Our analyses of data from two large, long-term, prospective cohort studies indicate a J-shaped association between BMI immediately before a diagnosis of type 2 diabetes and all-cause mortality. This relationship was linear among participants who had never smoked but was nonlinear among those who had ever smoked. We did not observe a benefit of excess adiposity with regard to the risk of death; thus, our findings support the current recommendation that patients with diabetes achieve or maintain a normal weight.28

Although our findings are largely consistent with the results of previous analyses in the general population,1-4 they contradict the results of several studies of BMI and mortality among participants with diabetes. Prior studies largely suggest inverse,10 J- or U-shaped,11,29,30 or flat or null associations9,31; however, notable limitations include a short follow-up duration,9,11,30 a small number of deaths,10,29,31,32 and a lack of analyses assessing biases from smoking or undiagnosed chronic diseases.9-11,29-32 The majority of these studies involved patients who already had diabetes, with BMI assessed up to several decades after the diagnosis; these factors substantially increase susceptibility to reverse-causation bias.9,29-32

Recently, Carnethon et al.10 analyzed pooled data from five large U.S. cohorts and concluded that adults who were of normal weight at the time of a diabetes diagnosis had a risk of death that was twice as high as that among their overweight or obese counterparts (hazard ratio, 2.01; 95% CI, 1.44 to 2.81); however, several of the limitations outlined above apply to this study. Relatively low statistical power (449 total deaths) limited their BMI classification to two broad and heterogeneous exposure groups (participants with a BMI of 18.5 to 24.9 and those with a BMI ≥25.0). Subgroup analyses were also underpowered, such that conclusions could not be drawn. In addition, BMI was measured after the diabetes diagnosis for many participants, allowing additional bias from the initiation of diabetes treatment or the progression of other underlying illnesses.10

The attenuated relationship between BMI and mortality among smokers has frequently been observed in the general population.3,4,14,15 It is unclear whether this effect modification represents biologic differences between smokers and nonsmokers or is largely due to bias.13 Additional studies are needed to answer this question.

In our study, effect modification according to age at diagnosis indicated a direct linear trend among participants younger than 65 years of age but a null or weakened linear association among participants 65 years of age or older. These findings, which are consistent with the results of previous studies involving participants with type 2 diabetes32 and the general population,1,33 may reflect well-known limitations in analyses of mortality among older persons, including an increased prevalence of coexisting chronic diseases, which increases the potential for reverse-causation bias; an increased prevalence of competing risk factors, which reduces the proportional effect of a single factor; and decreased validity of BMI as a measure of adiposity owing to age-related declines in muscle mass and wasting.34 It has also been suggested that excess adiposity may confer a metabolic advantage and improved survival among the elderly. Therefore, caution should be taken in interpreting the results among the older participants.

Our findings with respect to the relationship between BMI and mortality due to specific causes are consistent with those of prior studies conducted in the general population.2-4,14,15 Among participants who had never smoked, the relationship of BMI to both cardiovascular mortality and cancer mortality appeared to be monotonic and linear. No significant association was observed between any BMI category and the risk of death from cardiovascular disease among participants who had ever smoked; however, participants in the lowest BMI category who had ever smoked had a significantly elevated risk of death from cancer.

Proposed biologic mechanisms of the alleged obesity paradox include an increased genetic influence and more severe diabetes among normal-weight persons with diabetes or the effect of a “metabolically obese normal weight” phenotype.35,36 However, normal-weight participants in our cohort were no more likely to report diabetes symptoms or coexisting chronic diseases or to require insulin than were overweight or obese participants. In contrast, normal-weight participants were more likely to be smokers and to have lost weight before a diagnosis of diabetes. Comparisons with this heterogeneous normal-weight group may therefore underestimate the risk of death among the overweight and obese.

Strengths of our study include the large sample (3083 deaths among 11,427 adults with incident diabetes), permitting detailed examination across multiple BMI categories and key analyses to address potential biases. Prospectively measured body weight, documented just before or at the time of a diabetes diagnosis, prevents misclassification from weight change due to early pharmacologic treatments or lifestyle changes shortly after diagnosis. Enrollment of health professionals has proved beneficial with respect to the reliability and validity of self-reported health-related exposures and outcomes, and it reduces confounding by educational and socioeconomic factors.

Limitations of the study include the reliance on self-reported weight measures, although erroneous reporting was shown to be very minimal in validation studies, and corrections of errors in BMI measurement produced similar findings. Information on weight was obtained an average of 11 months before diagnosis as a proxy for the weight at diagnosis, but this is unlikely to have resulted in appreciable error. Finally, the relative homogeneity of the NHS and HPFS cohorts may limit the generalizability of our findings to other racial and ethnic groups.

In conclusion, our results indicate a J-shaped relationship between BMI at the time of a diabetes diagnosis and the risk of death from all causes, with the lowest risk observed among normal-weight participants with a BMI of 22.5 to 24.9. Among participants who had never smoked, there was a direct linear relationship between BMI and mortality, whereas a nonlinear relationship was observed among those who had ever smoked. There was no evidence of a protective effect of overweight or obesity on mortality. In addition, given the relationship of overweight and obesity to other critical public health end points (e.g., cardiovascular disease and cancer), the maintenance of a healthy body weight should remain the cornerstone of diabetes management, irrespective of smoking status. Further evidence is needed to corroborate our findings in other populations.