In our pooled longitudinal study, participants who were normal weight at the time of incident diabetes experienced higher total and non-cardiovascular mortality as compared with those who were overweight or obese. Cardiovascular mortality was non-significantly elevated in participants who were normal weight as compared with those who were overweight or obese. Findings were consistent across demographic categories and smoking status and persisted following adjustment for known cardiovascular disease risk factors.
It was unexpected that weight status was not associated with cardiovascular mortality. However, crude cardiovascular mortality rates were higher in normal weight vs. overweight/obese participants and hazard ratios from fully adjusted models reflect elevated mortality. Consequently, we interpreted the absence of statistical significance as a byproduct of low statistical power due to the relatively smaller number of cardiovascular events.
Overweight and obese patients with end stage renal disease have better health outcomes than leaner patients.19–21
Similarly, lean hypertensives (the cutpoint for “lean” varies across studies)22
and persons with heart failure3
have worse health outcomes than their heavier counterparts. Even among persons without known chronic diseases, heavier weight may only be positively associated with long-term (>15 years) mortality.23
Our findings are consistent with the existing literature in other prevalent disease cohorts, including those of persons with diabetes.6, 7, 24, 25
Lower body weight in the presence of obesity-related metabolic disorders may reflect underlying illness that predisposes to mortality. Prior research has attempted to reduce the influence of latent illness by excluding those who died early (2–5 years) during the follow-up period. We did not have an adequate number of events over an extended follow-up period (> 15 years) to study long-term mortality,23
and so our findings could reflect higher mortality among persons who were already ill for reasons unrelated to diabetes. Statistical adjustment for demographic characteristics (e.g., socioeconomic status) and health behaviors (e.g., smoking) associated with other causes of mortality, did not change our findings. Despite having a leaner body habitus, cigarette smokers are more insulin resistant26
, more likely to develop diabetes,27
and have increased mortality as compared with non-smokers. However, we report that the elevated mortality in normal weight participants is not entirely attributable to higher smoking as findings are similar among smokers and non-smokers.
The primary features distinguishing our study from the contemporary PROactive trial7
and the TRIAD studies6
(as well as earlier studies addressing this question24, 25
) are that we 1) defined weight status at the time of incident diabetes; and, 2) identified an elevated risk of mortality in normal weight adults who did not have comorbid cardiovascular diseases (e.g., coronary heart disease, cerebrovascular disease). Although unexplained or unintentional weight loss, despite hunger and regular eating is most commonly described as a symptom of type 1 diabetes, it is often present in type 2 diabetes.8
Intentional weight loss is recommended following the identification of type 2 diabetes based on findings that adults who lose weight have better glycemic control and other cardiovascular disease risk factors.28
Both of these scenarios could confound the ability to describe the association between weight status and mortality if weight status is determined at the time of prevalent diabetes.
Latent Autoimmune Diabetes in Adults (LADA)29
is phenotypically similar to type 1 diabetes because of apparent β cell destruction and presentation in normal weight adults. Some normal weight adults with diabetes may have LADA, but it is not possible identify LADA without measuring autoantibodies such as GAD or C-peptide—neither of which were universally measured in these cohort studies. We did not have access to the type of diabetes control medication (oral hypoglycemic vs. insulin replacement) across all cohort studies in our analysis. Consequently, we are unable to determine whether participants who were normal weight at the time of diabetes incidence in our study have LADA. Despite this limitation, our findings suggest that regardless of diabetes type, normal weight status at the time of diabetes incidence may be a straightforward marker to identify elevated mortality risk.
In our epidemiologic study, normal weight is determined based on BMI and not on a direct measure of adiposity. Higher BMI could be the result of more lean muscle mass, which is more insulin sensitive than adipose tissue and, consequently, metabolically favorable. If, as suggested,30–32
insulin resistance is the primary underlying factor in cardiovascular disease, then unmeasured fat mass and insulin sensitivity may be a significant source of residual confounding among normal weight adults. Waist circumference was directly positively associated with mortality in our sample and the strength of association between normal weight status and total mortality became modestly stronger when waist circumference was included in our models. Our adjusted findings may reflect an adverse role of lower lean mass on mortality in participants who are normal weight at the time of incident diabetes. Because our initial hypothesis was for a threshold effect of BMI in the normal weight category, it was not unexpected that when BMI was studied continuously in relation to mortality that the effect we hypothesized was obscured and that there was no association.
Age-related loss of lean muscle mass and bone (i.e., sarcopenia) could result in a lower body weight despite greater fat mass in older adults. Older adults who are “frail” have elevated mortality from all causes.33
Although we did not directly assess frailty, we excluded underweight participants from our analyses, tested for interaction by age, excluded participants who died within two years of inception into the cohort and participants who lost weight. In each of these sensitivity analyses, normal weight status remained associated with higher mortality and there was no interaction by age. While the effect estimates for cardiovascular mortality in older adults included the null, our tests for statistical interaction indicate that there is no difference between strata.
Leaner adults with diabetes may have been screened less rigorously for diabetes and its complications by their healthcare providers. Consequently, cardiovascular disease risk factors may have gone untreated or under-treated. One strength of having carried out our investigation in a cohort study vs. a health practice plan is that all participants were examined at regular intervals independent of healthcare complaints and weight status. By including assessments of cardiovascular disease risk factors in our multivariable models, we were able to statistically adjust for the presence of other cardiovascular risk factors at the time of diabetes identification that could have precipitated mortality.
Strengths and Limitations
A cohort comprised of adults with incident disease (an inception cohort) is the strongest design to investigate our question because the likelihood of developing complications is positively associated with diabetes duration and because participants may have initiated weight loss because of their diagnosis. While participants could have developed diabetes in between study intervals, the length between exams across studies ranged from 2 to 5 years and variability in diabetes duration at baseline is truncated. Sensitivity analyses excluding participants using medications confirmed our findings. The robustness of our findings are reflected in the consistent associations within each cohort and in subgroups defined by age, race, sex and smoking status.
Smoking status is a potentially important modifier of the association and our ability to distinguish smoking burden (e.g., duration, timing and amount) was hindered by the inconsistent methods of capturing smoking across cohorts. As a result, we could only crudely stratify to compare participants who ever (comprised of current and former) reported smoking to those who never smoked. Because these cardiovascular disease cohort studies did not commonly validate non-cardiovascular causes of morbidity or mortality, and so we were unable to determine the specific causes of elevated non-cardiovascular mortality or of medical conditions that could promote the onset of diabetes in normal weight adults. Similarly, we could not study the contributions of medications for other illnesses that are associated with higher mortality and that could promote the onset of diabetes (e.g., antidepressants). Despite our attempts to rule out illness through our sensitivity analyses, it is possible that participants who were normal weight at the time of diabetes incidence may have had underlying non-cardiovascular illnesses predisposing them to mortality.
Mechanisms to explain our findings of higher mortality in adults who are normal weight at the time of incident diabetes are unknown. However, previous research suggests that normal weight persons with diabetes have a different genetic profile than overweight or obese persons with diabetes.34
If those same genetic variants that predispose to diabetes are associated with other illnesses, these individuals may be “genetically loaded” towards experiencing higher mortality. Future research in normal weight persons with diabetes should test these genetic hypotheses, along with other plausible mechanisms to account for higher mortality including inflammation, the distribution and action of adipose tissue, atherosclerosis burden and the composition of fatty plaques, and pancreatic β-cell function. In summary, findings from our observational study that adults who are normal weight at the time of diabetes incidence experienced higher mortality than overweight or obese adults with diabetes are relevant to growing segments of our population including older adults and non-whites (e.g., Asian35
) who are more likely to experience normal weight diabetes.