# Cardiometabolic effects of genetically decreased dipeptidyl peptidase-4 (DPP4)

> **NIH NIH K23** · MAYO CLINIC  JACKSONVILLE · 2022 · $54,000

## Abstract

Project Summary/Abstract
Cardiovascular disease is the leading cause of morbidity and mortality for patients with type 2 diabetes
(T2DM). Determining cardiovascular effects of T2DM therapies is of clinical importance. Human genetics
may be a strategy to provide insights to long-term effects of T2DM therapies and mechanisms linking T2DM
and cardiovascular risk. Dipeptidyl peptidase 4 (DPP4) inhibitors are used for the treatment of T2DM and
decrease degradation of substrates with possible metabolic or cardiovascular effects such as glucagon like
peptide-1 (GLP-1), neuropeptides, CXCL12, brain natriuretic peptide, and substance P. Although they have
the benefit of improving glucose dynamics through GLP-1 effects, DPP4 inhibitors are also associated with
increased risk of hospitalization for heart failure (such as during saxagliptin), potentially related to negative
effects of neuropeptides, CXCL12, and substance P. Long-term data on cardiovascular effects of DPP4
inhibition remain limited as the longest cardiovascular outcomes trial of DPP4 inhibitors was only three
years. Our preliminary data in among individuals in the Penn Medicine Biobank show that on gene burden
analysis for rare loss of function variants, DPP4 loss of function was significantly associated with heart
failure. Phenotyping individuals with DPP4 loss of function will provide further insights as to the possible
mechanism for this finding and long- term effects of decreased DPP4 activity and antigen in humans.
We hypothesize that genetic DPP4 loss of function will be associated with improved metabolic parameters
but also with heart failure and related biomarkers/ imaging. We will identify individuals in the Penn Medicine
Biobank and Mayo Clinic Biobank with DPP4 loss of function variants and their matched controls and recruit
them for a phenotyping study. We will also enroll participants in a pilot clinical trial to assess the response of
individuals heterozygous for DPP4 loss of function to pharmacologic DPP4 inhibition.
The candidate has a strong multi-disciplinary mentoring team with experts in patient oriented research,
genetics, endocrinology, cardiology (advanced heart failure), mathematical modeling/ biostatistics, and
metabolomics/ proteomics. The candidate will gain necessary skills and expertise during the award period in
the areas of: genetics, a genetic-based approach to clinical trials recruitment, mathematical modeling of
insulin sensitivity and insulin secretion, advanced biostatistics, and leadership skills. This will facilitate the
candidate in achieving necessary milestones to become an independent academic physician-scientist
specializing in the use of genetics and clinical trials approaches to answer questions in T2DM and
metabolism, cardiovascular risk, and related therapies.

## Key facts

- **NIH application ID:** 10631680
- **Project number:** 3K23HL145121-04S1
- **Recipient organization:** MAYO CLINIC  JACKSONVILLE
- **Principal Investigator:** Jessica Rose Wilson
- **Activity code:** K23 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $54,000
- **Award type:** 3
- **Project period:** 2022-09-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10631680

## Citation

> US National Institutes of Health, RePORTER application 10631680, Cardiometabolic effects of genetically decreased dipeptidyl peptidase-4 (DPP4) (3K23HL145121-04S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10631680. Licensed CC0.

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