Effects of Sitagliptin in Individuals With Genetically Decreased DPP4

Study Overview
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Brief Summary
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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
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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.

Official Title
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Effects of Sitagliptin in Individuals With Genetically Decreased DPP4

Conditions
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Genetics Disease, Type2 Diabetes, Heart Failure

Intervention / Treatment
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* Drug: Sitagliptin 100mg
* Drug: Placebo Oral Tablet


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: blinded 2:2 crossover, placebo-controlled
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Crossover AB<br>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. | Drug: Sitagliptin 100mg<br>* Sitagliptin will be administered daily for 7 days, with a study day on day 7.<br>* Other names: Januvia;Drug: Placebo Oral Tablet<br>* Placebo will be administered daily for 7 days, with a study day on day 7.<br>|
| Other: Crossover BA<br>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. | Drug: Sitagliptin 100mg<br>* Sitagliptin will be administered daily for 7 days, with a study day on day 7.<br>* Other names: Januvia;Drug: Placebo Oral Tablet<br>* Placebo will be administered daily for 7 days, with a study day on day 7.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dipeptidyl peptidase 4 (DPP4) | DPP4 activity and antigen concentration | during study days 1 and 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Before the meal and for 4 hours after (t=-15 through t=240 min) on study days 1 and 2 | 
| 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. | Before the meal (t=-15 or -1 min) on study days 1 and 2 | 
| 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. | Calculated from samples collected before the meal and for 4 hours after (t=-15 through t=240 min) on study days 1 and 2 | 
| Mean blood pressure | Measured via an automated blood pressure cuff approximately every 15 minutes | Before the meal and for 4 hours after (t=-15 through t=240 min) on study days 1 and 2 | 
| 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. | Before the meal and for 4 hours after (t=-15 through t=240 min) on study days 1 and 2 | 
| CD26 | CD26 is DPP4 on T cells and monocytes. | Before the meal or at baseline (t=-15 or -1 min) on study days 1 and 2 | 
| Surrogate markers of lipolysis | Triglycerides, free fatty acids; We will collect samples at least six time points after the meal. | Before the meal and for 4 hours after (t=-15 through t=240 min) on study days 1 and 2 | 
| Mean heart rate | Measured via an automated blood pressure cuff approximately every 15 minutes | Before the meal and for 4 hours after (t=-15 through t=240 min) on study days 1 and 2 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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genetics, sitagliptin, DPP4 inhibition, heart failure, type 2 diabetes