General Hospital Psychiatry 79 (2022) 33–41

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General Hospital Psychiatry

journal homepage: www.elsevier.com/locate/genhospsych

Association of comorbid mental disorders with cardiovascular disease risk

in patients with type 2 diabetes: A nationwide cohort study☆
Hyewon Kim a, Kyu-na Lee b, Dong Wook Shin c, Kyungdo Han d, **, 1, Hong Jin Jeon e, f, *, 1
a
Department of Psychiatry, Hanyang University Hospital, Seoul, South Korea
b
Department of Biomedicine & Health Science, College of Medicine, The Catholic University of Korea, Seoul, South Korea
c
Supportive Care Center/Department of Family Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
d
Department of Statistics and Actuarial Science, Soongsil University, Seoul, South Korea
e
Department of Psychiatry, Depression Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
f
Department of Health Sciences & Technology, Department of Medical Device Management & Research, Department of Clinical Research Design & Evaluation, Samsung
Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, South Korea

A R T I C L E I N F O A B S T R A C T

Keywords: Objective: To examine the association between comorbid mental disorders and cardiovascular disease (CVD) risk
Type 2 diabetes among patients with type 2 diabetes.
Cardiovascular diseases Method: This retrospective cohort study was conducted using the claims data of 2,227,394 South Korean patients
Macrovascular complications
with type 2 diabetes. We analyzed the occurrence of CVD including myocardial infarction (MI) and ischemic
Mental disorder
stroke, CVD-specific mortality, and all-cause mortality according to comorbid mental disorders including
Severe mental illness
depressive disorders, bipolar and related disorders, schizophrenia spectrum disorders, insomnia, and anxiety
disorders.
Results: Among the patients, 9.1% had a comorbid mental disorder. The adjusted hazard ratios (aHR) for MI,
ischemic stroke, CVD-specific mortality, and all-cause mortality in patients with any mental disorder were 1.20
(95% CI, 1.17–1.24), 1.13 (95% CI, 1.11–1.16), 1.16 (95% CI, 1.12–1.20), and 1.21 (95% CI, 1.19–1.23),
respectively. Each mental disorder increased the risk of all outcomes, particularly bipolar and related disorders
and schizophrenia spectrum disorders.
Conclusion: Comorbid mental disorders increased the CVD risk in patients with type 2 diabetes, with significantly
increased risks associated with schizophrenia spectrum disorders (aHR: 1.27 for MI and 1.50 for ischemic stroke)
and bipolar and related disorders (aHR: 1.27 for MI and 1.45 for ischemic stroke).

1. Introduction patients with type 2 diabetes, the subsequent occurrence of macro­

Globally, an estimated 537 million people had diabetes in 2021, up
from 151 million in 2000, and the number is expected to reach 783
million by 2045 [1]. Those with type 2 diabetes have been estimated to
constitute >90% of these patients [1]. Type 2 diabetes not only places a
considerable burden on patients but also impacts health expenditure,
which was estimated to be 966 billion USD in 2021 [1]. Moreover, in
vascular complications, including cardiovascular disease (CVD), con­
tributes to increased morbidity; these patients have a three to four times
increased risk of death compared with those without CVD [2]. Previous
studies have reported that both time related-variables (e.g., age and
longer diabetes duration) [3] and established risk factors for CVD (e.g.,
hypertension, high cholesterol level, and smoking) [4] increase the
likelihood of developing CVD in patients with type 2 diabetes.

☆
All authors agreed to this submission. The material is original research, has not been previously published, and has not been submitted for publication elsewhere
while under consideration.
* Correspondence to: H. J. Jeon, Department of Psychiatry, Depression Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Vice-dean
of Research, Sungkyunkwan University School of Medicine, Director of the Digital Therapeutics Research Center, Samsung Medical Center, Samsung Advanced
Institute for Health Sciences & Technology, 06355, 115 Irwon-Ro, Gangnam-gu, Seoul, South Korea.
** Correspondence to: K. Han, Department of Statistics and Actuarial Science, Soongsil University, Seoul, 06978, 369 Sangdo-ro, Dongjak-gu, Seoul, South Korea.
E-mail addresses: hkd917@naver.com (K. Han), jeonhj@skku.edu (H.J. Jeon).
1
These individuals contributed equally to this article as co-corresponding authors.

https://doi.org/10.1016/j.genhosppsych.2022.10.005
Received 7 July 2022; Received in revised form 16 September 2022; Accepted 6 October 2022
Available online 11 October 2022
0163-8343/© 2022 Elsevier Inc. All rights reserved.
H. Kim et al.
Moreover, social factors such as socioeconomic status and lower
educational attainment have been considered to influence the devel­
opment of CVD in patients with type 2 diabetes through health behav­
iors or access to care [5,6].
The prevalence of mental disorders in patients with diabetes is
higher than that in the general population. The relative risks of
depression, bipolar disorder, schizophrenia, insomnia, and anxiety dis­
orders among those with diabetes compared with the general population
have been reported as 1.4–2.0 [7–9], 1.6–1.7 [9], 1.5–3.4 [9,10], 1.3
[11], and 1.3–1.4 [8,9], respectively. Despite the increased effects of
diabetes in patients with mental disorders and CVD being the most
common physical illness–related cause of death among patients with
severe mental illness (SMI) [12], few studies have investigated the link
between comorbid mental disorders and CVD in patients with type 2
diabetes. Although the studies differ in methodology, comorbid
depression has been consistently reported to increase the risk of mac­
rovascular complications, with a relative risk of 1.1–2.2 [13–17].
However, the risks of macrovascular complications reported in patients
with diabetes who had comorbid schizophrenia have been inconsistent
between studies or subgroups [15,18,19]. Furthermore, limited studies
have comprehensively analyzed the impact of comorbid bipolar disorder
on the risk of macrovascular complications in patients with diabetes,
with one study reporting no significant increase in the risk [15].
Moreover, evidence on the risk associated with non-SMIs, such as anx­
iety disorder or insomnia, is limited, although one cross-sectional study
reported a positive correlation between anxiety and complications of
type 2 diabetes [20].
Despite the high prevalence of comorbid mental disorders in patients
with type 2 diabetes and their possible association with the occurrence
of CVD, how the risk of macrovascular complications varies according to
comorbid mental disorders has not been comprehensively analyzed.
Identifying the subsequent cardiovascular risk according to comorbid
mental disorders in patients with diabetes may aid the screening and
management of complications of diabetes. In addition, identifying fac­
tors linking comorbid mental disorders and subsequent cardiovascular
risk can be an important strategy for diabetes care for them. We aimed to
examine the association between comorbid mental disorders and the
occurrence of CVD, including myocardial infarction (MI) and ischemic
stroke, in patients with type 2 diabetes. We hypothesized that (1) pa­
tients with type 2 diabetes who have comorbid mental disorders would
have a higher risk of subsequent CVD than those without comorbid
mental disorders and (2) the magnitude of the risk would vary according
to the mental disorder.
2. Methods
2.1. Data source
This study used data from the National Health Insurance Sharing
Service (NHISS) database of the National Health Insurance Service
(NHIS) of South Korea [21,22]. The NHIS is a public organization and is
responsible for operating a mandatory universal health insurance pro­
gram. Nearly 97% of the South Korean population is enrolled in this
service, and the remaining population is covered by the Medical Aid
Program. The NHISS database contains claims data related to medical
services such as hospitalization, emergency room visits, outpatient clinic
visits, pharmaceutical services, and general health screening from 2002.
The National General Health Screening Program of South Korea is the
world's largest health screening program. It targets the prevention and
early management of common chronic diseases in the adult population
of South Korea [23].
NHISS data are anonymized, and the Institutional Review Board of
Soongsil University approved the protocol of this study (No. SSU-
202003-HR-201-01).
34
General Hospital Psychiatry 79 (2022) 33–41
2.2. Case identification
We extracted the data of 2,746,079 patients who underwent health
screening between 2009 and 2012 and were diagnosed with type 2
diabetes. When a patient participated in two or more health screening
programs during this period, the earlier one was considered the index
examination. The diagnosis of type 2 diabetes was determined based on
the presence of the International Statistical Classification of Disease and
Related Health Problems 10th revision (ICD-10) codes E11, E12, E13, or
E14 and at least one claim for prescribed antidiabetic medications or a
fasting glucose level ≥ 126 mg/dL. Diagnostic codes were recorded by
physicians when they evaluated a patient. We excluded 390 patients
aged <20 years and 117,446 patients with incomplete data. To evaluate
the first diagnosis of CVD, we excluded 112,933 patients with diagnostic
codes of MI and 254,897 patients with diagnostic codes of ischemic
stroke recorded between January 1, 2002, and the day of the health
screening program. We also excluded 33,019 patients who were diag­
nosed with CVD within 1 year of undergoing health screening to elim­
inate the effect of a temporary increase in the incidence of CVD due to its
detection at the health screening program. Finally, 2,227,394 patients
were eligible and included in the analyses. Their medical records until
December 31, 2018, were reviewed (Supplementary Figure).
2.3. Comorbid mental disorders
We identified the patients' history of diagnosis of mental disorders in
the 5 years before the index examination. Depressive disorders were
defined based on the diagnostic codes F32, F33, F34.1, and F34.81.
Bipolar and related disorders were defined based on the diagnostic codes
F30, F31, and F34.0. Schizophrenia spectrum disorders were defined
based on the diagnostic codes F20–29. Anxiety disorders were defined
based on the diagnostic codes F40 and F41, and insomnia was defined
based on the diagnostic codes F51.0 and G47.0. We only considered the
primary diagnostic codes to evaluate the diagnostic stability.
2.4. Outcomes
The main outcomes were newly diagnosed CVD, CVD-specific mor­
tality, and all-cause mortality. CVD included MI and ischemic stroke,
and each disease was defined by referring to a previous study: MI was
defined based on the diagnostic codes I21 or I22 during hospitalization,
and ischemic stroke was defined based on the diagnostic codes I63 or I64
and brain imaging examination (magnetic resonance imaging or
computed tomography) during hospitalization [24].
2.5. Covariates
Low income was defined as an income <25% of the national average
and was determined based on the health insurance premium. In South
Korea, the health insurance premium depends on the income level. From
the self-administrated questionnaire administered to each patient dur­
ing the health screening, we extracted data about their smoking status,
alcohol consumption, and physical activity. We calculated the body
mass index (BMI) from the weight and height. We obtained data on waist
circumference, fasting glucose level, systolic and diastolic blood pres­
sure, total cholesterol level, high/low-density lipoprotein level, tri­
glyceride level, and glomerular filtration rate from the health screening
data. Comorbid physical illnesses including hypertension (at least one
claim per year for prescribed antihypertensive drugs under the ICD-10
codes I10–13 and I15 or a blood pressure ≥ 140/90 mmHg), dyslipi­
demia (at least one claim per year for prescribed anti-hyperlipidemic
agents under the ICD-10 code E78 or a total cholesterol level ≥ 240
mg/dL), and chronic kidney disease (an estimated glomerular filtration
rate of <60 mL/min) were identified. In addition, we identified the
duration of diabetes (time from the date of the first prescription to the
day of health screening), whether insulin was used, and the number of
H. Kim et al. General Hospital Psychiatry 79 (2022) 33–41

oral hypoglycemic agents used.
2.6. Statistical analysis
The baseline characteristics have been presented as mean ± standard
deviation (SD) for continuous variables and as numbers and percentages
for categorical variables except for triglyceride levels. Because the tri­
glyceride levels exhibited a skewed distribution, we used log-
transformed data and presented them as geometric means and 95%
CIs. Student's t-tests and chi-square tests were used to compare the dif­
ferences in factors between groups. The incidence rates of MI, ischemic
stroke, and death have been presented per 1000 person-years. Cox
proportional hazards regression analyses were conducted to identify the
association between comorbid mental disorders and the occurrence of
outcomes. Regression analyses were independently performed for each
of the three outcomes (MI, ischemic stroke, and death) and censored by
each outcome or death. Hazard ratios (HR) and the corresponding 95%
confidence intervals (CIs) were determined to assess the magnitude of
the risk of outcomes for different comorbid mental disorders. Model 1
was non-adjusted, Model 2 was adjusted for age and sex, Model 3 was
adjusted for BMI, smoking, alcohol drinking, and physical activity in
addition to Model 2, and Model 4 was adjusted for hypertension,
dyslipidemia, chronic kidney disease, fasting glucose, duration of dia­
betes, insulin use, and number of oral hypoglycemic agents in addition
to model 3. The cumulative incidence rates of MI, ischemic stroke, CVD-
specific mortality, and all-cause mortality were plotted using
Kaplan–Meier curves. Statistical analyses were performed using SAS
version 9.4 (SAS Institute Inc., Cary, NC, USA).
3. Results
3.1. Baseline characteristics
Table 1 shows the baseline characteristics of the included patients.
Among the 2,227,394 eligible patients with type 2 diabetes, 202,042
(9.1%) had been diagnosed with mental disorders and 2,025,352
(90.9%) had not been diagnosed with mental disorders in the 5 years
before the index examination. The mean age at baseline of those with
and without mental disorders was 60.2 years (SD, 11.6 years) and 55.7
years (SD, 12.2 years), respectively. The proportion of women with and
without mental disorders was 58.5% and 36.8%, respectively. Patients
with mental disorders were more likely to be non-smokers and/or non-
drinkers; to have hypertension, dyslipidemia, or chronic kidney disease;
and to use insulin and/or ≥ 3 oral hypoglycemic agents than those

Table 1
Baseline characteristics of the patients.
Comorbid mental disorders Odds ratio (95% confidence Adjusted odds ratioa (95% confidence
intervals) intervals)
No (N = 2,035,352) Yes (N = 202,042)

Age (years) 55.7 ± 12.2 60.2 ± 11.6 1.03 (1.03, 1.03) 1.03 (1.03, 1.03)
Age group
<40 years 186,706 (9.2) 7229 (3.6) 1 (Ref.) 1 (Ref.)
40–64 years 1,341,108 (66.2) 118,521 (58.7) 2.28 (2.23, 2.34) 1.96 (1.92, 2.01)
≥65 years 497,538 (24.6) 76,292 (37.8) 3.96 (3.86, 4.06) 3.00 (2.93, 3.08)
Sex
Male 1,279,976 (63.2) 83,807 (41.5) 1 (Ref.) 1 (Ref.)
Female 745,376 (36.8) 118,235 (58.5 2.42 (2.40, 2.45) 2.13 (2.11, 2.15)
Low income 423,103 (20.9) 4311 (22.9) 1.13 (1.11, 1.14) 1.08 (1.07, 1.10)
Smoking
Non-smokers 1,071,814 (52.9) 136,980 (67.8) 1 (Ref.) 1 (Ref.)
Ex-smokers 380,559 (18.8) 27,873 (13.8) 0.57 (0.57, 0.58) 1.07 (1.05, 1.08)
Current smokers 572,979 (28.3) 37,189 (18.4) 0.51 (0.50, 0.51) 1.05 (1.03, 1.06)
Drinking
Non-drinkers 1,072,807 (53.0) 143,785 (71.2) 1 (Ref.) 1 (Ref.)
Mild drinkers 726,856 (35.9) 45,698 (22.6) 0.47 (0.46, 0.47) 0.74 (0.73, 0.75)
Heavy drinkers 225,689 (11.1) 12,559 (6.2) 0.42 (0.41, 0.42) 0.73 (0.71, 0.74)
Regular physical activity 419,902 (20.7) 42,100 (20.8) 1.01 (1.00, 1.02) 1.06 (1.05, 1.08)
Hypertension 1,070,455 (52.9) 117,134 (58.0) 1.23 (1.22, 1.24) 0.98 (0.97, 0.99)
Dyslipidemia 785,940 (38.8) 94,204 (46.6) 1.38 (1.37, 1.39) 1.18 (1.17, 1.19)
Chronic kidney disease 191,412 (9.5) 27,156 (13.4) 1.49 (1.47, 1.51) 1.07 (1.05, 1.08)
Duration of diabetes
<1 year 843,791 (41.7) 61,738 (30.6) 1 (Ref.) 1 (Ref.)
1–5 years 617,878 (30.5) 75,045 (37.1) 1.66 (1.64, 1.68) 1.30 (1.28, 1.31)
≥5 years 563,683 (27.8) 65,259 (32.3) 1.58 (1.56, 1.60) 1.15 (1.13, 1.16)
Insulin use 143,636 (7.1) 20,578 (10.2) 1.49 (1.46, 1.51) 1.30 (1.28, 1.32
Use of ≥3 oral hypoglycemic agents 272,014 (13.4) 30,600 (15.2) 1.15 (1.14, 1.17) 1.01 (1.00, 1.03)
Body mass index (kg/m2) 25.1 ± 3.4 24.9 ± 3.5 0.98 (0.98, 0.98) 0.98 (0.98, 0.99)
Waist circumference (cm) 85.4 ± 8.7 84.6 ± 8.9 0.99 (0.99, 0.99) 1.00 (1.00, 1.00)
Systolic blood pressure (mmHg) 129.0 ± 15.7 127.4 ± 15.6 0.99 (0.99, 0.99) 0.99 (0.99, 0.99)
Diastolic blood pressure (mmHg) 79.3 ± 10.3 77.9 ± 10.1 0.99 (0.99, 0.99) 0.99 (0.99, 0.99)
Fasting glucose (mg/dL) 146.8 ± 47.2 138.2 ± 43.9 1.00 (1.00, 1.00) 1.00 (1.00, 1.00)
Total cholesterol (mg/dL) 198.4 ± 42.4 197.0 ± 43.2 1.00 (1.00, 1.00) 1.00 (1.00, 1.00)
High-density lipoprotein (mg/dL) 52.2 ± 23.5 52.8 ± 25.5 1.00 (1.00, 1.00) 1.00 (1.00, 1.00)
Low-density lipoprotein (mg/dL) 112.2 ± 41.0 112.4 ± 41.7 1.00 (1.00, 1.00) 1.00 (1.00, 1.00)
Estimated glomerular filtration rate (mL/min/ 86.4 ± 36.3 83.6 ± 35.3 1.00 (1.00, 1.00) 1.00 (1.00, 1.00)
1.73 m2)
Triglyceride (mg/dL) 148.3 141.3
(148.2–148.4) (140.9–141.6)
Depressive disorders 0 (0) 88,903 (44.0)
Bipolar and related disorders 0 (0) 6427 (3.2)
Schizophrenia spectrum disorders 0 (0) 12,144 (6.0)
Insomnia 0 (0) 59,681 (29.5)
Anxiety disorders 0 (0) 84,708 (41.9)
a
Adjusted for age and sex.

35
H. Kim et al.
without mental disorders; further, they had a lower income and longer
duration of diabetes than those without mental disorders. Among the
patients with mental disorders, 44.0%, 3.2%, 6.0%, 29.5%, and 41.9%
had depressive disorders, bipolar and related disorders, schizophrenia
spectrum disorders, insomnia, and anxiety disorders, respectively. The
patients' baseline characteristics according to comorbid mental disor­
ders are listed in Supplementary Table 1.
3.2. Incidence of outcomes
Among the 2,227,394 eligible patients, 57,214 had been newly
diagnosed with MI during an average follow-up period of 6.86 years (SD,
1.58 years), with an incidence rate of 3.75 per 1000 person-years;
Fig. 1. Incidence rates of outcomes among patients with and without comorbid mental disorders.
36
General Hospital Psychiatry 79 (2022) 33–41
81,122 had been newly diagnosed with ischemic stroke during an
average follow-up period of 6.82 years (SD, 1.63 years), with an inci­
dence rate of 5.34 per 1000 person-years; and 176,448 died during an
average follow-up period of 6.92 years (SD, 1.51 years), with a mortality
rate of 11.4 per 1000 person-years.
Patients with comorbid mental disorders showed higher incidence
rates of MI (3.61 vs. 5.11 per 1000 person-years), ischemic stroke (5.17
vs.7.14 per 1000 person-years), CVD-specific mortality (1.89 vs. 2.94
per 1000 person-years), and all-cause mortality (10.95 vs. 16.51 per
1000 person-years) than those without comorbid mental disorders
(Fig. 1).
H. Kim et al.
3.3. Risk of outcomes by mental disorder
Table 2 and Fig. 2 show the HRs and corresponding 95% CIs for MI,
ischemic stroke, CVD-specific mortality, and all-cause mortality ac­
cording to comorbid mental disorder. In the Model 4, both the presence
of any mental disorder and that of each mental disorder in isolation were
associated with increased risks of all outcomes. Patients with at least one
mental disorder had increased risks of MI (HR, 1.20; 95% CI, 1.17–1.24)
and ischemic stroke (HR, 1.13; 95% CI, 1.11–1.16) compared with those
without mental disorders. Bipolar and related disorders and schizo­
phrenia spectrum disorders were associated with increased risks of
ischemic stroke, with HRs of 1.45 (95% CI, 1.30–1.62) and 1.50 (95% CI,
1.37–1.64), respectively. Patients with mental disorders had a higher
risk of CVD-specific mortality (HR, 1.16; 95% CI, 1.12–1.20) than those
without mental disorders, and those with schizophrenia spectrum dis­
orders had the highest risk, with an HR of 2.15 (95% CI, 1.89–2.45).
Patients with mental disorders had an increased risk of all-cause mor­
tality than those without mental disorders (HR, 1.21; 95% CI,
1.19–1.23). Patients with bipolar and related disorders and schizo­
phrenia spectrum disorders were associated with significantly increased
risks than those without mental disorders, with an HR of 1.73 (95% CI,
1.61–1.86) and 2.22 (95% CI, 2.11–2.34), respectively.
3.4. Subgroup analyses
Supplementary Table 2 shows the results of the subgroup analyses
according to demographic characteristics, lifestyle factors, comorbid
physical illnesses, and diabetes treatment factors. There were significant
interaction effects of age group (P for interaction <0.001 with ischemic
stroke), sex (P for interaction <0.001 with MI and P for interaction =
0.036 with ischemic stroke), income level (P for interaction = 0.003
with MI), and hypertension (P for interaction = 0.034 with ischemic
stroke), and the number of oral hypoglycemic agents (P for interaction
= 0.030 with ischemic stroke) with comorbid mental disorders on the
occurrence of CVD. Age < 40 years, female sex, no history of hyper­
tension, and the use of ≥3 oral hypoglycemic agents were associated
with an increased risk of CVD in patients with a comorbid mental
disorder.
The results of the subgroup analyses according to mental disorders
are shown in Supplementary Table 3. The interaction effect between age
group and mental disorders on the occurrence of CVD was significant in
schizophrenia spectrum disorders, insomnia, and anxiety disorders; in
patients aged <40 years, comorbid schizophrenia spectrum disorder was
associated with increased risks of MI (adjusted hazard ratio [aHR], 2.47;
95% CI, 1.46–4.19) and ischemic stroke (aHR, 2.71; 95% CI, 1.45–5.06),
comorbid insomnia was associated with an increased risk of ischemic
stroke (aHR, 2.33; 95% CI, 1.46–3.71), and comorbid anxiety disorder
was associated with an increased risk of ischemic stroke (aHR 1.94; 95%
CI, 1.28–2.94).
4. Discussion
The major findings of this nationwide cohort study, which was
conducted on patients with type 2 diabetes using South Korean claims
data, are as follows: First, presence of mental disorders were associated
with an increased risk of MI, ischemic stroke, CVD-specific mortality,
and all-cause mortality. Second, the increased risk was particularly
significant in patients with schizophrenia spectrum disorders and bi­
polar and related disorders. Third, young adults, women, those with the
lowest income level, those with no history of hypertension, and those
using ≥3 oral hypoglycemic agents had a significantly increased risk of
CVD when they had comorbid mental disorders.
Our results reinforced the findings of previous studies [13–17]
demonstrating the increased risk of CVD in patients with type 2 diabetes
and depression and built upon the evidence by evaluating outcomes
such as MI, ischemic stroke, CVD-specific mortality, and all-cause
37
General Hospital Psychiatry 79 (2022) 33–41
mortality while considering individual, lifestyle, and clinical risk fac­
tors for diabetes complications. We found that the aHR of comorbid
depression for CVD ranged from 1.18 to 1.19 across the different models,
which was similar to the aHRs between 1.1 and 2.2 reported in previous
studies [13–17]. Additionally, patients with type 2 diabetes who had
depression had an approximately 15% higher risk of CVD-specific
mortality than those who did not have depression. In patients with
schizophrenia spectrum disorders, we found an approximately 27–55%
increased risk of CVD, which is consistent with the results of a cohort
study conducted in Taiwan [19]. In addition to the factors adjusted for in
a previous study, our model included adjustment for individual risk
factors as potential confounders associated with the risk of CVD [19].
Our study also showed that the risk of CVD-specific mortality more than
doubled when schizophrenia spectrum disorders were present, which is
a new finding; a previous study reported an adjusted diabetes-related
mortality ratio of 1.8 in those with schizophrenia compared with
those without schizophrenia [18]. This high risk of CVD-specific mor­
tality in patients with diabetes who had schizophrenia spectrum disor­
ders highlights the need for early detection of and active intervention for
CVD in these patients.
We observed a 27–45% increased risk of CVD and a 28% increased
risk of CVD-specific mortality in patients with bipolar and related dis­
orders. This is inconsistent with the results of a previous study [15] that
reported a relative risk of 1.00–1.06 for CVD occurrence associated with
comorbid bipolar disorder in patients with diabetes. This discrepancy is
possibly because the previous study broadly defined CVD to include
ischemic heart disease, heart failure, atrial fibrillation, cerebrovascular
disease, hypertension, and macrovascular atherosclerotic disease, and
approximately 40% of the patients in that study had CVD.
Although previous studies have focused on SMIs, we additionally
report an increased risk of CVD in patients with type 2 diabetes who had
comorbid anxiety disorders and insomnia, which are less severe but
more common than SMIs. Among all the included patients, 2.68% and
3.80% had primary diagnoses of insomnia and anxiety disorders,
respectively. These proportions are smaller than that of depressive dis­
orders (3.99%) but greater than those of bipolar and related disorders
(0.29%) and schizophrenia spectrum disorder (0.55%). Our results
showed that comorbid anxiety disorders or insomnia in patients with
type 2 diabetes was associated with an increased risk of CVD and CVD-
specific mortality. Therefore, physicians should pay attention to manage
diabetes and monitor for complications not only in those with SMI but
also in those with non-SMI. Moreover, among the patients with mental
disorders in this study, a significantly high risk of CVD was observed in
young adults, women, those with no history of hypertension, and those
with a short duration of diabetes, although these patients are usually
considered to be at a low risk of macrovascular complications of diabetes
[25]. This suggests that even in patients with type 2 diabetes at low risk,
the risk of CVD can significantly increase when comorbid mental dis­
orders are present, and greater attention to the psychiatric condition of
patients with diabetes, which can worsen their prognosis, is needed.
The potential mechanisms that explain the increased risk of CVD in
patients with type 2 diabetes and comorbid mental disorders are as
follows: First, a suboptimal lifestyle, including physical inactivity,
alcohol consumption, tobacco smoking, and an unhealthy diet [26–28],
in addition to poor compliance with treatment [29,30] may result in
poor glycemic control. Second, psychotropic agents such as antipsy­
chotics, antidepressants, and mood stabilizers may be associated with
the occurrence of CVD. Several commonly prescribed psychotropic
medications (e.g., amitriptyline, mirtazapine, lithium, valproate, and
olanzapine) can lead to substantial weight gain [31], which may in­
crease the risk of CVD. However, because the potential weight gain
associated with each drug differs and some drugs have anorexigenic
properties [31], future research should identify the effect of individual
drugs on the occurrence of complications of diabetes. We observed an
increased risk of CVD and mortality particularly in patients with
schizophrenia spectrum disorders and bipolar and related disorders,
H. Kim et al. General Hospital Psychiatry 79 (2022) 33–41

Table 2
Hazard ratios and 95% CIs of cardiovascular events and mortality.
N Events Duration (person- Incidence rate (per 1000 Hazard ratios (95% confidence intervals)
year) person-years)
Model 1 Model 2 Model 3 Model 4

Myocardial infarction
No 2,025,352 50,314 13,921,936 3.61 1 (Ref.) 1 (Ref.) 1 (Ref.) 1 (Ref.)
Composite of mental
1.42 (1.39, 1.23 (1.20, 1.21 (1.18, 1.20 (1.17,
disorders Yes 202,042 6900 1,350,827 5.11
1.46) 1.26) 1.24) 1.24)
No 2,138,491 54,167 14,673,938 3.69 1 (Ref.) 1 (Ref.) 1 (Ref.) 1 (Ref.)
Depressive disorders 1.38 (1.33, 1.21 (1.17, 1.20 (1.16, 1.18 (1.14,
Yes 88,903 3047 598,825 5.09
1.44) 1.26) 1.24) 1.23)
No 2,220,967 57,013 15,230,284 3.74 1 (Ref.) 1 (Ref.) 1 (Ref.) 1 (Ref.)
Bipolar and related
1.28 (1.11, 1.36 (1.19, 1.29 (1.12, 1.27 (1.11,
disorders Yes 6427 201 42,479 4.73
1.47) 1.56) 1.48) 1.46)
No 2,215,250 56,883 15,194,282 3.74 1 (Ref.) 1 (Ref.) 1 (Ref.) 1 (Ref.)
Schizophrenia spectrum
1.15 (1.03, 1.40 (1.26, 1.27 (1.14, 1.27 (1.14,
disorders Yes 12,144 331 78,481 4.22
1.28) 1.56) 1.41) 1.42)
No 2,167,713 54,978 14,884,561 3.69 1 (Ref.) 1 (Ref.) 1 (Ref.) 1 (Ref.)
Insomnia 1.58 (1.52, 1.24 (1.19, 1.23 (1.18, 1.23 (1.18,
Yes 59,681 2236 388,202 5.76
1.65) 1.30) 1.29) 1.28)
No 2,142,686 54,207 14,703,042 3.69 1 (Ref.) 1 (Ref.) 1 (Ref.) 1 (Ref.)
Anxiety disorders 1.44 (1.39, 1.23 (1.19, 1.23 (1.18, 1.23 (1.19,
Yes 84,708 3007 569,721 5.28
1.49) 1.28) 1.27) 1.28)

Ischemic stroke
No 2,025,352 71,551 13,846,627 5.17 1 (Ref.) 1 (Ref.) 1 (Ref.) 1 (Ref.)
Composite of mental
1.39 (1.36, 1.12 (1.10, 1.12 (1.10, 1.13 (1.11,
disorders Yes 202,042 9571 1,341,025 7.14
1.42) 1.15) 1.15) 1.16)
No 2,138,491 76,696 14,593,895 5.26 1 (Ref.) 1 (Ref.) 1 (Ref.) 1 (Ref.)
Depressive disorders 1.42 (1.38, 1.19 (1.15, 1.19 (1.15, 1.19 (1.16,
Yes 88,903 4426 593,757 7.45
1.46) 1.22) 1.23) 1.23)
No 2,220,967 80,819 15,145,550 5.34 1 (Ref.) 1 (Ref.) 1 (Ref.) 1 (Ref.)
Bipolar and related
1.36 (1.21, 1.47 (1.31, 1.44 (1.29, 1.45 (1.30,
disorders Yes 6427 303 42,102 7.20
1.52) 1.65) 1.62) 1.62)
No 2,215,250 80,630 15,109,755 5.34 1 (Ref.) 1 (Ref.) 1 (Ref.) 1 (Ref.)
Schizophrenia spectrum
1.19 (1.09, 1.55 (1.42, 1.48 (1.36, 1.50 (1.37,
disorders Yes 12,144 492 77,897 6.32
1.31) 1.70) 1.62) 1.64)
No 2,167,713 78,035 14,802,360 5.27 1 (Ref.) 1 (Ref.) 1 (Ref.) 1 (Ref.)
Insomnia 1.53 (1.48, 1.10 (1.06, 1.10 (1.06, 1.11 (1.07,
Yes 59,681 3087 385,292 8.01
1.59) 1.14) 1.14) 1.15)
No 2,142,686 77,220 14,621,272 5.28 1 (Ref.) 1 (Ref.) 1 (Ref.) 1 (Ref.)
Anxiety disorders 1.31 (1.27, 1.06 (1.02, 1.06 (1.03, 1.08 (1.04,
Yes 84,708 3902 566,379 6.89
1.35) 1.09) 1.10) 1.11)

Cardiovascular disease-specific mortality

No 2,025,352 26,522 14,053,602 1.89 1 (Ref.) 1 (Ref.) 1 (Ref.) 1 (Ref.)
Composite of mental
1.57 (1.51, 1.16 (1.12, 1.15 (1.12, 1.16 (1.12,
disorders Yes 202,042 4017 1,368,358 2.94
1.62) 1.20) 1.19) 1.20)
No 2,138,491 28,806 14,815,313 1.94 1 (Ref.) 1 (Ref.) 1 (Ref.) 1 (Ref.)
Depressive disorders 1.47 (1.40, 1.15 (1.10, 1.15 (1.10, 1.15 (1.09,
Yes 88,903 1733 606,647 2.86
1.55) 1.21) 1.21) 1.21)
No 2,220,967 30,445 15,378,969 1.98 1 (Ref.) 1 (Ref.) 1 (Ref.) 1 (Ref.)
Bipolar and related
1.12 (0.92, 1.27 (1.04, 1.26 (1.03, 1.28 (1.04,
disorders Yes 6427 94 42,991 2.19
1.38) 1.56) 1.55) 1.56)
No 2,215,250 30,309 15,342,720 1.98 1 (Ref.) 1 (Ref.) 1 (Ref.) 1 (Ref.)
Schizophrenia spectrum
1.51 (1.32, 2.24 (1.97, 2.10 (1.84, 2.15 (1.89,
disorders Yes 12,144 230 79,240 2.90
1.71) 2.55) 2.39) 2.45)
No 2,167,713 29,149 15,028,152 1.94 1 (Ref.) 1 (Ref.) 1 (Ref.) 1 (Ref.)
Insomnia 1.85 (1.75, 1.14 (1.08, 1.13 (1.07, 1.13 (1.07,
Yes 59,681 1390 393,808 3.53
1.95) 1.21) 1.19) 1.19)
No 2,142,686 28,921 14,844,342 1.95 1 (Ref.) 1 (Ref.) 1 (Ref.) 1 (Ref.)
Anxiety disorders 1.44 (1.37, 1.08 (1.02, 1.07 (1.02, 1.08 (1.03,
Yes 84,708 1618 577,618 2.80
1.52) 1.13) 1.13) 1.14)

All-cause mortality
No 2,025,352 153,856 14,053,602 10.95 1 (Ref.) 1 (Ref.) 1 (Ref.) 1 (Ref.)
Composite of mental
1.51 (1.49, 1.22 (1.21, 1.21 (1.19, 1.21 (1.19,
disorders Yes 202,042 22,592 1,368,358 16.51
1.54) 1.24) 1.23) 1.23)
No 2,138,491 166,437 14,815,313 11.23 1 (Ref.) 1 (Ref.) 1 (Ref.) 1 (Ref.)
Depressive disorders 1.47 (1.44, 1.26 (1.23, 1.25 (1.22, 1.24 (1.22,
Yes 88,903 10,011 606,647 16.50
1.50) 1.28) 1.28) 1.27)
No 2,220,967 175,705 15,378,969 11.43 1 (Ref.) 1 (Ref.) 1 (Ref.) 1 (Ref.)
Bipolar and related
1.53 (1.43, 1.75 (1.63, 1.76 (1.63, 1.73 (1.61,
disorders Yes 6427 743 42,991 17.28
1.65) 1.88) 1.89) 1.86)
No 2,215,250 174,997 15,342,720 11.41 1 (Ref.) 1 (Ref.) 1 (Ref.) 1 (Ref.)
(continued on next page)

38
H. Kim et al. General Hospital Psychiatry 79 (2022) 33–41

Table 2 (continued )
N Events Duration (person- Incidence rate (per 1000 Hazard ratios (95% confidence intervals)
year) person-years)
Model 1 Model 2 Model 3 Model 4

Schizophrenia spectrum 1.63 (1.55, 2.35 (2.23, 2.22 (2.11, 2.22 (2.11,
Yes 12,144 1451 79,240 18.31
disorders 1.72) 2.48) 2.33) 2.34)
No 2,167,713 168,395 15,028,152 11.21 1 (Ref.) 1 (Ref.) 1 (Ref.) 1 (Ref.)
Insomnia 1.85 (1.81, 1.24 (1.21, 1.21 (1.19, 1.22 (1.19,
Yes 59,681 8053 393,808 20.45
1.89) 1.27) 1.24) 1.24)
No 2,142,686 167,618 14,844,342 11.29 1 (Ref.) 1 (Ref.) 1 (Ref.) 1 (Ref.)
Anxiety disorders 1.36 (1.33, 1.10 (1.08, 1.10 (1.07, 1.10 (1.08,
Yes 84,708 8830 577,618 15.29
1.39) 1.13) 1.12) 1.13)

Model 1: unadjusted; Model 2: adjusted for age and sex; Model 3: adjusted for age, sex, low income, body mass index, smoking status, alcohol consumption, and
physical activity; Model 4: adjusted for age, sex, low income, body mass index, smoking status, alcohol consumption, physical activity, hypertension, dyslipidemia,
chronic kidney disease, fasting glucose level, duration of diabetes, insulin use, and number of oral hypoglycemic agents.

Fig. 2. Risk of cardiovascular diseases and mortality according to comorbid mental disorders in patients with type 2 diabetes.
ALL, any mental disorder; DEP, depressive disorders; BD, bipolar and related disorders; SPR, schizophrenia spectrum disorders; INS, insomnia; ANX, anxiety dis­
orders.
The hazard ratio was adjusted for age, sex, low income, body mass index, smoking status, alcohol consumption, physical activity, hypertension, dyslipidemia, chronic
kidney disease, fasting glucose level, duration of diabetes, insulin use, and number of oral hypoglycemic agents.

39
H. Kim et al.
where severe psychiatric symptoms, such as concomitant psychotic
symptoms, might adversely affect functioning and lead to the use of
high-dose or multiple psychiatric medications.
Our results might also be explained by the shared biological mech­
anisms of mental disorders, diabetes, and CVD, including hypothalamic-
pituitary-adrenal axis dysregulation and altered immunity and inflam­
mation [32]. In addition, genetic predisposition may lead to an
increased risk of CVD in those with mental disorders; previous studies
have reported a genetic predisposition to CVD among patients with
depression [33,34] and schizophrenia [35]. Moreover, we should
consider that there are several barriers to the diagnosis and management
of diabetes and its complications in patients with mental disorders; these
patients may not be cognizant of physical problems due to their mental
symptoms [36], may not seek appropriate physical care [37], and may
have difficulties communicating their physical needs [38]. Furthermore,
physicians may tend to focus on their mental status rather than the
physical problem [39] and may regard physical complaints as psycho­
somatic symptoms [26].
In order to consider the effect of these factors on the association
between comorbid mental disorders and diabetic macrovascular com­
plications, the adjusting variables were included in the regression
analysis models as they were sequentially added from unadjusted
(Model 1) to age and sex (Model 2), lifestyle and social factors (Model 4),
and diabetes care factors and other known risk factors for CVD (Model
4). Although there were some differences according to comorbid mental
disorders and outcomes, overall, when age and sex were adjusted, the
changes in HR were substantial, but when other factors were addition­
ally adjusted, the changes in HR were small, excluding that the risks of
MI in diabetic patients with bipolar and related disorders or schizo­
phrenia spectrum disorders were considerably weakened when lifestyle
and social factors were additionally adjusted. These implicate that co­
morbid mental disorders are associated with a significantly increased
risk of macrovascular complications even after adjusting lifestyle and
social factors, diabetes care factors, and known CVD risk factors, while
in those who have comorbid bipolar disorder or schizophrenia, lifestyle
and social factors also seem to considerably affect the increased risk of
diabetic macrovascular complications.
In the subgroup analyses, we attempted to identify the effect of po­
tential moderators and confounders on the associations between co­
morbid mental disorders and the subsequent occurrence of CVD. We
assumed that age and sex would be potential moderators because they
are very important factors related to the clinical manifestations of
mental illness. In addition, the interaction effects of individual factors (i.
e., BMI, smoking status, alcohol consumption, and physical activity) and
factors related to diabetes (i.e., hypertension, dyslipidemia, chronic
kidney disease, fasting glucose level, duration of diabetes, insulin use,
and number of oral hypoglycemic agents) on the association were
analyzed. We found several significant interaction effects with clinical
implications that among patients with comorbid mental disorders, the
risk of macrovascular complications of diabetes may further increase in
young adults, women, those with the lowest income level, those with no
history of hypertension, and those using ≥3 oral hypoglycemic agents.
The strengths of this study include its considerable statistical power
based on the large sample comprising 57,214 patients with MI and
81,122 patients with ischemic stroke. In addition, we could determine
the CVD-specific and all-cause mortality of the patients. In the analytic
models, we comprehensively included risk factors for major cardiovas­
cular events such as smoking status; alcohol consumption; physical ac­
tivity; BMI; metabolic conditions including hypertension, dyslipidemia,
and chronic kidney disease; and diabetes treatment factors including the
duration of diabetes, insulin use, and use of oral hypoglycemic agents.
However, several methodological issues limit the interpretation and
generalization of our findings. First, because we only extracted and
included data of patients who underwent health examinations in the
analyses, selection bias might be present. Second, comorbid mental
disorders were identified using diagnostic codes not through a
40
General Hospital Psychiatry 79 (2022) 33–41
structured diagnostic evaluation because claims data were used. How­
ever, we attempted to ensure diagnostic stability by only considering the
primary diagnosis recorded by physicians to eliminate the effects of
duplicate diagnoses caused by clinical issues such as the prescription of
certain medications. Third, we only identified the comorbidity of mental
disorders, and the temporal relationship between the onsets of type 2
diabetes and the mental disorder was not considered. However, given
the bidirectional association between diabetes and mental disorders
[40], further research is needed on whether the risk of developing CVD
differs depending on which of the two occurred first. Fourth, several
potential risk factors were not included in the analyses since they were
not captured in the dataset used in this study. For example, clinical
variables related to mental disorders (e.g., the severity of symptoms and
use of psychotropic medications) were not included in the analyses, but
they might have a mediating effect on the relationship between co­
morbid mental disorders and the occurrence of CVD in patients with
type 2 diabetes. Fifth, in the regression analyses, competing risk factors
that preclude the occurrence of CVD were not considered since non-CVD
causes of death could not be identified from the dataset used in this
study. In addition to CVD, premature death in patients with type 2
diabetes can be caused by cancer or other systemic conditions such as
liver or kidney disease [41]. Moreover, mental disorders are associated
with an increased risk of suicide, with patients with SMI having a 10–20
times higher risk of death by suicide than the general population [42].
These competing risks could have led to the overestimation of the
incidence of CVD in this study [43].
In conclusion, this nationwide cohort study found that the comor­
bidity of mental disorders was associated with increased risks of MI,
ischemic stroke, CVD-specific mortality, and all-cause mortality in pa­
tients with type 2 diabetes, with a significant increase in risk associated
with schizophrenia spectrum disorders and bipolar and related disor­
ders. Our findings suggest the need for additional interventions for the
detection of macrovascular complications in patients with type 2 dia­
betes and mental disorders.
Funding
This research was supported by the the Bio & Medical Technology
Development Program of National Research Foundation (NRF) funded
by the Ministry of Science & ICT (No. 2021M3A9E4080784) and by the
Korea Health Technology R&D Project through the Korea Health In­
dustry Development Institute (KHIDI), sponsored by the Ministry of
Health & Welfare, Republic of Korea (No. HR21C0885).
Role of funding sources
Funding sources had no role in study design, data collection, data
analysis, data interpretation, writing of this paper, or the decision to
submit this paper for publication.
CRediT authorship contribution statement
Hyewon Kim: Conceptualization, Writing – original draft, Writing –
review & editing. Kyu-na Lee: Formal analysis, Writing – review &
editing. Dong Wook Shin: Writing – review & editing. Kyungdo Han:
Conceptualization, Project administration, Formal analysis, Writing –
review & editing. Hong Jin Jeon: Conceptualization, Project adminis­
tration, Supervision, Writing – review & editing.
Declaration of Competing Interest
None.
Data availability
This study analyzed data provided by the National Health Insurance
H. Kim et al.
Sharing Service (NHISS). NHISS provides data to support policy and
academic research after a review, and researchers can request data here:
https://nhiss.nhis.or.kr/.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.genhosppsych.2022.10.005.
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