Quantitative gastrointestinal and psychological traits associated with obesity and response to weight-loss therapy

Abstract

Background & aims: Weight loss after pharmacotherapy varies greatly. We aimed to examine associations of quantitative gastrointestinal and psychological traits with obesity, and to validate the ability of these traits to predict responses of obese individuals to pharmacotherapy.

Methods: In a prospective study, we measured gastric emptying of solids and liquids, fasting and postprandial gastric volume, satiation by nutrient drink test (volume to fullness and maximal tolerated volume), satiety after an ad libitum buffet meal, gastrointestinal hormones, and psychological traits in 328 normal-weight, overweight, or obese adults. We also analyzed data from 181 previously studied adults to assess associations betwecen a subset of traits with body mass index and waist circumference. Latent dimensions associated with overweight or obesity were appraised by principal component analyses. We performed a proof of concept, placebo-controlled trial of extended-release phentermine and topiramate in 24 patients to validate associations between quantitative traits and response to weight-loss therapy.

Results: In the prospective study, obesity was associated with fasting gastric volume (P = .03), accelerated gastric emptying (P < .001 for solids and P = .011 for liquids), lower postprandial levels of peptide tyrosine tyrosine (P = .003), and higher postprandial levels of glucagon-like peptide 1 (P < .001). In a combined analysis of data from all studies, obesity was associated with higher volume to fullness (n = 509; P = .038) and satiety with abnormal waist circumference (n = 271; P = .016). Principal component analysis identified latent dimensions that accounted for approximately 81% of the variation among overweight and obese subjects, including satiety or satiation (21%), gastric motility (14%), psychological factors (13%), and gastric sensorimotor factors (11%). The combination of phentermine and topiramate caused significant weight loss, slowed gastric emptying, and decreased calorie intake; weight loss in response to phentermine and topiramate was significantly associated with calorie intake at the prior satiety test.

Conclusions: Quantitative traits are associated with high body mass index; they can distinguish obesity phenotypes and, in a proof of concept clinical trial, predicted response to pharmacotherapy for obesity. ClinicalTrials.gov Number: NCT01834404.

Keywords: BMI; Incretin; Phentermine; Satiety; Topiramate.

Figure 1

a) CONSORT flow chart for randomized controlled trial of effects of phentermine-topiramate-ER on weight loss and quantitative traits in obesity b) Study protocol for randomized controlled trial of effects of phentermine-topiramate-ER on weight loss and quantitative traits measured on days 12 to 14 of treatment

Figure 1

a) CONSORT flow chart for randomized controlled trial of effects of phentermine-topiramate-ER on weight loss and quantitative traits in obesity b) Study protocol for randomized controlled trial of effects of phentermine-topiramate-ER on weight loss and quantitative traits measured on days 12 to 14 of treatment

Figure 2

Upper panel: Relationship of kcal intake at prior ad-libitum meal and kcal intake in response to randomized treatment; note that there are significant associations in both treatment groups. Lower panel: Association of change in body weight (in response to randomized treatment with placebo or phentermine-topiramate-ER) and kcal intake at prior ad-libitum meal. Note the kcal intake at baseline prior to treatment is associated with the degree of weight loss on treatment with phentermine-topiramate-ER with no observed effect with placebo treatment. This is illustrated by p=0.029 for the drug treatment interaction.