Obesity prevalence continues to increase worldwide; 69% of U.S. adults are overweight or obese. Despite advances in understanding obesity pathophysiology, weight loss with current non-surgical treatments (diet and medications) is highly variable, and predictors of weight loss with obesity pharmacotherapy are unknown. In studies funded by RO1-DK67071 in 509 participants, obesity was associated with greater fasting gastric volume, accelerated gastric emptying (solids and liquids), lower postprandial peak plasma PYY, and greater calories consumed to achieve satiation (volume to fullness) and to evoke satiety with an ad-libitum meal. We showed that a short-acting GLP-1 agonist, exenatide, 5g, SQ, BID for 30 days, delays gastric emptying and induces weight loss. Thus, quantitative gastrointestinal (GI) traits are associated with higher BMI, distinguish obesity phenotypes, and may predict efficacy of obesity drug therapy. In the R56-DK67071-funded pilot randomized, placebo-controlled trial of the longer-acting GLP-1 agonist, liraglutide, 3mg, SQ daily, we showed: (a) feasibility to recruit and randomize, over 8 months, 30 patients into a 4-month study (only 2 dropouts on treatment, to date); (b) safety data in all 30 randomized patients; (c) baseline quantitative traits of gastric emptying of solids and liquids, fasting and postprandial gastric volumes; satiation and satiety data; postprandial plasma incretins (GLP-1 and PYY) in all randomized patients; (d) gastric emptying data at fully escalated dose of liraglutide (weeks 5-6) in 30 patients; (e) repeat measurement (as in c) of quantitative traits at 16 weeks' treatment in 28 patients; (f) monthly weight data for duration on treatment in 28 patients. Our overall hypothesis is that weight loss with pharmacological agents may be individualized, based on specific abnormalities in quantitative GI traits. We propose a randomized, controlled clinical and pharmacodynamics trial, using a 2-treatment stratified design, to assess the hypothesis that a quantitative trait (gastric emptying rate) can impact the weight loss response among overweight (BMI >27kg/m2 plus obesity co- morbidities) or obese (BMI >30kg/m2) patients to treatment with the FDA-approved GLP-1 receptor agonist, liraglutide (dose escalated to maximum of 3mg, SQ, per day for 12 weeks) compared to placebo. Effects will be compared for those with baseline accelerated in comparison with normal gastric emptying.
Our aims are: first, to assess the effects of liraglutide, 3mg/day, on gastric motor functions, satiation, satiety, weight loss and incretins; and second, to appraise the association of baseline accelerated gastric emptying on weight loss in response to liraglutide treatment. By measuring quantitative Gl traits at baseline and after 12 weeks of liraglutide treatment, we shall further understand the mechanism of action of this GLP-1 agonist. Significance: Our study addresses the treatment of obesity, introducing an era of individualizing drug therapy for obesity based on quantitative biomarkers. Therefore, it addresses an important public health challenge.

Public Health Relevance

/ Relevance Obesity is associated with differences in stomach function, feeling of fullness after meals, and total calories consumed at a buffet meal. Based upon previous research, our study hypothesis is that weight loss with pharmacological agents [e.g. liraglutide (SAXENDA)] may be individualized, based on the abnormality in those gastrointestinal functions (e.g. stomach emptying of solid food). These studies will provide support for the principle that specific obesity medications should be selected according to individual characteristics of people with obesity in order to enhance efficacy of medication treatment of obesity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK067071-15
Application #
9999560
Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Maruvada, Padma
Project Start
2004-09-30
Project End
2021-08-31
Budget Start
2020-09-01
Budget End
2021-08-31
Support Year
15
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Chedid, V; Vijayvargiya, P; Carlson, P et al. (2018) Allelic variant in the glucagon-like peptide 1 receptor gene associated with greater effect of liraglutide and exenatide on gastric emptying: A pilot pharmacogenetics study. Neurogastroenterol Motil 30:e13313
Camilleri, M (2018) Cannabinoids and gastrointestinal motility: Pharmacology, clinical effects, and potential therapeutics in humans. Neurogastroenterol Motil 30:e13370
Halawi, H; Vijayvargiya, P; Busciglio, I et al. (2018) Effects of naloxegol on whole gut transit in opioid-naïve healthy subjects receiving codeine: A randomized, controlled trial. Neurogastroenterol Motil 30:e13298
Chedid, Victor; Vijayvargiya, Priya; Camilleri, Michael (2018) Advantages and Limitations of the Federal Adverse Events Reporting System in Assessing Adverse Event Reporting for Eluxadoline. Clin Gastroenterol Hepatol 16:336-338
Chedid, Victor; Vijayvargiya, Priya; Halawi, Houssam et al. (2018) Audit of the diagnosis of rectal evacuation disorders in chronic constipation. Neurogastroenterol Motil :e13510
Acosta, Andres; Camilleri, Michael (2017) A working paradigm for the treatment of obesity in gastrointestinal practice. Tech Gastrointest Endosc 19:52-60
Camilleri, Michael; Malhi, Harmeet; Acosta, Andres (2017) Gastrointestinal Complications of Obesity. Gastroenterology 152:1656-1670
Camilleri, Michael; McCallum, Richard W; Tack, Jan et al. (2017) Efficacy and Safety of Relamorelin in Diabetics With Symptoms of Gastroparesis: A Randomized, Placebo-Controlled Study. Gastroenterology 153:1240-1250.e2
Nelson, A D; Camilleri, M; Acosta, A et al. (2016) Effects of ghrelin receptor agonist, relamorelin, on gastric motor functions and satiation in healthy volunteers. Neurogastroenterol Motil 28:1705-1713
Camilleri, Michael; Acosta, Andres (2016) Gastrointestinal traits: individualizing therapy for obesity with drugs and devices. Gastrointest Endosc 83:48-56

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