Obesity (body mass index [BMI]≥30 kg/m²) increases the risk for numerous adverse health outcomes, including most major chronic diseases [1]–[3]. Class III, or extreme, obesity (BMI≥40 kg/m²) [4] is emerging as a major public health problem in several developed countries [5]–[7], most notably in the US, where BMI>30, 40, or 50 kg/m² among adults has increased more than 2-, 4-, and 10-fold, respectively, since the mid-1980s [8]. While class III obesity currently affects 6% of the US adult population [8],[9], those belonging to this group accounted for 20% of the total per capita health-care expenditures in 2000 [10].

Effective interventions and accurate projections of future health-care costs requires a better understanding of the health risks associated with class III obesity, but the necessary data are scarce. Because class III obesity was relatively uncommon in the recent past, the few studies that have specifically evaluated mortality rates associated with class III obesity generally had limited sample sizes (e.g., fewer than 400 deaths [2],[11]) or did not separately evaluate risks of death for BMI of 50 kg/m² or higher [2],[3]. As such, there is little quantitative information about the burden of disease, including total and cause-specific mortality rates, for individuals with BMI values of 40 kg/m² and above.

We combined original data from 20 prospective studies from the United States, Sweden, and Australia to evaluate—in what is to our knowledge the largest study on this topic to date—the excess rates of death overall and due to a wide range of specific causes, as well as the expected number of years of life lost attributable to class III obesity.

A description of participants with BMI in the class III obesity range from each of the 20 cohorts is shown in Table 1. In total, 1,036 of the 9,564 participants died during the follow-up period (median = 9 y, maximum = 27 y).

Compared with participants in the normal-weight range at baseline, those in the class III obesity range included a higher proportion of women, more individuals with baseline age 50 to 69 y (as opposed to younger [19–49 y] or older [70–83 y] individuals), fewer non-Hispanic white individuals, fewer individuals with a college education, more individuals with lower alcohol intake, and more individuals with lower levels of physical activity (Table 2). Among participants within the range of class III obesity, we observed little variation in baseline age, sex, education, and alcohol intake. By contrast, the prevalence of non-Hispanic black race/ethnicity, low physical activity, and history of diabetes, as well as median waist circumference, was generally higher for the top BMI categories.

Table 3 compares total and cause-specific mortality rates (deaths per 100,000 persons per year) for the class III obesity and normal-weight groups separately by sex. Total mortality rates for class III obesity participants were 856.0 in men and 663.0 in women. The differences in mortality rates for the two BMI groups were 509.3 and 382.5 in men and women, respectively. Heart disease was the most common underlying cause of death for the class III obesity group (mortality rate differences were 238.9 and 132.8 in men and women, respectively), followed by malignant neoplasms (mortality rate differences were 36.7 and 62.3 in men and women, respectively), and diabetes (mortality rate differences were 51.2 and 29.2 in men and women, respectively). Higher rates of death were also observed for nearly every other major cause of death that we examined, apart from cerebrovascular disease in men and malignant neoplasms of respiratory and intrathoracic organs and diseases of the arteries, arterioles, and capillaries in women, although not all of these differences were statistically significant because of the relatively small numbers of deaths in the class III obesity group for some of the major causes (e.g., malignant neoplasms, chronic lower respiratory disease, and nephritis/nephrotic syndrome/nephrosis deaths in men). The negative rate differences that were observed were also based on small numbers of deaths in the class III obesity group (five, eight, and five deaths due to cerebrovascular disease, malignant neoplasms of respiratory and intrathoracic organs, and diseases of the arteries, arterioles, and capillaries, respectively).

As an internal comparison, in the subset of participants in the pooled dataset without heart disease, cancer, stroke, or emphysema and having BMI values between 18.5 and 24.9 kg/m², differences in mortality rates for current versus never smokers were 721.0 and 519.6 in men and women, respectively.

Table 4 shows the minimally adjusted and multivariable-adjusted HRs for death across categories of BMI and for continuous (per 5 kg/m²) values of BMI restricted to the BMI 40.0–59.9 kg/m² range. In minimally adjusted models, we observed a sharp gradient in relative risk with higher values of BMI across the class III obesity levels that was consistent with a linear increase. The HRs from models of BMI categories were slightly, but not fully, attenuated with additional adjustment for race/ethnicity, education, alcohol intake, and physical activity level. Compared with adults with BMI in the 18.5–24.9 kg/m² range, multivariable-adjusted HRs (95% CIs) for those with BMI of 40.0–44.9, 45.0–49.9, 50.0–54.9, and 55.0–59.9 kg/m² were 2.25 (2.07–2.43), 3.32 (2.92–3.77), 3.48 (2.82–4.31), and 5.91 (4.24–8.24), respectively. This trend of increasing risk of death with increasing level of BMI was apparent in categorical and continuous models (HR per 5 kg/m² = 1.40, 95% CI: 1.31–1.51) after restricting to the BMI 40.0–59.9 kg/m² range.

Although the pooled HRs calculated from random effects meta-analysis models were similar to those based on the aggregate dataset (BMI 40.0–59.9 versus 18.5–24.9 kg/m², HR = 2.57, 95% CI: 2.23–2.96; per 5 kg/m² BMI, HR = 1.42, 95% CI: 1.25–1.62), the heterogeneity estimates for differences in the associations by cohort were statistically significant (Figures 1 and 2). We evaluated potential sources of heterogeneity in Table 5, which shows the multivariable-adjusted HRs conducted overall and by population subgroup. Overall, we observed a 2.57-fold (95% CI: 2.41–2.74) increased risk of death in the BMI 40.0–59.9 kg/m² versus the 18.5–24.9 kg/m² group, and the association increased linearly for BMI values above 40 kg/m² (HR per 5 kg/m² = 1.40, 95% CI: 1.31–1.51). As observed in studies of BMI across the entire range of values in relation to mortality [3], these associations were significantly modified by sex (p-interaction = 0.03), by geographic location (US versus non-US, p-interaction = 0.03), and follow-up time before and after age 65 y (p-interaction <0.001), with stronger associations observed for men (HR = 2.83, 95% CI: 2.45–3.26), for US cohorts (HR = 2.60, 95% CI: 2.44–2.78), and for follow-up before age 65 y (HR = 3.10, 95% CI: 2.77–3.47). The interaction by geographic location may have arisen due to chance, as there were only 37 deaths in the class III obesity group among non-US cohorts. No differences were observed for follow-up time occurring before versus after the year 2000. The HR for BMI 40.0–59.9 kg/m² versus 18.5–24.9 kg/m² did not change importantly after excluding the largest cohort, NIH-AARP, though the continuous HR for BMI values over 40 kg/m² was slightly attenuated after this exclusion (HR = 1.32, 95% CI: 1.20–1.45). Exclusion of participants who reported a history of diabetes at baseline slightly attenuated the HR for BMI 40.0–59.9 kg/m² versus 18.5–24.9 kg/m² (HR = 2.27, 95% CI: 2.10–2.45). Exclusion of the first 2 y of follow-up did not appreciably change the HRs (<5% change). Although physical activity could confound or mediate these associations, removal of the physical activity variable also had little influence on the HRs (<5% change).

Multivariable-adjusted HRs for select major causes of death for BMI 40.0–59.9 kg/m² compared with 18.5–24.9 kg/m² are shown in Table 6. HRs were significantly elevated for deaths due to heart disease, malignant neoplasms, cerebrovascular disease, diabetes mellitus, nephritis/nephritic syndrome/nephrosis, chronic lower respiratory disease, influenza/pneumonia, accidents, and septicemia, ranging from 1.69 for deaths due to malignant neoplasms to 9.57 for deaths due to nephritis/nephrotic syndrome/nephrosis. Additional adjustment for self-reported history of diabetes and hypertension attenuated the HRs for all specific causes of death apart from malignant neoplasms, though all remained statistically significant. Within the BMI 40.0–59.9 kg/m² range, greater BMI values were linearly associated with increasing HRs for all of these major causes of death apart from cerebrovascular disease, accidents, and septicemia; additional adjustment for history of diabetes and hypertension had little influence on these continuous HRs.

We estimated that BMI categories of 40–44.9, 45–49.9, 50–54.9, and 55–59.9 kg/m² were associated with an estimated 6.5 (95% CI: 5.7–7.3), 8.9 (95% CI: 7.4–10.4), 9.8 (95% CI: 7.4–12.2), and 13.7 (95% CI: 10.5–16.9) y of life lost (Table 7). These estimates (95% CIs) were 6.5 (5.6–7.4), 10.8 (9.3–12.3), 10.6 (7.6–13.6), and 17.0 (12.9–21.1) in men and 6.9 (6.1–7.7), 9.1 (7.9–10.3), 10.3 (8.3–12.3), and 13.1 (9.0–17.2) in women. By comparison, in the subset of participants in the pooled dataset without heart disease, cancer, stroke, or emphysema and having BMI values between 18.5 and 24.9 kg/m², current versus never cigarette smoking was associated with an estimated 8.9 y of life lost (95% CI: 8.6–9.3).

To our knowledge, this is the largest study to date on the association between class III obesity and mortality, and the first to show that class III obesity is associated with excess rates of total mortality and mortality due to a wide range of causes, particularly heart disease, cancer, and diabetes, and that the risk of death overall and from these specific causes continues to rise with increasing values of BMI. The accumulating excess risk resulted in major reductions in life expectancy after the age of 40 y that were comparable to those of cigarette smoking.

The estimated 6.5 to 13.7 y of life lost for BMI values between 40 and 59 kg/m² versus 18.5–24.9 kg/m² were in line with those of a previous pooled analysis that found that individuals with BMI values of 35–50 kg/m² had a median 8–10 fewer years of life than those with BMI 22.5–24.9 kg/m² [2]. Our study further demonstrates that the expected number of years of life lost continued to increase for BMI values beyond 50 kg/m², at which point the loss in life expectancy (9.8 y) exceeded that observed for current versus never smoking (8.9 y) in this study. These results have great relevance to the current era, during which class III obesity rates have increased dramatically at the same time that smoking rates have declined. That we observed a 7.2-y decrease in life expectancy from BMI 40.0–44.9 to 55.0–59.9 kg/m² suggests that otherwise healthy, non-smoking adults having BMI values within the class III obesity range may considerably expand their life expectancy by avoiding additional weight gain.

We observed significant differences in the relative risks for class III obesity and total mortality by cohort, which may reflect differences in the ages, sex distribution, and geographical location of the participants, as these factors were shown to be significant effect modifiers in our study. Similar to observations from previous studies based on lower values of BMI [3], these results suggest that the risks associated with class III obesity may be even greater for men than women, and for younger compared to older adults. These results could be considered in the development of public health interventions aimed at reducing health risks associated with extreme obesity, particularly those that are targeted toward susceptible populations.

The clear finding of excess risk for nearly every major cause of death suggests that excess weight can have a wide range of physiological effects. In particular, the results of our study suggest that diabetes and hypertension are common mechanisms that might explain the majority of the excess mortality burden in the class III obesity group. Most of this excess was attributable to heart disease, diabetes, cancer, and kidney and liver diseases, and risks of death due to these causes were largely attenuated with additional adjustment for diabetes and hypertension. Obesity is strongly associated with metabolic abnormalities, including insulin resistance, type 2 diabetes, hypertension, and dyslipidemia, mediated in part by the chronic inflammatory state induced by the secretion of adipocytokines, such as angiotensinogen, transforming growth factor–beta, tumor necrosis factor–alpha, and interleukin-six [42]–[45]. The severity of these conditions has been shown to increase with increasing BMI [44] and improve after weight loss either due to lifestyle modification or bariatric surgery [46]–[49]. Diabetes, hypertension, and other obesity-related aspects of the metabolic syndrome have been shown to play an important role in the development of heart disease, chronic kidney disease, and end-stage renal disease [42],[45], among other major causes of death observed to be elevated in the class III obesity group. Thus, these metabolic conditions could be effect targets in efforts to reduce the burden of morbidity and mortality in individuals with extreme obesity. Individuals with extreme obesity may experience other physiological impairments that could explain the higher rates of death from other causes. Specifically, deaths due to chronic lower respiratory disease were shown in this and the much smaller National Health and Nutrition Examination Survey III study to be elevated at extreme levels of BMI due to reduced lung capacity and airway obstruction [50]. It is possible that excess risks associated with class III obesity may decline as treatments for these co-morbid conditions improve.

An important strength of this pooling study is its large size. With sufficient numbers, we were able to quantify the risks of total and cause-specific deaths associated with class III obesity with greater precision than has been possible in previous studies. Furthermore, our results were based on a population of never smokers without prevalent disease, thereby reducing the potential for confounding due to major preexisting illness and smoking. Our results were also based on original, as opposed to published, data, which allowed for standardization of the variables and statistical methods across studies, and thereby reduced the potential for methodological heterogeneity between studies.

Some limitations of this study include the use of mostly self-reported, as opposed to measured, height and weight. Objectively measured values are ideal, but epidemiologic studies have reported high correlations between self-reported and measured height and weight [51],[52]. Nonetheless, misclassification across BMI categories due to self-reported height and weight has been shown to yield stronger relative risks than those based on measured values [53]. This potential source of bias may have inflated our relative risk estimates, although this effect is likely to have been modest [3]. Another limitation is that height and weight were ascertained only once at the beginning of follow-up, which precluded us from examining risks associated with weight change. Although BMI is the most commonly used indicator of adiposity in epidemiologic studies, it does not directly measure the amount of adipose tissue and cannot distinguish between fat and lean body mass [54],[55]. Nonetheless, BMI has been shown to be just as strongly correlated with obesity-related metabolic indicators as more accurate methods for measuring total fat mass and body fat percent, such as dual-energy X-ray absorptiometry [55]. BMI also does not provide information on central versus peripheral body fat distribution, each posing different risks in relation to the metabolic syndrome and related chronic diseases [56]. Studies that combine BMI with measures of central adiposity may yield more accurate estimates of disease risks associated with high levels BMI [57],[58]. For instance, in a pooled analysis based on data from the same 20 cohort studies, waist circumference was positively associated with all-cause mortality, even among individuals at the highest range of BMI (35.0–49.9 kg/m²) [58]. There has been some concern about the accuracy of cause of death reports [59], which may be differential by BMI level. The excess deaths due to both diabetes mellitus and overweight and obesity that we observed in the class III obesity group may reflect greater difficulty in identifying the primary cause of death among individuals with multiple co-morbid conditions. Our results may not be generalizable to all populations, as the pooled dataset comprised mostly non-Hispanic white individuals from affluent countries (the majority being from the US). Also, our estimates rely on prospective cohort studies, whose volunteer participants typically are healthier than those in the general population.

In this large pooled analysis of 20 prospective studies, participants with BMI in the class III obesity range (40.0–59.9 kg/m²) experienced substantially higher rates of death compared with those in the normal BMI range (18.5–24.9 kg/m²), with most of the excess due to deaths from heart disease, cancer, and diabetes. These higher rates appear to be largely attributable to metabolic abnormalities associated with excess adiposity, including diabetes and hypertension. We found that the reduction in life expectancy associated with class III obesity was similar to (and, for BMI values above 50 kg/m², even greater than) that observed for current smoking. If current global trends in obesity continue, we must expect to see substantially increased rates of mortality due to these major causes of death, as well as rising health-care costs. These results underscore the need to develop more effective interventions to combat this growing public health problem.