Pharmacogenomics of GLP1 Receptor Agonists

NCT05762744 | Terminated Phase 1 Results FDA Drug

• 1 other identifier: HP-00067574
• Study Type: interventional
• Target: 63
• Locations: 1 country
• Sites: 1

Brief Summary

Healthy volunteers were recruited from the Old Order Amish population in Lancaster County, Pennsylvania. After providing informed consent, research participants were screened for eligibility. The clinical trial was designed as a randomized crossover study in which participants underwent two frequently sampled intravenous glucose tolerance tests - one after receiving a subcutaneous injection of saline and one after receiving a subcutaneous injection of rapid-acting exenatide (BYETTA). The study sought to determine whether genetic variants are associated with the magnitude of the effect of exenatide. However, because the study fell far short of its recruitment targets, it was under-powered to evaluate genetic association. Thus, the data analysis focused on testing the hypothesis that the order of testing (whether the placebo FSIGT was conducted before the exenatide-stimulated FSIGT or whether the FSIGTs were conducted in the reverse order) does not alter the magnitude impact of exenatide on responses to a frequently sampled iv glucose tolerance test.

Conditions

Type 2 Diabetes

Keywords

GLP1; insulin; glucose; exenatide; GLP1 receptor agonist; insulin secretion; glucagon receptor; GIP receptor

Outcome Measures

Primary Outcomes (2)

• Exenatide Effect on First Phase Insulin Secretion

  The ratio of the area-under-the-curve (AUC) for 1st phase insulin secretion in the exenatide-stimulated FSIGT divided by the AUC for 1st phase insulin secretion in the saline FSIGT.

  0-10 minutes

• Exenatide Effect on Glucose Disappearance Rate

  The ratio of the glucose disappearance rate (exenatide) divided by the glucose disappearance rate (placebo). Glucose disappearance rates were calculated as the slope of the plot of the logarithm of the glucose concentration as a function of time.

  25-50 minutes

Secondary Outcomes (6)

• Glucose Disappearance Rate (Exenatide)

  25-50 minutes

• Glucose Disappearance Rate (Placebo)

  25-50 minutes

• First Phase Insulin Secretion (Exenatide)

  0-10 minutes

• First Phase Insulin Secretion (Placebo)

  0-10 minutes

• Drug Effect on First-Phase Insulin Secretion (Genotype-specific)

  0 - 10 min during the FSIGT

Study Arms (2)

Exenatide followed by saline

OTHER

Participants were randomized to receive exenatide 15 min before the first frequently sampled iv glucose tolerance test and saline 15 min before the second frequently sampled iv glucose tolerance test

Drug: Exenatide Injection (before the first FSIGT)

Saline followed by exenatide

OTHER

Participants were randomized to receive saline15 min before the first frequently sampled iv glucose tolerance test and exenatide15 min before the second frequently sampled iv glucose tolerance test

Drug: Exenatide injection before the second FSIGT)

Interventions

Exenatide Injection (before the first FSIGT) DRUG

Nurses administered exenatide (5 mcg) subcutaneously 15 minutes prior to conducting the first frequently sampled intravenous glucose tolerance test. In this crossover study, participants will also be "crossed over" to receive saline rather than exenatide: Nurses administered saline (0.2 mL) subcutaneously 15 minutes prior to conducting a frequently sampled intravenous glucose tolerance test.

Also known as: BYETTA, Exenatide

Exenatide followed by saline

Exenatide injection before the second FSIGT) DRUG

Nurses administered exenatide (5 mcg) subcutaneously 15 minutes prior to conducting the second frequently sampled intravenous glucose tolerance test.

Also known as: BYETTA, Exenatide

Saline followed by exenatide

Eligibility Criteria

• Age: 18 Years+
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Member of the Old Order Amish community in Lancaster County, Pennsylvania
• BMI: 18-40 kg/sq.m.

You may not qualify if:

• Known allergy to exenatide
• History of diabetes, random glucose \>200 mg/dL, or HbA1c \> 6.5%
• Significant debilitating chronic cardiac, hepatic, pulmonary, or renal disease or other diseases that the investigator judges will make interpretation of the results difficult or increase the risk of participation
• Seizure disorder
• Pregnant by self-report or known pregnancy within 3 months of the start of study
• Currently breast feeding or breast feeding within 3 months of the start of the study
• Estimated glomerular filtration rate \<60 mL/min/1.73m2
• Hematocrit \<35%
• Liver function tests greater than 2 times the upper limit of normal
• Abnormal thyroid stimulating hormone
• History of pancreatitis or pancreatic cancer. Personal or family history of medullary carcinoma of the thyroid.

Sponsors & Collaborators

• University of Maryland, Baltimore: lead

Study Sites (1)

Amish Research Clinic

Lancaster, Pennsylvania, 17602, United States

Location

Related Publications (2)

• Taylor SI, Montasser ME, Yuen AH, Fan H, Yazdi ZS, Whitlatch HB, Mitchell BD, Shuldiner AR, Muniyappa R, Streeten EA, Beitelshees AL. Acute pharmacodynamic responses to exenatide: Drug-induced increases in insulin secretion and glucose effectiveness. Diabetes Obes Metab. 2023 Sep;25(9):2586-2594. doi: 10.1111/dom.15143. Epub 2023 Jun 1.

  PMID: 37264484 BACKGROUND

• Beitelshees AL, Streeten EA, Shahidzadeh Yazdi Z, Whitlatch HB, Mitchell BD, Shuldiner AR, Montasser ME, Taylor SI. Acute pharmacodynamic responses to sitagliptin: Drug-induced increase in early insulin secretion in oral glucose tolerance test. Clin Transl Sci. 2024 May;17(5):e13809. doi: 10.1111/cts.13809.

  PMID: 38700326 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Insulin Resistance

Interventions

Exenatide

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Hyperinsulinism

Intervention Hierarchy (Ancestors)

Peptides; Amino Acids, Peptides, and Proteins; Venoms; Complex Mixtures; Toxins, Biological; Biological Factors

Limitations and Caveats

The study was terminated before achieving the recruitment targets of 24 participants for each genotype group. Thus, the study was under-powered. The data analysis tested the null hypothesis that the order in which participants received exenatide or normal saline does not affect the response to a frequently sampled intravenous glucose tolerance test. The database is too small to permit meaningful analysis of the incidence of relatively minor adverse events (headaches, nausea, and vomiting).

Results Point of Contact

• Title: Simeon Taylor, MD, PhD (Professor of Medicine0
• Organization: University of Maryland School of Medicine

staylor2@som.umaryland.edu

4107066439

Study Officials

• Simeon I Taylor, MD

  University of Maryland, Baltimore

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: Participants were not informed whether the nurse was administering saline or exenatide injections.
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Model Details: Research participants all received the same two interventions (saline or exenatide) but the order of the interventions was randomized.

Study Record Dates

• First Submitted: February 23, 2023
• First Posted: March 10, 2023
• Study Start: June 1, 2016
• Primary Completion: November 30, 2018
• Study Completion: October 31, 2022
• Last Updated: July 1, 2025
• Results First Posted: July 1, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: ICF
• Time Frame: 12 months after publication in a peer reviewed journal.
• Access Criteria: Must sign data transfer agreement to protect confidentiality of research participants. Requester must be on faculty at an accredited academic institution such as a medical school.

Locations

US (1)