Pharmacogenetics of Response to GLP1R Agonists (PORT)

Overweight/obese otherwise healthy volunteers will be recruited from the Old Order Amish population in Lancaster County, PA. Lancaster County, PA. Pharmacodynamic responses to GLP1R agonist will be assessed by conducting frequently sampled intravenous glucose tolerance tests (FSIGT) both before and after semaglutide for six weeks. The proposal proposes two specific aims:

1. Specific Aim #1. To identify genetic variants associated with effects of a GLP1R agonist to enhance glucose-stimulated first phase insulin secretion in the two FSIGTs (before and after administration of drug).
2. Specific Aim #2. To identify genetic variants associated with the effect of a GLP1R agonist to accelerate the rate of glucose disappearance as assessed in the two FSIGTs (before and after administration of drug).

Genotyping will be conducted using a high-density array with comprehensive coverage of DNA sequence variants. In addition, the analysis will leverage a global imputation panel generated from 1,025 Amish individuals.

Study Overview

• Status: Recruiting
• Conditions: Obesity; Diabetes Type 2
• Intervention / Treatment: Drug: Semaglutide Pen Injector [Ozempic]

Detailed Description

Overweight/obese otherwise healthy volunteers will be recruited from the Old Order Amish population in Lancaster County, PA. In order to assess pharmacodynamic responses, research participants will undergo two frequently sampled intravenous glucose tolerance tests (FSIGT). The first FSIGT will be conducted at baseline prior to administration of drug. The second FSIGT will be conducted after six weeks of treatment with semaglutide (0.25 mg/wk X 4 wks; 0.5 mg/sk X 2 wks). The proposal proposes two specific aims:

• Specific Aim #1. To identify genetic variants associated with effects of a GLP1R agonist to enhance glucose-stimulated first phase insulin secretion in the two FSIGTs (before and after administration of drug).
• Specific Aim #2. To identify genetic variants associated with the effect of a GLP1R agonist to accelerate the rate of glucose disappearance as assessed in the two FSIGTs (before and after administration of drug).

After being determined to be eligible and after having given informed consent, participants will undergo two frequently samples intravenous glucose tolerance tests conducted at two clinic visits as described below:

Visit #1 - Research participants will be transported to the Amish Research clinic in the fasting state (minimum of 8 hour, maximum of 24 hour fast) where height, weight, waist and hip measurements, and vital signs will be measured. Women of child-bearing potential will undergo a urine pregnancy test. An FSIVGTT will be conducted as follows: IV (intravenous) access will be established in both arms of the research participant, one for glucose infusion and the other for frequent blood sampling. NSS (normal saline solution) will be used to maintain patency of IV. Intravenous glucose (0.3 g/kg) will be infused over 2 min at time=0, and 31 blood samples will be obtained between -15 and +180 minutes. Approximately 180 ml (36 tsp.) of blood will be drawn. Upon completion of the FSIVGTT, the participant will be instructed in the self-administration of subcutaneous (s.c.) injection of semaglutide. The first dose of semaglutide .25mg will be administered at this time. The participant will be provided with a post-fasting meal.

Home self-administration of weekly semaglutide: The participant will self-administer s.c. semaglutide weekly for 5 weeks (.25 mg for weeks 2,3,4 and .5 mg for weeks 5,6) A research nurse may observe the participant self-administering the first home dose and will make additional home visits as needed to ensure successful self-injection. The participant will use the study provided scale to obtain and record daily weights in the morning before breakfast throughout the medication weeks.

Visit #2 - This visit will be scheduled within 1 week of the final (6th) dose of semaglutide +/- 5 days. The FSIVGTT will be conducted exactly as during the previous clinic visit.

Genotyping will be conducted using a high-density array with comprehensive coverage of DNA sequence variants. The project will leverage a global imputation panel generated from whole genome sequence data on ~ 100K subjects including 1,025 Amish individuals obtained through the NHLBI-sponsored Trans-Omics for Precision Medicine (TOPMed) program.

• Study Type: Interventional
• Enrollment (Estimated): 600
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Amber L Beitelshees, PharmD; Phone Number: (410)706-0118; Email: abeitels@som.umaryland.edu
• Study Contact Backup: Name: Simeon I Taylor, MD, PhD; Phone Number: (410)706-6439; Email: staylor2@som.umaryland.edu

Study Locations

• United States
  • Pennsylvania
    • Lancaster, Pennsylvania, United States, 17602
      • Recruiting
      • Amish Research Clinic
      • Contact: Susan Shaub, RN; Phone Number: 717-392-4948; Email: sshaub@som.umaryland.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 89 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• BMI greater than or equal to 27 kg/m2
• Of Amish Descent

Exclusion Criteria:

• Woman of childbearing age who is sexually active
• History of diabetes (HbA1c > 6.5% or random glucose >200 mg/dL)
• Known allergy to semaglutide
• Medical issues, which in the judgment of the research physician or PIs might increase the risk associated with participation in the study
• eGFR < 60 mL/min/1.73 sq. m.
• Hematocrit < 35%
• TSH < 0.4 o4 > 5.5
• AST or ALT in excess of 2X the upper limit of normal
• Unable to discontinue a drug, vitamin, or nutritional supplement, which in the judgment of the research physician or PIs might alter the response to semaglutide
• Personal or family history of medullary carcinoma of the thyroid or multiple endocrine neoplasia, type 2

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Open label administration of semaglutide; Semaglutide: 0.25 mg, sc, q.week for 4 weeks followed by 0.5 mg, sc, q.week for 2 weeks	Drug: Semaglutide Pen Injector [Ozempic]; Participants will receive subcutaneously injected semaglutide (0.25 mg/wk) for 4 weeks followed by semaglutide (0.5 mg/wk) for an additional two weeks.; Other Names: Ozempic; Wegovy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
First phase insulin secretion	Area under the curve for plasma insulin levels measured at times between 0-10 min after administration of intravenous glucose (0.3 g/kg)	Measured both at baseline and after completing 6 weeks of semaglutide therapy
Second phase insulin secretion	Area under the curve for plasma insulin levels measured at times between 10-50 min after administration of intravenous glucose (0.3 g/kg)	Measured both at baseline and after completing 6 weeks of semaglutide therapy
Rate of glucose disappearance	Slope of the plot of log(glucose concentration) as a function of time. This will be calculated based on a linear regression using data points between 25-50 minutes after administration of intravenous glucose (0.3 g/kg)	Measured both at baseline and after completing 6 weeks of semaglutide therapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Weight loss	This will be measured as the baseline weight in kg minus the weight after completing 6 weeks of semaglutide therapy.	Assessed after completing 6 weeks of semaglutide therapy

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Insulin sensitivity (Si)	Estimated using Bergman's minimal model	Measured both at baseline and after completing 6 weeks of semaglutide therapy
Glucose effectiveness (Sg)	Estimated using Bergman's minimal model	Measured both at baseline and after completing 6 weeks of semaglutide therapy

Collaborators and Investigators

• Sponsor: University of Maryland, Baltimore
• Investigators: Principal Investigator: Amber L Beitelshees, PharmD, University of Maryland, Baltimore

Study record dates

Study Major Dates

• Study Start (Actual): April 11, 2022
• Primary Completion (Estimated): November 30, 2026
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: September 27, 2021
• First Submitted That Met QC Criteria: September 27, 2021
• First Posted (Actual): October 8, 2021

Study Record Updates

• Last Update Posted (Actual): June 7, 2023
• Last Update Submitted That Met QC Criteria: June 6, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Semaglutide; Insulin sensitivity; Pharmacogenomics; Insulin secretion; GLP-1 receptor agonist
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2
• Other Study ID Numbers: HP00097563

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Within the constraints of assuring confidentiality of research participants, we plan to share deidentified IPD within two years after the study investigators have published the results of the research.
• IPD Sharing Time Frame: Two years after PIs have published the results of the clinical trial
• IPD Sharing Access Criteria: Academic researchers who sign data sharing agreement to protect the confidentiality of the participants.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; 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