Nature’s Way

Omega-3s for Cardiovascular Disease

Philip Frost, MD

Nature not only provides humans a full list of nutrients to forestall chronic disease (if we chose to eat them habitually) but stocks the lipidologist’s tool chest with offerings to thwart cardiovascular disease.

Since the appreciation that the Greenland Inuit had a low mortality from Chronic Heart Disease (CHD) despite a diet rich in fat, the marine omega-3 fatty acids (n-3 FFAs) have been studied in the clinical arena. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), C-20 and C-22, respectively, are products of microalgae, are essential fatty acids, and are concentrated in marine animals. DHA is produced commercially from microalgae and is FDA-approved for infant formula. EPA and DHA in fish and in concentrates have been studied together and as components. EPA and DHA not only provoke lipoprotein concentrations but have other potential health benefits.

Recent Observations

Multiple studies suggest that higher intake of the marine n-3 fatty acids in the diet reduce the risk of sudden death. In Seattle, a total of 334 case patients with primary cardiac arrest attended by paramedics were studied, along with 493 population-based control cases. Diet histories were taken from spouses and blood specimens collected from cases (n=82) and controls (n=108). Compared to no fish intake, an intake of 5.5g of n-3 FFAs per month was associated with a 50% reduction in risk of primary cardiac arrest. Compared with a red blood cell (RBC) n-3 FFA level of 3.3% of total FFAs (lowest quartile), an RBC n-3 FFAs of 5.0% of total FFAs was associated with a 70% reduction in the risk of primary cardiac arrest (Siscovick 1995). This result was echoed in the Physician’s Health Study conducted in apparently healthy men. Ninety-four men in whom sudden death occurred as the first manifestation of CHD were matched with 184 controls. As compared with men whose blood levels of long-chain n-3 FFAs were in the lowest quartile, the relative risk of sudden death was significantly lower in the third quartile (adjusted relative risk [RR] was 0.28) and lower yet in the fourth quartile (RR 0.19) (Albert 2002).

The GISSI-Prevenzione Investigators recruited 11, 234 subjects who had survived a recent (<3 months) myocardial infarction (MI) and were randomly assigned supplements of n-3 FFAs 1 g, vitamin E, both, or neither for 3.5 years. Primary endpoint was combined death, nonfatal MI, and stroke. Results were provided in two-way and four-way analyses, respectively. Treatment with n-3 FFAs, but not vitamin E, significantly lowered risk of primary endpoint (RR decrease 10% and 15%). Benefit was attributed to decrease in risk of death (14% and 20%) and cardiovascular death (17% and 30%) (GISSI 1999).

The relationship between n-3 fatty acids (EPA + DHA) intake and cardiovascular disease has been reviewed recently (He 2004, Studer 2005, Wang 2006). The He review looked at accumulated evidence on fish consumption and CHD mortality and concluded, “The pooled multivariate relative risks for CHD mortality were 0.89 (95% CI, 0.79 to 1.01) for fish intake one to three times per month, 0.85 (95% CI 0.76 to 0.96) for once per week, 0.77 (95% CI 0.66 to 0.89) for two to four times per week, and 0.62 (95% CI 0.46 to 0.82) for five or more times per week.”

The Studer review concluded, “Statin and n-3 fatty acids are the most favorable lipid-lowering interventions with reduced risk of overall and cardiac mortality. Any potent reduction in cardiac mortality from fibrates is offset by an increased risk of death from noncardiovascular causes.” 

In the editorial accompanying the Wang review, it is stated, “In total, the evidence indicates that increased consumption of the n-3 fatty acids EPA and DHA, either through fish or supplements or both, reduced the rates of all-cause mortality, myocardial infarction, and sudden cardiac death.” Important is that no or very few complications of supplements were encountered (Deckelbaum 2006).

The NIH convened a working group on future clinical research directions on omega-3 fatty acids and Cardio Vascular Disease (CVD) on June 2, 2004. They concluded that the body of evidence is consistent with the hypothesis that intake of omega-3 fatty acids reduced CVD but that a definitive trial is needed (NIH 2004).

There is recent trial data from Japan now that the five-year Japan EPA Lipid Interventions Study (JELIS) has been presented. Subjects with a total cholesterol >250 mg./dL were recruited, 14,981 in primary prevention and 3,664 in secondary prevention arms. All were randomized to low-dose statin (10 mg. pravastatin or 5 mg. simvastatin) or low-dose statin plus EPA (1800 mg. daily) in a randomized, open-label, blinded end point trial. Primary end point was defined as major coronary events: sudden death, fatal and nonfatal MI, and unstable angina including hospitalization for documented ischemic event and angioplasty/stenting or coronary artery bypass grafting. At mean follow-up of four to six years, there was a significant 19% lower event rate in the EPA plus statin compared with statin alone. This was true in both strata, but in subgroup analysis it was significant only in the secondary strata (Koba 2006).

The Lipidologist’s Perspective

Early data suggested that normalizing blood cholesterol and associated lipoprotein abnormalities was likely to reduce CVD events and total mortality. History has proven this to be the case.

The question now is how to achieve lipid goals. To an investigator active in studies of diet and single therapeutic agents, it became evident that combination regimens would be required in most cases to achieve goals. The ATP III updated goals for high-risk individuals are an LDL cholesterol (well) below 70 and non-HDL cholesterol (again well) below 100 mg./dL. Normalizing HDL cholesterol is important (Grundy 2004). Common lipoprotein abnormalities include not only elevated LDL but elevated VLDL (surrogate triglycerides) and low HDL. While most therapeutic regimens are statin-based, we need effective, safe statin combinations. N-3 fatty acids clearly step to the plate. EPA + DHA predominately lower the triglyceride-rich lipoproteins. In a blinded comparison of gemfibrozil 1,200 mg. with 3,225 mg. EPA + DHA in hypertriglyceridemic subjects, both agents lowered total cholesterol, triglycerides, VLDL, and raised HDL similarly. LDL cholesterol increase was attributable largely to an increase in the less dense LDL subspecies (Stalenhoff 2000). In terms of lipoprotein response, we can think of n-3 fatty acids as nature’s fibrate but, as noted above, with additional attributes. The response to statin, EPA + DHA, and combinations has been studied and the lipoprotein response to combination is additive (Contacos 1993). Importantly, there have been no associated side effects with n-3 FFAs + statin, and specifically no increased risk of the myopathy syndrome, which is a concern with the statin fibrate combination.

I have been using this combination as part of my armamentarium since 1994, as have many other lipidologists. It is particularly useful for patients with type II diabetes where the primary lipoprotein abnormality includes elevated VLDL and associated low HDL.

The case below is illustrative.

Sixty-five-year-old sedentary woman referred for lipid management in 1990 (current age 82). Past history: Type II diabetes mellitus, 1984. Interval history: Subsequent diagnosis of angina pectoris, resolved with diabetes, lipid management. PE: She was obese (BMI 37.7), normotensive. Weight unchanged over interval seventeen years.

Clinical course: She failed efforts to control diabetes with diet and sulfonylureas. After years of discussion, she acquiesced in fall 1993 to initiating insulin therapy, first NPH and then 70/30 bid. Diabetes regimen expanded with the addition of metformin in fall 1995, and pioglitazone in summer 2004.

In reviewing individual values and pooled data presented above, the lipids clearly track to the combined lipid regimen (n-3 fatty acids [EPA + DHA] 3.0 g plus simvastatin 40 mg.) and diabetes control.

The long-chain omega-3 fatty acids EPA and DHA are likely to protect against CVD by lipid independent and lipid dependent mechanisms (Din 2004). Low dose (about 1 g. of EPA plus DHA) consumed as fish or supplements is associated with reduced sudden death and total mortality. Higher dosage regimens (about 3–4 g.) lead to reduced VLDL cholesterol and triglycerides, a modest increase in HDL cholesterol, and, on occasion, increase in LDL cholesterol, a response similar to that observed with the fibrate drug class. In contradistinction to the fibrates, there are no known drug interactions with the n-3 fatty acids, and specifically no increased risk of the myopathy syndrome when prescribed with statins. Also in contradistinction to the fibrates, studies to date demonstrate not only reduced cardiac events but reduced total mortality. The n-3 FFAs are valuable agents used in combination lipid perturbing regimens.

Dr. Frost is a Clinical Professor in the Department of Medicine, Cardiovascular Research Institute (CVRI) at UCSF. He attended UCLA School of Medicine, interned in New York City, and completed his medical residency at Stanford University. After two years in the USPHS, he was an NIH Special Fellow in Metabolism CVRI, UCSF. He has been an active clinical investigator since 1969. He currently sees patients with lipid disorders at the UCSF Lipid Clinic and in his private practice. He can be reached with questions at phf@stopheartattack.org or by telephone at (415) 673-2241.

References

(1999). "Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico." Lancet 354(9177): 447-55.

(2004). "National Institutes of Health Office of Dietary Supplements and National Heart, Lung, and Blood Institute Working Group Report on Future Clinical Research Directions On Omega-3 Fatty Acids and Cardiovascular Disease, Meeting Held Bethesda, Maryland June 2, 2004." Internet: http://www.nhlbi.nih.gov/meetings/workshops/omega-3/omega-3-rpt.htm.

Albert, C. M., H. Campos, et al. (2002). "Blood levels of long-chain n-3 fatty acids and the risk of sudden death." N Engl J Med 346(15): 1113-8.

Contacos, C., P. J. Barter, et al. (1993). "Effect of pravastatin and omega-3 fatty acids on plasma lipids and lipoproteins in patients with combined hyperlipidemia." Arterioscler Thromb 13(12): 1755-62.

Deckelbaum, R. J. and S. R. Akabas (2006). "n-3 Fatty acids and cardiovascular disease: navigating toward recommendations." Am J Clin Nutr 84(1): 1-2.

Din, J. N., D. E. Newby, et al. (2004). "Omega 3 fatty acids and cardiovascular disease--fishing for a natural treatment." Bmj 328(7430): 30-5.

Grundy, S. M., J. I. Cleeman, et al. (2004). "Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines." Circulation 110(2): 227-39.

He, K., Y. Song, et al. (2004). "Accumulated evidence on fish consumption and coronary heart disease mortality: a meta-analysis of cohort studies." Circulation 109(22): 2705-11.

Koba, S. and J. Sasaki (2006). "Treatment of hyperlipidemia from Japanese evidence." J Atheroscler Thromb 13(6): 267-80.

Siscovick, D. S., T. E. Raghunathan, et al. (1995). "Dietary intake and cell membrane levels of long-chain n-3 polyunsaturated fatty acids and the risk of primary cardiac arrest." Jama 274(17): 1363-7.

Stalenhoef, A. F., J. de Graaf, et al. (2000). "The effect of concentrated n-3 fatty acids versus gemfibrozil on plasma lipoproteins, low density lipoprotein heterogeneity and oxidizability in patients with hypertriglyceridemia." Atherosclerosis 153(1): 129-38.

Studer, M., M. Briel, et al. (2005). "Effect of different antilipidemic agents and diets on mortality: a systematic review." Arch Intern Med 165(7): 725-30.

Wang, C., W. S. Harris, et al. (2006). "n-3 Fatty acids from fish or fish-oil supplements, but not alpha-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies: a systematic review." Am J Clin Nutr 84(1): 5-17.