Pharmacogenomics of GLP1 Receptor Agonists

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.

Study Overview

• Status: Terminated
• Conditions: Type 2 Diabetes
• Intervention / Treatment: Drug: Exenatide Injection (before the first FSIGT); Drug: Exenatide injection before the second FSIGT)

Detailed Description

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 (FSIGT) - one after receiving a subcutaneous injection of saline and one after receiving a subcutaneous injection of rapid-acting exenatide (BYETTA). Based on data obtained from the FSIGT, participants' response to exenatide was assessed -- specifically, the effect of exenatide to enhance insulin secretion and accelerate metabolism of glucose. 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.

• Study Type: Interventional
• Enrollment (Actual): 63
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Lancaster, Pennsylvania, United States, 17602
      • Amish Research Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

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

Exclusion Criteria:

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Exenatide followed by saline; 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); 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.; Other Names: BYETTA; Exenatide
Other: Saline followed by exenatide; 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); Nurses administered exenatide (5 mcg) subcutaneously 15 minutes prior to conducting the second frequently sampled intravenous glucose tolerance test.; Other Names: BYETTA; Exenatide

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glucose Disappearance Rate (Exenatide)	The slope of the line plotting the logarithm of glucose concentrations as a function of time during the exenatide frequently sampled intravenous glucose tolerance test. The slope of the line was estimated as the slope of the least-squares fit to the data points between 25-50 minutes.	25-50 minutes
Glucose Disappearance Rate (Placebo)	The slope of the line plotting the logarithm of glucose concentrations as a function of time during the placebo frequently sampled intravenous glucose tolerance test. The slope of the line was estimated as the slope of the least-squares fit to the data points between 25-50 minutes.	25-50 minutes
First Phase Insulin Secretion (Exenatide)	The area under the curve for plasma insulin levels during a frequently sampled intravenous glucose tolerance test after participants received exenatide	0-10 minutes
First Phase Insulin Secretion (Placebo)	The area under the curve for plasma insulin levels during a frequently sampled intravenous glucose tolerance test after participants received saline	0-10 minutes
Drug Effect on First-Phase Insulin Secretion (Genotype-specific)	The effect of exenatide to increase first-phase insulin secretion was defined as the ratio of area-under-the-curve (AUC) for insulin levels during the first 10 minutes of the exenatide-stimulated FSIGT divided by the AUC for first phase insulin secretion during the saline FSIGT..	0 - 10 min during the FSIGT
Exenatide's Effect on the Rate of Glucose-disappearance (Genotype Specific)	The rate of glucose disappearance was calculated as the slope of a least-squared line fitted to the logarithms of glucose concentrations during time 25-50 min of FSIGTs	25-50 min during the FSIGT

Collaborators and Investigators

• Sponsor: University of Maryland, Baltimore
• Investigators: Principal Investigator: Simeon I Taylor, MD, University of Maryland, Baltimore

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2016
• Primary Completion (Actual): November 30, 2018
• Study Completion (Actual): October 31, 2022

Study Registration Dates

• First Submitted: February 23, 2023
• First Submitted That Met QC Criteria: March 6, 2023
• First Posted (Actual): March 10, 2023

Study Record Updates

• Last Update Posted (Estimated): July 1, 2025
• Last Update Submitted That Met QC Criteria: June 26, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: insulin; exenatide; insulin secretion; glucose; GLP1; glucagon receptor; GLP1 receptor agonist; GIP receptor
• Additional Relevant MeSH Terms: Glucagon-Like Peptide-1 Receptor Agonists; Physiological Effects of Drugs; Hypoglycemic Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Anti-Obesity Agents; Incretins; Exenatide
• Other Study ID Numbers: HP-00067574

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Subject to protection of confidential information of research participants, we will share data with qualified researchers.
• IPD Sharing Time Frame: 12 months after publication in a peer reviewed journal.

IPD Sharing 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.

• IPD Sharing Supporting Information Type: ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No