Behavioral and hormonal measures of hunger, satiety, and energy intake to predict weight-loss response to Liraglutide
Weight loss for treating obesity requires a sustained negative energy balance. Various pharmacological agents facilitate weight loss by helping reduce energy intake. Pharmacotherapy for obesity has limitations, and efficacy and safety profiles of obesity drugs vary. Therefore, predicting responders to drug treatment early on can avoid undue exposure of potential non-responders to drug side effects. This study was conducted to predict weight-loss response to anti-obesity drug liraglutide, an FDA-approved glucagon-like peptide-1 (GLP-1) receptor agonist that helps reduce food intake and promote weight loss. It is expected that subjective (visual analog scale [VAS] ratings) and objective (ad libitum intake and hunger and satiety hormones) measures of energy intake, hunger, and satiety work in consort with food cue reactivity in the brain to influence food intake, which in turn impacts weight and objective measures of energy intake, hunger, and satiety in response to liraglutide would predict weight loss and that responders to liraglutide (defined by at least 4% weight loss at 16 weeks) have stronger interplay between measures of hunger and satiety. This would strongly reduce food intake and, in turn, may induce greater weight loss. To test this, analysis of the interaction between measures of hunger and satiety with FCR in the brain and weight loss are needed. This study focused on the relationship between gut hormones, subjective measures of hunger and satiety, and food intake and weight loss. We tested this in a 16-week randomized, double-blind, placebo-controlled trial. Subjects with obesity (age 18-60 years; body mass index 30-50 kg/m2) were recruited via advertisement. Sixty-three individuals initiated the study. An initial 4-week dose escalation phase for liraglutide (or placebo) was followed by 12 weeks of maintenance of the therapeutic dose (3.0 mg). At baseline, week 4, and week 16, subjects attended testing sessions for functional magnetic resonance imaging-food cue reactivity (fMRI-FCR) scans. During the visit, they were offered a standardized breakfast and responded to VAS, provided blood samples for measuring hormone levels and other parameters at several timepoints and after an ad libitum lunch. Changes in body weight, hormonal (ghrelin, PYY, and GLP-1) response to food intake, and behavioral (ad libitum food intake and self-reported hunger/satiety assessed with VAS) responses from baseline to week 4 and baseline to week 16 were analyzed (while blinded to group allocation) using R statistical software and intention-to-treat with multiple imputation to handle missingness. Comparisons were performed using linear models (continuous outcomes) or logistic regression (binary outcomes), with analyses within imputations pooled into a single, final analysis using Rubin’s Rules. Sixty-three subjects were included in the intention-to-treat analysis. After 16 weeks, mean weight loss in the placebo group (n=30) was 3.1±5.9% (mean ± SEM) and -10.2±3.8% in the liraglutide group (n=33; p=0.326). Placebo or liraglutide group did not differ significantly in changes in area-under-the-curve (AUC) and area-under-the-curve correcting for the baseline value (cAUC) in VAS in baseline to week 4 and baseline to week 16 changes. Baseline to week 4 change in VAS, ad libitum lunch intake, and PYY, GLP-1, and ghrelin did not predict percent weight loss or responder status (at least 4% weight loss) at 16 weeks in the liraglutide group (all p>0.05). Sex (p=0.399), age (p=0.205), and initial BMI (from baseline scan visit; p=0.421) did not predict liraglutide responder status at 16 weeks. Liraglutide responders did not have significantly different baseline PYY, GLP-1, and ghrelin AUCs or cAUCs than non-responders (all p>0.05). There were no significant differences between responders and non-responders for baseline to week 4 and baseline to week 16 changes in PYY, GLP-1, and ghrelin (all p>0.05). We did not observe a statistically significant difference between placebo and liraglutide groups for measures of hunger and satiety, energy intake, and weight loss in this trial of 63 participants. This is expected because sample size calculations were based on observing FCR for those exposed to liraglutide and placebo and not for detecting differences in weight loss or weight-loss related subjective and objective measures of hunger and satiety between groups. The next phase of analyses will determine if FCR is linked to measures of hunger and satiety, energy intake, and weight-loss response. This collective interaction would be crucial for testing study hypotheses and for early prediction of responders to liraglutide treatment.
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