From the Department of Preventive Medicine, Northwestern University Medical School, Chicago, IL.
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ABSTRACT |
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body mass index; body weight; body weight changes; cardiovascular diseases; mortality; weight gain; weight loss
Abbreviations: BMI, body mass index; CI, confidence interval; ICD-8, International Classification of Diseases, Eighth Revision.
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INTRODUCTION |
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One approach used to control for unintentional illness-related weight loss is exclusion of early deaths (2, 4
6
, 16
19
, 21
23
, 33
). However, the length of follow-up for which early deaths have been excluded has exceeded 5 years in only one study (22
). In that study, which excluded deaths occurring during the first 8 years, there was still an association between weight loss and increased cardiovascular disease mortality in some subgroups. In a previous report from the Chicago Western Electric Company Study on associations of body mass index (BMI) and other measures of adiposity with coronary heart disease mortality (34
), we found U-shaped relations with mortality through the first 14 years of follow-up for each measure of adiposity. However, for follow-up years 1522, mortality was progressively higher with greater baseline adiposity. Hence, exclusion of deaths occurring in the first few years of follow-up may not be adequate to remove effects of illness on weight.
Few studies of weight change and/or weight variability have reported on associations with mortality for 20 years of follow-up (1
, 6
, 16
, 27
). Hence, there is a paucity of data on the long term associations of weight change with mortality.
In this study, we examined associations of variations and trends in BMI over 8 years with subsequent 25-year mortality from cardiovascular causes and all causes in the Chicago Western Electric Company Study. Because weight loss and weight variability could be consequences of preexisting disease, rather than antecedents, we also examined associations separately for deaths occurring in the first 15 years of follow-up and deaths occurring in years 1625.
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MATERIALS AND METHODS |
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Variables
BMI (weight (kg)/height (m)2) was computed for each weight measurement. The slope of the regression line relating each man's BMI values to the time from baseline was computed to assess his yearly rate of change. Two additional slope variables representing weight loss and weight gain, respectively, were also computed to account for nonlinear associations between slope and mortality. The weight loss slope was defined as the computed slope if it was less than or equal to zero, and zero otherwise. The weight gain slope was defined as the computed slope when it was greater than zero, and zero otherwise. The standard deviation of BMI and the standard deviation about the regression, which assesses variation about the trend in BMI over the period, were computed as measures of weight fluctuation or variation. The average of all body mass measurements between 1958 and 19651966 was used to assess overall level of BMI. Other variables included in the analyses were age at the time of the last weight measurement in 1965 or 1966 and number of cigarettes smoked per day, which was the average of all values reported between baseline and 19651966.
Vital status was determined periodically by mailed questionnaire and telephone interview through the 25th anniversary of the initial examination, when vital status was known for all 2,107 men. Subsequently, vital status was ascertained through the National Death Index. Death certificates were obtained for all decedents and coded with regard to underlying cause of death. These analyses utilized mortality follow-up through December 31, 1990, which corresponds to an average of 25 years from the examination in 1965 or 1966. Underlying cause of death was classified according to the International Classification of Diseases, Eighth Revision (ICD-8), adapted for use in the United States (39). The mortality endpoints were death from all causes and death due to cardiovascular diseases (ICD-8 codes 400.0444.9).
Statistical procedures
Cox proportional hazards regression (40) was used to assess associations of BMI variability and trends with mortality. We first divided each variability measure into quintiles. To categorize slope, we divided the nonpositive slopes at the median and the positive slopes into tertiles, again creating five categories. Relative risks were then computed for each category or quintile, with adjustment for age and number of cigarettes smoked per day. The purpose of these analyses was to assess the shapes of the relations of these variables with mortality.
We next included each measure of variability or the two slope variables as continuous variables in Cox models, along with age and cigarettes/day. We then fitted models that included the two slope variables and either the standard deviation of BMI or the standard deviation about the regression, along with age, cigarettes/day, and average BMI. We did not adjust for blood pressure or total cholesterol in these analyses, because the associations between adiposity measures and mortality may be partially mediated by risk factors related to body size and obesity (33).
Because weight loss and weight variability could be a consequence of preexisting disease rather than an antecedent, we examined associations with 25-year mortality and then with deaths occurring in the first 15 years of follow-up and deaths occurring during years 1625 of follow-up. We did this to determine whether associations were similar across these two follow-up periods, and thus whether associations might reflect effects of illness on weight rather than a true effect on mortality of weight change or weight variability. This division of the follow-up period was based on a previous report which suggested that it may be necessary to exclude deaths for as many as 15 years before a positive association between adiposity and mortality emerges (34).
We also compared associations of these measures with mortality for 685 men aged 4855 years and 596 men aged 5666 years and for 644 nonsmokers and 637 smokers to assess the consistency of findings by age and smoking status.
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RESULTS |
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For the first 15 years of follow-up, risk generally increased progressively from the first quintile through the fifth quintile for both endpoints for the standard deviation about the regression (table 4). This measure was significantly related to cardiovascular disease mortality for both years 115 and years 1625, with little or no difference in relative risks being seen for the two follow-up periods for either endpoint. For the standard deviation of BMI (table 3), the association with 15-year cardiovascular disease mortality was J-shaped, and the risk of all-cause mortality generally increased progressively as the standard deviation increased. This measure was significantly related to both endpoints during the first 15 years of follow-up and to cardiovascular mortality in years 1625. There was no clear pattern for the association with all-cause mortality for years 1625.
Trends in BMI and mortality
Table 5 gives age- and smoking-adjusted relative risks by category for the slope of BMI, as well as the relative risks for the two slope variables entered as continuous variables in Cox models. In these analyses, the referent category was the first tertile for men with positive slopes. In the continuous variable Cox models, the relative risks were calculated for a difference of +1 standard deviation in the weight gain slope and a difference of -1 standard deviation in the weight loss slope (a larger weight loss).
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For men who gained weight, relative risks for 25-year all-cause mortality differed little across positive slope tertiles, while the relative risk for cardiovascular disease mortality was increased for men in the third tertile. For 15-year follow-up, relative risks for both endpoints were largest among men who had the greatest increases in BMI, with values similar to those observed for the men who lost the most weight. However, in years 1625, men with increases in the top tertile had relative risks for both endpoints that were less than 1.0. While the weight gain slope showed a positive association with each endpoint for both 25- and 15-year follow-up, only the association with 15-year all-cause mortality was significant. Regression coefficients for the weight gain slope also differed significantly between years 115 and years 1625 for all-cause mortality (p < 0.05). Regression coefficients did not differ significantly between men aged 4855 years and men aged 5666 years or between smokers and nonsmokers for the two slope variables or the standard deviation of BMI for either endpoint in any follow-up period. For example, in the two age groups, with 15-year follow-up, relative risks for a slope more negative by 0.12 kg/m2 per year were 1.23 (95 percent confidence interval (CI): 0.96, 1.57) and 1.26 (95 percent CI: 1.11, 1.41), respectively, for all-cause mortality and 1.47 (95 percent CI: 1.07, 2.01) and 1.27 (95 percent CI: 1.09, 1.48), respectively, for cardiovascular disease mortality. In smokers and nonsmokers, respectively, relative risks were 1.28 (95 percent CI: 1.13, 1.45) and 1.28 (95 percent CI: 1.03, 1.59) for all-cause mortality and 1.35 (95 percent CI: 1.16, 1.57) and 1.30 (95 percent CI: 0.99, 1.72) for cardiovascular disease mortality. While regression coefficients for the weight loss slope did not differ significantly by age in follow-up years 1625 for either endpoint, the relative risk for cardiovascular disease mortality among men aged 4855 years was close to 1.0, i.e., 0.98 (95 percent CI: 0.67, 1.45), while the relative risk among men aged 5666 years was 1.19 (95 percent CI: 1.02, 1.40), a value significantly different from 1.0. The regression coefficient for the standard deviation about the regression for 16- to 25-year cardiovascular disease mortality was significantly larger in men aged 4855 years than in men aged 5666 years, with relative risks for a difference of 0.34 kg/m2 of 1.42 (95 percent CI: 1.19, 1.71) and 1.03 (95 percent CI: 0.86, 1.25), respectively. The regression coefficients for this variable did not differ significantly for either endpoint for 25- or 15-year follow-up.
Multivariable associations with mortality
Table 6 gives relative risks for associations of BMI variables with mortality for each follow-up period from Cox models that included either the standard deviation about the regression (model 1) or the standard deviation of BMI (model 2), the two slope variables, and average BMI, age, and cigarettes/day. The weight loss slope was significantly related to both endpoints for both 15- and 25-year follow-up in the analyses that included the standard deviation about the regression. However, this variable was significantly related only to 15-year mortality if the standard deviation of BMI was included instead. The weight gain slope was also significantly related to all-cause mortality in 15-year follow-up in model 1. Regression coefficients for both slope variables differed significantly for years 115 and years 1625 for all-cause mortality in both model 1 and model 2 (p < 0.05).
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Table 7 gives multivariable model results for the standard deviation about the regression and the two slope variables for 15-year and 16- to 25-year follow-up among men aged 4855 and 5666 years and among smokers and nonsmokers. Associations were adjusted for age and average BMI, as well as cigarettes/day for the age subgroups. Regression coefficients for each variable did not differ significantly by age for 15-year follow-up or by smoking status for either follow-up period. For years 1625, the regression coefficients for the standard deviation about the regression differed significantly by age for both endpoints, and the coefficients for the weight loss slope differed by age for cardiovascular disease mortality. In these analyses, mortality increased with increasing variability for the younger men and with greater weight loss in the older men. While the standard deviation about the regression was significantly related to both endpoints in the younger men for this follow-up period, the weight loss slope was not significantly related to either endpoint in the older men. The standard deviation of BMI was also significantly related to both endpoints for years 1625 in comparable multivariable models in the younger men (data not shown).
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DISCUSSION |
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Several studies have found weight variability or weight fluctuation to be associated with increased risk for all-cause mortality and cardiovascular disease morbidity or mortality (15
). In a previous report from the Chicago Western Electric Company Study (1
), men who had large fluctuations in weight between the ages of 20 and 40 years, where fluctuation was defined as a loss of at least 10 percent of body weight in one 5-year period and a gain of at least 10 percent in another 5-year period, had twice the 25-year risk of coronary heart disease mortality as men who reported no substantial change in weight. In the Framingham Heart Study (2
), the coefficient of variation of BMI, defined on the basis of recalled weight at age 25 and weight at the first eight examinations, was significantly related to 18-year mortality from all causes and coronary heart disease in both men and women, with relative risks ranging from 1.27 to 1.93 for men or women in the highest tertile compared with those in the lowest. In these analyses, deaths occurring in the first 4 years of follow-up were excluded. In the Multiple Risk Factor Intervention Trial (3
), the standard deviation of weight calculated from weights measured during clinic visits over a 6- to 7-year period was significantly related to 3.8-year mortality from all causes and cardiovascular diseases, with relative risks of 1.64 and 1.85, respectively, for men in the fourth quartile compared with those in the first. In the Gothenburg prospective studies of men and women (4
), the coefficient of variation of BMI, based on three weights measured over a 10- or 11-year period, was significantly related to 15-year mortality from all causes and coronary heart disease in men and 13-year all-cause mortality in women. In the Honolulu Heart Study (5
), the standard deviation about the regression of BMI, based on three weights measured over a 6-year period, was significantly related to 14.5-year mortality from all causes, cardiovascular diseases, and causes other than cardiovascular disease or cancer, with relative risks of 1.25, 1.41, and 1.53, respectively, for men in the fifth quintile compared with those in the first. In these analyses, deaths occurring in the first 5 years of follow-up were excluded.
In contrast to these findings, in the Charleston Heart Study (6) the coefficient of variation of BMI, defined on the basis of weight at age 25 and weights in 1960 and 1963, was not significantly related to 23-year all-cause mortality in Black men, White men, Black women, or White women. In these analyses, deaths occurring in the first 2 years of follow-up were excluded. In the Baltimore Longitudinal Study of Aging (7
), the standard deviation about the regression of BMI, based on three weight measurements, was not significantly related to 16.5-year all-cause or coronary heart disease mortality in men.
The rationale for using the standard deviation about the regression as the measure of weight variability rather than the coefficient of variation or standard deviation in this study and in two other studies (5, 7
) was to remove from the measure of weight variability that portion of variability due to systematic gain or loss in weight. In this study, the correlation between the standard deviation of BMI and the slope was 0.08 when the direction of the trend in weight was ignored. However, the correlation was 0.77 in men who lost weight (negative slope) over the period and 0.75 in men who gained weight (positive slope). These high correlations with weight loss and weight gain make it difficult to assess whether an association of variability with increased mortality is a true association or rather reflects associations of weight loss and/or weight gain with mortality. The use of the standard deviation about the regression did not entirely eliminate the problem of distinguishing between variability and the trend in weight over time, since the correlation with the slope was 0.42 in men who lost weight and 0.24 in men who gained weight. While these values are substantially smaller than those for the standard deviation of BMI, they nonetheless indicate some overlap between this measure of variability and the trend in weight.
In the Honolulu Heart Study (5), the standard deviation about the regression was related to all-cause and cardiovascular disease mortality in a multivariate model that included the trend in weight. In the present analyses, the standard deviation of BMI was significantly related to 25-year cardiovascular mortality and to 15-year all-cause and cardiovascular disease mortality if the slope was included as a single continuous variable in the model. However, with inclusion of slope variables that took into account the direction of the trend, neither measure of variability was significantly related to either endpoint.
In the Framingham Heart Study (2), the slope of BMI had a significant inverse association with mortality from all causes and coronary heart disease in both men and women in models that included the average and coefficient of variation of BMI. Similarly, in the Gothenburg studies (4
), change in BMI was also inversely related to all-cause mortality in men and women. Among men in the Multiple Risk Factor Intervention Trial (3
), the trend in weight over the 6- to 7-year study period was not included as a covariate in the analyses. It is unclear whether the results of these three studies would have been altered if the analytical models had included terms taking into account both positive and negative trends in weight. However, it seems likely that the strength of the associations of the variability of BMI with mortality would have been reduced in such analyses. It is also unclear how such an analytical approach might have affected the results from the Honolulu Heart Study (5
), since only a single variable for the slope appears to have been included in the analyses involving variation in BMI. In that study, weight loss was also associated with increased mortality.
Increased risk of mortality with weight loss or an inverse association with weight change has been found in many studies (25
, 7
24
), although a number of studies have also shown no increased risk with weight loss and/or increased risk associated with weight gain or weight change (9
, 10
, 12
,
32
). Studies of weight change can generally be divided into four groups based on the methodology used to define weight change or the time period over which weight change is measured. These four groups include studies which calculate weight change as: 1) the difference in weight between two study examinations (3
5
, 8
, 12
, 14
17
, 19
, 23
25
); 2) the difference between current weight and a recalled weight in young adulthood, e.g., age 18 or age 25 (1
, 9
11
, 13
, 24
, 26
32
); 3) the difference between current weight and highest lifetime weight (12
, 18
, 20
22
); and 4) the trend of weight over a series of examinations (2
, 7
).
The associations of weight change with mortality vary across these different types of studies. Studies that have examined the association using the difference between current weight and the highest lifetime weight have consistently shown weight loss to be associated with increased risk of mortality from both all causes (12, 18
, 21
, 22
) and cardiovascular diseases (18
, 20
21
22
). In contrast to these findings, only a handful of the studies defining weight change as the difference between current weight and weight during young adulthood have shown increased risk with weight loss (9
11
, 13
). Most of these studies have shown no association between weight loss and mortality (30
, 31
) or a positive association between weight gain or change and mortality (24
, 27
32
). Furthermore, two of the studies showing increased risk with weight loss also found weight gain to be associated with increased risk (9
, 10
). Studies defining weight change as the difference in weight between two examinations are relatively consistent in showing weight loss to be associated with increased risk (3
5
, 8
, 14
17
, 19
, 23
, 24
). Only a few of these studies have shown weight gain to be associated with increased risk (15
, 17
, 24
, 25
). The two studies which examined an association between trends in weight and mortality showed inverse associations (2
, 7
), although only the results in the Framingham Heart Study (2
) were statistically significant. In the present study, a negative trend in weight was associated with higher mortality. However, in follow-up years 1625 this association was present only for cardiovascular disease mortality in the men aged 5666 years.
It is unclear whether weight loss is causally related to increased mortality, however, since underlying reasons for weight loss or weight change are usually not determined in these types of studies. Therefore, it is generally unknown whether weight changes are intentional or unintentional, and thus whether changes in weight are an antecedent of illness or a consequence of it. Only three studies have divided weight loss into categories of intentional and unintentional loss (23, 41
, 42
). In the first of these studies (23
), intentional weight loss among overweight women aged 4064 years with obesity-related conditions was generally associated with decreased mortality. However, among women with no preexisting illness, the association was equivocal. In the Iowa Women's Health Study, a study of women aged 5069 years (41
), having one or more intentional weight loss episodes of
20 pounds (
9.1 kg) was not significantly associated with higher total or cardiovascular disease mortality risk in comparison with never losing
20 pounds. However, having one or more unintentional weight loss episodes was associated with a 2657 percent higher total mortality risk and a 51114 percent higher cardiovascular disease mortality risk in comparison with never losing
20 pounds. In the third study (42
), among overweight men aged 4064 years, neither intentional nor unintentional weight loss of
20 pounds was associated with total or cardiovascular disease mortality, either in those with existing health conditions or in those without them.
Differences in the results of the various weight change studies may also be attributable to the influences of illness-related weight loss. In particular, weight change over a relatively short period of time, e.g., between two examinations, is more likely to be influenced by illness-related weight loss than is weight change since young adulthood. Similarly, change in weight from the highest lifetime weight would also appear to be more likely to be influenced by illness-related weight loss. Hence, it is perhaps not surprising that studies using weight change since young adulthood are the studies showing increased risk with weight gain and little or no increased risk with weight loss, whereas the other types of studies show an increased risk associated with weight loss.
One approach used to control for illness-related weight loss is exclusion of early deaths (2, 4
6
, 16
19
, 21
23
, 33
). However, the length of follow-up for which early deaths have been excluded has exceeded 5 years in only one study (22
), and in that study, which excluded deaths occurring in the first 8 years, there was still an association between weight loss and increased cardiovascular disease mortality among men and women with body mass indices of 2629. In a previous report from the present study (34
), we found U-shaped relations with coronary heart disease mortality through the first 14 years of follow-up for BMI and other measures of adiposity. However, for years 1522, mortality was progressively higher with higher baseline adiposity. In the present analyses, weight loss was not associated with increased risk in years 1625 among men aged 4855. These results suggest that the effects of illness-related weight loss may persist far beyond the exclusion periods used in most epidemiologic studies.
In conclusion, these results indicate that the increased risk of mortality associated with weight loss and/or weight fluctuation/variability which is observed in many studies may not persist beyond 15 years, and that weight variability may not be related to mortality independently of weight loss and weight gain.
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ACKNOWLEDGMENTS |
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The authors thank the many physicians who participated in the annual examinations of this cohort (35). In addition, they thank Dan Garside for his technical assistance with the study data.
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NOTES |
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REFERENCES |
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