10th December, 2018, Dr Chee L Khoo
Elevated triglyceride (TG) level serves as an independent marker for an increased risk of ischaemic events, as shown in epidemiologic and mendelian randomisation studies (1-5). However, in most of the statin trials, patients with high TG are generally excluded. There is confusion out there as to whether fish oils is useful or not for cardiovascular protection. The issues are actually simple: Fish oil supplement can reduce triglyceride levels but do they translate to CV outcomes?
In the original Japanese EPA Lipid Intervention Study (JELIS) (6), 18,645 Japanese patients with hypercholesterolemia were randomly assigned to receive either low-intensity statin therapy plus 1.8 g of eicosapentaenoic acid (EPA) daily or statin therapy alone. Major coronary events were reduced by 19% in the EPA intervention group. The GISSI-Prevenzione trial in MI patients, and the GISSI-HF trial in heart failure patients found benefits for fish oil supplements in their respective populations (7). However, many subsequent and more contemporary trials that looked at reducing TG with niacin, fibrates or fish oil supplements have not been shown to reduce cardiovascular events (8-11).
The Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT) published its results this month (12). 8179 patients > 45 years old and had established CV disease (30%) or > 50 years old and had diabetes and one other risk factor were enrolled (70%). Patients’ TG levels were between 1.69 to 5.63 mmo/L and LDL between 1.06 to 2.59 mmol/L. They had been on statins for at least 4 weeks. Patients were excluded if they had severe heart failure, active severe liver disease, a glycated haemoglobin level greater than 10.0%, a planned coronary intervention or surgery, a history of acute or chronic pancreatitis, or known hypersensitivity to fish, shellfish, or ingredients of icosapent ethyl or placebo.
The primary efficacy end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularisation or unstable angina.
The results?
The median duration of follow-up was 4.9 years (maximum, 6.2 years). At one year, E-EPA reduce TG by 18% compared with 2.2% in the placebo group. LDL rose by 3.1% in the E-EPA group compared with 10.2% in the placebo group. Great efficacy but did it reduced CV events? A primary end-point event occurred in 17.2% of the patients in the icosapent ethyl group as compared with 22.0% of the patients
in the placebo group, a 25% (P<0.001) reduction in CV events. The number needed to treat to avoid one primary end-point event was 21 over a median follow-up of 4.9 years.
Safety
There were no increase incident of heart failure in the E-EPA group but the E-EPA group had higher hospitalisation for AF (3.1% vs. 2.1%, p=0.0004) and serious bleeding (2.7% vs 2.1% p=0.06) but there were no fatal bleeding.
Ethyl eicosapentaenoic acid (E-EPA, icosapent ethyl) is a derivative of the omega-3 fatty acid eicosapentaenoic acid (EPA) that is used in combination with changes in diet to lower triglyceride levels in adults with severe (≥ 500 mg/dL) hypertriglyceridemia. This was the second class of fish oil-based drug to be approved for use as a drug and was approved by the FDA in 2012. These fish oil drugs are similar to fish oil dietary supplements but the ingredients are better controlled and have been tested in clinical trials.
It is not known whether the lack of benefit from n−3 fatty acids in previous trials may be attributable to the low dose or to the low ratio of EPA to docosahexaenoic acid (DHA). The plasma EPA level in this trial was fairly equivalent to the plasma levels in the JELIS trial.
Mechanisms responsible for the benefit of icosapent ethyl observed in REDUCE-IT are currently not known. It is also possible that the difference in high-sensitivity C-reactive protein level observed in REDUCE-IT may contribute to the benefit.
Ongoing trials of moderate-to-high doses of pure EPA ethyl ester will provide further information on the effects of these agents.10,36 These trials include the Randomized Trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy–Statin and EPA (RESPECT-EPA). Effect of Vascepa on Improving Coronary Atherosclerosis in People with High Triglycerides Taking Statin Therapy (EVAPORATE) looking at a secondary prevention outcomes trial involving statin-treated patients in Japan.
For now at least we can say there are studies which suggest high dose fish oil supplements have been shown to reduce cardiovascular events in patients with established cardiovascular disease or in patients with diabetes and high cardiovascular risk factors.
Access the abstract here.
References:
- Libby P. Triglycerides on the rise: should we swap seats on the seesaw? Eur Heart J 2015; 36: 774-6.
- Klempfner R, Erez A, Sagit BZ, et al. Elevated triglyceride level is independently associated with increased all-cause mortality in patients with established coronary heart disease: twenty-two-year follow-up of the Bezafibrate Infarction Prevention Study and Registry. Circ Cardiovasc Qual Outcomes 2016; 9: 100-8.
- Nichols GA, Philip S, Reynolds K, Granowitz CB, Fazio S. Increased cardiovascular risk in hypertriglyceridemic patients with statin-controlled LDL cholesterol. J Clin Endocrinol Metab 2018; 103: 3019-27.
- Nichols GA, Philip S, Reynolds K, Granowitz CB, Fazio S. Increased residual cardiovascular risk in patients with diabetes and high versus normal triglycerides despite statin-controlled LDL cholesterol. Diabetes Obes Metab 2018 September 17 (Epub ahead of print).
- Toth PP, Granowitz C, Hull M, Liassou D, Anderson A, Philip S. High triglycerides are associated with increased cardiovascular events, medical costs, and resource use: a real-world administrative claims analysis of statin-treated patients with high residual cardiovascular risk. J Am Heart Assoc 2018; 7(15): e008740.
- Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet 2007; 369: 1090-8.
- GISSI-Prevenzione Investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet. 1999; 354: 447-455
- Ganda OP, Bhatt DL, Mason RP, Miller M, Boden WE. Unmet need for adjunctive dyslipidemia therapy in hypertriglyceridemia management. J Am Coll Cardiol 2018; 72: 330-43.
- The ORIGIN Trial Investigators. n−3 Fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med 2012; 367: 309-18.
- The ASCEND Study Collaborative Group. Effects of n−3 fatty acid supplements in diabetes mellitus. N Engl J Med 2018; 379: 1540-50.
- Aung T, Halsey J, Kromhout D, et al. Associations of omega-3 fatty acid supplement use with cardiovascular disease risks: meta-analysis of 10 trials involving 77 917 individuals.
- Deepak L. Bhatt, P. Gabriel Steg, Michael Miller et al. Cardiovascular Risk Reduction with Icosapent Ethyl for hypertriglyceridemia. New Engl J Med November 10, 2018