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A Randomized, placebo-controlled trial of the effects of Long-Acting GLP-1 or Dual Incretin (GLP-1 and GIP) Modulation on Gastrointestinal Functions and Relationship to Weight Loss

Award Number: R01DK142606
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2025
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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A Randomized, placebo-controlled trial of the effects of Long-Acting GLP-1 or Dual Incretin (GLP-1 and GIP) Modulation on Gastrointestinal Functions and Relationship to Weight Loss - ABSTRACT Obesity prevalence continues to increase in our country and worldwide. The incretins, GIP and GLP-1, facilitate disposal of ingested nutrients and lead to glucose-dependent insulin secretion or inhibition of glucagon secretion. Medications targeting these receptors are effective in inducing weight loss; however, they are frequently associated with gastrointestinal (GI) adverse events (AEs), particularly nausea, and possibly development of gastroparesis. We previously demonstrated that the daily-administered GLP-1 receptor agonist (GLP-1RA), liraglutide (3mg SQ), slowed gastric emptying of solids (GES) and induced mean weight loss of 5.6kg at 16 weeks. Among patients treated with liraglutide, 60% had documented GES T1/2 >174 minutes (“gastroparesis range”) at 5 weeks and 30% at 16 weeks, suggesting that tachyphylaxis occurs with continued treatment with the daily-administered GLP-1RA liraglutide. GLP-1RA treatment has been associated with risk of lung aspiration during endoscopy, suggesting clinically relevant slowing of GES. The overall hypothesis is that pharmacological incretin-based agents administered weekly, semaglutide (GLP-1RA) and tirazepatide (dual GLP-1 and GIP receptor agonist), significantly retard GES, but the effect on GES is heterogeneous, associated with tachyphylaxis, and may persist after cessation of treatment with these agents. Effects of the weekly administered semaglutide on GES beyond 4 weeks’ treatment is unknown. Tirzepatide administered for 4 weeks delayed GE of liquids; effects on GES are unknown. GES is more relevant for risk of pulmonary aspiration with these medications. The effects of semaglutide and tirzepatide on gastric functions (accommodation and emptying of solids) and on GES at 4 weeks after stopping these medications are unknown. We propose one specific hypothesis and aim in obese/overweight adults eligible for these medications. Hypothesis: Semaglutide or tirzepatide result in slowing of GES and increased satiation with considerable inter-individual heterogeneity and evidence of tachyphylaxis. Specific Aim: To compare effects of weekly SQ semaglutide 2.4mg SQ, SQ tirzepatide 10mg, and placebo administered for 24 weeks on GES measured repeatedly at baseline, 16 weeks, 24 weeks, 28 weeks, 4 weeks after stopping the medication, and accommodation and satiation at 24 weeks compared to baseline. Significance: Our study will document heterogeneity in the effects of semaglutide or tirzepatide on gastric motor functions and satiation, the potential for tachyphylaxis in the effect on GES or the persistence in slowing of GES after stopping treatment. This pilot trial will also provide initial data on the coefficient of variation of the effects on GES and satiation in response to the 2 drugs in order to develop the power statement for future clinical trial comparison of semaglutide and tirzepatide.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $322,800 )
2026	2026	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	4/9/2026	NON-COMPETING CONTINUATION	$322,800
														Subtotal = $322,800

Issue Date FY: 2025 ( Subtotal = $322,800 )
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	6/20/2025	NEW	$322,800
														Subtotal = $322,800

Grand Total All Awards = $645,600

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A Randomized, placebo-controlled trial of the effects of Long-Acting GLP-1 or Dual Incretin (GLP-1 and GIP) Modulation on Gastrointestinal Functions and Relationship to Weight Loss

Award Number: R01DK142606

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2025

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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