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Effects of Sitagliptin in Individuals With Genetically Decreased DPP4

Primary Purpose

Genetics Disease, Type2 Diabetes, Heart Failure

Status

Recruiting

Phase

Phase 4

Locations

United States

Study Type

Interventional

Intervention

Sitagliptin 100mg

Placebo Oral Tablet

About this trial

This is an interventional other trial for Genetics Disease focused on measuring genetics, sitagliptin, DPP4 inhibition, heart failure, type 2 diabetes

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Participant of the Penn Medicine Biobank who is willing to be recontacted to participate in future research.
Cases are defined as adults 18-70 years with likely decreased DPP4.
Controls are defined as adults who are matched to cases by: age, gender, race, BMI, hypertension status, diabetes status, renal function, and medication use that may affect outcomes of interest.

Exclusion Criteria:

The study will exclude volunteers with any significant medical conditions that may interfere with study participation, data interpretation, or pose safety risk(s) to the subject.
Recent hospitalization or acute illness such as infection within the past two weeks
Pregnancy
Use of insulin
Use of a GLP-1 agonist or DPP4 inhibitor medication
Use of oral diabetes agents other than metformin unless matched with controls
Type 1 diabetes
Chronic steroid use or use within the last 30 days
Significant liver disease including liver enzymes >3 x upper limit of normal range
Renal dysfunction defined as eGFR< 50mL/min/1.73m2
Significant cardiac disease such as heart transplantation
Significant gastrointestinal conditions that may interfere with drug absorption or GLP-1 release including bariatric surgery
Significant hematologic disease such as hematocrit <35%
Use of chronic anticoagulation
Severe pulmonary disease
Severe neurologic or psychiatric disease
Inability to comprehend study procedures

Sites / Locations

University of PennsylvaniaRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Other

Arm Label

Crossover AB

Crossover BA

Arm Description

Subjects in arm A will first receive placebo daily for 7 days in the first intervention followed by sitagliptin 100mg/d for 7 days in the crossover intervention.

Subjects in arm B will first receive sitagliptin 100mg/d for 7 days in the first intervention followed by placebo for 7 days in the crossover intervention.

Outcomes

Primary Outcome Measures

Dipeptidyl peptidase 4 (DPP4)

DPP4 activity and antigen concentration

Secondary Outcome Measures

Glucose Area Under the Curve

Glucose will be measured before after the mixed meal during sitagliptin and placebo. Area under the curve will be calculated based on at least 10 time points after the meal.

Intact DPP4 substrates with cardiovascular properties (other than GLP-1)

Cardiovascular biomarkers include: CXCL12, substance P, neuropeptide Y, and brain natriuretic peptide. These are peptides that are also DPP4 substrates and are rapidly inactivated by this peptidase.

Disposition index

Disposition index will be calculated from insulin sensitivity and insulin secretion. These variables will be computed using mathematical modeling of insulin and c-peptide. We will collect insulin and c-peptide at least 10 time points after the meal.

Mean blood pressure

Measured via an automated blood pressure cuff approximately every 15 minutes

Glucagon-like peptide-1 (GLP-1)

This is released in response to a meal and rapidly degraded by DPP4. We will collect samples for at least six time points after the meal.

CD26

CD26 is DPP4 on T cells and monocytes.

Surrogate markers of lipolysis

Triglycerides, free fatty acids; We will collect samples at least six time points after the meal.

Mean heart rate

Measured via an automated blood pressure cuff approximately every 15 minutes

Full Information

NCT ID

NCT04323189

First Posted

March 25, 2019

Last Updated

March 3, 2023

Sponsor

University of Pennsylvania

1. Study Identification

Unique Protocol Identification Number

NCT04323189

Brief Title

Effects of Sitagliptin in Individuals With Genetically Decreased DPP4

Official Title

Effects of Sitagliptin in Individuals With Genetically Decreased DPP4

Study Type

Interventional

2. Study Status

Record Verification Date

March 2023

Overall Recruitment Status

Recruiting

Study Start Date

August 26, 2020 (Actual)

Primary Completion Date

January 30, 2024 (Anticipated)

Study Completion Date

February 1, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University of Pennsylvania

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

This is a pilot clinical trial to test the hypothesis that during sitagliptin (DPP4 inhibitor), individuals heterozygous for DPP4 loss of function variants will have a reduction in DPP4 activity and antigen, lower glucose after a mixed meal, and higher levels of intact DPP4 substrates compared to during placebo and compared to matched controls.

Detailed Description

Participants of this pilot clinical trial will be randomized in a blinded 2:2 crossover manner to receive placebo and sitagliptin 100 mg/d (DPP4 inhibitor), in random order. Subjects will receive each intervention for seven days, with a study day on day 7. Each intervention will be separated by a 4-week washout period. Each subject will have up to four separate visits: 1) DXA, echocardiogram, 2) cardiac MRI, 3) mixed meal during placebo, 4) mixed meal during sitagliptin. The study will include 10 cases and 10 controls. Among these, there will be five heterozygous cases and five matched controls with elevated blood pressure (history of blood pressure 130/80 on more than one occasion or prior diagnosis of hypertension by a medical provider) and five cases and five controls without hypertension.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Genetics Disease, Type2 Diabetes, Heart Failure

Keywords

genetics, sitagliptin, DPP4 inhibition, heart failure, type 2 diabetes

7. Study Design

Primary Purpose

Other

Study Phase

Phase 4

Interventional Study Model

Crossover Assignment

Model Description

blinded 2:2 crossover, placebo-controlled

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Masking Description

Neither subjects, nor the investigator or key study personnel will know drug randomization until after data analyses are completed.

Allocation

Randomized

Enrollment

20 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Crossover AB

Arm Type

Other

Arm Description

Subjects in arm A will first receive placebo daily for 7 days in the first intervention followed by sitagliptin 100mg/d for 7 days in the crossover intervention.

Arm Title

Crossover BA

Arm Type

Other

Arm Description

Subjects in arm B will first receive sitagliptin 100mg/d for 7 days in the first intervention followed by placebo for 7 days in the crossover intervention.

Intervention Type

Drug

Intervention Name(s)

Sitagliptin 100mg

Other Intervention Name(s)

Januvia

Intervention Description

Sitagliptin will be administered daily for 7 days, with a study day on day 7.

Intervention Type

Drug

Intervention Name(s)

Placebo Oral Tablet

Intervention Description

Placebo will be administered daily for 7 days, with a study day on day 7.

Primary Outcome Measure Information:

Title

Dipeptidyl peptidase 4 (DPP4)

Description

DPP4 activity and antigen concentration

Time Frame

during study days 1 and 2

Secondary Outcome Measure Information:

Title

Glucose Area Under the Curve

Description

Glucose will be measured before after the mixed meal during sitagliptin and placebo. Area under the curve will be calculated based on at least 10 time points after the meal.

Time Frame

Before the meal and for 4 hours after (t=-15 through t=240 min) on study days 1 and 2

Title

Intact DPP4 substrates with cardiovascular properties (other than GLP-1)

Description

Cardiovascular biomarkers include: CXCL12, substance P, neuropeptide Y, and brain natriuretic peptide. These are peptides that are also DPP4 substrates and are rapidly inactivated by this peptidase.

Time Frame

Before the meal (t=-15 or -1 min) on study days 1 and 2

Title

Disposition index

Description

Time Frame

Calculated from samples collected before the meal and for 4 hours after (t=-15 through t=240 min) on study days 1 and 2

Title

Mean blood pressure

Description

Measured via an automated blood pressure cuff approximately every 15 minutes

Time Frame

Before the meal and for 4 hours after (t=-15 through t=240 min) on study days 1 and 2

Title

Glucagon-like peptide-1 (GLP-1)

Description

This is released in response to a meal and rapidly degraded by DPP4. We will collect samples for at least six time points after the meal.

Time Frame

Before the meal and for 4 hours after (t=-15 through t=240 min) on study days 1 and 2

Title

CD26

Description

CD26 is DPP4 on T cells and monocytes.

Time Frame

Before the meal or at baseline (t=-15 or -1 min) on study days 1 and 2

Title

Surrogate markers of lipolysis

Description

Triglycerides, free fatty acids; We will collect samples at least six time points after the meal.

Time Frame

Before the meal and for 4 hours after (t=-15 through t=240 min) on study days 1 and 2

Title

Mean heart rate

Description

Measured via an automated blood pressure cuff approximately every 15 minutes

Time Frame

Before the meal and for 4 hours after (t=-15 through t=240 min) on study days 1 and 2

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Participant of the Penn Medicine Biobank who is willing to be recontacted to participate in future research. Cases are defined as adults 18-70 years with likely decreased DPP4. Controls are defined as adults who are matched to cases by: age, gender, race, BMI, hypertension status, diabetes status, renal function, and medication use that may affect outcomes of interest. Exclusion Criteria: The study will exclude volunteers with any significant medical conditions that may interfere with study participation, data interpretation, or pose safety risk(s) to the subject. Recent hospitalization or acute illness such as infection within the past two weeks Pregnancy Use of insulin Use of a GLP-1 agonist or DPP4 inhibitor medication Use of oral diabetes agents other than metformin unless matched with controls Type 1 diabetes Chronic steroid use or use within the last 30 days Significant liver disease including liver enzymes >3 x upper limit of normal range Renal dysfunction defined as eGFR< 50mL/min/1.73m2 Significant cardiac disease such as heart transplantation Significant gastrointestinal conditions that may interfere with drug absorption or GLP-1 release including bariatric surgery Significant hematologic disease such as hematocrit <35% Use of chronic anticoagulation Severe pulmonary disease Severe neurologic or psychiatric disease Inability to comprehend study procedures

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Jessica R Wilson, MD, MS

Phone

(215) 898-3389

jessica.wilson3@uphs.upenn.edu

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Jessica R Wilson, MD, MS

Organizational Affiliation

University of Pennsylvania

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of Pennsylvania

City

Philadelphia

State/Province

Pennsylvania

ZIP/Postal Code

19104

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Jessica R Wilson, MD, MS

Phone

215-898-3389

jessica.wilson3@uphs.upenn.edu

First Name & Middle Initial & Last Name & Degree

Esther Oyerinde

esther.oyerinde@pennmedicine.upenn.edu

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

Results will be deidentified for outcomes of interest from this pilot study.

IPD Sharing Time Frame

Deidentified data will become available upon completion of the pilot study

Learn more about this trial

Effects of Sitagliptin in Individuals With Genetically Decreased DPP4

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