulin resistance and type 2 diabetes mellitus are hallmarked by excess fat storage in visceral adipose tissue (VAT), liver, skeletal muscle, myocardial tissue and epicardial fat [1]
One participant in the liraglutide group withdrew consent before having received the study drug and was not included in intention-to-treat analysis, and one participant was withdrawn from the study because of frequent hypoglycaemic events
This study shows that, compared with placebo, liraglutide reduced body weight and subcutaneous fat but not visceral fat, hepatic steatosis, myocardial steatosis, epicardial fat, paracardial fat or pericardial fat
Summary
Insulin resistance and type 2 diabetes mellitus are hallmarked by excess fat storage in visceral adipose tissue (VAT), liver, skeletal muscle, myocardial tissue and epicardial fat [1]. VAT is tightly linked to insulin resistance and cardiovascular disease, independent of general obesity [1]. Diet-induced reduction of VAT has greater impact on markers of insulin sensitivity and cardiometabolic risk than reduction of subcutaneous adipose tissue (SAT) [2]. Hepatic steatosis is an independent predictor of cardiovascular disease, possibly by contributing to hepatic insulin resistance resulting in atherogenic dyslipidaemia [1]. Therapeutic interventions aimed at reducing excess ectopic fat storage might have a major impact on the cardiovascular prognosis of individuals with type 2 diabetes mellitus
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