C H Hennekens

Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease.

BACKGROUND Observational studies suggest that people who consume more fruits and vegetables containing beta carotene have somewhat lower risks of cancer and cardiovascular disease, and earlier basic research suggested plausible mechanisms. Because large randomized trials of long duration were necessary to test this hypothesis directly, we conducted a trial of beta carotene supplementation. METHODS In a randomized, double-blind, placebo-controlled trial of beta carotene (50 mg on alternate days), we enrolled 22,071 male physicians, 40 to 84 years of age, in the United States; 11 percent were current smokers and 39 percent were former smokers at the beginning of the study in 1982. By December 31, 1995, the scheduled end of the study, fewer than 1 percent had been lost to follow-up, and compliance was 78 percent in the group that received beta carotene. RESULTS Among 11,036 physicians randomly assigned to receive beta carotene and 11,035 assigned to receive placebo, there were virtually no early or late differences in the overall incidence of malignant neoplasms or cardiovascular disease, or in overall mortality. In the beta carotene group, 1273 men had any malignant neoplasm (except nonmelanoma skin cancer), as compared with 1293 in the placebo group (relative risk, 0.98; 95 percent confidence interval, 0.91 to 1.06). There were also no significant differences in the number of cases of lung cancer (82 in the beta carotene group vs. 88 in the placebo group); the number of deaths from cancer (386 vs. 380), deaths from any cause (979 vs. 968), or deaths from cardiovascular disease (338 vs. 313); the number of men with myocardial infarction (468 vs. 489); the number with stroke (367 vs. 382); or the number with any one of the previous three end points (967 vs. 972). Among current and former smokers, there were also no significant early or late differences in any of these end points. CONCLUSIONS In this trial among healthy men, 12 years of supplementation with beta carotene produced neither benefit nor harm in terms of the incidence of malignant neoplasms, cardiovascular disease, or death from all causes.

Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.

Summary Background Low-dose aspirin is of definite and substantial net benefit for many people who already have occlusive vascular disease. We have assessed the benefits and risks in primary prevention. Methods We undertook meta-analyses of serious vascular events (myocardial infarction, stroke, or vascular death) and major bleeds in six primary prevention trials (95 000 individuals at low average risk, 660 000 person-years, 3554 serious vascular events) and 16 secondary prevention trials (17 000 individuals at high average risk, 43 000 person-years, 3306 serious vascular events) that compared long-term aspirin versus control. We report intention-to-treat analyses of first events during the scheduled treatment period. Findings In the primary prevention trials, aspirin allocation yielded a 12% proportional reduction in serious vascular events (0·51% aspirin vs 0·57% control per year, p=0·0001), due mainly to a reduction of about a fifth in non-fatal myocardial infarction (0·18% vs 0·23% per year, p<0·0001). The net effect on stroke was not significant (0·20% vs 0·21% per year, p=0·4: haemorrhagic stroke 0·04% vs 0·03%, p=0·05; other stroke 0·16% vs 0·18% per year, p=0·08). Vascular mortality did not differ significantly (0·19% vs 0·19% per year, p=0·7). Aspirin allocation increased major gastrointestinal and extracranial bleeds (0·10% vs 0·07% per year, p<0·0001), and the main risk factors for coronary disease were also risk factors for bleeding. In the secondary prevention trials, aspirin allocation yielded a greater absolute reduction in serious vascular events (6·7% vs 8·2% per year, p<0.0001), with a non-significant increase in haemorrhagic stroke but reductions of about a fifth in total stroke (2·08% vs 2·54% per year, p=0·002) and in coronary events (4·3% vs 5·3% per year, p<0·0001). In both primary and secondary prevention trials, the proportional reductions in the aggregate of all serious vascular events seemed similar for men and women. Interpretation In primary prevention without previous disease, aspirin is of uncertain net value as the reduction in occlusive events needs to be weighed against any increase in major bleeds. Further trials are in progress. Funding UK Medical Research Council, British Heart Foundation, Cancer Research UK, and the European Community Biomed Programme.BACKGROUND Low-dose aspirin is of definite and substantial net benefit for many people who already have occlusive vascular disease. We have assessed the benefits and risks in primary prevention. METHODS We undertook meta-analyses of serious vascular events (myocardial infarction, stroke, or vascular death) and major bleeds in six primary prevention trials (95,000 individuals at low average risk, 660,000 person-years, 3554 serious vascular events) and 16 secondary prevention trials (17,000 individuals at high average risk, 43,000 person-years, 3306 serious vascular events) that compared long-term aspirin versus control. We report intention-to-treat analyses of first events during the scheduled treatment period. FINDINGS In the primary prevention trials, aspirin allocation yielded a 12% proportional reduction in serious vascular events (0.51% aspirin vs 0.57% control per year, p=0.0001), due mainly to a reduction of about a fifth in non-fatal myocardial infarction (0.18%vs 0.23% per year, p<0.0001). The net effect on stroke was not significant (0.20%vs 0.21% per year, p=0.4: haemorrhagic stroke 0.04%vs 0.03%, p=0.05; other stroke 0.16%vs 0.18% per year, p=0.08). Vascular mortality did not differ significantly (0.19%vs 0.19% per year, p=0.7). Aspirin allocation increased major gastrointestinal and extracranial bleeds (0.10%vs 0.07% per year, p<0.0001), and the main risk factors for coronary disease were also risk factors for bleeding. In the secondary prevention trials, aspirin allocation yielded a greater absolute reduction in serious vascular events (6.7%vs 8.2% per year, p<0.0001), with a non-significant increase in haemorrhagic stroke but reductions of about a fifth in total stroke (2.08%vs 2.54% per year, p=0.002) and in coronary events (4.3%vs 5.3% per year, p<0.0001). In both primary and secondary prevention trials, the proportional reductions in the aggregate of all serious vascular events seemed similar for men and women. INTERPRETATION In primary prevention without previous disease, aspirin is of uncertain net value as the reduction in occlusive events needs to be weighed against any increase in major bleeds. Further trials are in progress. FUNDING UK Medical Research Council, British Heart Foundation, Cancer Research UK, and the European Community Biomed Programme.

Physical activity and incidence of non-insulin-dependent diabetes mellitus in women

The potential role of physical activity in the primary prevention of non-insulin-dependent diabetes mellitus (NIDDM) is largely unknown. We examined the association between regular vigorous exercise and the subsequent incidence of NIDDM in a prospective cohort of 87,253 US women aged 34-59 years and free of diagnosed diabetes, cardiovascular disease, and cancer in 1980. During 8 years of follow-up, we confirmed 1303 cases of NIDDM. Women who engaged in vigorous exercise at least once per week had an age-adjusted relative risk (RR) of NIDDM of 0.67 (p less than 0.0001) compared with women who did not exercise weekly. After adjustment for body-mass index, the reduction in risk was attenuated but remained statistically significant (RR = 0.84, p = 0.005). When analysis was restricted to the first 2 years after ascertainment of physical activity level and to symptomatic NIDDM as the outcome, age-adjusted RR of those who exercised was 0.5, and age and body-mass index adjusted RR was 0.69. Among women who exercised at least once per week, there was no clear dose-response gradient according to frequency of exercise. Family history of diabetes did not modify the effect of exercise, and risk reduction with exercise was evident among both obese and nonobese women. Multivariate adjustments for age, body-mass index, family history of diabetes, and other variables did not alter the reduced risk found with exercise. Our results indicate that physical activity may be a promising approach to the primary prevention of NIDDM.

Moderate Alcohol Intake, Increased Levels of High-Density Lipoprotein and Its Subfractions, and Decreased Risk of Myocardial Infarction

BACKGROUND Previous studies have suggested that moderate alcohol intake exerts a protective effect against coronary heart disease. Alterations in plasma lipoprotein levels represent one plausible mechanism of this apparent protective effect. METHODS We therefore examined the interrelation among alcohol consumption, plasma lipoprotein levels, and the risk of myocardial infarction in 340 patients who had had myocardial infarctions and an equal number of age- and sex-matched controls. The case patients were men or women less than 76 years of age with no history of coronary disease who were discharged from one of six hospitals in the Boston area with a diagnosis of a confirmed myocardial infarction. Alcohol consumption was estimated by means of a food-frequency questionnaire. RESULTS We observed a significant inverse association between alcohol consumption and the risk of myocardial infarction (P for trend, < 0.001 after control for known coronary risk factors). In multivariate analyses, the relative risk for the highest intake category (subjects who consumed three or more drinks per day) as compared with the lowest (those who had less than one drink a month) was 0.45 (95 percent confidence interval, 0.26 to 0.80). The levels of total high-density lipoprotein cholesterol (HDL) and its HDL2 and HDL3 subfractions were strongly associated with alcohol consumption (P for trend, < 0.001 for each). The addition of HDL or either of its subfractions to the multivariate model substantially reduced the inverse association between alcohol intake and myocardial infarction, whereas the addition of the other plasma lipid measurements did not materially alter the relation. CONCLUSIONS These data confirm the inverse association of moderate alcohol intake with the risk of myocardial infarction and support the view that the effect is mediated, in large part, by increases in both HDL2 and HDL3.

Alcohol consumption and mortality among women.

BACKGROUND Studies in men suggest that light-to-moderate alcohol intake is associated with a reduction in overall mortality, due primarily to a reduced risk of coronary heart disease. Among women with similar levels of alcohol consumption, an increased risk of breast cancer has been noted that complicates the balance of risks and benefits. METHODS We conducted a prospective study among 85,709 women, 34 to 59 years of age and without a history of myocardial infarction, angina, stroke, or cancer, who completed a dietary questionnaire in 1980. During the 12-year follow-up period, 2658 deaths were documented. RESULTS The relative risks of death in drinkers as compared with nondrinkers were 0.83 (95 percent confidence interval, 0.74 to 0.93) for women who consumed 1.5 to 4.9 g of alcohol per day (one to three drinks per week), 0.88 (95 percent confidence interval, 0.80 to 0.98) for those who consumed 5.0 to 29.9 g per day, and 1.19 (95 percent confidence interval, 1.02 to 1.38) for those who consumed 30 g or more per day, after adjustment for other predictors of mortality. Light-to-moderate drinking (1.5 to 29.9 g per day) was associated with a decreased risk of death from cardiovascular disease; heavier drinking was associated with an increased risk of death from other causes, particularly breast cancer and cirrhosis. The benefit associated with light-to-moderate drinking was most apparent among women with risk factors for coronary heart disease and those 50 years of age or older. CONCLUSIONS Among women, light-to-moderate alcohol consumption is associated with a reduced mortality rate, but this apparent survival benefit appears largely confined to women at greater risk for coronary heart disease.

A prospective study of whole-grain intake and risk of type 2 diabetes mellitus in US women.

OBJECTIVES This study examined the association between intake of whole vs refined grain and the risk of type 2 diabetes mellitus. METHODS We used a food frequency questionnaire for repeated dietary assessments to prospectively evaluate the relation between whole-grain intake and the risk of diabetes mellitus in a cohort of 75,521 women aged 38 to 63 years without a previous diagnosis of diabetes or cardiovascular disease in 1984. RESULTS During the 10-year follow-up, we confirmed 1879 incident cases of diabetes mellitus. When the highest and the lowest quintiles of intake were compared, the age and energy-adjusted relative risks were 0.62 (95% confidence interval [CI] = 0.53, 0.71, P trend < .0001) for whole grain, 1.31 (95% CI = 1.12, 1.53, P trend = .0003) for refined grain, and 1.57 (95% CI = 1.36, 1.82, P trend < .0001) for the ratio of refined- to whole-grain intake. These findings remained significant in multivariate analyses. The findings were most evident for women with a body mass index greater than 25 and were not entirely explained by dietary fiber, magnesium, and vitamin E. CONCLUSIONS These findings suggest that substituting whole- for refined-grain products may decrease the risk of diabetes mellitus.

Moderate Alcohol Consumption and the Risk of Breast Cancer

In 1980, 89,538 U.S. women 34 to 59 years of age, with no history of cancer, completed an independently validated dietary questionnaire that included the use of beer, wine, and liquor. During the ensuring four years, 601 cases of breast cancer were diagnosed among cohort members. Among the women consuming 5 to 14 g of alcohol daily (about three to nine drinks per week), the age-adjusted relative risk of breast cancer was 1.3 (95 percent confidence limits, 1.1 and 1.7). Consumption of 15 g of alcohol or more per day was associated with a relative risk of 1.6 (95 percent confidence limits, 1.3 and 2.0; Mantel extension chi for linear trend = +4.2; P less than 0.0001). Adjustment for known breast cancer risk factors and a variety of nutritional variables did not materially alter this relation. Significant associations were observed for beer and liquor when considered separately. Among women without risk factors for breast cancer who were under 55 years of age, the relative risk associated with consumption of 15 g of alcohol or more per day was 2.5 (95 percent confidence limits, 1.5 and 4.2). These prospective data derived from measurements of alcohol intake recorded before the diagnosis of breast cancer confirm the findings of several previous case-control studies. Viewed collectively, they suggest that alcohol intake may contribute to the risk of breast cancer.

Trans-fatty acids intake and risk of myocardial infarction.

BACKGROUND Concern that trans-fatty acids formed in the partial hydrogenation of vegetable oils may increase the risk of coronary disease has existed for several decades, but direct evidence on this relation in humans is limited. METHODS AND RESULTS With a case-control design, we studied the association between intake of trans-fatty acids and a first acute myocardial infarction among 239 patients admitted to one of six hospitals in the Boston area and 282 population control subjects. Intake of trans-fatty acids was estimated using a previously validated food frequency questionnaire. After adjustment for age, sex, and energy intake, intake of trans-fatty acids was directly related to risk of myocardial infarction (relative risk for highest compared with lowest quintile, 2.44; 95% confidence interval, 1.42, 4.19; for trend P < .0001). This relation remained highly significant after adjustment for established coronary risk factors, multivitamin use, and intake of saturated fat, monounsaturated fat, linoleic acid, dietary cholesterol, vitamins E and C, carotene, and fiber. Intake of margarine--the major source of trans-isomers--was significantly associated with risk of myocardial infarction. CONCLUSIONS These data support the hypothesis that intake of partially hydrogenated vegetable oils may contribute to the risk of myocardial infarction.

Cigarette smoking and the risk of diabetes in women.

OBJECTIVES Noninsulin-dependent diabetes mellitus, a major risk factor for cardiovascular disease, is prevalent in more than 12 million Americans. A voluminous amount of data demonstrates that cigarette smoking is an important cause of cancer and coronary heart disease. However, the association between cigarette smoking and the risk of diabetes is virtually unexplored, especially in women. METHODS We examined the association between smoking and the incidence of noninsulin-dependent diabetes mellitus among 114,247 female nurses who were free of diabetes, cardiovascular disease, and cancer in 1976. We collected exposure information and disease status prospectively for 12 years from biennially self-administered questionnaires. RESULTS Current smokers had an increased risk of diabetes, and we observed a significant dose-response trend for higher risk among heavier smokers. During 1,277,589 person-years of follow-up, 2333 women were clinically diagnosed with diabetes. The relative risk of diabetes, adjusted for obesity and other risk factors, was 1.42 among women who smoked 25 or more cigarettes per day compared with nonsmokers. CONCLUSIONS These data suggest that cigarette smoking may be an independent, modifiable risk factor for noninsulin-dependent diabetes mellitus.

Decreased HDL2 and HDL3 cholesterol, Apo A-I and Apo A-II, and increased risk of myocardial infarction.

BackgroundA large and consistent body of evidence supports the judgment that elevation of total plasma blood cholesterol is a cause of myocardial infarction (MI) and that high levels of low density lipoprotein (LDL) cholesterol have a positive relation and high levels of high density lipoprotein (HDL) cholesterol an inverse relation with MI. At present, however, the roles, if any, of the major subfractions of HDL, namely, HDL2 and HDL3, have not been clarified. In addition, the relation of plasma apolipoprotein concentrations to MI and whether they provide predictive information over and above their lipoprotein cholesterol associations is unknown. Methods and ResultsWe evaluated these questions in a case-control study of patients hospitalized with a first MI and neighborhood controls of the same age and sex. Cases had significantly lower levels of total HDL (p < 0.0001) as well as HDL2 (p < 0.0001) and HDL3 (p < 0.000l) cholesterol. These differences persisted after controlling for a large number of demographic, medical history, and behavioral risk factors and levels of other lipids. There were significant (p < 0.0001) inverse dose-response relations with odds ratios for those in the highest quartile relative to those in the lowest of 0.15 for total HDL, 0.17 for HDL2, and 0.29 for HDL3 cholesterol levels. Levels of LDL and very low density lipoprotein cholesterol and triglycerides were also higher among cases than controls, but only for triglycerides was the difference statistically significant after adjustment for coronary risk factors and other lipids (p = 0.044). Apolipoproteins A-I and A-II were both significantly (p < 0.0001) lower in cases, and differences remained even after adjustment for coronary risk factors and lipids. There were significant dose-response relations for both apolipoprotein A-I (p = 0.026) and A-II (p = 0.002). Neither apolipoprotein B nor E was significantly related to MI after adjustment for lipids and other coronary risk factors. When all four apolipoproteins were taken together, there was an increased level of prediction of MI over the information provided by the lipids and other coronary risk factors (p = 0.003), but this appeared present only for the individual apolipoproteins A-I (p = 0.027) and A-II (p = 0.011) ConclusionsThese data indicate that both HDL2 and HDL3 cholesterol levels are significantly associated with MI. They also raise the possibility that apolipoprotein levels, especially A-I and A-II, may add importantly relevant information to determination of risk of MI.