Background
Obesity and diabetes mellitus, or diabetes, are not only highly prevalent in both the general US and international populations [
1‐
4], but these factors are also prevalent among individuals who have been diagnosed with an ischemic stroke [
5]. It is estimated that between 18 and 44% of individuals who previously had an ischemic stroke are obese, and between 25 and 45% of individuals who previously had an ischemic stroke have diabetes [
5].
Stroke is a leading cause of long-term disability and death [
6]. As a result, it is important to target modifiable factors in order to reduce the burden of these post stroke outcomes. Obesity and diabetes are independently associated with functional disability [
7‐
12] and all-cause mortality [
7,
13‐
26] following an ischemic stroke. Although obesity is a modifiable risk factor for ischemic stroke [
27,
28], the reported effects of obesity on post-stroke outcomes of functional disability and of all-cause mortality have been conflicting. Whereas studies of the general population have found that increasing body mass concurrently increases the risk of functional disability [
29] and of all-cause mortality [
30,
31], a number of observational studies in a stroke population have reported that obesity is associated with a decreased risk of functional disability [
7‐
9] and all-cause mortality [
7,
13‐
18,
20]; this apparent discrepancy is referred to as the obesity paradox. As a result of these findings, the American Heart Association and American Stroke Association recommend all individuals who are diagnosed with an ischemic stroke be screened for obesity [
5]. However, these agencies do not recommend weight reduction for overweight or obese individuals due to the null results of the Look Action for Health in Diabetes trial, a clinical trial that randomized overweight and obese individuals with type 2 diabetes to intensive behavioral intervention or usual care to compare the risk of vascular events (e.g.
, stroke, myocardial infarction, or vascular death) [
5,
32]. Despite evidence supporting the obesity paradox in the stroke literature as well as in the literature of other chronic diseases such as myocardial infarction, heart failure, and renal disease [
33,
34], several investigators have questioned the validity of studies supporting the ‘obesity paradox,’ citing methodological issues (e.g.
, the measurement of obesity, duration of obesity, treatment and/or selection bias due to the study population) or residual confounding as potential explanations [
33‐
36]. In contrast to the conflicting reported effects of obesity on functional disability and all-cause mortality following a stroke, prior studies have established that diabetes is consistently associated with higher rates of functional disability [
10‐
12] and higher risk of all-cause mortality [
21‐
26] following a stroke.
Although obesity is a strong predictor of diabetes [
37,
38], it is unknown whether diabetes modifies the inflammatory effects of obesity on functional disability or on all-cause mortality after an ischemic stroke. Research has recently supported the heterogeneity of the metabolic profile among obese individuals [
39,
40], which suggests that the effect of obesity on functional disability and all-cause mortality following an ischemic stroke may differ according to diabetes status. The primary objective of this post-hoc analysis was to explore whether the effect of obesity on functional disability and all-cause mortality following an ischemic stroke differed by diabetes status.
Discussion
The purpose of this post-hoc analysis of data from the IMS III clinical trial of acute ischemic stroke patients with at least a moderate stroke severity was to explore the presence of a joint effect of obesity and diabetes on functional disability and on all-cause mortality following an ischemic stroke. Overall, there was not sufficient evidence to determine that the effect of obesity differed by diabetes status on functional disability at 3-months, or on all-cause mortality at 1-year, following an ischemic stroke on either the multiplicative scale or the additive scale. In addition, although obesity [
7,
13‐
19] and diabetes [
21‐
26] have been previously shown to be independently associated with all-cause mortality following a stroke, there was not sufficient evidence to determine that each factor was independently associated with all-cause mortality after adjusting for potential confounders in this cohort of acute ischemic stroke patients with at least a moderate stroke severity. In contrast, the point estimates for the independent associations between each factor and functional disability at 3-months following an ischemic stroke were consistent with the findings from the literature [
7‐
12].
In comparison to some of the studies that cite the obesity paradox on post-stroke outcomes, there are several potential reasons for the discrepant results in the present study. First, the population only consisted of acute ischemic stroke subjects [
33,
35,
50]. Some of the results from this study are consistent with several other studies that included only ischemic stroke subjects whereas the majority of the studies that support the obesity paradox included different patient populations (i.e.
, only hemorrhagic [
20], only ischemic [
8,
9,
11‐
14,
16,
50,
51], stroke or TIA [
7,
17], or both ischemic and hemorrhagic strokes [
10,
15,
18,
19]). It is important to point out these differences in the study population because the pathogenesis of ischemic stroke is markedly different from that of hemorrhagic stroke, thus the effect of obesity on post-stroke outcomes may not be the same [
52]. However, results of this study were similar to several other studies that only included recent ischemic stroke subjects [
8,
9,
51]. Second, the outcomes of interest in studies that support the association between obesity and a decreased risk of all-cause mortality post-stroke were assessed at widely varying periods ranging from a week to 10 years [
33,
35,
50]. However, the studies that had time points similar to the time points of acute stroke trials (IMS III, for example) determined that there was no functional or survival benefit for obese subjects [
8,
50,
53]. Third, the inclusion of important prognostic factors, such as stroke severity and smoking use, as potential confounders differed across studies [
33,
35,
50]. It is critical to account for these important confounders to reduce residual confounding, however many of the studies that assessed these associations did not account for these confounding variables. Lastly, the measure of obesity is nearly always body mass index (BMI). Although BMI is the most commonly used diagnostic tool for obesity in clinical practice [
5,
54], BMI is unable to differentiate between body fat percentage and lean mass which leads to misclassification [
55] nor does it tell the distribution of body fat. Rather than using BMI to measure obesity, it is critical to determine alternative diagnostic tools capable of differentiating risk of poor clinical outcomes following an ischemic stroke such as waist circumference or waist-to-hip ratio [
33,
56].
The present study has a number of limitations that could influence the interpretation of the study results. Due to the restrictive criteria of the IMS III clinical trial, the results of the present study may not be generalizable to all acute ischemic stroke patients. For example, patients were excluded if they had mild stroke severity (NIHSS < 8). The generalizability of the results of this study is therefore limited to ischemic stroke patients with at least a moderate stroke severity who met all of the study eligibility criteria. Thus, the potential for selection bias cannot be excluded. Future research could be performed to determine if the results demonstrated among a cohort of acute ischemic stroke subjects with at least a moderate stroke severity would be similar to the results among a cohort of acute ischemic stroke subjects.
Additional identified limitations are associated with the measurement of the exposures of interest. Results of this study were limited in the interpretability of the results partially due to how obesity and diabetes information were captured (i.e.
, binary summary measures). There may be measurement error based on the how obesity and diabetes information was ascertained. Specifically, no further definition of these variables was provided in the IMS III Case Report Form Guidelines. Therefore, we were not able to accurately define obesity or diabetes based on their BMI or fasting blood glucose levels, respectively. Although these measures are based on high-quality data, the degree of obesity or diabetes could not be determined at baseline. Thus, the potential for measurement bias cannot be excluded. Future studies could capture multiple measures of obesity, specifically BMI, waist circumference, and/or waist-to-hip ratio, rather than a summary indicator for obesity and/or utilize the World Health Organization’s public health action points [
57] to further define subjects’ degree of obesity. These alternative measures would allow for greater interpretability. Additionally, the exposures of interest are only snapshots of subjects’ history of obesity and/or diabetes. As a result, it was not possible to determine the cumulative effect, or allostatic load, of either exposure of interest. Future studies could collect information on subjects’ weight histories in addition to the duration of diabetes to accurately determine whether the effect of obesity on post-ischemic stroke outcomes differs by diabetes status.
Additionally, IMS III was not designed to answer the research questions of the present study. Examining joint effects, or interactions, is challenging because tests for interactions are typically underpowered [
58]. Despite these limitations and the confines of statistical power, this study was able to demonstrate the joint effect of obesity and diabetes on functional disability and on all-cause mortality following an ischemic stroke is insignificant. Although other analytical strategies were applied to offset these problems, it is imperative to strive for sufficient power to examine the potential joint effect of obesity and diabetes on clinical outcomes following an ischemic stroke. Thus, it is critical to utilize a national or international ischemic stroke registry that would provide sufficient resources and power for future studies to address these research questions.
Despite some limitations, the present study includes several notable strengths. First, this is the first study to explore the potential multiplicative and additive joint effects of obesity and diabetes on functional disability and all-cause mortality following an ischemic stroke. Results of this research provide evidence for generating hypotheses for future studies investigating how obesity and diabetes could potentially interact with one another to affect the clinical outcomes following an ischemic stroke. Second, the rigorous data collection of the IMS III trial reduced information bias. Rather than relying on subjects self-reporting their medical history, the use of source documentation to verify sociodemographic characteristics, clinical characteristics, and risk factors and comorbidities prevented bias that may have resulted from self-reporting. Third, IMS III investigators followed strict study procedures, which minimized the potential bias from incorrect documentation of the trial’s outcomes.
Conclusions
Overall, it is important to continue to study joint effects of these common modifiable factors to identify susceptible subgroups of individuals that would potentially benefit from effective interventions targeted at reducing the burden of functional disability and all-cause mortality [
58]. This topic is of high public health priority. Obesity and diabetes are not only highly prevalent in both the general US and international populations [
1,
3,
4,
59], but they are also prevalent among individuals who have been diagnosed with a stroke [
5]. It is estimated that between 18 and 44% of individuals who previously had an ischemic stroke are obese, and between 25 and 45% of individuals who previously had an ischemic stroke have diabetes [
5]. Recent research has supported the heterogeneity of the metabolic profile among obese individuals [
39,
40]. Overall, the underlying mechanisms by which obesity and diabetes may interact to affect functional disability or all-cause mortality following an ischemic stroke remain unclear. Thus, future studies should differentiate between metabolically healthy and metabolically unhealthy patients within BMI categories (or other diagnostic tools for obesity) to determine if the effect of obesity on post-ischemic stroke outcomes differs by diabetes (or some other metabolic health measure).