Genetic-Dependent Cardiovascular Response to PPAR-Alpha Agonist Fenofibrate

Cardiovascular Diseases Clinical Trial

— MAGNETIC  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05542147
• Other study ID #: AOP2225
• Status: Recruiting
• Phase: N/A
• Start date: July 3, 2022
• Est. completion date: December 31, 2024

Study information

• Verified date: January 2024
• Source: University Hospital Padova
• Contact: Mario Luca Morieri, MD PhD
• Phone: 00390498217094
• Email: marioluca.morieri[@]aopd.veneto.it
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 200
• Est. completion date: December 31, 2024
• Est. primary completion date: December 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Cardiovascular Diseases
• Type 2 Diabetes

Intervention

Drug:
• Fenofibrate 145 mg
1 tablet per day
• Placebo
1 tablet per day

Locations

Country	Name	City	State
Italy	University Hospital of Padova	Padova	Padua

Sponsors (1)

Lead Sponsor	Collaborator
Mario Luca Morieri

Country where clinical trial is conducted

Italy, 

References & Publications (3)

Morieri ML, Gao H, Pigeyre M, Shah HS, Sjaarda J, Mendonca C, Hastings T, Buranasupkajorn P, Motsinger-Reif AA, Rotroff DM, Sigal RJ, Marcovina SM, Kraft P, Buse JB, Wagner MJ, Gerstein HC, Mychaleckyj JC, Pare G, Doria A. Genetic Tools for Coronary Risk Assessment in Type 2 Diabetes: A Cohort Study From the ACCORD Clinical Trial. Diabetes Care. 2018 Nov;41(11):2404-2413. doi: 10.2337/dc18-0709. Epub 2018 Sep 27. — View Citation

Morieri ML, Shah H, Doria A; the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Genetic Study Group. Variants in ANGPTL4 and the Risk of Coronary Artery Disease. N Engl J Med. 2016 Dec 8;375(23):2304-2305. doi: 10.1056/NEJMc1607380. No abstract available. — View Citation

Morieri ML, Shah HS, Sjaarda J, Lenzini PA, Campbell H, Motsinger-Reif AA, Gao H, Lovato L, Prudente S, Pandolfi A, Pezzolesi MG, Sigal RJ, Pare G, Marcovina SM, Rotroff DM, Patorno E, Mercuri L, Trischitta V, Chew EY, Kraft P, Buse JB, Wagner MJ, Cresci S, Gerstein HC, Ginsberg HN, Mychaleckyj JC, Doria A. PPARA Polymorphism Influences the Cardiovascular Benefit of Fenofibrate in Type 2 Diabetes: Findings From ACCORD-Lipid. Diabetes. 2020 Apr;69(4):771-783. doi: 10.2337/db19-0973. Epub 2020 Jan 23. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Arterial Stiffness - Augmentation Index (AI)	Differences in fenofibrate induced-changes in AI across rs6008845 genotypes	Baseline and 12 weeks
Other	Haematopoietic stem/progenitor cells (HSPCs)	Differences in fenofibrate induced-changes in circulating levels of HSPC across rs6008845 genotypes.	Baseline and 12 weeks
Primary	Endothelial Function	Differences in fenofibrate induced-changes in Reactive Hyperemia Index (RHI) across rs6008845 genotypes. [RHI is a non-invasive measure of endothelial function, and it is inversely associated with risk of cardiovascular disease].	baseline and 12 weeks
Secondary	Arterial Stiffness - Pulse Wave Velocity (PWV)	Differences in fenofibrate induced-changes in PWV across rs6008845 genotypes. [PWV is directly associated with risk of cardiovascular disease]	baseline and 12 weeks
Secondary	Endothelial progenitor cells (EPCs)	Differences in fenofibrate induced-changes in circulating levels of EPC across rs6008845 genotypes.	baseline and 12 weeks
Secondary	Inflammatory markers and chemokines	Differences in fenofibrate induced-changes in CCL11, CCL27 sVCAM, sE-Selectin, Endothelin-1 across rs6008845 genotypes.	baseline and 12 weeks
Secondary	Platelet aggregation induced by adenosine diphosphate (ADP)	Anti-platelet effects will be evaluated as the differences in fenofibrate induced-changes in platelet aggregation induced by adenosine diphosphate (ADP) (i.e. ADPtest) across rs6008845 genotypes.	baseline and 12 weeks
Secondary	Platelet aggregation induced by arachidonic acid	Anti-platelet effects will be evaluated as the differences in fenofibrate induced-changes in platelet aggregation induced by arachidonic acid (ASPI test) across rs6008845 genotypes.	baseline and 12 weeks