# Pharmacogenetic discovery in the GRADE comparative effectiveness type 2 diabetes clinical trial

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $622,623

## Abstract

Type 2 diabetes has a heterogeneous pathophysiology, and is treated with various
glucose-lowering medications from classes that differ in their mechanisms of action.
Variability in treatment efficacy may be due to genetic variation, but data are needed to
guide specific pharmacotherapy addressing the pathogenic mechanisms affecting an
individual patient. The Glycemia Reduction Approaches in Diabetes: A Comparative
Effectiveness (GRADE) Study is evaluating the effectiveness of each of the four most
commonly employed glucose-lowering medications (sulfonylurea, GLP-1 receptor
agonist, DPP-4 inhibitor, basal insulin) added to a background of metformin. Among
5,047 randomized participants, 4,730 have consented to genetic analyses. We propose
to use a genome-wide association approach to test 1) whether specific genomic regions
or polygenic scores associate with the glycemic response to each of the four drugs, or to
a specific mode of action; 2) whether specific genomic regions or polygenic scores
associate with key intermediate traits of glucose homeostasis (e.g. insulin sensitivity, β-
cell function), or the occurrence of side effects and diabetes complications; 3) in a
subset of 1,600 participants with available DNA who have undergone continuous
glucose monitoring, whether specific genomic regions or polygenic scores associate with
the mismatch between glycated hemoglobin and average glycemia, or with glycemic
variability while on each drug; and 4) whether variants known to be associated with type
2 diabetes or related traits, polygenic scores constructed from such variants, or
physiology-driven partitioned genetic scores, are associated with response to each of
the four agents employed in GRADE. This proposal represents a full pharmacogenetic
exploration in the GRADE clinical trial designed to advance precision medicine in type 2
diabetes.

## Key facts

- **NIH application ID:** 10814158
- **Project number:** 5R01DK123019-04
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** JOSE CARLOS FLOREZ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $622,623
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10814158

## Citation

> US National Institutes of Health, RePORTER application 10814158, Pharmacogenetic discovery in the GRADE comparative effectiveness type 2 diabetes clinical trial (5R01DK123019-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10814158. Licensed CC0.

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