In this collaborative analysis of data from almost 900 000 adults in 57 prospective studies, overall mortality was lowest at about 22·5–25 kg/m2 in both sexes and at all ages, after exclusion of early follow-up and adjustment for smoking status. Above this range, each 5 kg/m2 higher BMI was associated with about 30% higher all-cause mortality (40% for vascular; 60–120% for diabetic, renal, and hepatic; 10% for neoplastic; and 20% for respiratory and for all other mortality) and no specific cause of death was inversely associated with BMI. Below 22·5–25 kg/m2, the overall inverse association with BMI was predominantly due to strong inverse associations for smoking-related respiratory disease (including cancer), and the only clearly positive association was for ischaemic heart disease.
In laboratory studies, BMI is moderately strongly correlated (30–50%) with fat-free mass, but it is much more strongly correlated (60–90%) with fat mass.15
BMI is also strongly correlated (80–85%) with measured waist circumference;16,17
in the EPIC prospective study of 360 000 adults in Europe, for example, the two variables have about an 85% correlation, so each has a similar association with mortality.16
(In EPIC, waist-to-hip ratio was not quite as strongly related either to BMI or to mortality.) In such populations, either measurement can thus be used to help assess the causal relevance of obesity to mortality, and each could well add some predictive information to the other. Neither, however, directly measures visceral fat.
Although BMI and waist circumference are not directly causal, both are closely correlated in such populations with aspects of adiposity that directly affect blood pressure, lipoprotein particles, and diabetes (). Effective interventions for weight loss lower blood pressure, favourably affect lipoprotein particles, and increase insulin sensitivity,18
and drugs that substantially lower blood pressure19
or LDL particle numbers20
reduce vascular disease. At least some of the major adverse effects of obesity are, therefore, reversible.
For ischaemic heart disease, the magnitude of the positive association with BMI in this study can be largely accounted for by blood pressure, lipoprotein particles, and diabetes. The associations of baseline BMI with baseline measurements of SBP and of the non-HDL/HDL cholesterol ratio () can be taken as the associations of BMI with the usual levels of these variables over the past and next few years, so they would predict at least a doubling of mortality from ischaemic heart disease between 20 kg/m2
and 30 kg/m2
(if the combined effects of SBP and the ratio of cholesterol fractions were approximately additive10,11
), which is what was observed. (Merely adjusting regression analyses for single measurements of blood pressure and total cholesterol would underestimate the mediating effects of blood pressure and, especially, of lipoprotein particles.21,22
) Above 30 kg/m2
, further increases in BMI have little further effect on the ratio of cholesterol fractions (), but could be associated with other adverse changes in lipoprotein particles that cannot be inferred from cholesterol fractions (eg, an increase in the number of small dense LDL particles). Diabetes becomes particularly important at BMI greater than 30 kg/m2
(). Other hypothesised intermediate factors (eg, fibrinogen, C-reactive protein, obstructive sleep apnoea) were not assessed.
Confounding by diet, physical activity, or socioeconomic status could have somewhat affected the ischaemic heart disease results. The cardioprotective effects of physical activity might not be due solely to reduced adiposity,23
so variation in physical activity could have caused the independent effects of adiposity to be somewhat overestimated. Confounding by socioeconomic status could have caused the independent effects to be either overestimated or underestimated. In the three prospective studies of US health professionals, however, there would have been relatively little socioeconomic confounding, yet for all-cause mortality in the upper BMI range (there were too few deaths to subdivide by cause), the association seemed to be broadly similar across these three studies to that in the PSC as a whole (webappendix p 14
The weakening of the association between BMI and mortality from ischaemic heart disease above age 70 years is probably a result of the weaker associations at older ages of blood pressure and cholesterol with risk,10,11
and the slightly weaker associations of BMI with these intermediate variables. (At older ages, BMI might depend increasingly on muscle loss.24
For stroke, the findings in the upper and lower BMI ranges were quite different from each other. In the upper range, BMI was associated positively with ischaemic, haemorrhagic, and total stroke, and each of these associations can be largely accounted for by the effects of BMI on blood pressure. In the lower BMI range, however, there was no evidence of a positive association for ischaemic, haemorrhagic, or total stroke, despite the strong positive association between BMI and blood pressure. (For a specific blood pressure, therefore, BMI in this lower range would actually be inversely related to stroke.) These findings for stroke in the lower BMI range were not materially affected by exclusion of participants who had ever smoked (by contrast with the findings reported from a large Chinese prospective study25
). The evidence from previous large studies of BMI and stroke subtype is not as consistent as might be expected,1,3,26–28
but generally suggests that the association of BMI with stroke risk is strongly positive at BMI greater than 25 kg/m2
for both ischaemic and haemorrhagic stroke, and, less definitely, that at BMI less than 25 kg/m2
it is still positive for ischaemic but not for haemorrhagic stroke. In the lower BMI range, however, the PSC found no evidence of an association for ischaemic stroke (although the possibility of a weak positive association is not excluded), and found only slight evidence of an inverse association for haemorrhagic stroke. These findings for stroke in the lower BMI range are not fully explained.
For kidney and liver disease,8,9
the positive associations with BMI could have resulted mainly from the effects of adiposity on blood pressure, diabetes, and blood lipids. Central adiposity can cause non-alcoholic fatty liver disease, which could predispose to cirrhosis or hepatocellular carcinoma (the commonest type of liver cancer).9
The positive associations of BMI with cirrhosis and liver cancer are unlikely to have been due to confounding by alcohol, since drinking was not strongly related to BMI in males and was inversely related to it in females.
For cancer, the evidence of several positive associations complements that from other million-person prospective studies (eg, the Cancer Prevention Study-II4
and the Million Women Study5
). Possible mechanisms by which obesity could cause cancer at particular sites have been summarised elsewhere.29
The overall inverse association with cancer mortality in the lower BMI range (15–25 kg/m2
) was mainly due to inverse associations with cancers of the lung and oesophagus. Most of the oesophageal cancer deaths occurred before the 1990s, so most are likely to have been squamous cell carcinomas,30
which are reported to be associated inversely with BMI, rather than adenocarcinomas, which are reported to be associated positively:5,31
histological subtype is, however, not available in the PSC. The inverse association for lung and upper aerodigestive cancer combined was still strongly negative even after exclusion of the first 10 years of follow-up, implying that it was not chiefly a result of reverse causality.
For COPD and other respiratory diseases, the inverse associations with BMI in the range 15–25 kg/m2 were remarkably strong. In each sex, the inverse association for respiratory mortality accounted for about 60% of the difference in all-cause mortality between 15–20 kg/m2 and 22·5–25 kg/m2 (). COPD can cause weight loss over many years, so the inverse association (even after exclusion of the first 15 years of follow-up) might have been due mainly to reverse causality (ie, to low BMI being an indicator of progressive COPD). However, some close correlate of low BMI itself could increase COPD progression and, hence, mortality.
The inverse associations with COPD, lung cancer, and upper aerodigestive cancer were much steeper in smokers than in non-smokers. Smoking is a major cause of all three diseases, and the greater steepness in smokers might have been due at least partly to uncontrolled confounding by smoking intensity. Smoking can cause weight loss,32
and if greater intensity of smoking were to cause increased weight loss, then there would be a substantially greater proportion of intensive smokers in the lower BMI categories, who would be at greater risk of these conditions (both through direct effects and, possibly, as a result of being less likely to quit). Although cigarettes smoked per day varied little with BMI in this study, other evidence (webappendix p 13
) suggests that, for a specific number of cigarettes per day, leaner smokers have substantially higher blood cotinine concentrations than other smokers do (and also substantially more lung cancer, upper aerodigestive cancer, and COPD). Hence, smoking intensity might confound associations with BMI even in the absence of an association between BMI and daily cigarette consumption. Alternatively, lower BMI might somehow exacerbate the effects of smoking on respiratory cancer or other respiratory disease. The steep inverse associations for these diseases among smokers are still largely unexplained.
This study did not assess measures of central obesity, but other large epidemiological studies have done so. In the ten-country EPIC prospective study (with 12 000 deaths of known cause, of which 3000 were vascular [vs
36 000 vascular deaths in the PSC]),16
waist circumference improved the ability of BMI to predict vascular and all-cause mortality. In the 52-country INTERHEART case–control study of acute myocardial infarction (with 12 000 cases),33
a difference of 5 kg/m2
in BMI seems, for reasons that are not clear, to be of much less relevance to heart disease (odds ratio ~1·12 [95% CI 1·08–1·16]) than it was in the PSC (HR 1·39 [1·34–1·44]) or in EPIC (HR ~1·4), and hence to be of much less relevance than measures of central obesity are. Since case–control studies have greater potential for some types of bias, disentangling the interdependent associations of closely correlated anthropometric variables with particular diseases might need prospective studies that are even larger than this PSC study.
This report cannot quantify the effects of present levels of childhood obesity on adult mortality over the next few decades; the relevance of obesity to mortality in different ethnic groups; the substantial effects of obesity on disability, quality of life, or non-fatal disease (eg, osteoarthritis, obstructive sleep apnoea); or the positive effects of some types of adiposity on prognosis after some chronic disorders (eg, heart failure,34
) have already developed. It does, however, quantify particularly reliably both the excess mortality associated with low BMI (much of which could be non-causal) and that associated with high BMI (which would be even greater if full allowance could be made for the extent to which chronic disease can cause weight loss). If the overall inverse association at low BMI is partly non-causal, then the real optimum BMI might be somewhat lower than the apparent optimum of about 23 kg/m2
or 24 kg/m2
The absolute excess mortality at BMI greater than 22·5–25 kg/m2
was mainly vascular, but also partly neoplastic, and was probably largely causal (ie, due to causal factors closely associated with BMI). shows, for different BMI levels in middle age, estimates of the lifetime probabilities of surviving from age 35 years, which are calculated by applying the relative risks that were considered likely to be causal (webappendix p 18
) to disease-specific mortality rates at ages 35–79 years from the EU in 2000.13
(The year 2000 EU probability of surviving from birth to age 35 years is 98%.) For both sexes, the median survival () is reduced by 0–1 year for people who would, by about age 60 years, reach a BMI of 25–27·5 kg/m2
, by 1–2 years for those who would reach 27·5–30 kg/m2
, and by 2–4 years for those who would become obese (30–35 kg/m2
). Much less information was available for BMI greater than 35 kg/m2
(hence the dashed lines in ), but the median survival seems to be reduced by about 8–10 years in those who would become morbidly obese (40–50 kg/m2
, which in the PSC is mainly 40–45 kg/m2
BMI versus lifespan in western Europe, year 2000
The extreme reduction in survival with morbid obesity is about as great as the 10-year reduction caused by persistent cigarette smoking in male British doctors born in 1900–30, for whom the cigarette smoker versus non-smoker mortality rate ratio was about 2·5 not only at 35–69 years but also at 70–79 years of age.13,36
In the present report, the smoker versus non-smoker mortality rate ratio is slightly less than 2·5 for men aged 35–69 years, and much less than 2·5 for women aged 70–79 years (webappendix p 7
). In both cases this was partly because many who were current smokers at baseline did not smoke as many cigarettes when young as the British doctors did (or, indeed, as young smokers do nowadays), and partly because many who were current smokers at baseline in the PSC would have quit during follow-up (which is taken account of in the doctors' study,36
but not in the PSC). The difference in mortality between smokers and non-smokers in therefore underestimates the effects of smoking throughout adult life, but it could likewise underestimate the effects of becoming obese well before middle age.
These PSC relative risks for BMI, combined with recent population BMI values,37,38
suggest that in the present decade, about 29% of vascular deaths and 8% of neoplastic deaths in late middle age in the USA (where mean BMI6
at age 50 years was 28·5–29 kg/m2
in 2000) would have been attributable to having a BMI greater than 25 kg/m2
; for the UK (where mean BMI38
at that age was about 1 kg/m2
lower), the corresponding proportions would have been about 23% and 6%, respectively. In both countries, as elsewhere, these proportions will probably increase if average BMI in middle age continues to rise, even if rates of vascular and neoplastic mortality continue to fall because of decreases in smoking, improvements in treatment, or other reasons. Moreover, since BMI is an imperfect measure of visceral and other adiposity, the number of vascular and other deaths attributable to all adiposity-related factors is probably appreciably greater than these calculations suggest.
In adult life, it may be easier to avoid substantial weight gain than to lose that weight once it has been gained. By avoiding a further increase from 28 kg/m2 to 32 kg/m2, a typical person in early middle age would gain about 2 years of life expectancy. Alternatively, by avoiding an increase from 24 kg/m2 to 32 kg/m2 (ie, to a third above the apparent optimum), a young adult would on average gain about 3 extra years of life.