Raised triglycerides and risk of coronary artery disease

• fish-oil preparations are useful in the treatment of severe hypertriglyceridaemia; however treatment with fish-oil preparation can occasionally aggravate hypercholesterolaemia
  
  
• the primary mechanisms of fish oils involve suppression of hepatic VLDL and triglyceride production, as well as increased catabolism of VLDL to LDL and enhanced post-prandial triglyceride clearance. The effects on total cholesterol, LDL and HDL appear non-significant and inconsistent (1)
  
  
• caution advised in conditions such as haemorrhagic disorders, anticoagulant treatment, diabetes mellitus, aspirin-sensitive asthma
  
  
• there is evidence that increasing consumption of omega-3 fatty acids from fish, fish oil supplements, or plant sources is an effective strategy in helping to prevent coronary heart disease (2,6,8,9)
  
  
• there is evidence of the effectiveness of using omega-3 fatty acids following myocardial infarction (3)
  • the early effect of low-dose (1 g/d) omega-3 fatty acids on total mortality and sudden death supports the hypothesis of an antiarrhythmic effect of this drug. Such a result is consistent with the wealth of evidence coming from laboratory experiments on isolated myocytes, animal models, and epidemiological and clinical studies (4)
    
    
• it has been stated that a raised fasting triglyceride (> 1.7 mmol/l) increases the cardiovascular risk of an individual by a factor of 1.3 (5)

Notes:

• a systematic review was undertaken (7):
  • investigating the premise that omega-3 polyunsaturated fatty acids from oily fish (long-chain omega-3 (LCn3)), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)), as well as from plants (alpha-linolenic acid (ALA)) may benefit cardiovascular health
  • systematic review investigated the effects of increased intake of fish- and plant-based omega-3 fats for all-cause mortality, cardiovascular events, adiposity and lipids
    
    • moderate- and low-certainty evidence suggests that increasing LCn3 slightly reduces risk of coronary heart disease mortality and events, and reduces serum triglycerides (evidence mainly from supplement trials). Increasing ALA slightly reduces risk of cardiovascular events and arrhythmia
• a prospective randomised controlled trial (JELIS) was undertaken in Japanes patients and suggested benefit for use of omega 3 fatty acids in reducing the risk of cardiovascular disease (8):
  • 18 645 patients with a total cholesterol of 6.5 mmol/L or greater were recruited from local physicians throughout Japan between 1996 and 1999. Patients were randomly assigned to receive either 1800 mg of eicosapentaenoic acid (EPA) daily with statin (EPA group; n=9326) or statin only (controls; n=9319) with a 5-year follow-up
  • at mean follow-up of 4.6 years, we detected the primary endpoint in 262 (2.8%) patients in the EPA group and 324 (3.5%) in controls-a 19% relative reduction in major coronary events (p=0.011)
    • post-treatment LDL cholesterol concentrations decreased 25%, from 4.7 mmol/L in both groups. Serum LDL cholesterol was not a significant factor in a reduction of risk for major coronary events
    • in patients with a history of coronary artery disease who were given EPA treatment, major coronary events we. re reduced by 19% (secondary prevention subgroup: 158 [8.7%] in the EPA group vs 197 [10.7%] in the control group; p=0.048)
    • in patients with no history of coronary artery disease, EPA treatment reduced major coronary events by 18%, but this finding was not significant (104 [1.4%] in the EPA group vs 127 [1.7%] in the control group; p=0.132)
    • the authors concluded that EPA is a promising treatment for prevention of major coronary events, and especially non-fatal coronary events, in Japanese hypercholesterolaemic patients
      
      
• the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT), has shown reduction in cardiovascular risk in patients using fish oil based supplements (9):
  • in 8179 high-risk patients who had elevated triglyceride levels and had been receiving statin therapy were randomly assigned to receive 2 g of icosapent ethyl (icosapent ethyl or ethyl eicosapentaenoic acid is a synthetic derivative of the omega-3 fatty acid eicosapentaenoic acid) twice daily or placebo containing mineral oil
  • patients were enrolled mostly on the basis of secondary prevention (71%), and almost 60% had diabetes
  • at baseline
    • low-density lipoprotein (LDL) cholesterol levels were well controlled among the patients (median value,1.94 mmol per liter [75.0 mg per deciliter]), and triglyceride levels were slightly elevated (median value, 2.44 mmol per liter, [216.0mg per deciliter])
  • after a median follow-up of 4.9 years
    • the primary efficacy end point (a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina in a time-to-event analysis) was reported in 22.0% of the patients in the placebo group and in 17.2% of the patients in the icosapent ethyl group - a 25% lower risk in the icosapent ethyl group
      
      
• a systematic review and meta-analysis was performed to examine the potential heterogeneity across omega-3 FAs trials, with a focus on effectiveness and safety of omega-3 FAs on fatal on non-fatal CV outcomes (10)
  • secondary outcome was the potential variability in effects of EPA vs. combination of EPA and DHA treatment
  • authors concluded:
    • omega-3 FAs reduced cardiovascular mortality and improved cardiovascular outcomes
    • cardiovascular risk reduction was more prominent with EPA monotherapy than with EPA+DHA
      
      
• atrial fibrillation and omega-3 FAs
  • Advice for healthcare professionals (11):
    • atrial fibrillation is now listed as an adverse drug reaction with a “common” frequency (may affect up to 1 in 10 people) for medicines containing omega-3-acid ethyl esters licensed for the treatment of hypertriglyceridaemia
    • the observed risk was found to be highest with a dose of 4 g/day
    • advise patients taking omega-3-acid ethyl ester medicines for the treatment of hypertriglyceridaemia to seek medical attention if they develop symptoms of atrial fibrillation
    • if a patient develops atrial fibrillation whilst taking these medicines for the treatment of hypertriglyceridaemia then the medicine should be discontinued permanently
    • report suspected adverse drug reactions associated with omega-3-acid ethyl ester medicines on a Yellow Card

The summary of product characteristics should be consulted before prescribing this drug.

Reference:

• (1) The British Journal of Diabetes and Vascular Disease 2003; 3(3): 204-10.
• (2) JAMA. 2002 Nov 27;288(20):2569-78.
• (3) Lancet. 1999 Aug 7;354(9177):447-55
• (4) Circulation. 2002 Apr 23; 105(16): 1897-903.
• (5) JBS2. Guidelines on prevention of cardiovascular dsease in clinical practice. Heart 2005;91:Supp 5.
• (6) Harper CR, Jacobson TA. Usefulness of omega-3 fatty acids and the prevention of coronary heart disease. Am J Cardiol 2005;96:1521-9.
• (7) Abdelhamid AS et al. Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease. Cochrane Database of Systematic Reviews 2020, Issue 3. Art. No.: CD003177. DOI: 10.1002/14651858.CD003177.pub5
  
• (8) Yokoyama M et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet. 2007 Mar 31;369(9567):1090-8
• (9) Bhart DL et al. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia.N Engl J Med. 2018 Nov 10.
• (10) Khan SU, Lone AN, Khan MS et al. Effect of omega-3 fatty acids on cardiovascular outcomes: A systematic review and meta-analysis.EClinicalMedicine 2021, doi:10.1016/j.eclinm.2021.100997
• (11) Drug Safety Update volume 17, issue 6, January 2024: 3.