Longer‐term liraglutide administration at the highest dose approved for obesity increases reward‐related orbitofrontal cortex activation in response to food cues: Implications for plateauing weight loss in response to anti‐obesity therapies

Abstract

Aims GLP‐1 analogs have recently risen to the forefront as effective medications for lowering weight through actions in the central nervous system (CNS). However, their actions in the CNS have not yet been studied in the human brain after longer‐term administration at the highest dose approved for obesity (liraglutide 3.0 mg). Materials and Methods A total of 20 participants with obesity were treated with placebo and liraglutide (3.0 mg) in the context of a randomized, placebo‐controlled, double‐blind, cross‐over trial after 5 weeks of dose escalation. Neurocognitive and neuroimaging (fMRI) responses to food cues were examined at the clinical research center of Beth Israel Deaconess Medical Center. Results While using liraglutide, patients lost more weight (placebo‐subtracted −2.7%; P < .001), had decreased fasting glucose (P < .001) and showed improved cholesterol levels. In an uncontrolled analysis, brain activation in response to food images was not altered by liraglutide vs placebo. When controlled for BMI/weight, liraglutide increased activation of the right orbitofrontal cortex (OFC) in response to food cues (P < .016, corrected for multiple comparisons). Conclusions In contrast to prior studies, we demonstrate for the first time that liraglutide treatment, administered over a longer period at the highest doses approved for obesity, does not alter brain activation in response to food cues. A counter‐regulatory increase in reward‐related OFC activation in response to food cues can be observed when neuroimaging data are controlled for BMI changes, indicating changes in CNS that could lead to later plateaus of weight loss. These data point to a promising focus for additional interventions which, by contributing to the CNS reward system, could provide tangible benefits in reversing the plateauing phenomenon and promoting further weight loss.

Short-term treatment with high dose liraglutide improves lipid and lipoprotein profile and changes hormonal mediators of lipid metabolism in obese patients with no overt type 2 diabetes mellitus: a randomized, placebo-controlled, cross-over, double-blind clinical trial

“…No differences were detected between the groups in heart rate (bpm), systolic and diastolic blood pressures (mmHg) ( p = 0.61, 0.37 and 0.44 respectively) [3].…”

“…A randomized, placebo-controlled, cross-over, double-blind study was conducted in order to examine whether liraglutide 3 mg influences mechanisms underlying obesity and its comorbidities and identify target metabolites [3]. The study was performed in Beth Israel Deaconess Medical Center (BIDMC) MA, USA, with prior approval of Institutional Review Board (IRB) from 2016 till 2018.…”

“…Liraglutide is a long-acting glucagon-like peptide (GLP) 1 receptor agonist (GLP-1RA) originally approved for treatment of type 2 diabetes mellitus at doses up to 1.8 mg and later for treatment of obesity at higher doses up to 3 mg daily [1, 2]. In general, liraglutide is known to be well-tolerated and the most common side effect is transient nausea [3, 4]. Liraglutide (at 1.8 mg) reduces the frequency of cardiovascular events and improves all-cause and cardiovascular mortality in patients with type 2 diabetes at high risk for cardiovascular disease (CVD) [5] and is currently under investigation among patients without diabetes.…”

Treatment of overweight and obesity during and after a pandemic. Let’s not wait for the development of complications – new guidelines for doctors

“…Isolated studies suggesting an effect of liraglutide on the reward system come from animal studies. In a study using functional magnetic resonance imaging in a group of 20 patients treated for five weeks with liraglutide 5.0 mg or placebo no differences in the response of reward system areas to food images were found between the study groups [29]. The choice of the combination of bupropion and naltrexone as the first-line drug proposed in this document and liraglutide as the second-line drug is not a common recommendation in many existing documents and expert group positions.…”

Can GLP-1 Be a Target for Reward System Related Disorders? A Qualitative Synthesis and Systematic Review Analysis of Studies on Palatable Food, Drugs of Abuse, and Alcohol

“…Short-term liraglutide administration in T2DM patients increased GLP-1, gastrointestinal peptide (GIP), and decreased percent change of leptin levels (Farr et al, 2016b ). Liraglutide, when administered for a more extended period (5 weeks) at the highest dose, increased OFC activation to food vs. non-food cues when corrected for BMI/weight in obese patients (Farr et al, 2019 ). These results further support ten Kulve (Jennifer et al, 2016 ) as longer-term treatments of GLP-1 failed to reach significance in the weight loss process (ten Kulve et al, 2016 ).…”