d i a b e t e s r e s e a r c h a n d c l i n i c a l p r a c t i c e 191 (2022) 110048

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Diabetes Research and Clinical Practice

journal homepage: www.journals.elsevier.com/diabetes-research-and-clinical-practice

Long-term influence of type 2 diabetes and metabolic syndrome on

all-cause and cardiovascular death, and microvascular and macrovascular
complications in Chinese adults — A 30-year follow-up of the Da Qing
diabetes study
Siyao He a, Jinping Wang b, Xiaoxing Zhang a, Xin Qian a, Shuang Yan c, Wenjuan Wang d,
Bo Zhang e, Xiaoping Chen e, Yali An a, Qiuhong Gong a, Lihong Zhang a, Xiaolin Zhu f, Hui Li b,
Yanyan Chen a, Guangwei Li a, e, *
a
Endocrinology Centre, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing China
b
Department of Cardiology, Da Qing First Hospital, Da Qing, China
c
Department of Endocrinology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
d
Division of Non-Communicable Disease Control and Community Health, Chinese Center for Disease Control and Prevention, Beijing, China
e
China–Japan Friendship Hospital, Beijing, China
f
University of Alabama at Birmingham, Diabetes Research and Training Center, Birmingham, AL 35233, USA

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

Keywords: Aims: To examine the long-term influence of metabolic syndrome (MetS) on death and vascular complications.
Metabolic syndrome Methods: Altogether, 1419 individuals with different levels of glycemia and MetS were recruited for this study.
Hyperglycaemia The participants were followed up for 30 years to assess outcomes.
Type 2 diabetes
Results: Compared with the non_MetS, individuals with impaired glucose tolerance (IGT) plus MetS had a higher
Long-term
incidence (per 1000 person-years) of all-cause death (20.98 vs 11.70, hazard ratio [HR] = 1.84), macrovascular
Macrovascular events
Microvascular complication events (29.25 vs 15.94, HR = 1.36), and microvascular complications (10.66 vs 3.57, HR = 1.96). The incidence
of these outcomes was even higher in participants with type 2 diabetes mellitus (T2DM) plus MetS. The T2DM
without MetS shared a comparable risk profile of the outcomes with the T2DM plus MetS group (HRs were 3.45
vs 3.15, 2.21 vs 2.65, and 6.91 vs 7.41, respectively).
Conclusions: The degree of hyperglycemia in MetS is associated with the severity of death and both micro- and
macrovascular complications. T2DM was associated with a comparable risk for all outcomes as T2DM plus MetS.
The findings highlight the need of early prevention of diabetes in individuals with IGT plus MetS, while the
justification to redefine a subgroup of patients with T2DM as having MetS remains to be clarified.

1. Introduction
Globally, the prevalence of metabolic syndrome (MetS) is increasing
[1–3]. In China, 14.4% of the adult population (approximately 130
million adults) is estimated to have MetS [4]. However, the term MetS as
a clinical construct is undermined by several controversies [5]. The
numerous definitions used in practice have been cited as the provenance
of these disputes [6,7]. While all MetS definitions share the components
of obesity, hypertension, dyslipidemia, and hyperglycaemia, the diag­
nostic criteria and weight thresholds for the risk factors vary between
these definitions [6,7]. For example, the criteria for hyperglycemia
include impaired glucose tolerance (IGT), impaired fasting glucose

Abbreviations: AACE, American Association of Clinical Endocrinologists; CDS, Chinese Diabetes Society; CHD, coronary heart disease; CI, confidence interval;
CVD, cardiovascular disease; EGIR, European Group for the Study of Insulin Resistance; HHF, hospitalized heart failure; HR, hazard ratios; IDF, International Diabetes
Federation; IGT, impaired glucose tolerance; IFG, impaired fasting glucose; MetS, metabolic syndrome; MI, myocardial infarction; NCEP-ATP III, National Cholesterol
Education Program Adult Treatment Panel III; NGT, normal glucose tolerance; OGTT, oral glucose tolerance test; PG2h, 2-hour plasma glucose level; PPG, post­
prandial plasma glucose; T2DM, type 2 diabetes mellitus; UKPDS, United Kingdom Prospective Diabetes Study.
* Corresponding author.
E-mail address: guangwei_li45@126.com (G. Li).

https://doi.org/10.1016/j.diabres.2022.110048
Received 20 April 2022; Received in revised form 3 August 2022; Accepted 19 August 2022
Available online 24 August 2022
0168-8227/© 2022 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
S. He et al.
(IFG), or type 2 diabetes mellitus (T2DM), as recommended by the
World Health Organization (WHO), National Cholesterol Education
Program Adult Treatment Panel III (NCEP-ATP III), International Dia­
betes Federation (IDF), and Chinese Diabetes Society [8–13].
Conversely, the European Group for the Study of Insulin Resistance and
American Association of Clinical Endocrinologists (AACE) include IGT
or IFG only, without T2DM, as criteria for hyperglycaemia [14,15]. They
argue that T2DM itself is a strong risk factor for cardiovascular disease
(CVD) [16,17], that many patients with T2DM have MetS [18], and that
reclassification of this syndrome in individuals with T2DM may not
provide additional clinical value [19–21]. However, longitudinal studies
evaluating the impact of MetS irrespective of T2DM diagnosis (i.e., MetS
with T2DM vs MetS without T2DM) on the prospective impact on both
macrovascular and microvascular outcomes are lacking.
In this study, we used 30-year follow-up data from the Da Qing
Diabetes Prevention Study to examine the long-term influence of MetS,
either with or without T2DM, on death and macrovascular and micro­
vascular outcomes, and to assess the contribution of hyperglycemia,
which is a component of MetS, to the development of these outcomes.
2. Materials and methods
2.1. Study design and participants
The details of the design, methods, and study population of the Da
Qing Diabetes Prevention Study and its subsequent 20-, 23–, and 30-year
follow-up studies have been previously reported [22–25]. Briefly,
110,660 adults were screened for T2DM based on a 2-hour postprandial
plasma glucose (PG2h) test, and 106,704 participants with PG2h < 6.7
mmol/L were excluded. A 75-g oral glucose tolerance test (OGTT) on the
remaining 3,956 participants with PG2h ≥ 6.7 mmol/L was used to
identify individuals with IGT. Based on the PG2h and OGTT results, 630
and 577 individuals were identified as having newly diagnosed diabetes
(NDD) and IGT, respectively. This hyperglycemia group included all
patients with NDD and IGT, whereas 192 people with type 1 or type 2
diabetes who had been diagnosed before this diabetes survey or had
been treated with antidiabetic medications were excluded. In addition,
519 age- and sex-matched individuals with normal glucose tolerance
(NGT) and IGT were included as controls. Since the diagnostic criteria of
diabetes ware revised to FPG ≥ 7 mmol/L (126 mg/dL), 35 patients
diagnosed with IGT according to the WHO 1985 criteria were reclassi­
fied as having diabetes and were transferred to the NDD group. In
addition, two participants (one with IGT and the other with NGT) with
missing baseline information, 28 NGT with MetS, and 277 without MetS
were also excluded. Therefore, 1419 people, including 490 with NGT,
264 with IGT, and 665 with NDD, were included in the present analysis
(Fig. 1). The participants were stratified based on the presence of MetS at
Fig. 1. Flowchart of the recruitment of participants. AACE ¼ American Association of Clinical Endocrinologists; IGT ¼ impaired glucose tolerance; MetS ¼
metabolic syndrome; NDD ¼ newly diagnosed diabetes; NG ¼ normal glucose; NGT ¼ normal glucose tolerance; and T2DM ¼ type 2 diabetes mellitus.
2
Diabetes Research and Clinical Practice 191 (2022) 110048
baseline to evaluate its influence on the risk of death and macrovascular
and microvascular outcomes over the 30-year follow-up period.
2.2. MetS diagnosis criteria and study groups
MetS was defined according to the AACE criteria with modifications
(any three of the five following criteria): 1) hyperglycemia (T2DM; IFG,
between 6.1 and 7.0 mmol/L; or PG2h between 7.8 and 11.1 mmol/L);
2) hypertension (>130/85 mm Hg); 3) dyslipidemia (triglycerides ≥
1.69 mmol/L; high-density lipoprotein cholesterol, male < 40 mg/dL,
female < 50 mg/dL); 4) obesity (body mass index [BMI] ≥ 25 kg/m2)
[26]; and 5) other risk factors such as family history of T2DM, high
blood pressure or CVD, polycystic ovary syndrome, sedentary lifestyle,
elderly, or an ethnicity prone to high CVD risk [15].
The study population was further divided into four subgroups: 1)
non_MetS (individuals with NGT without MetS) as control group; 2)
IGT_MetS (IGT plus MetS); 3) T2DM (T2DM without MetS); and 4)
T2DM_MetS (T2DM plus MetS). The conventional AACE MetS definition
excluded patients with T2DM, however, in this study, participants with
T2DM were included.
2.3. Outcomes
The clinical outcomes included all-cause mortality, CVD mortality,
and macrovascular and microvascular events. CVD mortality included
death due to coronary heart disease (CHD) or stroke. Macrovascular
events (CV events) included nonfatal or fatal myocardial infarction,
stroke, and hospitalized heart failure (HHF). Microvascular complica­
tions included severe retinopathy, an aggregate outcome of retinopathy,
defined as a history of photocoagulation, blindness from retinal disease,
or proliferative retinopathy; nephropathy, defined as a history of end-
stage renal disease, renal dialysis, renal transplantation, or death from
chronic kidney disease; and neuropathy, defined as a history of leg,
ankle, or foot ulceration, gangrene, or amputation. Definitions of these
microvascular outcomes were those used in previous reports from the Da
Qing Diabetes Prevention Outcomes Study. The follow-up period was
from 1986 to December 2016. The median follow-up duration was 28
years (interquartile range [IQR] 16–30).
2.4. Statistical analysis
Continuous variables were expressed as means (±standard deviation
[SD]) and categorical variables are expressed as frequencies and per­
centages. Descriptive statistics were used to compare baseline differ­
ences between the groups. The means of continuous variables were
compared using an analysis of variance and multiple comparison tests
using the chi-square test or Fisher’s exact probability method (when the
S. He et al. Diabetes Research and Clinical Practice 191 (2022) 110048

expected frequency was > 25% or < 5%) for categorical variables.
Multiple comparison tests were used for proportions. The Bonferroni’s
method was used to correct for multiplicity. The incidence for each
clinical outcome was calculated as the number of events divided by
person-years of exposure censored at the time of diagnosis, loss to
follow-up, death, or December 31, 2016 (whichever came first). The
Kaplan-Meier method was used to determine the time-to-first-event
survival curves for each outcome, and log-rank tests were used to
compare the differences between each group. The proportional hazards
assumption for MetS subgroups and clinical outcomes was tested using
Schoenfeld residuals and log (time) relationship diagrams. Cox regres­
sion adjusted for age, sex, and current smokers was used to calculate
hazard ratios (HR) with 95% confidence intervals (95 %CI). Stepwise
regression analysis using the PHREG procedure was used to evaluate the
impact of the risk factors on the outcomes. The significance level for all
tests was set to 0.05 (two-sided). All data were prospectively analyzed
using SAS, version 9.4 (Cary, North Carolina, USA).
3. Results
3.1. Baseline characteristics
At baseline, 48.9% (264/541) of the participants with IGT and 49.3%
(323/665) with T2DM had MetS, whereas only 5% (28/518) of the
participants with NGT had MetS (Fig. 1). All baseline variables in the
MetS group were significantly higher than those in the non_MetS group,
while the baseline characteristics of the T2DM_MetS and IGT_MetS
groups demonstrated no significant differences, except for age, blood
glucose levels, and number of individuals with obesity. Participants in
the T2DM_MetS group had significantly higher BMI, blood pressure, and
triglycerides levels than those in the T2DM group, with no significant
difference in age, sex, current smoking, blood glucose, cholesterol at
baseline, and the use of medications over the 30 years follow-up period
(Table 1).
3.2. Comparison of the risks of clinical outcomes in the IGT_MetS group vs
the non_MetS control group
Compared with the non_MetS group, IGT_MetS participants dis­
played approximately a 2–3 fold higher risk of all outcomes, including
all-cause death (HR = 1.84, 95% CI 1.45–2.34), CVD death (HR = 2.83,
95% CI 1.99–4.01) than the non_MetS group, and the first composite
microvascular (HR = 3.02, 95% CI 2.08–4.39) and macrovascular
complications (HR = 1.96, 95 %CI 1.57–2.44) (Fig. 2). As for the risks
and frequency of its individual components of the composite micro- and
macrovascular complications, the HR value was even higher (HR = 3.66
for retinopathy, HR = 7.15 for neuropathy, and HR = 7.07 for HHF)
(Fig. 3).
3.3. Comparison of the risks of clinical outcomes in the IGT_MetS group vs
the T2DM_MetS group
We examined the influence of the severity of hyperglycemia (i.e., IGT
vs T2DM) on the risk of macrovascular and microvascular events in
patients with MetS. Considering the non_MetS group as a reference, the
T2DM_MetS group had a higher risk of all-cause (HR = 3.15, 95% CI
2.55–3.90 vs HR = 1.84, 95% CI 1.45–2.24), CVD death (HR = 4.41,
95% CI 3.20–6.10 vs HR = 2.83, 95 %CI 1.99–4.01), and CV events (HR
= 2.65, 95% CI 2.16–3.26 vs HR = 1.96, 95% CI 1.57–2.44) than the
IGT_MetS group. Likewise, the risk of microvascular complications was
significantly higher in the T2DM_MetS subgroup (HR = 7.41, 95% CI
5.29–10.38 vs HR = 3.02, 95% CI 2.08–4.39) (Fig. 2).
3.4. Comparison of the risks of clinical outcomes in the T2DM group vs
the T2DM_MetS group
When we compared the outcomes between the T2DM group and the
T2DM_MetS group, the participants with T2DM exhibited a similar
yearly incidence of all-cause death irrespective of their MetS diagnosis
(35.86 vs 35.41) per 1000 person years (Table 2). The Kaplan–Meier and
Cox regression analyses, using the non_MetS as a reference group,
revealed that the risk of all-cause death for the T2DM and T2DM_MetS
groups were similar, with an HR = 3.45 (95 %CI 3.79–4.30) and HR =

Table 1
Baseline participant characteristics by MetS and hyperglycemia diagnosis.
Non_MetS IGT_MetS T2DM_MetS T2DM P value† P value‡ P value§

n = 490 n = 264 n = 342 n = 323

Age, years 43.8 ± 9.0 47.0 ± 9.0 49.2 ± 8.3 47.2 ± 9.4 < 0.001 0.01 0.14
Male sex, n (%) 263 (53.8) 136 (51.1) 152 (44.4) 165 (51.1) 0.81 0.13 0.16
BMI, kg/m2 23.4 ± 3.3 28.1 ± 2.9 27.6 ± 3.0 23.3 ± 2.8 < 0.001 0.24 < 0.001
Obese, n (%) 135 (27.6) 252 (95.5) 301 (88.0) 63 (19.5) < 0.001 0.002 < 0.001
Blood pressure, mm Hg
Systolic 121.1 ± 20.4 144.8 ± 21.6 144.5 ± 21.2 125.9 ± 23.0 < 0.001 0.83 < 0.001
Diastolic 81.0 ± 13.5 94.1 ± 11.8 93.9 ± 13.0 82.0 ± 13.0 < 0.001 0.64 < 0.001
Hypertension, n (%) 190 (38.8) 244 (92.4) 308 (90.1) 125 (38.7) < 0.001 0.32 < 0.001
Total cholesterol, mmol/L 4.7 ± 1.1 5.3 ± 1.5 5.4 ± 1.8 5.1 ± 1.4 < 0.001 0.467 0.4
Triglyceride, mmol/L 1.2 ± 0.9 2.3 ± 1.9 2.6 ± 2.6 1.3 ± 1.0 < 0.001 0.197 < 0.001
Hypertriglyceridemia, n (%) 48 (9.8) 102 (38.6) 176 (51.5) 24 (7.4) < 0.001 0.126 < 0.001
Fasting glucose, mmol/L 4.7 ± 0.5 5.6 ± 0.7 8.7 ± 3.1 8.5 ± 3.1 < 0.001 < 0.001 0.782
2-hour glucose, mmol/L 5.0 ± 0.8 9.0 ± 0.9 15.2 ± 3.4 15.2 ± 4.0 < 0.001 < 0.001 0.94
Hyperglycemia, n (%) 0 (0.0) 264 (1 0 0) 342 (100.0) 323 (100.0) < 0.001 < 0.001 NA
Current smoker, n (%) 217 (44.4) 97 (36.7) 107 (31.3) 120 (37.2) 0.24 0.31 0.294
OHA, n (%) 60 (12.2) 85(32.2) 60(17.5) 58(18.0) < 0.001 < 0.001 0.89
OHA and/or insulin, n (%) 47(9.6) 113(42.8) 102(29.8) 97(30.0) < 0.001 0.001 0.96
Antihypertensives, n (%) 181(36.9%) 131(49.6) 97(28.4) 83(25.7) 0.001 0.001 0.44
Lipids-lowing Agents, n (%) 103(21.0%) 78(29.5) 59(17.3) 49(15.2) 0.01 0.0004 0.47

Values are mean ± SD unless specified otherwise. P values comparing means are based on ANOVA for continuous variables and chi-square test or Fisher’s exact
probability method for discrete variables. Bonferroni’s method was used to adjust for multiplicity.
*28 cases without hyperglycemia were included in the non-T2DM_MetS group; † IGT_MetS versus non_MetS; ‡T2DM_MetS versus IGT_ MetS; §T2DM_MetS versus
T2DM.
BMI = body mass index; IGT = impaired glucose tolerance; MetS = metabolic syndrome; NA = not applicable; NGT = normal glucose tolerance; non_MetS = no MetS;
SE = standard error; T2DM = type 2 diabetes mellitus.

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S. He et al. Diabetes Research and Clinical Practice 191 (2022) 110048

Fig. 2. Kaplan–Meier curves of death and vascular complications in people with and without metabolic syndrome. HR, hazard ratio calculated using cox
regression analysis and adjusted for age, sex, and current smokers; CI, confidence interval; non_Mets, non-metabolic syndrome; DM, type 2 diabetes without
metabolic syndrome; IGT_MetS, metabolic syndrome plus impaired glucose tolerance; DM_MetS, type 2 diabetes plus metabolic syndrome. CVD death, cardiovascular
death; First CVD events, including fatal and non-fatal myocardial infarction, stroke, and heart failure hospitalization; First microvascular complications, including
severe retinopathy, neuropathy, and nephropathy.

3.15 (95% CI 2.55–3.90) after the adjustment of confounders, respec­
tively (Fig. 2). The T2DM_MetS group had marginally higher incidence
rates for CVD death (17.26 vs 14.14 per 1000 person years) and CV
events (38.68 vs 30.13 per 1000 person-years) than the T2DM group
(Table 2). However, reference to the non_MetS group, both the risks of
CVD death (HR = 4.41 vs 4.09) and CV events (HR = 2.65 vs 2.21) were
comparable between the T2DM_MetS and T2DM groups after the
adjustment for age, sex, and smoking status. The risk of developing
composite microvascular complications was also comparable (HR =
7.41 vs 6.91) between the two subgroups. The T2DM_MetS group had a
higher risk of microvascular complications than macrovascular risks.
The HRs for microvascular complications experienced by the T2DM and
T2DM_MetS groups were 6.91 and 7.41, respectively, while those for the
macrovascular complications were 2.21 and 2.65, respectively (Fig. 2).
A further analysis adjusted for the potential influence of medications
used during the 30-years follow-up period, such as antihypertensives
and lipid-lowering and hypoglycemic agents, did not alter the similar­
ities in the risk of death and macrovascular and microvascular compli­
cations between the T2DM and T2DM_MetS groups (data not shown).
3.5. Impact of different definitions of obesity on the risk of outcomes in
MetS
If the definition of obesity was omitted from the MetS criteria, the
findings of the analysis indicated that the risk of all-cause death did not
significantly differ between the T2DM_MetS and T2DM groups (HR =

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S. He et al. Diabetes Research and Clinical Practice 191 (2022) 110048

Fig. 3. Forest plot for macrovascular and microvascular complications in people with and without metabolic syndrome. HR, hazard ratio calculated using
cox regression analysis and adjusted for age, sex, and current smokers; CI, confidence interval; non_MetS, non-metabolic syndrome; DM, type 2 diabetes without
metabolic syndrome; IGT_MetS, metabolic syndrome plus impaired glucose tolerance; DM_MetS, type 2 diabetes plus metabolic syndrome.

1.10, 95 %CI 0.88–1.38, p = 0.39). Similar trend was seen in the risk of CVD death; HR = 1.07, 95 %CI 0.82–1.39, p = 0.60 for CVD events)
CVD events (HR = 1.21, 95% CI 0.95–1.54, p = 0.12) and the risk of (Supplementary Fig. 1).
microvascular complications (HR = 1.10, 95 %CI 0.81–1.46, p = 0.54).
When BMI ≥ 30 (the cut-off point of obesity suitable for Europeans) was
3.6. Exploration of risk factors that were the most associated with clinical
used as the cut-off point of obesity in MetS, the results revealed that the
outcomes in patients with MetS plus hyperglycemia
T2DM_MetS and T2DM groups still had a similar risk for all-cause death
(HR = 1.11, 95 %CI 0.88–1.30, p = 0.38), and microvascular compli­
A stepwise analysis showed that for microvascular complications, the
cations (HR = 1.05, 95 %CI 0.78–1.40, p = 0.77) (Supplementary
higher post-load 2-hour plasma glucose level was the strongest risk
Table 1). Although BMI ≥ 30 amplified the cardiovascular risk in the
factor. As for other adverse clinical outcomes, in addition to age, the
IGT_MetS group, making it closer to that of the T2DM group, the risk of
higher post-load 2-hour plasma glucose level indicated that hypergly­
CVD death and CVD events of the T2DM group was not different from
cemia was the dominant risk factor, followed by hypertension, dyslipi­
that of the IGT_MetS group (HR = 1.16, 95% CI 0.8–1.69, p = 0.43 for
demia and smoking (Table 3).

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S. He et al. Diabetes Research and Clinical Practice 191 (2022) 110048

Table 2 Table 3
Incidence rates of clinical outcomes among groups with or without MetS. Stepwise PHREG analysis of risk factors of clinical outcomes in participants with
Outcome n Cumulative Incidence/1,000 pys
hyperglycemia plus metabolic syndrome.
incidence Clinical outcome Step Variable Wald X2 P value
in
% (95% CI) % (95% CI)
All death 1 Age 95.05 < 0.0001
All-cause mortality
2 PG2h 35.91 < 0.0001
Control 140 30.16 25.66–35.08 11.70 9.95–13.61 3 SBP 9.05 0.0026
IGT_MetS 130 49.57 42.67–56.48 20.86 17.96–23.77 4 Triglyceride 10.01 0.0016
T2DM 209 69.30 63.38–74.65 35.86 32.79–38.62 5 Smoking 9.12 0.0025
T2DM_MetS 236 70.21 64.44–75.40 35.41 32.50–38.03 CVD death 1 Age 41.82 < 0.0001
CVD mortality 2 PG2h 21.97 < 0.0001
Control 54 11.22 8.63–14.46 4.35 3.35–5.61 3 SBP 11.17 0.0008
IGT_MetS 77 27.71 22.47–33.65 11.66 9.46–14.16 4 Triglyceride 5.99 0.0144
T2DM 94 27.32 22.55–32.68 14.14 11.67–16.91 First CVD event 1 Age 43.30 < 0.0001
T2DM_MetS 126 34.22 29.09–39.74 17.26 14.67–20.04 2 PG2h 28.57 < 0.0001
First CV events 3 SBP 8.20 0.0042
Control 170 36.43 32.10–41.0 15.94 14.05–17.94 4 Triglyceride 7.83 0.0052
IGT_MetS 150 57.45 51.24–63.44 29.25 26.09–32.30 5 Smoking 7.21 0.0072
T2DM 163 50.77 45.14–56.38 30.13 26.79–33.46 First microvascular 1 PG2h 123.0 < 0.0001
T2DM_MetS 218 63.79 58.32–68.94 38.68 35.36–41.80 complications
First microvascular
events CVD event indicates cardiovascular disease, include myocardial infarction,
Control 50 9.01 6.80–11.83 3.57 2.69–4.68 stroke, and heart failure.
IGT_MetS 62 23.36 18.56–28.97 10.66 8.47–13.22 Microvascular complications include retinopathy, nephropathy, and neuropa­
T2DM 109 33.92 28.81–39.44 20.33 17.27–23.63 thy.
T2DM_MetS 126 38.47 33.17–44.06 22.24 19.1825.47 Note: No (additional) effects met the 0.05 level for entry into the model.

Individual vascular
complications NCEP-ATP III criteria have an elevated risk of microvascular disease
Myocardial infarction than participants without MetS [31,32]. To the best of our knowledge,
Control 48 10.28 7.82–13.41 4.08 3.10–5.32 this is the first study to investigate the long-term influence of MetS-
IGT_MetS 49 18.14 13.89–23.33 7.92 6.06–10.19
associated macrovascular and microvascular complications over a 30-
T2DM 68 20.47 16.34–25.32 11.06 8.83–13.69
T2DM_MetS 98 27.38 22.73–32.57 14.3 11.90–17.06 year follow-up period in a Chinese population. The present study pro­
Stroke vides evidence that MetS increases the risk of not only macrovascular
Control 144 30.29 26.24–34.68 13.07 11.33–14.97 complications, but also microvascular complications, at least for those
IGT_MetS 117 44.47 38.44–50.68 22.14 19.14–25.23 with MetS with IGT or overt diabetes. Furthermore, this study demon­
T2DM 110 33.79 28.72–39.27 19.66 16.71–22.85
T2DM_MetS 160 46.77 41.30–52.32 28.04 24.76–31.37
strates that the MetS group with hyperglycemia as one of its components
Heart failure causes more microvascular complications than macrovascular compli­
Control 11 2.31 1.28–4.14 0.90 0.50–1.61 cations. However, our data were insufficient to evaluate the influence of
IGT_MetS 34 13.01 9.40–17.75 5.51 3.99–7.52 MetS with isolated IFG on the risk of these vascular outcomes.
T2DM 17 5.31 3.31–8.41 2.76 1.72–4.37
As for the association between the degree of hyperglycemia in MetS
T2DM_MetS 31 9.03 6.33–12.73 4.60 3.22–6.48
Retinopathy and the severity of adverse clinical outcomes, the IGT_MetS group dis­
Control 33 4.99 3.47–7.12 1.97 1.37–2.81 played approximately a 2–3-fold higher risk of all-cause death, CVD
IGT_MetS 48 17.9 12.94–22.23 7.77 5.88–10.11 death, and the first composite microvascular and macrovascular com­
T2DM 87 26.04 21.34–31.37 15.46 12.67–18.62 plications than the non_MetS group. Importantly, all these outcomes
T2DM_MetS 98 30.25 25.24–35.78 17.34 14.47–20.51
Neuropathy
were significantly amplified in participants with MetS and T2DM. This
Control 3 0.52 0.17–1.64 0.20 0.06–0.64 clearly demonstrated that participants with MetS with increasing
IGT_MetS 9 3.39 1.76–6.44 1.43 0.74–2.73 severity of hyperglycemia (from IGT to T2DM) experienced increasing
T2DM 19 5.94 3.79–9.21 3.12 1.99–4.83 vascular outcomes, which suggests that preventing progression from IGT
T2DM_MetS 19 6.25 4.0–9.65 3.20 2.05–4.94
to T2DM is an upstream approach to reduce the healthcare system
Nephropathy
Control 16 3.30 2.02–5.34 1.28 0.79–2.08 burden. The importance of this approach is reinforced by the following
IGT_MetS 14 5.45 3.25–9.0 2.30 1.37–3.80 points: approximately 50% of Chinese participants with IGT were
T2DM 45 14.28 10.80–18.65 7.50 5.67–9.80 diagnosed with MetS in this study, and the number of pre-diabetes (IGT
T2DM_MetS 40 12.09 8.91–16.22 6.16 4.53–8.26 plus IFG) in Chinese adults increased to 388 million in 2013, accounting
CVD = cardiovascular disease; CI = confidence interval; CV = cardiovascular; for 35.7% of the total adult population [33]. Moreover, IGT in 67% of
IGT = impaired glucose tolerance; MetS = metabolic syndrome; Control = no individuals would subsequently progress into T2DM in approximately 6
MetS; pys = person-years; T2DM = type 2 diabetes mellitus. years without lifestyle intervention [22]. Encouragingly, lifestyle in­
terventions in patients with IGT have become a cornerstone in pre­
4. Discussion venting the onset of diabetes [22,34,35]. Active lifestyle and
pharmacological interventions, if needed, in this high-risk population
Previously studies have reported that individuals with MetS will effectively prevent developing diabetes plus MetS, and patients with
demonstrated an increased risk of death and macrovascular complica­ IGT may most benefit from intensive intervention.
tions than individuals without MetS [27–29]. However, the impact of Another important finding of our study was that the T2DM and
MetS on the development of microvascular complications remains T2DM_MetS groups shared a comparable risk of death and both mac­
debatable [30]. For example, Cull et al. have demonstrated that the rovascular and microvascular complications. Even if the adjudicated
WHO, NCEP-ATP III, and IDF criteria for diagnosing MetS distinguished MetS group did not include obesity as a component, the risk of all-cause
patients with T2DM who were at risk for macrovascular complications, mortality and macrovascular and microvascular complications was still
but not for microvascular complications [21]. By contrast, other studies comparable between both groups. The underlying mechanism is that
have reported that patients diagnosed with T2DM and MetS based on the T2DM and T2DM_MetS share a common biological basis. Studies have

6
S. He et al.
demonstrated that diabetes is triggered by high insulin requirements
induced by insulin resistance. MetS was named as “insulin resistance
syndrome” by diabetologists. In response to insulin resistance, beta cells
secrete more insulin to maintain blood glucose homeostasis at the
expense of compensatory hyperinsulinemia. Hyperinsulinemia then in­
duces hypertension through various vascular mechanisms and promotes
the renal tubular reabsorption of sodium. In addition, the weakened
antilipolytic effect of insulin in insulin-resistant status may result in
hypertriglyceridemia and hypo-high-density lipoproteinemia. Once in­
sulin secretion decompensates, hyperglycemia occurs. Clearly, diabetes
that develops in this way is a natural MetS. However, insulin resistance
may promote the development of diabetes several years before the
occurrence of other components of MetS in patients with poor beta cell
function. Here, 20%–39% of the patients with T2DM having concomi­
tant obesity and hypertension. Moreover, in a certain proportion of the
participants, the blood pressure and BMI levels were very close to the
cut-off points for diagnosing hypertension and obesity; development of
T2DM and MetS may then easily occur. Therefore, it may be logical that
T2DM and T2DM_MetS have similar long-term risks for vascular com­
plications and death.
The finding that participants with T2DM and T2DM_MetS shared a
comparable risk of these important clinical outcomes is a thorny issue
regarding the relationship between MetS and T2DM. Thus, this leads to
the question of whether the current definition of MetS should be re-
evaluated. Consistent predictions across components of the MetS are
lacking owing to the inconsistency in MetS definitions. In clinical
practice, the varied definitions of MetS have consistently limited their
predictions across MetS components. For example, the same prospective
study in the diabetes population in Japan concluded different outcomes
over time in terms of MetS prediction on CVD due to a different cutoff
point of the waist circumference for obesity in the MetS [36–38].
Interestingly, several studies have supported the exclusion of pa­
tients with T2DM from MetS diagnosis [39–41] since T2DM itself is a
risk factor for CV complications. Clinically, the reclassification of this
syndrome in the patients with diabetes may not add additional value
from a cardiovascular risk management perspective [16,17,21]. In this
context, results of the present 30-year follow-up study may provide
supportive evidence since participants with T2DM with and without
MetS shared a comparable risk profile regarding CV complications and
death. Nevertheless, changing the current definition of MetS is difficult
because of the lack of consensus. Meanwhile, the risk patterns associated
with T2DM and MetS are different in Asian and Western populations. In
Western countries, where obesity is very common, the metabolic risk
factors for MetS other than hyperglycemia may have a greater risk than
in the Chinese population. In Canada, Lamarche et al. [41] conducted a
prospective study that did not include diabetes and concluded that
hyperinsulinemia and hyperlipidemia of low-density lipoprotein (LDL)
were associated with the risk of ischemic heart disease in individuals
with MetS. Alexander et al. observed that in the NHANES population,
the risk factors for MetS other than hyperglycemia have a greater car­
diovascular risk. Their findings favor the development of hyperglycemia
as one of the five metabolic risk factors. Logically, to simplify the
identification of cardiovascular risk and to treat all risk factors simul­
taneously, there is a practical reason for combining MetS and T2DM in
Western countries. Compared to hyperglycemia, other metabolic risk
factors, such as hypertension and dyslipidemia, may have less impact in
China. Evidence from a genome-wide association study has demon­
strated that Asian population with T2DM were more likely to have poor
β-cell function. This defect may cause more challenges in controlling
hyperglycemia in Asian patients with T2DM. Therefore, hyperglycemia
having an outstanding contribution to the adverse clinical outcomes in
the Asian population is plausible. Overall, the finding that hyperglyce­
mia ranked as the most important factor among components of MetS in
the present study highlighted that the management of glycemia should
not be ignored in the Chinese population, although limited evidence
exists for risk reduction of atherosclerotic disease by treating
7
Diabetes Research and Clinical Practice 191 (2022) 110048
hyperglycemia per se in patients with T2DM. Hopefully, the current
study inspires a discussion of the important role of hyperglycemia in
MetS in China.
In the clinical setting, for individuals who meet the diagnostic
criteria of both diabetes and MetS, a ‘dual’ diagnosis of ‘diabetes and
MetS, rather than simply the diagnosis of MetS, is conducive to not only
adequate statin treatment but also the intervention of multiple risk
factors. Interestingly, in EASD 2021, Ildiko Lingvay et al. proposed that
the primary goal of treating diabetes is obesity management (i.e., losing
≥ 15% of body weight, which may also be the primary goal of diabetes
plus MetS treatment in the future) [42].
Regarding whether the different obesity cutoff points in the defini­
tion of MetS had a significant impact on the risk assessment of clinical
outcomes, T2DM and T2DM_MetS still had similar risks for most clinical
outcomes, including death and macrovascular and microvascular com­
plications, even if indicators of obesity were not considered. Using
obesity criteria suitable for Europeans to determine the risk of clinical
outcomes in Asians did not change the conclusion that T2DM and
T2DM_MetS have similar risks of all-cause mortality and microvascular
disease. However, it amplified the cardiovascular risk of participants
with IGT_MetS closer to that of those with T2DM, indicating that
different obesity criteria have a significant effect on cardiovascular risk
in non-diabetic MetS in the Chinese population. Therefore, a national or
regional cutoff point for obesity should be used currently, although a
single set of cutoff points for all components of MetS worldwide is
welcome in future studies.
4.1. Study strengths and limitations
Our study has some strengths and limitations, a few of which have
been previously addressed [23,24]. The key strength of this study was its
population-based longitudinal study design. A 30-year follow-up period
and sample size yielded an adequate number of macrovascular and
microvascular events. Furthermore, 110,660 Da Qing residents were
screened using a standardized 75 g OGTT and identified as having newly
diagnosed T2DM, IGT, and NGT.
A key shortcoming of this study was the use of a single MetS defi­
nition. The absence of waist circumference data for the study population
limited the use of other MetS diagnostic criteria. A systematic evaluation
of the clinical outcomes of the participants in this study at regular in­
tervals was not feasible. Moreover, we had some data on medications
used for dealing with hypertension, hyperglycemia, and dyslipidemia
over the 30-year follow-up period; however, detailed information on the
time of initial prescription, dose adjustment, and duration of adminis­
tration was not available for individual medications. This made it
impossible to evaluate the exact impact on the outcomes. However, the
results of the medication-adjusted analysis demonstrated that these
medications did not conclusively influence the main findings of the
study (Supplementary Data).
5. Conclusions
MetS leads to a higher incidence of macrovascular and microvascular
complications and deaths over a 30-year follow-up period. The degree of
hyperglycemia in patients with MetS was associated with the severity of
adverse clinical outcomes, while screening-based T2DM was associated
with a comparable risk of death and vascular complications as those of
T2DM plus MetS. The findings highlight the urgent needs to prevent
diabetes and monitor the progression of IGT from MetS to diabetes plus
MetS at an early stage, while the justification to redefine a subgroup of
patients with T2DM as MetS remains to be clarified.
Ethics approval and consent to participate
Institutional review boards at the Chinese Centers for Disease Con­
trol and Prevention and the Fuwai Hospital approved the study.
S. He et al.
Surviving participants and proxies who served as informants for the
deceased gave written informed consent.
Funding
The Da Qing Diabetes Prevention Study and the Da Qing Diabetes
Prevention Outcomes Study were supported from 1986 to 1992 by the
World Bank, the Ministry of Public Health of the People’s Republic of
China, and Da Qing First Hospital; from 2004 to 2009 by the US Centers
for Disease Control and Prevention (CDC)–WHO Cooperative Agreement
(U58/CCU424123–01–02), China–Japan Friendship Hospital, and Da
Qing First Hospital; and from 2015 to 2018 by the US CDC–Chinese
Center for Disease Control and Prevention Cooperative Agreement
(5U19GH000636–05).
Authors’ contributions
Guangwei Li, Siyao He, Jinping Wang and Xiaoxing Zhang conceived
and designed the analysis. Shiyao He, Jinping Wang, Wenjuan Wang,
Shuang Yan, Bo Zhang, Xiaoping Chen and Lihong Zhang collected the
data. Guangwei Li, Yali An, Xin Qian, Qiuhong Gong, Hui Li, performed
the data analysis. Guangwei Li, Yanyan Chen, Siyao He, Jinping Wang,
Xiaoxing Zhang, and Xiaolin Zhu wrote and reviewed the manuscript.
Siyao He and Jinping Wang, as joint first authors, contributed equally to
the design and preparation of the report.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Acknowledgments
We thank all the study participants and their relatives. We thank Dr
Yan Li for the preparation of the report and for participating in the study
design. We thank Yanjun Liu (306 PLA Hospital, Beijing, China), and
Yuqing Zhu (China–Japan Friendship Hospital, Beijing, China) for their
help with data collection. Our special thanks go to the late Professor Pan
Xiao Ren (China–Japan Friendship Hospital, Beijing, China).
Appendix A. Supplementary material
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.diabres.2022.110048.
References
[1] Ervin RB. Prevalence of metabolic syndrome among adults 20 years of age and
over, by sex, age, race and ethnicity, and body mass index: United States, 2003-
2006. Natl Health Stat Report. 2009:1-7.
[2] O’Neill S, O’Driscoll L. Metabolic syndrome: a closer look at the growing epidemic
and its associated pathologies. Obes Rev 2015;16:1–12. https://doi.org/10.1111/
obr.12229.
[3] Ranasinghe P, Mathangasinghe Y, Jayawardena R, Hills AP, Misra A. Prevalence
and trends of metabolic syndrome among adults in the asia-pacific region: a
systematic review. BMC Public Health 2017;17:101. https://doi.org/10.1186/
s12889-017-4041-1.
[4] Lan Y, Mai Z, Zhou S, Liu Y, Li S, Zhao Z, et al. Prevalence of metabolic syndrome in
China: an up-dated cross-sectional study. PLoS ONE 2018;13:e0196012. https://
doi.org/10.1371/journal.pone.0196012.
[5] Kahn R, Buse J, Ferrannini E, Stern M, American Diabetes A. European Association
for the Study of D. The metabolic syndrome: time for a critical appraisal: joint
statement from the American Diabetes Association and the European Association
for the Study of Diabetes. Diabetes Care 2005;28:2289–304. https://doi.org/
10.2337/diacare.28.9.2289.
[6] Johnson LW, Weinstock RS. The metabolic syndrome: concepts and controversy.
Mayo Clin Proc 2006;81:1615–20. https://doi.org/10.4065/81.12.1615.
[7] Kassi E, Pervanidou P, Kaltsas G, Chrousos G. Metabolic syndrome: definitions and
controversies. BMC Med 2011;9:48. https://doi.org/10.1186/1741-7015-9-48.
8
Diabetes Research and Clinical Practice 191 (2022) 110048
[8] Alberti KG, Definition ZPZ. diagnosis and classification of diabetes mellitus and its
complications. Part 1: diagnosis and classification of diabetes mellitus provisional
report of a WHO consultation. Diabet Med 1998;15:539–53. https://doi.org/
10.1002/(SICI)1096-9136(199807)15:7<539::AID-DIA668>3.0.CO;2-S.
[9] Expert Panel on Detection E, Treatment of High Blood Cholesterol in A. Executive
Summary of The Third Report of The National Cholesterol Education Program
(NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood
Cholesterol In Adults (Adult Treatment Panel III). JAMA. 2001;285:2486-97.
10.1001/jama.285.19.2486.
[10] Alberti KG, Zimmet P, Shaw J. Metabolic syndrome–a new world-wide definition. a
Consensus Statement from the International Diabetes Federation. Diabet Med
2006;23:469–80. https://doi.org/10.1111/j.1464-5491.2006.01858.x.
[11] Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, et al.
Harmonizing the metabolic syndrome: a joint interim statement of the
International Diabetes Federation Task Force on Epidemiology and Prevention;
National Heart, Lung, and Blood Institute; american heart association; world heart
federation; international atherosclerosis society; and international association for
the study of obesity. Circulation 2009;120:1640–5. https://doi.org/10.1161/
CIRCULATIONAHA.109.192644.
[12] society MsscgoCd. Suggestions about metabolic syndrome of Chinese diabetes
society. Chin J Diab. 2004;12:156-61.
[13] Xing Y, Xu S, Jia A, Cai J, Zhao M, Guo J, et al. Recommendations for revision of
Chinese diagnostic criteria for metabolic syndrome: a nationwide study. J Diabetes
2018;10:232–9. https://doi.org/10.1111/1753-0407.12578.
[14] Balkau B, Charles MA. Comment on the provisional report from the WHO
consultation. european Group for the Study of Insulin Resistance (EGIR). Diabet
Med 1999;16:442–3. https://doi.org/10.1046/j.1464-5491.1999.00059.x.
[15] Einhorn D, Reaven GM, Cobin RH, Ford E, Ganda OP, Handelsman Y, et al.
American College of Endocrinology position statement on the insulin resistance
syndrome. Endocr Pract 2003;9:237–52.
[16] Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary
heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and
without prior myocardial infarction. N Engl J Med 1998;339:229–34. https://doi.
org/10.1056/NEJM199807233390404.
[17] Einarson TR, Acs A, Ludwig C, Panton UH. Prevalence of cardiovascular disease in
type 2 diabetes: a systematic literature review of scientific evidence from across the
world in 2007–2017. Cardiovasc Diabetol 2018;17:83. https://doi.org/10.1186/
s12933-018-0728-6.
[18] Alexander CM, Landsman PB, Grundy SM. Metabolic syndrome and
hyperglycemia: congruence and divergence. Am J Cardiol 2006;98:982–5. https://
doi.org/10.1016/j.amjcard.2006.04.046.
[19] Stern MP, Williams K, Gonzalez-Villalpando C, Hunt KJ, Haffner SM. Does the
metabolic syndrome improve identification of individuals at risk of type 2 diabetes
and/or cardiovascular disease? Diabetes Care 2004;27:2676–81. https://doi.org/
10.2337/diacare.27.11.2676.
[20] Shin JA, Lee JH, Lim SY, Ha HS, Kwon HS, Park YM, et al. Metabolic syndrome as a
predictor of type 2 diabetes, and its clinical interpretations and usefulness.
J Diabetes Investig 2013;4:334–43. https://doi.org/10.1111/jdi.12075.
[21] Cull CA, Jensen CC, Retnakaran R, Holman RR. Impact of the metabolic syndrome
on macrovascular and microvascular outcomes in type 2 diabetes mellitus: United
Kingdom Prospective Diabetes Study 78. Circulation 2007;116:2119–26. https://
doi.org/10.1161/CIRCULATIONAHA.107.733428.
[22] Pan XR, Li GW, Hu YH, Wang JX, Yang WY, An ZX, et al. Effects of diet and exercise
in preventing NIDDM in people with impaired glucose tolerance. the Da Qing IGT
and Diabetes Study. Diabetes Care 1997;20:537–44. https://doi.org/10.2337/
diacare.20.4.537.
[23] Li G, Zhang P, Wang J, Gregg EW, Yang W, Gong Q, et al. The long-term effect of
lifestyle interventions to prevent diabetes in the China Da Qing Diabetes
Prevention Study: a 20-year follow-up study. Lancet 2008;371:1783–9. https://doi.
org/10.1016/S0140-6736(08)60766-7.
[24] Li G, Zhang P, Wang J, An Y, Gong Q, Gregg EW, et al. Cardiovascular mortality,
all-cause mortality, and diabetes incidence after lifestyle intervention for people
with impaired glucose tolerance in the Da Qing Diabetes Prevention Study: a 23-
year follow-up study. Lancet Diabetes Endocrinol 2014;2:474–80. https://doi.org/
10.1016/S2213-8587(14)70057-9.
[25] Gong Q, Zhang P, Wang J, Ma J, An Y, Chen Y, et al. Morbidity and mortality after
lifestyle intervention for people with impaired glucose tolerance: 30-year results of
the Da Qing Diabetes Prevention Outcome Study. Lancet Diabetes Endocrinol
2019;7:452–61. https://doi.org/10.1016/S2213-8587(19)30093-2.
[26] Garvey WT, Mechanick JI, Brett EM, Garber AJ, Hurley DL, Jastreboff AM, et al.
American association of clinical endocrinologists and american college of
endocrinology comprehensive clinical practice guidelines for medical care of
patients with obesity: Complete Guidelines available at https://www aace com/
publications/guidelines 2016;22:842–84.
[27] Mottillo S, Filion KB, Genest J, Joseph L, Pilote L, Poirier P, et al. The metabolic
syndrome and cardiovascular risk a systematic review and meta-analysis. J Am Coll
Cardiol 2010;56:1113–32. https://doi.org/10.1016/j.jacc.2010.05.034.
[28] Galassi A, Reynolds K, He J. Metabolic syndrome and risk of cardiovascular
disease: a meta-analysis. Am J Med 2006;119:812–9. https://doi.org/10.1016/j.
amjmed.2006.02.031.
[29] Ninomiya JK, L’Italien G, Criqui MH, Whyte JL, Gamst A, Chen RS. Association of
the metabolic syndrome with history of myocardial infarction and stroke in the
third national health and nutrition examination survey. Circulation 2004;109:
42–6. https://doi.org/10.1161/01.CIR.0000108926.04022.0C.
S. He et al.
[30] Migdalis I, Czupryniak L, Lalic N, Leslie RD, Papanas N, Valensi P. Diabetic
Microvascular Complications. Int J Endocrinol 2018;2018:5683287. https://doi.
org/10.1155/2018/5683287.
[31] Wong J, Molyneaux L, Constantino MI, Twigg SM, Yue DK. The metabolic
syndrome in type 2 diabetes: when does it matter? Diabetes Obes Metab 2006;8:
690–7. https://doi.org/10.1111/j.1463-1326.2005.00565.x.
[32] Lee MY, Hsiao PJ, Huang JC, Hsu WH, Chen SC, Shin SJ. Association between
metabolic syndrome and microvascular and macrovascular disease in Type 2
Diabetic Mellitus. Am J Med Sci 2018;355:342–9. https://doi.org/10.1016/j.
amjms.2017.12.004.
[33] Wang L, Gao P, Zhang M, Huang Z, Zhang D, Deng Q, et al. Prevalence and Ethnic
Pattern of Diabetes and Prediabetes in China in 2013. JAMA 2017;317:2515–23.
https://doi.org/10.1001/jama.2017.7596.
[34] Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H, Ilanne-Parikka P,
et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects
with impaired glucose tolerance. N Engl J Med 2001;344:1343–50. https://doi.
org/10.1056/NEJM200105033441801.
[35] Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA,
et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or
metformin. N Engl J Med 2002;346:393–403. https://doi.org/10.1056/
NEJMoa012512.
[36] Ninomiya T, Kubo M, Doi Y, Yonemoto K, Tanizaki Y, Rahman M, et al. Impact of
metabolic syndrome on the development of cardiovascular disease in a general
Japanese population: the Hisayama study. Stroke 2007;38:2063–9. https://doi.
org/10.1161/STROKEAHA.106.479642.
Diabetes Research and Clinical Practice 191 (2022) 110048
[37] Sone H, Mizuno S, Fujii H, Yoshimura Y, Yamasaki Y, Ishibashi S, et al. Is the
diagnosis of metabolic syndrome useful for predicting cardiovascular disease in
asian diabetic patients? Analysis from the Japan Diabetes Complications Study.
Diabetes Care 2005;28:1463–71. https://doi.org/10.2337/diacare.28.6.1463.
[38] Sone H, Tanaka S, Ishibashi S, Yamasaki Y, Oikawa S, Ito H, et al. The new
worldwide definition of metabolic syndrome is not a better diagnostic predictor of
cardiovascular disease in Japanese diabetic patients than the existing definitions:
additional analysis from the Japan Diabetes Complications Study. Diabetes Care
2006;29:145–7. https://doi.org/10.2337/diacare.29.1.145.
[39] Mente A, Yusuf S, Islam S, McQueen MJ, Tanomsup S, Onen CL, et al. Metabolic
syndrome and risk of acute myocardial infarction a case-control study of 26,903
subjects from 52 countries. J Am Coll Cardiol 2010;55:2390–8. https://doi.org/
10.1016/j.jacc.2009.12.053.
[40] Sun DL, Wang JH, Jiang B, Li LS, Li LS, Wu L, et al. Metabolic syndrome vs. its
components for prediction of cardiovascular mortality: a cohort study in Chinese
elderly adults. J Geriatr Cardiol 2012;9:123–9. https://doi.org/10.3724/SP.
J.1263.2012.01172.
[41] Lamarche B, Tchernof A, Mauriege P, Cantin B, Dagenais GR, Lupien PJ, et al.
Fasting insulin and apolipoprotein B levels and low-density lipoprotein particle size
as risk factors for ischemic heart disease. JAMA 1998;279:1955–61. https://doi.
org/10.1001/jama.279.24.1955.
[42] Lingvay I, Sumithran P, Cohen RV, le Roux CW. Obesity management as a primary
treatment goal for type 2 diabetes: time to reframe the conversation. Lancet 2022;
399:394–405. https://doi.org/10.1016/S0140-6736(21)01919-X.