# Genotype-dependent cardiovascular and anti-inflammatory effects of fenofibrate

> **NIH NIH R21** · JOSLIN DIABETES CENTER · 2021 · $134,992

## Abstract

SUMMARY
Treatment with PPAR-α agonists such as fibrates has been proposed as a strategy to prevent major
cardiovascular events (MACE) in patients with type 2 diabetes (T2D). However, clinical trials have shown
inconsistent benefits of these drugs in this population. Pursuing a personalized approach to CVD prevention
in diabetes, we have recently identified a common non-coding variant (rs6008845, C/T), flanking the
PPARA gene, which can be used to distinguish individuals who are more likely to derive benefit from
fenofibrate than other T2D patients. In the ACCORD Lipid trial, rs6008845 T/T homozygotes experienced a
50% MACE reduction in response to fenofibrate whereas no benefit was observed in C/T heterozygotes or
C/C homozygotes (p for interaction=3.7x10-4). Preliminary evidence from our group suggests that
rs6008845 acts by enhancing the anti-inflammatory effects of fenofibrate rather than its triglyceride-lowering
properties. The goal of this R21 application, written in response to RFA-HL-17-22, is to explore this
hypothesis further by leveraging the ACCORD samples and data banked in the NHLBI repository as well as
the multiplexing capabilities of the OLINK proteomic platform. We intend to study a 1:3 case-control set
nested in ACCORD Lipid, including all T/T participants who had a MACE (n=80) and serum aliquots stored
in BioLINCC, and a sample of three times as many (n=240) T/T participants who did not have a MACE.
Through this set, we will address the following Specific Aims: 1. To characterize the anti-inflammatory
response to fenofibrate among rs6008845 T/T homozygotes with T2D. Serum samples collected at
baseline and 12 months after randomization will be assayed for 93 inflammation-related serum proteins (92
included in the OLINK “Inflammation” multiplex panel + the chemokine CTACK). The effect of fenofibrate, as
compared to placebo, will be evaluated on individual biomarkers as well as by means of supervised and
unsupervised data reduction techniques, such as hierarchical cluster analysis, allowing the identification of
multi-marker inflammatory signatures influenced by this treatment. 2. To estimate the extent to which
anti-inflammatory effects contribute to the cardiovascular benefit exerted by fenofibrate on T/T
homozygotes. Using the biomarker data generated in Aim 1, we will use triangulation techniques to
estimate the proportion of the fenofibrate benefit on MACE risk that can be ascribed to the effect of this drug
on inflammatory biomarkers, given their association with MACE incidence. Understanding the mechanisms
through which fenofibrate prevents MACE among T2D patients homozygous for the rs6008845 T allele
would provide further support for the possible use of this genetic marker to personalize CVD prevention in
T2D and would pave the way for pharmacogenetic clinical trials, in which randomization to fibrate or
placebo is stratified by rs6008845 genotype. Importantly, it would also point to critical nodes in the path
between T2D...

## Key facts

- **NIH application ID:** 10223436
- **Project number:** 5R21HL153559-02
- **Recipient organization:** JOSLIN DIABETES CENTER
- **Principal Investigator:** Alessandro Doria
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $134,992
- **Award type:** 5
- **Project period:** 2020-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10223436

## Citation

> US National Institutes of Health, RePORTER application 10223436, Genotype-dependent cardiovascular and anti-inflammatory effects of fenofibrate (5R21HL153559-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10223436. Licensed CC0.

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