*3.4. Multiple Imputation for Missing Data*

We analyzed 3,455,798 participants (1,996,118 men and 1,459,680 women) after multiple imputations for missing data. Among these participants, 22,444 and 11,273 total stroke events occurred in men and women, respectively. In this model, overweight and obesity were associated with a higher incidence of total stroke and ischemic stroke in both men and women. Both obesity and underweight were associated with a greater risk of hemorrhagic stroke in men, but not in women (Table 3).

**Table 3.** Association between Body Mass Index Category and Stroke Events Stratified by Sex after Multiple Imputation for Missing Data.


The incidence rate was per 10,000 person-years. Model 1 = Unadjusted, Model 2 = Adjusted for age, Model 3 = Adjusted for age, hypertension, diabetes mellitus, dyslipidemia, cigarette smoking, alcohol consumption, and physical inactivity.

*3.5. Non-Hypertensive Participants*

After excluding hypertensive participants, we analyzed 1,199,658 men and 1,060,380 women in this model. Among them, 9310 and 6619 total stroke events occurred in men and women, respectively. Overweight and obesity were associated with a higher risk of total stroke or ischemic stroke in both men and women. Overweight and underweight were associated with a greater risk of hemorrhagic stroke in men. Notably, overweight, obesity, and underweight were not associated with a risk of hemorrhagic stroke in women (Table 4).


**Table 4.** Association between Body Mass Index Category and Stroke Events Stratified by Sex in Non-Hypertensive Participants.

The incidence rate was per 10,000 person-years. Model 1 = Unadjusted, Model 2 = Adjusted for age, Model 3 = Adjusted for age, diabetes mellitus, dyslipidemia, cigarette smoking, alcohol consumption, and physical inactivity.

#### **4. Discussion**

The current analyses using a nationwide epidemiological database including approximately 2,700,000 people without a prevalent history of CVD, demonstrated that overweight and obesity were associated with a greater risk of total stroke and ischemic stroke in both men and women. Furthermore, underweight was associated with a greater incidence of hemorrhagic stroke in men, but not in women. These results did not change after multiple imputations for missing data or excluding hypertensive participants.

Various studies have been conducted to explore the relationship between BMI and future stroke events [10–12]. Prospective studies including approximately 900,000 people showed that the mortality due to stroke increased in a dose-dependent manner with baseline BMI after it exceeded 25 kg/m<sup>2</sup> [28]. A population-based case–control study including 1,201 patients with ischemic stroke and 1154 controls aged 15–49 years showed that obesity defined as BMI > 30 kg/m2 was associated with an increased risk (odds ratio, 1.57; 95% CI, 1.28–1.94) [29]. Additionally, a higher BMI in adolescents was associated with a greater risk of ischemic stroke [30]. The analysis of the Atherosclerosis Risk in Communities (ARIC) Study including approximately 13,000 black and white people showed that obesity was associated with a greater risk of ischemic stroke irrespective of race [31]. Ischemic stroke was a major subtype of total stroke [1,32], and the majority of the studies focused on the relationship between BMI and ischemic stroke. However, there have been several studies on the association between BMI and hemorrhagic stroke. A recent analysis of the China National Stroke Screening and Intervention Program showed that obesity was associated with a higher risk of total and ischemic stroke, whereas underweight was associated with an elevated risk of hemorrhagic stroke [16]. An analysis of 234,863 Korean men aged 40–64 years reported a positive association between BMI and incident ischemic

stroke, whereas a J-shaped association was observed between BMI and hemorrhagic stroke [17].

Our results were generally in line with previous studies, as described above. The present study had several strengths. First, this study included a large number of participants without a prior history of CVD. Additionally, the JMDC Claims Database included the medical claims records from employees' insurance programs. Therefore, as long as each individual remained under coverage of the same insurance, the JMDC Claims Database could track the individuals' clinical information, including the diagnosis of stroke events, even if the individual visits different medical institutions. Second, sex differences are important in the risk stratification and prevention of CVD, including stroke. Furthermore, the value of BMI is different between sexes; therefore, we separately analyzed men and women. The positive association of overweight/obesity with the incidence of total stroke and ischemic stroke was consistent in both men and women. However, underweight was associated with a higher incidence of hemorrhagic stroke only in men. Therefore, there could be a gender difference in the relationship between BMI and incident stroke, particularly hemorrhagic stroke. Although similar findings were reported in a previous study including Korean men [17], data including men in the United States did not show an increase in the risk of hemorrhagic stroke in individuals having lower BMI [10]. A previous study including 39,053 women in the United States examined the relationship between BMI and incident stroke and showed that BMI was a risk factor for total or ischemic stroke but not for hemorrhagic stroke, and this relationship was attenuated after adjustment for hypertension, diabetes mellitus, and hypercholesterolemia [12]. Compared with this study including women in the United States, the relationship between BMI and incident stroke (particularly ischemic stroke) was seemingly more obvious even after adjustment for covariates in women of this study. Therefore, further investigations are required to verify our results. However, these associations in men and women did not change after multiple imputations for missing data. Furthermore, because hypertension is known to be a strong risk factor for both ischemic and hemorrhagic stroke, we conducted a sensitivity analysis after excluding hypertensive participants. Even in this model, the main results did not change. Third, because the association between BMI and incident stroke could change depending on the cut-off value of BMI for underweight, overweight, and obesity, we conducted the RCS of BMI for incident stroke to deal with BMI as a continuous value. Similar to the association of overweight, obesity, and underweight with the risk of stroke, RCS demonstrated a dose-dependent increase in the risk of total stroke and ischemic stroke with BMI in men and women, and a U-shaped relationship between BMI and future hemorrhagic stroke risk in men. These results suggest a potential difference in the association of BMI with risk of future events between ischemic and hemorrhagic stroke, particularly in men.

This study has several limitations. Due to the nature of retrospective observational studies, our study could not conclude a causal relationship between baseline BMI and incident stroke. For example, our study showed that overweight and obesity were associated with an elevated risk of ischemic stroke. However, whether body weight loss could reduce the future risk of ischemic stroke in overweight or obese participants could not be discussed in this study. Similarly, although underweight was associated with a greater incidence of hemorrhagic stroke in men, the underlying mechanism for this association and the optimal management strategy for this population should be elucidated in future studies. For example, malnutrition and specific comorbidities may contribute to the elevated incidence of hemorrhagic stroke in underweight participants. However, the JMDC Claims Database does not include sufficient data to consider this point. Although the incidence of CVD in this database is acceptable compared with other epidemiological data in Japan, the recorded diagnoses of administrative databases are generally considered less well-validated. Since the JMDC Claims Database primarily included an employed population of working age, a selection bias (e.g., healthy worker bias) might exist. Therefore, further investigations are needed to determine whether our findings can be expanded to other populations of

different races, ethnicities, and socioeconomic status. The main results did not change after multiple imputations for missing data. However, the substantial proportion of missing data should be considered a major study limitation. Although we used BMI in this study, dual energy X-ray absorptiometry is a standard method to evaluate a body composition including fat. This discrepancy might have contributed to the wide confidence intervals at high and low BMI levels on the RCS curve in women. Data on medication status were limited in this study. For example, use of antithrombotic medication or statin could influence the results. However, we were unable to analyze these data. Although the change in mediation status could also influence the results, data on the change in medication status were not available in this study.

In conclusion, we analyzed a nationwide epidemiological database including a general population of 2,740,778 individuals with no prevalent history of CVD and found that overweight and obesity were associated with a higher incidence of total stroke and ischemic stroke in both sexes. Underweight was associated with a greater risk of future hemorrhagic stroke events in men, but not in women. Similarly, RCS showed that the risk of ischemic stroke dose-dependently increased with BMI in men and women, whereas there was a U-shaped relationship between BMI and future hemorrhagic stroke risk in men. Our results suggest that the association of BMI with subsequent risk differs between ischemic and hemorrhagic stroke, particularly in men.

**Author Contributions:** (1) Conception and design: H.K. (Hidehiro Kaneko), M.S., and I.K. (2) Analysis of data: M.S., H.I., K.M., S.M., H.K. (Hiroyuki Kiriyama), T.K., K.F., N.M., T.J., and H.Y. (3) Interpretation of data: H.K. (Hidehiro Kaneko), M.S., A.O., H.M., K.N., H.Y., and I.K. (4) Drafting of the manuscript: H.K. (Hidehiro Kaneko), M.S., and H.Y. (5) Critical revision for important intellectual content: N.T., H.M., S.N., and K.N. All authors have read and agreed to the published version of the manuscript.

**Funding:** This work was supported by grants from the Ministry of Health, Labour and Welfare, Japan (21AA2007) and the Ministry of Education, Culture, Sports, Science and Technology, Japan (20H03907, 21H03159, and 21K08123). The funding sources had nothing with regard to the current study.

**Institutional Review Board Statement:** This study was conducted according to the ethical guidelines of our institution (approval by the Ethical Committee of The University of Tokyo: 2018–10862) and in accordance with the principles of the Declaration of Helsinki. The requirement for in-formed consent was waived because all the data from the JMDC Claims Database were de-identified.

**Informed Consent Statement:** The requirement for in-formed consent was waived because all the data from the JMDC Claims Database were de-identified.

**Data Availability Statement:** The data from the JMDC Claims Database are available for anyone who would purchase it from JMDC Inc. (JMDC Inc.; Tokyo, Japan; https://www.jmdc.co.jp/en/index), which is a healthcare venture company in Tokyo, Japan.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **Disclosures**

Research funding and scholarship funds (Hidehiro Kaneko and Katsuhito Fujiu) from Medtronic Japan CO., LTD, Boston Scientific Japan CO., LTD, Biotronik Japan, Simplex QUANTUM CO., LTD, and Fukuda Denshi, Central Tokyo CO., LTD.

#### **Non-Standard Abbreviations and Acronyms**

