Adiposity and Mortality in Men

Inkyung Baik1, Alberto Ascherio1,2, Eric B. Rimm1,2, Edward Giovannucci3, Donna Spiegelman2,4, Meir J. Stampfer1,2,3 and Walter C. Willett1,2,3

1 Department of Nutrition, Harvard School of Public Health, Boston, MA.
2 Department of Epidemiology, Harvard School of Public Health, Boston, MA.
3 Channing Laboratory, Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, MA.
4 Department of Biostatistics, Harvard School of Public Health, Boston, MA.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The relation between measures of adiposity and mortality has been a controversial topic. The authors examined prospectively the relation between several measures of adiposity and risks of overall and cause-specific mortality in 39,756 US men aged 40–75 years. During 10 years of follow-up (1986–1996), 1,972 deaths (747 from cancer, 423 from cardiovascular disease, and 802 from other causes) were documented. An elevated risk of death among the leanest men was partly accounted for by excess mortality during early follow-up and high mortality among those with a history of recent weight loss. After exclusion of men with substantial recent weight loss and deaths occurring during the first 4 years of follow-up, overall and cardiovascular disease mortality among men aged <65 years increased linearly with greater body mass index (BMI) (weight (kg)/height (m)2); multivariate relative risks for overall mortality were 1.0 (referent) for a BMI of <23, 1.21 for a BMI of 23–24.9, 1.19 for a BMI of 25–26.9, 1.39 for a BMI of 27–29.9, and 1.97 for a BMI of >=30 (test for trend: p < 0.001). Among men aged >=65 years, there were no significant relations between BMI and overall, cardiovascular disease, or cancer mortality risk. However, waist circumference strongly predicted risk of death from cardiovascular disease among the older men. These findings indicated that the relation between body fat and mortality was influenced by reverse causation and varied by age. Am J Epidemiol 2000;152:264–71.

age factors; body constitution; body mass index; men; mortality

Abbreviations: CI, confidence interval.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The relation between body fat, usually assessed as body mass index (weight (kg)/height (m)2), and mortality has been a controversial topic. Some have proposed that there is no distinct relation (1GoGoGo–4Go), while others have proposed that the relation is J-shaped (1Go, 3Go, 5GoGoGoGoGo–10Go), U-shaped (3Go, 11GoGoGoGoGo–16Go), directly linear (4Go, 6Go, 17GoGoGo–20Go), or inversely linear (21GoGoGo–24Go). Many previous investigations relating body weight to mortality have had important methodological limitations, including failure to consider the effects of preexisting illness on weight or confounding by cigarette smoking (which is associated with both leanness and increased mortality) and inappropriate control for physiologic and metabolic effects of obesity, such as hypertension and diabetes (25Go). In an analysis that attempted to address these issues in a large population of female nurses, we found a direct linear relation between body mass index in midlife and total mortality and an increased risk of death associated with a weight gain of more than 10 kg after age 18 years (20Go). The association between body mass index and mortality is likely to be modified by age, partly because low body weight in the elderly may be due to depletion of lean body mass from preclinical or chronic illness and reduced physical activity (26GoGo–28Go). Therefore, simplistic analyses relating body weight to mortality in the elderly can be particularly misleading. Indeed, in a recent large prospective study limited to nonsmoking men and women, body mass index was linearly related to higher overall and cardiovascular disease mortality, but this relation weakened with increasing age, and after age 75 years, little association remained (29Go). In older populations, measures of body fat, such as waist and hip circumferences or waist:hip circumference ratio, may more specifically reflect body fatness (30Go) and thus be better indicators than body mass index for risk of overall and cardiovascular disease mortality (10Go, 31Go). The purpose of this report is to examine indicators of adiposity–specifically, body mass index, waist and hip circumferences, and waist:hip circumference ratio–in relation to mortality among men, including how these relations depend on age.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Study population
The Health Professionals Follow-up Study is a prospective investigation of 51,529 male health professionals between 40 and 75 years of age in 1986. The cohort includes dentists, veterinarians, pharmacists, optometrists, osteopaths, and podiatrists who completed a detailed dietary and lifestyle questionnaire in 1986 and who have been followed by biennial mailed questionnaires (31GoGoGo–34Go). In this analysis, we excluded 10,751 men who, on the baseline questionnaire, reported previous myocardial infarction (n = 2,290), angina (n = 760), coronary artery bypass grafting or angioplasty (n = 1,016), stroke (n = 283), transient cerebral ischemia (n = 211), peripheral venous thrombosis (n = 220), intermittent claudication (n = 134), pulmonary embolus (n = 177), paroxysmal atrial tachycardia and other heart-rhythm disturbances (n = 4,049), cancer (except for nonmelanoma skin cancer) (n = 1,527), chronic renal failure (n = 39), and chronic pulmonary disease (n = 45). Subjects who did not specify body weight (n = 919), who had a body mass index outside the range of 15–50 (n = 37), or whose death had not been confirmed (n = 66) were also excluded. The remaining 39,756 men were eligible in this analysis for follow-up for all-cause mortality.

Measures
On the 1986 questionnaire, we gathered information on age, current height (in inches) and weight (in pounds), weight at age 21 years (in pounds), current and past smoking status, marital status, family history of coronary heart disease and cancer, and weight change in the last 5 years (using 11 categories ranging from -15 pounds (6.8 kg) or more to +30 pounds (13.6 kg) or more). We also obtained dietary information from a semiquantitative food frequency questionnaire (35Go35) and a metabolic equivalent-hour score from a standardized physical activity questionnaire (36Go). We calculated body mass index using weight and height in 1986 and also recalled weight at age 21. In 1987, we mailed a paper tape and a pictorial instruction guide to participants to obtain self-measured waist circumference at the umbilicus and the largest hip circumference between the waist and thighs. Sixty-five percent of the initial participants provided circumference measurements.

The validity of the self-reported anthropometric measurements was examined among 123 men living in the Greater Boston, Massachusetts, area who had their waist, hips, and weight measured by technicians twice 6 months apart. After adjustment for age and within-person variability, the Pearson correlation coefficients between the self-reported measures and the average of the two technician assessments were 0.97 for weight, 0.95 for waist circumference, 0.88 for hip circumference, and 0.68 for waist:hip ratio. The correlations were essentially the same for all strata of age, smoking status, and body mass index (37Go).

Ascertainment of mortality
Deaths were ascertained by responses to follow-up questionnaires by family members or the postal service and by a search of the National Death Index (38Go). Participants who did not respond were assumed to be alive if they were not listed in the National Death Index. Whenever a death from cancer or cardiovascular disease was identified, we sought medical records to confirm the diagnosis. We obtained death certificates for all deaths whose cause was not confirmed from other sources. Cause of death was assigned on the basis of all available information, including death certificates, medical records, and autopsy results. We classified deaths that occurred through January 31, 1996, as being due to coronary heart disease (International Classification of Diseases, Ninth Revision, codes 410–414), cardiovascular disease (codes 390–459), cancer (codes 140–207), or all other causes.

Statistical analysis
We grouped men into six categories of body mass index using whole number cutpoints that included widely used definitions of overweight and obesity (25Go, 30Go) and into quintiles of waist circumference, hip circumference, and waist:hip ratio. To assess associations with waist circumference, hip circumference, and waist:hip ratio, we further excluded the men who died or were diagnosed with one of the diseases indicated above between 1986 and 1987. The number of deaths and the cumulative number of person-years of follow-up were assigned to each category of exposure as determined at baseline. We calculated relative risks adjusted for age (5-year categories) using the Mantel-Haenszel method (39Go), and we used the Mantel extension test (40Go) to test for a linear trend. We also estimated relative risks (adjusted for age, smoking, and other risk factors) as odds ratios using multiple logistic regression models. Each multiple logistic regression model included information on risk factors reported on the baseline questionnaire, such as family history of myocardial infarction or colon cancer before age 60, profession, marital status, height, and daily consumption of alcohol, antioxidant vitamins, and dietary fiber, because these factors may be associated with mortality, particularly mortality from cancer or cardiovascular disease. We obtained information on physical activity and on history of diabetes, hypertension, and hyperlipidemia, but we did not control for these factors in our multivariate analyses, because physical activity is a major determinant of body weight and the other variables are considered to be in the causal pathway between body weight and mortality. In our models, we tested for significant linear trends by using the median values of the categories to create a single continuous variable. In additional analyses as well as in cause- or age-specific analyses, to minimize the effects of preclinical or chronic illness on the association between body mass index and mortality, we excluded person-time from the first 4 years of follow-up and men who experienced a weight loss of 10 pounds or more (>=4.5 kg) in the 5 years before 1986. Separate analyses were also conducted for men aged <65 years in 1986 and men aged >=65 years in 1986. In age-specific analyses, we combined two categories of body mass index (<21 and 21–22.9) because of the small numbers of deaths among the leanest men, and then used the body mass index category of <23 as the reference group. In analyses for waist and hip circumferences and waist:hip ratio, we used the lowest quintile or tertile as the reference group.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Body mass index at baseline
During 10 years of follow-up (368,821 person-years), we documented 1,972 deaths. Of these, 747 deaths were from cancer (18 percent lung cancer, 12 percent prostate cancer, 10 percent pancreatic cancer, 9 percent colon cancer, and 51 percent other cancers), 423 were from cardiovascular disease (65 percent ischemic heart disease, 20 percent stroke, and 15 percent other circulatory diseases), and 802 were from other causes (19 percent sudden death, 18 percent external causes of injury and poisoning, 11 percent respiratory diseases, and 52 percent other causes).

Table 1 provides the mean values for anthropometric measurements and other potential risk factors according to categories of body mass index in 1986. Waist and hip circumferences, body mass index at age 21, and weight gain after age 21 were directly associated with body mass index at baseline. The leanest men were more likely to smoke at the beginning of the study, but the prevalence of current smoking was low. The prevalence of self-reported hypertension, diabetes, and hypercholesterolemia was 1.5–3 times higher among the heaviest men than among the leanest men. Men with greater body mass indices were also more likely to be sedentary, and they consumed slightly more fat and less fiber and vitamins.


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TABLE 1. Age-standardized baseline characteristics, by category of body mass index, in 39,756 US men aged 40–75 years in 1986: Health Professionals Follow-up Study, 1986–1996

 
We observed a U-shaped relation between body mass index and overall mortality in the age-adjusted and multivariate-adjusted analyses for all subjects. The lowest mortality was observed among men with body mass indices between 23 and 24.9. When we reduced bias due to preclinical or chronic illness by excluding men who had experienced weight loss of 10 pounds or more in the 5 years before 1986 (4,354 men) and deaths occurring during the first 4 years of follow-up (948 deaths), the excess mortality among the leanest men was reduced by about half (table 2).


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TABLE 2. Relative risk of overall mortality, by category of body mass index in 1986: Health Professionals Follow-up Study, 1986–1996

 
Although we attempted to exclude participants with major illness, men in the lowest body mass index category were still likely to have been a mix of those who were lean and healthy because of regular physical activity and those who were wasted as a result of chronic illness and at high risk of dying. Because level of physical activity may distinguish persons who are lean and healthy from those who are lean due to chronic disease, we stratified the data by this variable to examine the relation between low body mass index and mortality. Using the third model in table 2 (multivariate, excluding men with weight loss of >=10 pounds in the past 5 years), the elevated risk of death among men with a body mass index less than 21 was limited to those in the lowest quintile of physical activity in 1986. Among men in the lowest quintile of physical activity, the multivariate relative risk was 2.03 (95 percent confidence interval (CI): 1.26, 3.26) for a body mass index less than 21 compared with a body mass index of 23–24.9, and among men in the upper four quintiles of physical activity, the multivariate relative risk was 1.18 (95 percent CI: 0.88, 1.59) for the same body mass index comparison. These data indicate that men who are lean and active are not at appreciably higher risk of death, and that the overall excess mortality among the leanest men is concentrated in those who are also inactive.

In age-specific analyses, we confirmed a direct linear relation between body mass index and all-cause mortality among men younger than age 65 years in 1986 (table 3). In contrast, among men aged 65 years or older, a U-shaped relation between body mass index and overall mortality persisted. The number of deaths among men who had never smoked was insufficient for informative age-specific analyses.


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TABLE 3. Relative risk of overall and cause-specific mortality (1990–1996), by category of body mass index and by age (<65 and >=65 years), among men without weight loss of >=10 pounds in the past 5 years: Health Professionals Follow-up Study, 1986–1996

 
We next examined body mass index in relation to cause-specific mortality risk separately for men younger than age 65 years and those aged 65 years or more during the follow-up from 1990 through 1996 (table 3). After multivariate adjustment, body mass index was strongly related to death from cardiovascular disease among men younger than age 65; similar associations were seen for coronary heart disease (44 deaths). However, among the older men, there were no clear relations between body mass index and risk of death from cardiovascular disease (table 3) or coronary heart disease (29 deaths). In both age groups, there was no significant relation between body mass index and mortality due to overall cancer. For men aged 65 years or more, mortality from causes other than cardiovascular disease or cancer was elevated among both the leanest and the most obese (table 3). A major cause of death among the leanest men was re-spiratory disease (International Classification of Diseases, Ninth Revision, codes 460–519, mainly chronic respiratory diseases; 67 percent of all deaths due to other causes). Among the older men without weight loss of >=10 pounds in the past 5 years, the multivariate relative risks of respiratory disease mortality (19 deaths; 13.5 percent of deaths due to all other causes reported between 1990 and 1996), using a body mass index of <23 as the reference group, were 0.12 (95 percent CI: 0.02, 0.58) for a body mass index of 23–24.9 and 0.18 (95 percent CI: 0.06, 0.51) for a body mass index of >=25 (test for trend: p = 0.005). Among men younger than age 65 without weight loss of >=10 pounds in the past 5 years, only seven deaths were due to respiratory disease (3.4 percent of all other causes reported between 1990 and 1996).

Body circumference
Waist circumference, hip circumference, and waist:hip ratio were each positively related to overall mortality after adjustment for the same covariates used for the multivariate analysis of table 2. In analyses stratified by age, we observed strong positive associations between waist circumference and mortality among men younger than age 65 years in 1986 (table 4).


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TABLE 4. Relative risk of overall mortality (1987–1996), by quintile of body circumference: Health Professionals Follow-up Study, 1986–1996

 
In cause-specific analyses, waist circumference strongly predicted risk of cardiovascular disease mortality in both age groups. The multivariate relative risks of death from cardiovascular disease according to increasing quintiles, using the same categories and reference category for waist circumference as indicated in table 4, were 1.54 (95 percent CI: 0.79, 2.99), 0.74 (95 percent CI: 0.32, 1.73), 1.78 (95 percent CI: 0.93, 3.41), and 2.94 (95 percent CI: 1.56, 5.52) (test for trend: p < 0.001) among men younger than age 65 (119 deaths) and 0.72 (95 percent CI: 0.27, 1.96), 2.37 (95 percent CI: 1.03, 5.45), 1.98 (95 percent CI: 0.88, 4.48), and 3.50 (95 percent CI: 1.60, 7.66) (test for trend: p < 0.001) among the older men (116 deaths). Among the younger men, the multivariate relative risks of cancer mortality (250 deaths) according to increasing quintiles of waist circumference, using the same categories and reference group as in table 4, were 1.24 (95 percent CI: 0.79, 1.94), 1.45 (95 percent CI: 0.92, 2.29), 1.45 (95 percent CI: 0.94, 2.24), and 1.62 (95 percent CI: 1.04, 2.52) (test for trend: p = 0.03), but among the older men (206 cancer deaths), they were 1.34 (95 percent CI: 0.82, 2.19), 0.75 (95 percent CI: 0.43, 1.32), 0.96 (95 percent CI: 0.59, 1.59), and 0.93 (95 percent CI: 0.56, 1.55).

We found no significant relations between waist circumference and mortality from all causes other than cardiovascular disease and cancer combined in either age group (data are available from the authors upon request). However, we observed a strong inverse linear relation between waist circumference and mortality risk from respiratory diseases, especially among men aged 65 years or more. Using men in the lowest tertile of waist circumference as the reference group, the multivariate relative risks among the younger men (15 deaths) for increasing tertiles of waist circumference were 0.93 (95 percent CI: 0.26, 3.40) and 0.67 (95 percent CI: 0.17, 2.65) (test for trend: p = 0.53), and among the older men (34 deaths), the relative risks were 0.59 (95 percent CI: 0.27, 1.29) and 0.28 (95 percent CI: 0.10, 0.75) (test for trend: p = 0.01).


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In this 10-year prospective cohort study, we observed a direct relation between body mass index and overall mortality among men younger than age 65 years at baseline after attempting to account for possible confounding factors, including smoking status and reverse causation due to preclinical or chronic illness. Among men aged 65 years or more, body mass index was not appreciably related to risk of overall mortality. However, waist circumference was related directly to risk of death due to cardiovascular disease and coronary heart disease among the older men.

A direct association between body mass and overall mortality was noted in some previous studies. Jarrett et al. (6Go) examined the different relations according to age and confirmed a linear relation only among men below age 50 years. Lee et al. (19Go) reported a J-shaped relation for all subjects but observed a linear trend among men who had never smoked, after excluding deaths occurring during the first 5 years of follow-up. Accounting for sources of bias in previous studies, Manson et al. (20Go) observed a linear relation among women aged 30–55 years at baseline. In a recent large analysis of never smokers, a linear relation was seen up to the age of 75 years (29Go). Most of the remaining studies relating body mass to mortality reported J-shaped or U-shaped relations (1Go, 3Go, 5GoGoGoGoGoGoGoGoGoGoGo–16Go); some reported an inverse relation for elderly subjects (21Go, 22Go), but in few of these studies were the effects of confounding and reverse causation adequately addressed.

In an attempt to account for the effects of preclinical or chronic illness on body weight, we excluded men who reported having a chronic disease in 1986 or who experienced a weight loss of >=10 pounds in the 5 years before 1986, and we further eliminated the deaths occurring early in the follow-up period. These procedures substantially reduced the apparent excess risk of death among the leanest men.

In cause-specific analyses, we confirmed the previously reported associations between body mass index and mortality due to cardiovascular disease and coronary heart disease among men under the age of 65 years (6Go, 31Go, 41Go, 42Go). Among men aged 65 years or more, there were no clear relations between body mass index and risks of overall or cause-specific mortality, except for a strong inverse association with respiratory mortality. We also observed that approximately two thirds of the deaths occurring among the leanest elderly men were due to respiratory disease, mainly emphysema and chronic bronchitis. Thus, the interpretation of the elevated mortality among the leanest older men depends heavily on whether being lean causes chronic pulmonary disease or is the result of chronic pulmonary disease. There is no support for the first possibility, but chronic pulmonary disease may precede death by many years, and it is known to cause weight loss. Among patients with chronic obstructive pulmonary disease, progressive weight loss may be a marker of severity, since it is associated with poorer lung function, increased incidence of heart failure, and higher mortality (43GoGoGo–46Go).

We observed that mean levels of physical activity (in metabolic equivalent-hours per week) in 1986 were 20.4 for those who were still alive in 1996, 6.2 for those who died of chronic pulmonary disease, and 16.7 for those who died of other causes; this suggests that men who died of pulmonary disease were already sufficiently ill at baseline for their function to be substantially affected. Notably, of the 59 men who died of chronic lung disease during 10 years of follow-up, only two reported this at baseline in response to a question about "other major illness," even though this condition almost certainly existed at that time. In addition, compared with men with stable weight, the relative risk of death due to chronic lung disease for men with >=10 pounds of weight loss since age 21 was 5.25 (95 percent CI: 1.62, 17.0), but this was only reduced to 4.52 (95 percent CI: 1.08, 18.9) after exclusion of men with >=10 pounds of weight loss in the past 5 years. Thus, the most likely explanation for the increase in mortality risk among the lean men is reverse causation that we were unable to eliminate, despite exclusions made on the basis of existing diagnoses and weight loss in the past 5 years and the elimination of deaths occurring early in the follow-up period. The lack of increased mortality among the lean active men but presence of high mortality among the lean inactive men also supports a role for reverse causation as the explanation for the overall elevation in mortality observed among the leanest men. It is likely that a similar artifact also contributed to the increased risk seen among lean persons in other studies of body weight and mortality. Reverse causation from chronic pulmonary disease and other chronic illness is likely to contribute to the weaker associations between body mass index or waist circumference and overall mortality among older persons, because relatively few die of chronic pulmonary disease before age 65. Body mass index is an excellent measure of adiposity in young adults and middle-aged persons, but in the elderly it is likely to have reduced validity as an indicator of fatness (30Go). The correlation between body mass index and lean body mass tends to increase with age, and weight loss due to loss of lean mass is more common among the elderly because of inactivity and chronic disease (Go, 27Go, 30Go, 47Go). Because a large waist is an unambiguous indicator of excess body fat (ascites excluded), waist circumference may be a better measure of overall body fat than body mass index in the elderly. In addition, fat mass tends to accumulate intraabdominally with age (48Go), so the importance of abdominal adiposity in metabolic disturbances and health hazards is greater in the elderly (49Go). We previously reported during 3 years of follow-up of this cohort that waist circumference and waist:hip circumference ratio were stronger predictors of incident coronary heart disease in men over age 65 than was body mass index (31Go). Folsom et al. (10Go) found a linear relation between waist:hip ratio and mortality risk among 41,837 women aged 55–69 years, and Larsson et al. (50Go) also observed a linear relation in a small cohort of 855 men.

Our study had several limitations. Weight, height, and waist and hip circumferences were not measured directly but were self-reported by the participants. However, as our validation study showed, it is unlikely that this seriously biased our findings (37Go). The need to exclude persons with chronic conditions at baseline resulted in the elimination of a large number of deaths due to cardiovascular disease, which was the cause of death most strongly related to body fat. In the general US population, almost 40 percent of adult deaths are due to coronary heart disease (3Go, 14Go), in contrast to 18 percent in this analysis.

In summary, we found evidence that reverse causation strongly influenced the shape of the relation between body mass index and mortality in these data. Even with careful attempts to reduce this artifact by excluding persons who reported chronic disease at baseline and those with recent weight loss, we were unable to completely avoid the effects of reverse causation, especially that due to chronic pulmonary disease. Thus, weight guidelines should utilize data on disease incidence, which is less likely to be affected by reverse causation, as well as mortality. Despite these limitations, our prospective data indicated that adiposity is an important determinant of mortality for men. After we attempted to account for the effects of preclinical or chronic illness, among men younger than age 65 the lowest risk of overall mortality was seen for body mass indices below 23. For men aged 65 years or more, body mass index was not a good predictor of mortality risk, but waist circumference was strongly associated with cardiovascular disease mortality. These findings suggest that excessive body fat contributes to mortality at all ages, but that in older men guidelines based on waist circumference rather than weight alone may be most useful.


    ACKNOWLEDGMENTS
 
This study was supported by research grants HL 35464, CA 55075, and DK 46200 from the National Institutes of Health. Dr. Inkyung Baik was supported by a fellowship in science research from the Korea Research Foundation.


    NOTES
 
Reprint requests to Dr. Walter C. Willett, Department of Nutrition, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115.


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Received for publication March 3, 1999. Accepted for publication September 17, 1999.