Genetics Disease, Type2 Diabetes, Heart Failure
Conditions
Keywords
genetics, sitagliptin, DPP4 inhibition, heart failure, type 2 diabetes
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 (heterozygous for DPP4 loss of function variant) and 10 controls.
Interventions
Sitagliptin will be administered daily for 7 days, with a study day on day 7.
DRUGPlacebo Oral Tablet
Placebo will be administered daily for 7 days, with a study day on day 7.
Sponsors
University of Pennsylvania
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Neither subjects, nor the investigator or key study personnel will know drug randomization until after data analyses are completed.
Intervention model description
blinded 2:2 crossover, placebo-controlled
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dipeptidyl peptidase 4 (DPP4) | during study days 1 and 2 | DPP4 activity and antigen concentration |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disposition index | Calculated from samples collected before the meal and for 4 hours after (t=-15 through t=240 min) on study days 1 and 2 | 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 | Before the meal and for 4 hours after (t=-15 through t=240 min) on study days 1 and 2 | Measured via an automated blood pressure cuff approximately every 15 minutes |
| Glucagon-like peptide-1 (GLP-1) | Before the meal and for 4 hours after (t=-15 through t=240 min) on study days 1 and 2 | 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. |
| Glucose Area Under the Curve | Before the meal and for 4 hours after (t=-15 through t=240 min) on study days 1 and 2 | 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. |
| Surrogate markers of lipolysis | Before the meal and for 4 hours after (t=-15 through t=240 min) on study days 1 and 2 | Triglycerides, free fatty acids; We will collect samples at least six time points after the meal. |
| Mean heart rate | Before the meal and for 4 hours after (t=-15 through t=240 min) on study days 1 and 2 | Measured via an automated blood pressure cuff approximately every 15 minutes |
| CD26 | Before the meal or at baseline (t=-15 or -1 min) on study days 1 and 2 | CD26 is DPP4 on T cells and monocytes. |
Countries
United States
Outcome results
None listed