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Targeting visceral adiposity with pharmacotherapy - Effects of liraglutide on visceral and ectopic fat
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August 03, 2021 Lancet Diabees & Endocrinology
Editoral Commentary: Targeting visceral adiposity with pharmacotherapy - Mean (SD) change in VAT for the liraglutide group was -12⋅49% (9⋅3) and for the placebo group was -1⋅63% (12⋅3), over a median follow-up of approximately 36 weeks. In absolute numbers, both liraglutide and placebo groups had a baseline VAT of 4⋅5 L, and the average changes over time for the respective groups were -0⋅53 L and -0⋅10 L.. Liraglutide treatment was associated with 5⋅4% placebo-subtracted weight loss (-6⋅59% vs -1⋅19%). Hepatic fat decreased slightly more in the liraglutide group. As expected, liraglutide treatment led to greater reduction in fasting glucose whereas relative changes in other biomarkers were marginal or non-existent. In the current trial, liraglutide treatment yielded an average 6⋅6% weight loss with associated reductions of 9⋅59% in total body adipose tissue and 12⋅49% in VAT.
The relatively large VAT reduction led the authors to suggest that liraglutide might have a weight-loss independent effect on adipose tissue distribution. However, VAT is rapidly mobilised during periods of negative energy balance. Lifestyle interventions leading to 7% weight loss also report relatively large reductions in VAT,3 and thus liraglutide's effects on this highly lipolytic compartment might not be related to its pharmacological mechanisms of action. The hypothesis proposed by the authors can be tested in future studies using previously reported analytical methods designed to establish whether an agent or activity selectively targets the VAT compartment.4, 5
Separate from the question of the selective effects of liraglutide on mobilisation of VAT, so far there is no evidence that moderate weight loss or VAT reduction achieved with lifestyle and pharmaceutical interventions is associated with reduction in major adverse cardiovascular events among patients with obesity without diabetes. GLP-1 receptor agonists, including liraglutide, have been shown to reduce major adverse cardiovascular events among patients with overweight or obesity and comorbid type 2 diabetes, chronic kidney disease, and other complications, but not among patients with obesity without diabetes.6 The ongoing SELECT study (NCT03574597) of semaglutide, expected to be completed at the end of 2023, will answer whether anti-obesity pharmacotherapy can reduce major adverse cardiovascular events in patients with obesity and a history of cardiovascular disease, but without type 2 diabetes.
Despite the above-mentioned limitations, the study by Neeland and colleagues is a step in the right direction. Endpoints such as changes in VAT and liver fat have far more clinical relevance and pathophysiological implications than changes in bodyweight or BMI, typical primary endpoints in randomised, controlled trials of anti-obesity drugs. Advances in imaging methods7 now make it feasible to move beyond these classical primary endpoints towards inclusion of adipose tissue compartments and ectopic lipids as key outcome variables in future trials of new weight loss medicines.
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full research study
As of 2020, liraglutide was the most widely prescribed medication for obesity treatment, encompassing greater than 56% of the global market share.27 Given its widespread use, proven cardiometabolic benefit, and potential effect on high-risk body fat depots, we did a randomised, placebo-controlled, clinical trial to assess the effects of liraglutide 3⋅0 mg daily on visceral and ectopic fat in adults with overweight or obesity without type 2 diabetes at high cardiovascular disease risk. GLP-1 is a polypeptide incretin hormone that induces glucose-dependent insulin secretion, reduces plasma glucagon concentrations, delays gastric emptying, and suppresses appetite. 20 Liraglutide is a GLP-1 receptor agonist approved at the 3⋅0 mg daily dose for chronic weight management in eligible patients with and without diabetes.21, 22, 23
Liraglutide probably modifies body fat distribution through a combination of mechanisms related to reduction in plasma glucagon, delayed gastric emptying, and appetite suppression via neuronal pathways. Previous studies have proposed mechanisms for the modulation of visceral adiposity and its effect on cardiovascular risk. Early hypotheses associated excess VAT with cardiovascular risk by means of impaired liver metabolism, which in turn contributes to impaired glucose tolerance and hypertriglyceridaemia.45 However, more recent studies suggest that an overactive hypothalamic-pituitary-adrenal axis might be the primary driver of an unfavourable cardiometabolic profile resulting in increased VAT and cardiovascular disease risk.46 Accumulation of VAT is also believed to result in increased circulating blood volume and systemic proatherogenic inflammatory factors and adipokines, which together translate to an increased risk of developing cardiovascular disease.9 In our study, although participants randomly assigned to placebo had, on average, modest reductions in weight and VAT, there was an increase in CRP and glucose concentrations during the study. In contrast, participants randomly assigned to liraglutide had a significant reduction in CRP and glucose concentrations. Liraglutide might therefore affect all of these aforementioned pathways mediated through its modulation of VAT given its diverse effects on glucose homeostasis, atherogenic lipids,42 neuromediated appetite suppression, and inflammation.47
Interpretation
In adults with overweight or obesity at high cardiovascular disease risk, once-daily liraglutide 3⋅0 mg plus lifestyle intervention significantly lowered visceral adipose tissue over 40 weeks of treatment. Visceral fat reduction may be one mechanism to explain the benefits seen on cardiovascular outcomes in previous trials with liraglutide among patients with type 2 diabetes.
Liraglutide at a once-daily dose of 3⋅0 mg, when used as an adjunct to a reduced-calorie diet and increased physical activity counselling, resulted in significantly lower visceral and ectopic fat over a median 36 weeks on treatment compared with placebo in a population of adults with overweight and obesity at high cardiovascular disease risk. The relative effects of liraglutide on fat reduction were two times greater in the abdominal viscera and six times greater in the liver than seen on overall bodyweight. The treatment effect was consistent across race-ethnicity and baseline BMI categories, and among those with or without baseline prediabetes. Liraglutide also reduced fasting blood glucose and C-reactive protein in the trial population without diabetes, the majority of whom had normoglycaemia at baseline.
Liraglutide treatment also significantly reduced weight, BMI, waist circumference, total body fat, abdominal SAT, lower body SAT, liver fat, total body lean tissue, fasting blood glucose, and CRP compared with placebo (appendix p 7).
Taken together, although our study was not designed to directly examine the associations between liraglutide-mediated visceral adipose tissue loss, changes in biomarkers, and risk for cardiovascular disease events, our findings suggest that reductions in visceral fat and hepatic fat could be mechanisms underpinning the cardiovascular disease risk benefit that has been seen with liraglutide in patients with type 2 diabetes. Given the emerging recognition of visceral and ectopic fat as important cardiovascular risk factors, future pharmacological studies for weight loss should incorporate dedicated, gold-standard MRI imaging of visceral adipose tissue and liver fat as high-value, modifiable targets for obesity treatment.
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Effects of liraglutide on visceral and ectopic fat in adults with overweight and obesity at high cardiovascular risk: a randomised, double-blind, placebo-controlled, clinical trial
August 03, 2021
Summary
Background
Visceral and ectopic fat are key drivers of adverse cardiometabolic outcomes in obesity. We aimed to evaluate the effects of injectable liraglutide 3⋅0 mg daily on body fat distribution in adults with overweight or obesity without type 2 diabetes at high cardiovascular disease risk.
Methods
In this randomised, double-blind, placebo-controlled, phase 4, single centre trial, we enrolled community-dwelling adults, recruited from the University of Texas Southwestern Medical Center, with BMI of at least 30 kg/m2 or BMI of at least 27 kg/m2 with metabolic syndrome but without diabetes and randomly assigned them, in a 1:1 ratio, to 40 weeks of treatment with once-daily subcutaneous liraglutide 3⋅0 mg or placebo, in addition to a 500 kcal deficient diet and guideline-recommended physical activity counselling. The primary endpoint was percentage reduction in visceral adipose tissue (VAT) measured with MRI. All randomly assigned participants with a follow-up imaging assessment were included in efficacy analyses and all participants who received at least one dose of study drug were included in the safety analyses. The trial is registered on ClinicalTrials.gov: NCT03038620.
Findings
Between July 20, 2017 and Feb 21, 2020 from 235 participants assessed for eligibility, 185 participants were randomly assigned (n=92 liraglutide, n=93 placebo) and 128 (n=73 liraglutide, n=55 placebo) were included in the final analysis (92% female participants, 37% Black participants, 24% Hispanic participants, mean age 50⋅2 years (SD 9⋅4), mean BMI 37⋅7 kg/m2).
Mean change in VAT over median 36⋅2 weeks was -12⋅49% (SD 9⋅3%) with liraglutide compared with -1⋅63% (SD 12⋅3%) with placebo, estimated treatment difference -10⋅86% (95% CI -6⋅97 to -14⋅75, p<0⋅0001).
Effects seemed consistent across subgroups of age, sex, race-ethnicity, BMI, and baseline prediabetes. The most frequently reported adverse events were gastrointestinal-related (43 [47%] of 92 with liraglutide and 12 [13%] of 93 with placebo) and upper respiratory tract infections (10 [11%] of 92 with liraglutide and 14 [15%] of 93 with placebo).
Interpretation
In adults with overweight or obesity at high cardiovascular disease risk, once-daily liraglutide 3⋅0 mg plus lifestyle intervention significantly lowered visceral adipose tissue over 40 weeks of treatment. Visceral fat reduction may be one mechanism to explain the benefits seen on cardiovascular outcomes in previous trials with liraglutide among patients with type 2 diabetes.
Compared with placebo, liraglutide treatment also significantly reduced the secondary endpoints of total body fat, abdominal SAT, lower body SAT, liver fat, and total body lean tissue (table 2). Similar findings were seen when absolute changes in body composition and fat distribution were examined (table 2). Changes in weight were most highly correlated with changes in total body fat and abdominal SAT, and less so with VAT and liver fat (appendix p 4). Liraglutide also significantly reduced fasting blood glucose and CRP compared with placebo, but there were no significant differences in fasting insulin, triglyceride:HDL-C ratio, or NT-proBNP concentrations between the liraglutide and placebo treated groups (table 3). Weight loss and reduction in all fat depots were significantly correlated with reductions in fasting blood glucose and CRP, but not with fasting insulin or NT-proBNP. Reduction in CRP was most highly correlated with VAT loss. Only reduction in hepatic fat was significantly correlated with reduction in triglyceride:HDL-C ratio (appendix p 5).
Median follow-up time on treatment was 36⋅2 (IQR 8⋅4) weeks with no significant difference observed in follow-up time on treatment between liraglutide and placebo treated groups (36⋅2 vs 36⋅1 weeks, p=0⋅71). In addition to guideline recommended diet and physical activity counselling during the trial period, liraglutide significantly reduced weight (-5⋅40%, 95% CI -3⋅74 to -7⋅01, p<0⋅0001), BMI (kg/m2; -5⋅45%, 95% CI -3⋅75 to -7⋅15, p<0⋅0001), and waist circumference (-2⋅74%, 95% CI -0⋅56 to -4⋅92, p=0⋅021) compared with placebo (table 2 and appendix pp 9-11). In post-hoc analyses, a higher proportion of participants in the liraglutide versus placebo group achieved weight loss of at least 5% (63⋅0% vs 21⋅8%) or 10% (19⋅2% vs 3⋅6%), p less than 0⋅0001 for both (table 2).
Funding
NovoNordisk.
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