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.

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.

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

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

Deidentified data will become available upon completion of the pilot study

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