Atherosclerosis 319 (2021) 35–41

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Atherosclerosis
journal homepage: www.elsevier.com/locate/atherosclerosis

Fasting plasma glucose and subsequent cardiovascular disease among

young adults: Analysis of a nationwide epidemiological database
Hidehiro Kaneko a, b, *, Hidetaka Itoh a, Hiroyuki Kiriyama a, Tatsuya Kamon a,
Katsuhito Fujiu a, b, Kojiro Morita c, d, Nobuaki Michihata e, Taisuke Jo e, Norifumi Takeda a,
Hiroyuki Morita a, Hideo Yasunaga c, Issei Komuro a
a
The Department of Cardiovascular Medicine, The University of Tokyo, Japan
b
The Department of Advanced Cardiology, The University of Tokyo, Japan
c
The Department of Clinical Epidemiology and Health Economics, School of Public Health, The University of Tokyo, Japan
d
The Department of Health Services Research, Faculty of Medicine, University of Tsukuba, Japan
e
The Department of Health Services Research, The University of Tokyo, Japan

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

Keywords: Background and aims: Using a nationwide epidemiological database, we aimed to clarify the association of fasting
Hyperglycemia plasma glucose (FPG) with subsequent cardiovascular disease (CVD) risk among young adults.
Diabetes mellitus Methods and results: Medical records of 1,180,062 young adults (20–49 years old) without a prior history of CVD
Young adult
and who were not taking antidiabetic medications were extracted from the Japan Medical Data Center. We
Preventive cardiology
categorized the study population into four groups: normal, FPG level<100 mg/dL (1,007,747 individuals),
normal-high, FPG level of 100–109 mg/dL (126,602 individuals), impaired fasting glucose (IFG), FPG level of
110–125 mg/dL (32,451 individuals), and diabetes mellitus (DM), FPG level ≥126 mg/dL (13,262 individuals).
The mean age was 39.7 ± 6.9 years, and 57.0% of the study population were men. Mean follow-up period was
1201 ± 905 days on average. Multivariable Cox regression analysis showed that IFG (hazard ratio [HR]; 1.38)
and DM (HR; 2.09) increased the risk of myocardial infarction. Normal-high (HR; 1.11), IFG (HR; 1.18), and DM
(HR; 1.59) groups had an elevated angina pectoris risk. DM (HR; 1.31) increased the risk of stroke compared to
normal FPG levels. Normal-high levels (HR; 1.10), IFG (HR; 1.22) and DM (HR; 1.58) elevated the risk of heart
failure. DM (HR; 1.69) increased the risk of atrial fibrillation.
Conclusions: Our analysis of a nationwide epidemiological database demonstrated a close association of the FPG
category with subsequent CVD risk. Our results exemplify the importance of optimal FPG maintenance for the
primary prevention of CVD in young adults.

1. Introduction
Cardiovascular disease (CVD) is a major cause of death and
morbidity [1–3]. Epidemiological studies have demonstrated that the
incidence of CVD among young adults has been stagnating or increasing,
due to which the clinical significance of CVD prevention in young gen­
erations is now increasingly being recognized [4–7].
Diabetes mellitus (DM) is among the strongest risk factors for CVD
[8–10]. Furthermore, individuals with hyperglycemia also have a high
risk of CVD development even in the absence of DM [11,12]. Accord­
ingly, the American Diabetes Association defined prediabetes as a fast­
ing plasma glucose (FPG) level ≥100 mg/dL [13]. Furthermore,
according to the Japan Diabetes Society, an FPG level ≥110 mg/dL is
indicative of “impaired fasting glucose” (IFG) while a level ≥100 mg/dL
is considered “normal-high” [14].
However, data on the association of FPG category with the subse­
quent incidence of various CVDs, including coronary heart disease,
stroke, heart failure, and atrial fibrillation among young adults, are
currently scarce. In this study, we sought to explore the relationship
between FPG category and future CVD risk, using a nationwide epide­
miological database. Using the population attributable fraction, we also
assessed the proportion of CVD that was preventable when FPG of
normal-high FPG, IFG, and DM groups would be lowered to normal FPG.

* Corresponding author. The Department of Cardiovascular Medicine, The University of Tokyo Hospital, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
E-mail addresses: hidehikaneko-circ@umin.ac.jp, kanekohidehiro@gmail.com (H. Kaneko).

https://doi.org/10.1016/j.atherosclerosis.2020.12.024
Received 6 November 2020; Received in revised form 17 December 2020; Accepted 17 December 2020
Available online 16 January 2021
0021-9150/© 2020 Elsevier B.V. All rights reserved.
H. Kaneko et al. Atherosclerosis 319 (2021) 35–41

2. Materials and methods
This retrospective observational study analyzed data from the health
claims database of the Japan Medical Data Center (JMDC, Tokyo, Japan)
between January 2005 and August 2018 [15–18]. The JMDC has con­
tracts with more than 60 insurers and includes health insurance claims
data on insured individuals who are predominantly employees of rela­
tively large Japanese companies, and comprises more than 5 million
registered individuals. The JMDC database includes annual health
check-up data, including those on medical history and medication sta­
tus, as well as laboratory and clinical follow-up data, as obtained from
claims records. We defined the initial day of clinical follow-up as the day
of the first health check-ups. The incidence of CVD events, such as
myocardial infarction (I210, I211, I212, I213, I214, I219), angina pec­
toris (I200, I201, I208, I209), stroke (I630, I631, I632, I633, I634, I635,
I636, I638, I639, I600, I601, I602, I603, I604, I605, I606, I607, I608,
I609, I610, I611, I613, I614, I615, I616, I619, I629), heart failure (I500,
I501, I509, I110) and atrial fibrillation (I480, I418, I482, I483, I484,
I489) from each individual’s claims record was evaluated using the In­
ternational Classification of Disease, 10th Revision diagnostic codes
[19]. Each CVD event was analyzed separately. For example, if a
participant had myocardial infarction and then had stroke a month later,
both myocardial infarction and stroke events were counted as separate
outcomes.
This study was approved by the Ethical Committee of The University
of Tokyo (2018-10862) and conducted in accordance with the principles
of the Declaration of Helsinki. The requirement for informed consent
was waived as all data in the JMDC database were anonymized. All data
were compliant with the International Conference on Harmonization
guidelines [20].
We categorized the study population based on FPG at the initial
health check-up. Normal FPG was defined as an FPG level <100 mg/dL.
Norma-high and IFG were defined as 109 mg/dL ≥ FPG level ≥100 mg/
dL and 125 mg/dL ≥ FPG level ≥110 mg/dL, respectively. We defined
DM as an FPG level ≥126 mg/dL [14]. Obesity was defined as body mass
index ≥25 kg/m2. High waist circumference was defined as a value ≥ 85
cm for men and ≥90 cm for women [21]. Hypertension was defined as
systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90
mmHg, or the use of anti-hypertensive medications. For example, a
participant taking anti-hypertensive medications was diagnosed as hy­
pertension even if they had a normal blood pressure (systolic blood
pressure < 130 mmHg and diastolic blood pressure < 90 mmHg) at a
health check-up. Dyslipidemia was defined as low-density lipoprotein
cholesterol level ≥140 mg/dL or high-density lipoprotein cholesterol
level <40 mg/dL or triglyceride level ≥150 mg/dL or the reception of
ongoing lipid-lowering therapy. For example, a participant taking
lipid-lowering medications was diagnosed as dyslipidemia regardless of
the values of low-density lipoprotein cholesterol, high-density lipopro­
tein cholesterol, and triglyceride levels.
Categorical and continuous data are presented as numbers (%) and
mean ± standard deviation. We compared categorical and continuous
variables between the FPG categories using chi-square tests and one-way
analysis of variance. The long-term event rate was estimated using
Kaplan–Meier curves and the log-rank test was employed for the
assessment of the differences in the event rate. We conducted multi­
variable Cox regression analyses to identify the prognostic determinants
of FPG with subsequent CVD risk. In the multivariable model, unad­
justed hazard ratio (HR) of FPG (as a continuous variable) or FPG
category was adjusted for potential confounders including age, sex,
obesity, high waist circumference, hypertension, dyslipidemia, cigarette
smoking, and alcohol drinking. There were missing data on body mass
index, waist circumference, hypertension, dyslipidemia, cigarette
smoking, and alcohol drinking in our database as shown in Table 1.
Hence, we used multiple imputation to replace those missing values with
other plausible values through the creation of multiple filling-in patterns
to avert the bias caused by missing data as previously described [21];
this is recognized as an alternative approach in the analysis of incom­
plete data. Here, we replaced each missing value with a set of substituted
plausible values by the creation of 20 filled-in complete data sets using
multiple imputation with the chained equation method. Covariates
included in the multivariable Cox regression analysis were used in the
multiple imputation process. HRs and standard errors were obtained
using Rubin’s rules. As a sensitivity analysis, we adjusted the HRs of FPG
(as a continuous variable) or FPG category with age, sex, obesity, high
waist circumference, systolic blood pressure, anti-hypertensive medi­
cation use, low-density lipoprotein cholesterol level, high-density lipo­
protein cholesterol level, triglyceride, lipid-lowering medication use,
cigarette smoking, and alcohol drinking. We measured the population
attributable fraction (PAF) as the proportion of CVD events that would
be preventable if FPG of those with normal-high, IFG, and DM were
lowered to normal. The PAF with corresponding 95% confidence in­
terval (CI) was calculated using the STATA command ‘punafcc’ [22,23].
p values < 0.05 were considered statistically significant. We performed
all statistical analyses using SPSS software version 25 and STATA
version 16.

Table 1
Characteristics of study population.
Variable Missing Normal (n = Normal-high (n = Impaired fasting glucose (n = Diabetes mellitus (n = p-value
1,007,747) 126,602) 32,451) 13,262)

Glucose, mg/dL 0 88 ± 7 103 ± 3 115 ± 4 163 ± 49 <0.001

Age, years 0 39.3 ± 7.1 41.9 ± 5.7 42.6 ± 5.5 42.7 ± 5.5 <0.001
Male sex 0 541,146 (53.7) 95,082 (75.1) 26,043 (80.3) 10,678 (80.5) <0.001
Body mass index, kg/m2 550 22.2 ± 3.5 24.2 ± 4.0 25.7 ± 4.6 27.4 ± 5.2 <0.001
Obesity 550 186,480 (18.5) 46,274 (36.6) 16,610 (51.2) 8736 (66.0) <0.001
Waist circumference, cm 75,562 78.9 ± 9.5 84.3 ± 10.3 88.2 ± 11.5 92.3 ± 12.5 <0.001
High waist circumference 75,562 193,702 (20.6) 49,752 (41.0) 17,386 (56.1) 8861 (69.7) <0.001
Hypertension 1027 77,374 (7.7) 23,325 (18.4) 9507 (29.3) 5075 (38.4) <0.001
Systolic blood pressure, mmHg 1039 114 ± 14 122 ± 15 126 ± 16 131 ± 18 <0.001
Diastolic blood pressure, mmHg 1039 70 ± 11 76 ± 12 80 ± 12 82 ± 13 <0.001
Dyslipidemia 5284 287,446 (28.7) 60,049 (47.5) 19,267 (59.5) 9416 (71.2) <0.001
Low-density lipoprotein cholesterol, 5569 115 ± 30 125 ± 32 130 ± 34 135 ± 37 <0.001
mg/dL
High-density lipoprotein cholesterol, 366 64 ± 16 59 ± 16 56 ± 15 52 ± 14 <0.001
mg/dL
Triglyceride, mg/dL 639 93 ± 73 125 ± 98 151 ± 121 198 ± 180 <0.001
Cigarette smoking 11,789 247,339 (24.8) 38,933 (31.0) 11,350 (35.3) 5464 (41.5) <0.001
Alcohol drinking 151,210 163,686 (18.6) 32,698 (30.0) 8654 (31.1) 2681 (23.7) <0.001

Data are expressed as mean (standard deviation) or number (percentage).

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H. Kaneko et al. Atherosclerosis 319 (2021) 35–41

3. Results circumference, hypertension, dyslipidemia and cigarette smoking

We investigated 1,391,810 individuals, aged 20–49 years, in whom
FPG data were available. The exclusion criteria were as follows: 1) lack
of data on antidiabetic medications (n = 171,885), 2) use of antidiabetic
medications (n = 14,180), and 3) prior history of myocardial infarction,
angina pectoris, coronary revascularization, stroke, heart failure, atrial
fibrillation, and hemodialysis (n = 25,683). Finally, we analyzed data on
1,180,062 individuals in this study.
The clinical characteristics of the study population are shown in
Table 1. Normal-high values, IFG, and DM were observed in 126,602
(10.7%), 32,451 (2.7%), and 13,262 (1.1%) individuals, respectively.
The mean age was 39.7 ± 6.9 years, and 672,949 individuals (57.0%)
were men. Overall, the average FPG level was 91.0 ± 12.8 mg/dL. Age,
the proportion of men, and the prevalence of obesity, high waist
increased as the FPG level rose.
During the mean follow-up period of 1201 ± 905 days, myocardial
infarction, angina pectoris, stroke, heart failure, and atrial fibrillation
developed in 1443 (0.1%), 13,982 (1.2%), 4899 (0.4%), 12,577 (1.1%),
and 2828 (0.2%) individuals, respectively.
Table 2 summarized the number of events, corresponding incidence
rates, and HRs for CVD events. Multivariable Cox regression analysis
including FPG per 10 mg/dL, age, sex, obesity, high waist circumfer­
ence, hypertension, dyslipidemia, cigarette smoking, and alcohol
drinking, showed that FPG per 10 mmHg was associated with the inci­
dence of myocardial infarction (HR 1.08, 95% CI, 1.06–1.10, p <
0.001), angina pectoris (HR 1.05, 95% CI, 1.04–1.06, p < 0.001), stroke
(HR 1.03, 95% CI, 1.01–1.05, p = 0.001), heart failure (HR 1.05, 95% CI
1.04–1.06, p < 0.001), and atrial fibrillation (HR 1.05, 95% CI, 103-

Table 2
Frequency of events, corresponding incidence rates, and hazard ratios for cardiovascular disease events.
Overall (n= Normal (n= Normal-high (n= Impaired fasting glucose (n = Diabetes mellitus (n = Fasting plasma glucose per
1,180,062) 1,007,747) 126,602) 32,451) 13,262) 10 mg/dL

Myocardial infarction

Number of events 1443 (0.1) 1055 (0.1) 219 (0.2) 94 (0.3) 75 (0.6) –
Incidence rate 0.37 0.32 0.53 0.87 1.70 –
Unadjusted hazard ratio – 1 1.68 (1.46–1.95) 2.73 (2.21–3.38) 5.32 (4.21–6.73) 1.15 (1.13–1.16)
[Reference]
Adjusted hazard ratio – 1 1.05 (0.89–1.23) 1.38 (1.10–1.73) 2.09 (1.61–2.71) 1.08 (1.06–1.10)
[Reference]
Population attributable – Reference 4.9% (− 12.0- 27.6% (9.0–42.4%) 52.2% (37.9–63.3%) –
fraction +19.2%)

Angina pectoris

Number of events 13,982 10,957 (1.1) 1978 (1.6) 642 (2.0) 405 (3.1) –
(1.2)
Incidence rate 3.63 3.33 4.86 6.00 9.33 –
Unadjusted hazard ratio – 1 1.47 (1.40–1.54) 1.80 (1.67–1.95) 2.80 (2.54–3.10) 1.11 (1.10–1.12)
[Reference]
Adjusted hazard ratio – 1 1.11 (1.05–1.17) 1.18 (1.08–1.29) 1.59 (1.42–1.78) 1.05 (1.04–1.06)
[Reference]
Population attributable – Reference 9.7% (4.7–14.4%) 15.2% (7.3–22.4%) 37.2% (29.7–43.9%) –
fraction

Stroke

Number of events 4899 (0.4) 3860 (0.4) 686 (0.5) 220 (0.7) 133 (1.0) –
Incidence rate 1.27 1.17 1.67 2.04 3.02 –
Unadjusted hazard ratio – 1 1.44 (1.33–1.56) 1.75 (1.53–2.00) 2.59 (2.18–3.07) 1.10 (1.09–1.12)
[Reference]
Adjusted hazard ratio – 1 1.05 (0.96–1.15) 1.03 (0.88–1.20) 1.31 (1.07–1.59) 1.03 (1.01–1.05)
[Reference]
Population attributable – Reference 4.7% (− 4.3- 2.8% (− 13.1-+16.5%) 23.5% (6.9–37.2%) –
fraction +13.0%)

Heart failure

Number of events 12,577 9791 (1.0) 1765 (1.4) 626 (1.9) 395 (3.0) –
(1.1)
Incidence rate 3.26 2.97 4.33 5.84 9.07 –
Unadjusted hazard ratio – 1 1.47 (1.39–1.54) 1.97 (1.82–2.14) 3.05 (2.76–3.38) 1.12 (1.11–1.12)
[Reference]
Adjusted hazard ratio – 1 1.10 (1.04–1.16) 1.22 (1.11–1.33) 1.58 (1.41–1.78) 1.05 (1.04–1.06)
[Reference]
Population attributable – Reference 8.7% (3.4–13.8%) 17.7% (9.9–24.8%) 36.9% (29.2–43.8%) –
fraction

Atrial fibrillation

Number of events 2828 (0.2) 2157 (0.2) 439 (0.3) 142 (0.4) 90 (0.7) –
Incidence rate 0.73 0.65 1.07 1.31 2.03 –
Unadjusted hazard ratio – 1 1.66 (1.49–1.83) 2.02 (1.71–2.39) 3.12 (2.53–3.86) 1.12 (1.11–1.13)
[Reference]
Adjusted hazard ratio – 1 1.07 (0.95–1.20) 1.13 (0.93–1.36) 1.69 (1.35–2.13) 1.05 (1.03–1.07)
[Reference]
Population attributable – Reference 6.2% (− 5.2- 10.7% (− 8.0-+26.2%) 39.6% (23.8–52.1%) –
fraction +16.5%)

The incidence rate was per 1000 person-years. Hazard ratio of fasting plasma glucose category was adjusted with age, sex, obesity, high waist circumference, hy­
pertension, dyslipidemia, cigarette smoking, and alcohol drinking.

37
H. Kaneko et al.
1.07, p < 0.001). The occurrence rate of each CVD events increased in a
stepwise manner, in accordance with the FPG category. Kaplan-Meier
curves and the log-rank test showed that the FPG category was associ­
ated with the development of myocardial infarction, angina pectoris,
stroke, heart failure, and atrial fibrillation (all log-rank p < 0.001)
(Fig. 1). In an unadjusted model, normal high, IFG, and DM were asso­
ciated with a significantly higher risk of CVD events compared with
normal FPG (Table 2). Multivariable Cox regression analysis for in­
dividuals with no missing values (complete case analysis) demonstrated
that, compared to normal FPG levels, IFG (HR 1.38, 95% CI 1.10–1.73, p
= 0.006) and DM (HR 2.09, 95% CI 1.61–2.71, p < 0.001) were asso­
ciated with an increased risk of myocardial infarction. Compared to the
normal FPG group, the normal-high (HR 1.11, 95% CI 1.05–1.17, p <
0.001), IFG (HR 1.18, 95% CI 1.08–1.29, p < 0.001), and DM (HR 1.59,
95% CI 1.42–1.78, p < 0.001) groups had an elevated risk of angina
Fig. 1. Kaplan-Meier curves for cardiovascular disease event.
Crude cumulative incidence of myocardial infarction (A), angina pectoris (B), stroke (C), heart failure (D) and atrial fibrillation (E).
38
Atherosclerosis 319 (2021) 35–41
pectoris. DM (HR 1.31, 95% CI 1.07–1.59, p = 0.008) increased the risk
of stroke compared to normal FPG levels. Compared to normal FPG
levels, normal-high (HR 1.10, 95% CI 1.04–1.16, p = 0.001), IFG (HR
1.22, 95% CI 1.11–1.33, p < 0.001), and DM (HR 1.58, 95% CI
1.41–1.78, p < 0.001) elevated the risk of heart failure. DM (HR 1.69,
95% CI 1.35–2.13, p < 0.001) increased the risk of atrial fibrillation
compared to normal FPG levels (Table 2). The multivariable Cox
regression analyses performed after multiple imputation for missing
values confirmed these results (Supplementary Table 1).
Results of sensitivity analyses were also consistent with our results.
Sensitivity analyses showed that FPG per 10 mg/dL was associated with
the incidence of myocardial infarction (HR 1.07, 95% CI 1.04–1.09, p <
0.001), angina pectoris (HR 1.05, 95% CI 1.04–1.06, p < 0.001), stroke
(HR 1.02, 95% CI 1.00–1.04, p = 0.034), heart failure (HR 1.05, 95% CI
1.04–1.06, p < 0.001), and atrial fibrillation (HR 1.05, 95% CI
H. Kaneko et al.
1.03–1.08, p < 0.001). IFG (HR 1.31, 95% CI 1.04–1.64, p = 0.022) and
DM (HR 1.90, 95% CI 1.46–2.48, p < 0.001) were associated with
higher incidence of myocardial infarction compared with normal FPG
levels. Compared with normal FPG levels, normal-high (HR 1.09, 95% CI
1.04–1.15, p = 0.001), IFG (HR 1.15, 95% CI 1.05–1.25, p = 0.002), and
DM (HR 1.54, 95% CI 1.37–1.72, p <0.001) increased the incidence of
angina pectoris. DM was associated with elevated incidence of stroke
(HR 1.23, 95% CI 1.01–1.49, p = 0.043). Regarding heart failure,
normal-high (HR 1.08, 95% CI 1.02–1.14, p = 0.010), IFG (HR 1.18,
95% CI 1.08–1.30, p <0.001), and DM (HR 1.50, 95% CI 1.33–1.68, p
<0.001) were associated with increased incidence compared with
normal FPG levels. Finally, DM was associated with elevated incidence
of atrial fibrillation compared with normal FPG levels (HR 1.68, 95% CI
1.33–2.12, p <0.001).
PAFs for myocardial infarction associated with normal-high, IFG,
and DM were 4.9% (95% CI, − 12.0-+19.2%), 27.6% (95% CI,
9.0–42.4%), and 52.2% (95% CI, 37.9–63.3%). PAFs for angina pectoris
associated with normal-high, IFG, and DM were 9.7% (95% CI,
4.7–14.4%), 15.2% (95% CI, 7.3–22.4%), and 37.2% (95% CI,
29.7–43.9%). PAFs for stroke associated with normal-high, IFG, and DM
were 4.7% (95% CI, − 4.3-+13.0%), 2.8% (95% CI, − 13.1-+16.5%), and
23.5% (95% CI, 6.9–37.2%). PAFs for heart failure associated with
normal-high, IFG, and DM were 8.7% (95% CI, 3.4–13.8%), 17.7% (95%
CI, 9.9–24.8%), and 36.9% (95% CI, 29.2–43.8%). PAFs for atrial
fibrillation associated with normal-high, IFG, and DM were 6.2% (95%
CI, − 5.2-+16.5%), 10.7% (95% CI, − 8.0-+26.2%), and 39.6% (95% CI,
23.8–52.1%) (Table 2).
Totally, 908 participants died during the observation period (703 in
the normal FPG group, 126 in the high-normal group, 52 in the IFG
group, and 27 in the DM group). Kaplan-Meier curves and the log-rank
test showed that the FPG category was associated with all-cause mor­
tality (log-rank p < 0.001) (Supplementary Figure 1). Multivariable Cox
regression analyses showed that IFG (HR 1.39, 95% CI 1.03–1.88, p =
0.031) and DM (HR 1.52, 95% CI 1.00–2.30, p = 0.050) increased the
risk of all-cause mortality compared to normal FPG levels. PAFs for all-
cause death associated with normal-high, IFG, and DM were 5.1% (95%
CI, − 16.1-+22.5%), 26.7% (95% CI, 0.5–46.0%), and 34.1% (95% CI,
0.3–56.4%).
4. Discussion
Our analysis of a nationwide epidemiological database, including
over one million young adults without a prior history of CVD and
treatment for DM, demonstrated that FPG was associated with the
subsequent incidence of CVDs. Particularly, the risk of myocardial
infarction, angina pectoris, and heart failure began to increase before
the development of DM. Our results suggest the clinical significance of
optimal glycemic control in young adults for the primary prevention of
CVD. To the best of our knowledge, this is the first large scale epide­
miological study to provide data on the relationship between FPG and
the future risk of a wide range of CVDs, with a focus on young adults.
Previous epidemiological studies showed an increase in the preva­
lence of DM and impaired glucose tolerance in young people [24–26].
The International Diabetes Federation estimated that the proportion of
young adults with DM had increased from 23 million in 2000 to 63
million in 2013, worldwide [27]. Epidemiological data in the United
Kingdom also demonstrated a marked increase in the number of younger
DM patients between 1991 and 2010 [28].
Consistent with these reports, in our study population, approxi­
mately 15% of the participants had an FPG level ≥100 mg/dL even after
the exclusion of those receiving treatment with antidiabetic medications
at baseline. Therefore, hyperglycemia is not a rarely observed condition
even in young adults without a prior history of prevalent CVD.
Furthermore, the prevalence of obesity, high waist circumference, and
other CVD risk factors increased according to the FPG category, indi­
cating the clustering of CVD risk factors in participants with elevated
39
Atherosclerosis 319 (2021) 35–41
FPG levels.
As a result, the incidence of all CVDs assessed in this study increased
in a stepwise manner based on the FPG category. Even after adjustment
for other CVD risk factors using multivariable Cox regression analysis,
FPG, as a continuous variable, was still significantly associated with an
elevated incidence of CVDs. Similarly, the presence of DM also increased
the risk of all these CVDs independently. Notably, the risk of angina
pectoris and heart failure started to increase in the normal-high cate­
gory, and that of myocardial infarction began to increase in the IFG
category. Finally, the risk of all-cause death also began increasing in the
IFG category. These results suggest that the risk of CVD may increase
before the development of DM among young adults with hyperglycemia.
Our results are generally concordant with those of other studies.
Previous studies demonstrated that non-diabetic hyperglycemia may be
associated with an elevated risk of CVD [11,12]. However, most studies
explored the association of hyperglycemia with the risk of coronary
heart disease [29–33]. The strength of this study is that we analyzed the
association of the FPG category with the incidence of a wide range of
CVD events, including myocardial infarction, angina pectoris, stroke,
heart failure, and atrial fibrillation, using a largescale nationwide
database.
It is also interesting that the FPG thresholds varied for each CVD
type. Multivariable Cox regression analyses showed that the risk of
angina pectoris and heart failure started to increase in the normal-high
category and that of myocardial infarction began to rise in the IFG
category. However, the risks of stroke and atrial fibrillation were not
significantly different in the normal-high or IFG categories compared to
the normal FPG category, and were significantly higher only in the DM
category (FPG ≥126 mg/dL).
Particularly, it should be noted that the risk of heart failure increased
even in the normal-high FPG category. The Framingham Heart Study
demonstrated that the presence of DM increased the subsequent risk of
heart failure by up to 2-fold in men and 5-fold in women [34,35].
However, whether non-diabetic hyperglycemia could elevate the risk of
heart failure in the young general population has not been fully eluci­
dated. Considering that impaired glucose tolerance can result in
hyperinsulinemia, enhanced oxidative stress, neurohumoral factor
activation, microvascular dysfunction, and chronic inflammation, all of
which could contribute to the pathogenesis of heart failure [36–38], it is
reasonable that the risk of heart failure increased even in those with
hyperglycemia prior to the development of DM. The increasing preva­
lence of heart failure is a critical epidemiological problem in most
developed countries, and its prevention is recognized as an important
healthcare issue [39–41]. From this point of view, young adults with not
only DM but also high-normal FPG levels and IFG must be considered as
high-risk populations for heart failure and preventive measures should
be taken appropriately.
The results of PAFs are also important. Regarding heart failure, 8.7%
of heart failure in the normal-high FPG group, 17.7% of heart failure in
the IFG group, and 36.9% of heart failure in the DM group could be
preventable, if subjects with these groups had normal FPG. Similarly,
9.7% of angina pectoris in the normal-high FPG group, 15.2% of angina
pectoris in the IFG group, and 37.2% of angina pectoris in the DM group
could be preventable, if subjects with these groups had normal FPG.
Finally, 26.7% of all-cause death in the IFG group and 34.1% of all-cause
death in the DM group could be prevented, if these subjects had normal
FPG. Although the estimated preventive effects in normal-high FPG and
IFG were weaker than those in DM, these results suggest the potential
significance of preventable intervention in individuals with normal-high
FPG and IFG.
We believe that our study has clinical implications. FPG is widely
used in not only clinical practice but also general health check-ups. Our
study demonstrated that simple FPG measurements can aid the identi­
fication of populations at high risk for specific CVDs and all-cause death
even before the diagnosis of DM. Additionally, given that other CVD risk
factors frequently coexist in individuals with high FPG levels, as shown
H. Kaneko et al.
in this study, the establishment of preventive measures for these specific
populations may be a reasonable and rational approach.
This study has several limitations. Although we performed multi­
variable analyses, the presence of unmeasured confounders and residual
bias cannot be ruled out. The data obtained from the JMDC database
were predominantly obtained from an employed, working-age popula­
tion. Therefore, the presence of a healthy worker bias should be
acknowledged. From this point of view, although we calculated PAFs in
this study, the results of PAFs should be carefully considered. Further
studies are required for the generalization of our results in other pop­
ulations across different races, ethnicities, educational levels, and in­
come levels. Comparing with other epidemiological databases on CVD in
Japan [42,43], the incidence of CVD in this study is reasonable. How­
ever, recorded diagnoses are generally considered less well validated
due to the retrospective design and administrative database. There were
missing values in our database. However, the results of Cox regression
analysis after multiple imputation were consistent with the results of the
complete case analysis. Therefore, we believe that our results are
theoretically robust. Although we showed the association between FPG
category and all-cause mortality, data on CVD-related death were not
available. We assessed the association of FPG with incident CVD using
the data on FPG at the initial health check-up alone (single measure­
ment). However, considering that FPG level is variable, assessing FPG
using multiple measurement data would be more accurate. Lastly, in­
sulin tolerance and postprandial plasma glucose levels (such as 2-h
plasma glucose levels) were not assessed in this database.
4.1. Conclusion
Our analysis of a nationwide epidemiological database showed that
elevated FPG levels were associated with an increased risk of CVDs,
including myocardial infarction, angina pectoris, stroke, heart failure,
and atrial fibrillation among young adults without a prior history of
prevalent CVD, suggesting the clinical significance of an optimal gly­
cemic status maintenance in primary CVD prevention among young
adults.
Financial support
This work was supported by grants from the Ministry of Health,
Labour and Welfare, Japan (19AA2007 and H30-Policy-Designated-
004) and the Ministry of Education, Culture, Sports, Science and Tech­
nology, Japan (17H04141).
CRediT authorship contribution statement
Hidehiro Kaneko: Conception and design or analysis and interpre­
tation of data, Drafting of the manuscript. Hidetaka Itoh: Analysis of
data. Hiroyuki Kiriyama: Revising it critically for important intellec­
tual content. Tatsuya Kamon: Analysis of data. Katsuhito Fujiu:
Revising it critically for important intellectual content. Kojiro Morita:
Analysis and interpretation of data. Nobuaki Michihata: Analysis and
interpretation of data. Taisuke Jo: Data collection, Analysis and inter­
pretation of data. Norifumi Takeda: Revising it critically for important
intellectual content. Hiroyuki Morita: Revising it critically for impor­
tant intellectual content. Hideo Yasunaga: Analysis of data, Conception
and design or analysis and interpretation of data, Final approval of the
manuscript submitted. Issei Komuro: Final approval of the manuscript
submitted.
Author contributions
Hidehiro Kaneko: Corresponding author. Conception and design or
analysis and interpretation of data. Drafting of the manuscript. Hidetaka
Itoh: Analysis of data. Hiroyuki Kiriyama: Revising it critically for
important intellectual content. Tatsuya Kamon: Analysis of data.
40
Atherosclerosis 319 (2021) 35–41
Katsuhito Fujiu: Revising it critically for important intellectual content.
Kojiro Morita: Analysis and interpretation of data. Haruki Yotsumoto:
Analysis of data. Nobuaki Michihata: Analysis and interpretation of
data. Taisuke Jo: Data collection. Analysis and interpretation of data.
Norifumi Takeda: Revising it critically for important intellectual con­
tent. Hiroyuki Morita: Revising it critically for important intellectual
content. Hideo Yasunaga: Conception and design or analysis and inter­
pretation of data. Final approval of the manuscript submitted. Issei
Komuro: Final approval of the manuscript submitted.
Declaration of competing interest
Research funding and scholarship funds (Hidehiro Kaneko and Kat­
suhito Fujiu) from Medtronic Japan CO., LTD, Boston Scientific Japan
CO., LTD, Biotronik Japan, Simplex QUANTUM CO., LTD, and Fukuda
Denshi, Central Tokyo CO., LTD. The other authors have nothing to
disclose.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.atherosclerosis.2020.12.024.
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