Fish, omega-3 fatty acid intake, and CHD risk in diabetic women

From the Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts

Cardiovascular disease is the leading cause of death in persons with diabetes mellitus, which affects some 16 million Americans and 135 million people worldwide. Among diabetic individuals, cardiovascular disease accounts for more than 75% of deaths. Diabetic women are at particularly high risk of cardiovascular disease; diabetes eliminates the usual female advantage for coronary disease incidence and mortality.1,2 Thus, a major aim of dietary and lifestyle strategies is to reduce the risk of cardiovascular complications among diabetic patients.

Metabolic studies suggest that a higher consumption of long-chain omega-3 fatty acids may be beneficial for diabetic patients. Fish oil supplementation significantly lowers triglyceride levels in diabetics; hypertriglyceridemia is a hallmark of diabetic dyslipidemia and an important risk factor of cardiovascular complications in diabetes. In addition, fish oil reduces the ability of platelets to aggregate and has strong antiarrhythmic effects.3-5

Recently, we examined prospectively the association between fish and long-chain omega-3 fatty acid intake and incidence of coronary heart disease (CHD) and total mortality among diabetic women in the Nurses’ Health Study cohort.6

Methods

The Nurses’ Health Study cohort was established in 1976. The cohort comprised 121,700 female registered nurses ages 30 to 55 years residing in 11 large states in the United States. This study included 5,179 women who reported diabetes mellitus that was diagnosed by a physician. Onset of the disease was determined to occur at the age of 30 years or older by questionnaires filled out from 1976 to 1994. Diet was assessed by validated semiquantitative food frequency questionnaires. In 1980, women were asked how often on average during the previous year they had consumed 6 to 8 oz of fish. The dietary questionnaire was expanded in 1984, 1986, 1990, and 1994. Four specific fish and seafood items were included as follows: (a) 3 to 5 oz of dark-meat fish, such as mackerel, salmon, sardines, bluefish, or swordfish; (b) 3 to 4 oz of canned tuna; (c) 3 to 5 oz of other types of fish; and (d) 3.5 oz of shrimp, lobster, or scallops as a main dish. We multiplied the frequency of consumption of each item by its nutrient content per serving to calculate the average daily intake of nutrients. Then the nutrient intake for all food items was totaled. To calculate the long-chain omega-3 fatty acids, we used a standard formula. The energy-adjusted intake of eicosapentaenoic acid from fish also was correlated with percentage of this particular fatty acid in adipose tissue (Spearman correlation coefficient, 0.49; P < .01).7-9

The prevalence of consumption of this supplement in pill form was very low (1.6%). Thus, we did not specifically study the effects of fish oil supplements.

The end point for our study was the incidence of CHD, including CHD disease deaths and nonfatal myocardial infarction (MI) and all-cause mortality occurring after the 1980 questionnaires were returned but before June 1, 1996.

To analyze the data, we divided the women into five categories according to their frequency of fish consumption or quintiles of omega-3 fatty acids calculated as the percentage of total energy. Frequency of fish consumption was defined as less than once monthly, one to three times monthly, once weekly, two to four times weekly, and five times weekly or more. We calculated in-cidence rates by dividing the number of events by person-time of

follow-up in each category. To determine relative risk, we computed the rate in a specific category of fish or omega-3 fatty acid consumption divided by that in the lowest category. Adjustments were made for age in 5-year categories. A multivariate analysis was performed using a

Cox proportional hazards regres-sion model. Variables, such as cigarette smoking, body mass index, menopausal status and postmenopausal hormone use, physical activity, alcohol use, history of hypertension, high cholesterol, diabetes, and other cardiovascular risk factors were included simultaneously.

Results

During 16 years of follow-up, we documented 362 incident cases of CHD and 468 deaths from all causes. Figure 1 shows the relative risks of CHD and mortality according to fish intake. We observed significant inverse associations between fish intake and incidence of CHD. After further adjustment for other cardiovascular risk factors, relative risks ([RR], 95% confidence interval [CI]) for fish consumption were as follows: one to three times monthly,

RR = 0.70 (0.48—1.02); once weekly, RR = 0.60 (0.42–0.85); two to four times weekly, RR = 0.65 (0.43–0.99); and five or more times weekly,

RR = 0.38 (0.21—0.68; P for trend

< .01). When further adjustments were made for other dietary factors, the results were similar.

For total mortality, after adjustment for lifestyle and dietary factors, the relative risks in the same in-

tervals of fish consumption were

1.0, 0.75, 0.66, 0.67, and 0.48, respectively (P for trend < .01). The inverse association was observed for both cardiovascular disease mortality (multivariate RR comparing extreme categories of fish intake = 0.47; 95% CI, 0.21—1.03) and noncardiovascular mortality (corresponding RR = 0.50; 95% CI, 0.26–0.93).

Figure 2 shows the relative risks of CHD and mortality according to quintiles of average omega-3 fatty acid intake. Patients with a higher intake of omega-3 fatty acids had a lower risk for CHD in the age-adjusted analysis (P for trend = .03). The relative risk for CHD comparing extreme quintiles of omega-3 fatty acid intake was 0.69 (95% CI, 0.47—

1.03). For total mortality, the age-adjusted relative risks according to quintiles one through five of omega-3 fatty acid intake were as follows: 1.0, 0.83, 0.80, 0.75, and 0.63, respectively (P for trend < .01). When we adjusted for lifestyle and dietary factors, the relative risks for total mortality were similar (RR comparing extreme quintiles of omega-3 fatty acids = 0.63; 95% CI, 0.45—0.88; P for trend = .02).

Discussion

This prospective cohort study provides evidence that eating more fish and omega-3 fatty acids is associated with a lower incidence of CHD and total mortality among diabetic women. This finding held true when the data were adjusted for established cardiovascular risk factors.

Patients with type 2 diabetes have lipid and lipoprotein metabolism abnormalities, as well as increased platelet aggregation and clotting, endothelial dysfunction, and increased risk for cardiac arrhythmias. Omega-3 fatty acids may help to reduce CHD incidence and mortality in this population. The possible mechanisms involved may include reduction of blood triglycerides, reduced aggregation of platelets, and prevention of arrhythmias.5,10 Because cardiovascular risk factors are much more common among diabetics than nondiabetics, long-chain omega-3 fatty acids may be particularly beneficial for diabetic patients. This may explain why the inverse association between fish and omega-3 fatty acid intake and the risk of CHD observed among diabetic women appears to be stronger than that for the general population.

Endothelial dysfunction is considered an early marker of atherosclerosis, and growing evidence supports the theory that fish oil may improve endothelial function. In vi-tro studies consistently show that omega-3 fatty acids decrease the expression of adhesion molecules on the endothelium and also decrease interactions between leukocytes and the endothelium. Clinical experimental studies show that omega-3 fatty acid supplementation improves endothelial-dependent vasomotor function. In a recent study, fish oil reduced plasma E-selectin in diabetics and nondiabetics, but the reduction was more pronounced among diabetics; the reduction in vascular cell adhesion molecule-1 was observed only in diabetics.11-14 These findings suggest fish oil may be particularly important for altering endothelial cell activation among diabetic patients.

The antiarrhythmic effects of omega-3 fatty acids are well established. Animal studies have shown that feeding them fish oil effectively reduces the incidence and duration of cardiac arrhythmias. In a case-control study, Siscovick and colleagues found that dietary intake and cell membrane levels of long-chain omega-3 fatty acids were as-sociated with a significantly lower risk of primary sudden cardiac arrest.15 Several mechanisms have been proposed to explain the antiarrhythmic effect of fish oil, including modification of the eicosanoid system, which reduces the production of thromboxane A2, alteration of

the fatty acid composition of membrane phospholipids, effects on various enzymes and receptors, inhib-ition of the voltage-gated sodium channels, and changes in heart rate variability.5,15-18

Because diabetics are more prone to ventricular arrhythmias and sudden cardiac death, an adequate intake of long-chain omega-3 fatty acids may be particularly important for diabetic patients to reduce cardiovascular mortality.

Two secondary prevention trials, the Diet and Reinfarction Trial (DART) and the Gruppo Italiano

per lo Studio della Streptochinasi nell’Infarto Miocardio (GISSI)-Prevenzione trial, indicate that fish consumption or fish oil supplementation reduces coronary mortality among patients after MI.19,20 Controlled trials of fish oil supplementation on the prevention of CHD and mortality among diabetics are clearly needed.

Conclusion

Our prospective study provides evidence for the beneficial effects of fish and omega-3 fatty acid consumption on the risk of CHD and total mortality among diabetic women. These findings suggest that regular fish consumption can be included as part of a healthy diet for diabetes management.