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IPE-PREVENTION is a prospective, randomized, 3-month long, open-label study. A total of 70 individuals with elevated cardio-metabolic risk and heightened triglyceride levels, and who are on stable statin therapy will be randomized (1:1) to receive either icosapent ethyl (IPE) 2g BID or standard of care.
It is hypothesized that assignment to IPE will lower progenitor cell depletion as well as limit progenitor cell dysfunction. This study may offer some molecular and cellular insights into the mechanisms underlying the cardiovascular benefits of IPE therapy reported in the REDUCE-IT trial.
Full description
The development and natural history of atherothrombosis involves the pathophysiological interplay between inflammation, dyslipidemia, oxidative stress and endothelial dysfunction. Unregulated, these processes culminate in endothelial dysfunction, and ultimately cardio-metabolic chronic diseases. Aberrant lipid oxidation due to elevated triglycerides and cholesterol primes and activates innate immune cell activity resulting in elevated inflammation and oxidative stress.
The randomized, placebo-controlled REDUCE-IT trial enrolled individuals with established atherosclerotic heart disease, or diabetes and an additional risk factor, who were on pre-existing statin therapy with persistent hypertriglyceridemia. REDUCE-IT reported that the group allocated to the omega-3 fatty acid icosapent ethyl (IPE; 2g BID) exhibited a 25% relative risk reduction for the primary composite endpoint of CV death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina, and a 20% decreased risk of CV death when compared to standard of care. Vascepa® (IPE) is currently approved by Health Canada and the U.S. FDA for the reduction of cardiovascular risk in statin-treated individuals with elevated triglycerides who are either at heightened cardiovascular risk or who have diabetes and at least one risk factor.
The exact mechanism through which IPE decreased cardiovascular events in REDUCE-IT has not yet been elucidated.
The population and function of circulating pro-vascular progenitor cells have been shown to benefit from diminished lipid oxidation, inflammation and oxidative stress. A healthy population of circulating pro-vascular progenitor cells in turn affords timely and efficient blood vessel repair, regeneration and atheroprotection.
The omega-3 fatty acid eicosapentaenoic acid (EPA) has been reported to inhibit M1 macrophage polarization in a murine model and increase human endothelial progenitor cell (EPC) colony formation and functionality in vitro. In vivo, EPA levels have been observed to correlate significantly with circulating EPC number (CD34+CD133+VEGFR2+ cells). Collectively, these findings affirm that EPA, and potentially omega-3 fatty acids, can enhance the number and function of circulating pro-vascular progenitor cells and can alter M1/M2 macrophage balance towards a regenerative blood vessel phenotype.
IPE-PREVENTION is a prospective, 3-month long, open-label study that will randomize a total of 70 individuals with elevated cardio-metabolic risk and heightened triglyceride levels and who are on stable statin therapy to either IPE 2g BID or standard of care. Blood samples will be collected at the baseline and month 3 visits for evaluations of cell populations in the blood as well as measurements of biomarkers that contribute to the proinflammatory and pro-oxidant milieu of individuals at elevated cardio-metabolic risk. The study will utilize the AldefluorTM assay to differentiate between and enumerate hematopoietic progenitor cells, EPCs, granulocyte precursors and macrophage precursors. The overarching goal would be to document how assignment to IPE and standard-of-care impact on circulating progenitor cell depletion and dysfunction. The effect of IPE exposure on the inflammatory and oxidative profile will also be assessed.
The results of this investigation may offer some molecular and cellular insights into the mechanisms underlying the cardiovascular benefits of IPE therapy reported in the REDUCE-IT trial.
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Inclusion criteria
Women ≥65 years of age and men ≥40 years of age with established CVD (see criterion 'a' below) or ≥50 years of age with diabetes and one additional CV risk factor (see criterion 'b' below)
Those with established CVD should have ≥1 of the following clinical history
Documented coronary artery disease (CAD)
Documented cerebrovascular or carotid disease (≥1 of the following)
Documented peripheral artery disease (≥1 of the following)
Those with a history of diabetes (either type 1 or type 2 diabetes mellitus) but no CVD should also have ≥1 of the following:
Cigarette smoker or stopped smoking within 3 months before the baseline visit
Documented hypertension OR on antihypertensive agents
HDL-C ≤1.0 mmol/L for men or ≤1.3 mmol/L for women
High sensitivity C-reactive protein >3.0 mg/L
eGFR 30 to 60 mL/min/1.73m2
Documented micro- or macro-albuminuria
Retinopathy
ABI <0.9 without symptoms of intermittent claudication
Elevated triglycerides (≥1.5 mmol/L but <5.6 mmol/L)
On stable statin therapy for ≥4 weeks at the baseline visit
Willing to provide written informed consent and be compliant with the study requirements
Willing and able to follow the diet recommended by the study doctor
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70 participants in 2 patient groups
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Data sourced from clinicaltrials.gov
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