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. If an association were identified, this would help physicians to predict whether an individual patient is likely to have a large response to the class of diabetes drugs to which exenatide belongs (GLP1 receptor agonists).

Study Overview

• Status: Terminated
• Conditions: Type 2 Diabetes
• Intervention / Treatment: Drug: Exenatide Injection; Drug: Saline injection

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. If an association were identified, this would help physicians to predict whether an individual patient is likely to have a large response to the class of diabetes drugs to which exenatide belongs (GLP1 receptor agonists).

• Study Type: Interventional
• Enrollment (Actual): 78
• 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
• Genders Eligible for Study: All

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 TSH
• 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

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Homozygous for major alleles of GCGR and GIPR; Based on data in a genotype database, these individuals were homozygous for the "wild type" major alleles of both GCGR and GIPR.	Drug: Exenatide Injection; Nurses administered exenatide (5 mcg) subcutaneously 15 minutes prior to conducting a frequently sampled intravenous glucose tolerance test.; Other Names: BYETTA; Drug: Saline injection; Nurses administered saline (0.2 mL) subcutaneously 15 minutes prior to conducting a frequently sampled intravenous glucose tolerance test.
Other: Homozygous for missense variant in GIPR; Based on data in a genotype database, these individuals were homozygous for rs1800437 a missense variant (p.E354Q) in the GIP receptor gene (GIPR).	Drug: Exenatide Injection; Nurses administered exenatide (5 mcg) subcutaneously 15 minutes prior to conducting a frequently sampled intravenous glucose tolerance test.; Other Names: BYETTA; Drug: Saline injection; Nurses administered saline (0.2 mL) subcutaneously 15 minutes prior to conducting a frequently sampled intravenous glucose tolerance test.
Other: Homozygous for missense variant in GCGR; Based on data in a genotype database, these individuals were homozygous for rs1801483a missense variant (p.G40S) in the glucagon receptor gene (GCGR).	Drug: Exenatide Injection; Nurses administered exenatide (5 mcg) subcutaneously 15 minutes prior to conducting a frequently sampled intravenous glucose tolerance test.; Other Names: BYETTA; Drug: Saline injection; Nurses administered saline (0.2 mL) subcutaneously 15 minutes prior to conducting a frequently sampled intravenous glucose tolerance test.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
Exenatide effect on first phase insulin secretion	The difference between the logarithm of first phase insulin secretion (exenatide) minus the logarithm of the first phase insulin secretion (placebo)	0-10 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	25-50 minutes
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	25-50 minutes
Exenatide effect on glucose disappearance rate	The difference between glucose disappearance rate (exenatide) minus glucose disappearance rate (placebo)	25-50 minutes

Collaborators and Investigators

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

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 (Estimate): March 10, 2023

Study Record Updates

• Last Update Posted (Estimate): March 10, 2023
• Last Update Submitted That Met QC Criteria: March 6, 2023
• Last Verified: March 1, 2023

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: Hypoglycemic Agents; Physiological Effects of Drugs; 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