Genetic-Dependent Cardiovascular Response to PPAR-Alpha Agonist Fenofibrate

Physiopathological Study of Genetic Modulation of Cardiovascular Effect of PPAR-Alpha Activation (MAGNETIC-PPARA)

Fenofibrate, a peroxisome proliferator-activated receptor-alpha (PPAR-a) agonist known to improve diabetic dyslipidemia, has been proposed as a drug to prevent cardiovascular disease (CVD) in type 2 diabetes (T2D). However, the results of clinical trials have been mixed. Supporting the hypothesis that these disappointing results hide a genetic heterogeneity in the CVD response to fenofibrate, a common genetic variant (rs6008845) in the gene coding for PPAR-a has been found to dramatically influence the ability of this drug to reduce CVD events in the ACCORD Lipid trial (PMID:31974142).

The aim of this study is to validate these findings by dissecting the pathways and mechanism through which this variant exerts such a modulatory effect, by means of a randomized clinical trial.

If successful, this project will pave the way to a precision medicine approach to prescribe fenofibrate optimally, offering a cardio-protective drug to those patients that are most likely to experience a robust benefit from this medication.

The main hypothesis of this study is that underlying genetic heterogeneity in the CV response to fibrates can successfully identify subjects with a consistent benefit from this treatment. Supporting this postulate a common genetic variant (rs6008845) in the gene coding for PPAR-alpha has been found to dramatically influence the ability of this drug to reduce CVD events.

This genetic modulation of fenofibrate effectiveness has been found in whites, validated in black participants in the ACCORD Lipid trial, and then replicated in external cohorts. Interestingly, the genetic effect was independent of fenofibrate-induced changes in plasma lipids, suggesting a more complex mechanism of action of fibrates. (PMID:31974142).

Through this randomized study, subjects carrying the different rs6008845 genotypes (TT, TC, CC) will be randomized to receive fenofibrate or placebo for 12 weeks.

The specific aims are:

• To replicate the previous "rs6008845 by fenofibrate" interaction on MACE, testing the fenofibrate-induced changes in endothelial function, arterial stiffness, and markers of endothelium damage.
• To evaluate whether the fenofibrate-induced change on circulating biomarkers is modulated by rs6008845 genotypes. This will provide insight into the mechanism(s) behind the rs6008845 modulation of fenofibrate effectiveness by the identification of circulating biomarkers mirroring this genetic effect. Different known actions of fenofibrate, beyond lipid-lowering effects, such as fenofibrate anti-inflammatory and anti-platelet effects will be evaluated.

Inclusion Criteria:

• Type 2 diabetes with previous cardiovascular events or at least one CV risk factor (hypertension, obesity, smoke, age>65 years)
• HbA1c < 8%
• Triglycerides < 200 mg/dl
• On statin treatments and with LDLcholesterol < 100 mg/dl or at maximum statin-tolerated dose
• European ancestry (rational: given the relatively small sample size and the ancestry-differences in allele frequency of rs6008845 T allele [i.e. from 65% in whites to 20% in blacks subjects) this criteria allows to limit ethnic-confounding factors that would reduce the probability of success of this physiopathological study aiming to dissect the mechanism of the genetic modulation of fenofibrate effectiveness).

Exclusion Criteria:

• CKD III stage with eGFR<60 ml/min/1.73
• Uncontrolled hypertension with systolic blood pressure > 170 mmHg at enrollment.
• Hereditary muscle disorders
• Uncontrolled hypothyroidism
• Elevated alcohol consumption
• Hepatic failure
• Allergy to fenofibrate or excipients
• Acute / chronic pancreatitis
• Pregnancy and lactation