Diabetes Metabolism Res 2024 Huang Metabolically Healthy Obesity

Received: 8 October 2023
DOI: 10.1002/dmrr.3766
RESEARCH ARTICLE
- -Revised: 18 December 2023 Accepted: 15 January 2024
Metabolically healthy obesity, transition from metabolic

healthy to unhealthy status, and carotid atherosclerosis
Qin Huang1,2 | Zeyu Liu1 | Minping Wei1 | Jie Feng1 | Qing Huang1 |
Yunhai Liu1 | Zunjing Liu2 | XiaoJun Li3 | Li Yin3 | Jian Xia1,4,5
1
Department of Neurology, Xiangya Hospital,
Central South University, Changsha, Hunan, Abstract
China
Background: Evidence of the effects of metabolically healthy obesity (MHO) on
2
Department of Neurology, Peking University
atherosclerosis is limited; the transition effects of metabolic health and obesity
people's hospital, Beijing, China
3
Hunan Provincial Center for Disease Control
phenotypes have been ignored. We examined the association between metabolic
and Prevention, Changsha, China health and the transition to atherosclerosis risk across body mass index (BMI)
4
Clinical Research Center for Cerebrovascular categories in a community population.
Disease of Hunan Province, Central South
University, Changsha, China Methods: This cross‐sectional study was based on a national representative survey
5
National Clinical Research Center for that included 50,885 community participants aged ≥40 years. It was conducted
Geriatric Disorders, Xiangya Hospital, Central from 01 December 2017 to 31 December 2020, in 13 urban and 13 rural regions
South University, Changsha, China
across Hunan China. Metabolic health was defined as meeting less than three ab-
Correspondence normalities in blood pressure, glucose, high‐density lipoprotein cholesterol, tri-
Li Yin and Jian Xia, Hunan Provincial Center
glycerides, or waist circumference. The participants were cross‐classified at baseline
for Disease Control and Prevention, No.405,
Furong Road, Changsha 410005, Hunan, based on their metabolic health and obesity. In addition, the relationship between
China.
atherosclerosis and transitions in metabolic health status based on 4733 partici-
Email: [email protected]
pants from baseline to the second survey after 2 years was considered. The rela-
Department of Neurology, Xiangya Hospital,
tionship between metabolic health status and the risk of transition to Carotid
Central South University, No.87, Xiangya
Road, Changsha 410008, Hunan, China. atherosclerosis (CA) was assessed using logistic regression and Cox proportional
Email: [email protected]
hazards regression analyses.
Funding information Results: In this study, the mean age of the participants was 60.7 years (standard
National Science and Technology deviation [SD], 10.91), 53.0% were female, and 51.2% had CA. As compared with
Infrastructure Program
metabolically healthy normal weight (MHN), those with MHO phenotype (odd ratio
[OR] 1.10, 95% confidence interval [CI] 1.02–1.21), metabolically unhealthy normal
weight (OR 1.27, 95% CI 1.19–1.35), metabolically unhealthy overweight (OR 1.41,
95% CI 1.33–1.48), and metabolically unhealthy obese (OR 1.54, 95% CI 1.44–1.64)
had higher risk for CA. However, during the follow‐up of 2 years, almost 33% of the
participants transitioned to a metabolically unhealthy status. As compared with
stable healthy normal weight, transition from metabolically healthy to unhealthy
status (hazard ratios [HR] 1.21, 95% [CI] 1.02–1.43) and stable metabolically un-
healthy overweight or obesity (MUOO) (HR 1.32, 95% CI 1.17–1.48) were associ-
ated with higher risk of CA.
Conclusions: In the community population, obesity remains a risk factor for CA
-
despite metabolic health. However, the risks were highest for metabolically
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- HUANG ET AL.
unhealthy status across all BMI categories. A large proportion of metabolically

healthy overweight or participants with obesity converts to an unhealthy phenotype
over time, which is associated with an increased risk of CA.
KEYWORDS
carotid atherosclerosis, metabolic health, metabolic syndrome, obesity, transition
1 | INTRODUCTION 2 | METHODS
Cardiovascular diseases (CVDs), primarily stroke and ischemic 2.1 | Study population
heart disease (IHD), contribute to more than 18 million deaths
annually worldwide.1 Carotid atherosclerosis (CA) can be assessed The study data were supported by the China Stroke High‐Risk Pop-
non‐invasively by ultrasonography, which serves as a method for ulation Screen and Intervention Programme (CSHPSIP), an ongoing
the early detection of atherosclerosis.2 CA has a substantial nationwide population‐based programme launched by the China
3
global burden, particularly in the Western Pacific region. How- Stroke Prevention Project Committee. Details of the study design,
ever, the current treatments for reversing and curing athero- methods, and participants have been reported previously.20 The
sclerosis are limited. Thus, it is necessary to determine the risk CSHPSIP performs stroke screening nationwide each year and up-
factors for CA. dates the health status of the screened population every 2 years.21
Obesity and related metabolic disorders, including hyperglyce- All participants received information about the study and provided
mia, hypertension, and hypercholesterolaemia, are well‐established written informed consent. We used data generated from December
risk factors for heart failure4‐6 and CA.7‐9 However, recent interest 2017 to December 2020 from the CSHPSIP in Hunan Province.
has focused on a unique subgroup of individuals with normal meta- Around 133,489 community‐dwelling adults aged ≥40 years (resi-
8
bolic features despite their increased adiposity. Such individuals are dence for >6 months) were randomly enroled in this study, of which
usually considered to have metabolically healthy obesity (MHO)9 and 53,222 participants completed cervical vascular ultrasound. Partici-
may display distinct disease outcomes compared to metabolically pants who had missing values for weight, height, or information on
healthy normal weight (MHN) and metabolically unhealthy obesity metabolic disorders (n = 1017), or were underweight (BMI <18.5 kg/
10
(MUO) status, which could have important implications for tar- m2; n = 1320) were excluded from the study. Finally, 50,885 par-
geted preventive strategies in practice. According to recent large‐ ticipants were included in the analysis of the association between
scale cohort studies10‐12 and meta‐analyses,13‐15 the MHO pheno- metabolic health status, obesity at baseline, and the prevalence of
type is transient and dynamic; its transition to a metabolically un- CA. To explore the effects of the transitions in metabolic health
healthy phenotype is associated with an increased risk of CVDs and status over time (from 2017 to 2019 and from 2018 to 2020) on the
atherosclerosis; however, inconsistent findings have also been re- risk of CA, we further left 4733 residents who successfully completed
ported.14,16,17 This inconsistency might be due to ignoring the dy- the first and second surveys after 2 years face to face and had
namic nature of the MHO phenotype, a substantially limited sample complete information on metabolic disorders and the examination of
size, or a lack of a uniform definition of MHO. Given the importance cervical vascular ultrasound in the two periodic surveys to assess the
of primary prevention of CVDs, it is important to better understand risk of CA with transitions in metabolic health status. The sample
whether MHO represents the relatively benign nature of selection framework is presented in Figure S1.
atherosclerosis.
To the best of our knowledge, little is known about how
metabolic risk factors change in individuals with metabolic health 2.2 | Data collection
in different body mass index (BMI) groups and how the onset of
metabolic disorders affects atherosclerosis risk among healthy Participants completed a face‐to‐face interview questionnaire on
individuals, especially among Asian adults, whose adiposity distri- sociodemographic characteristics (age, sex, and educational level),
bution, lifestyle, risk of obesity, and disease patterns differ sub- lifestyle factors (physical inactivity, consumption of fruits and vege-
stantially from those in Western populations.18,19 Thus, we tables, diet, history of smoking and alcohol consumption), personal
conducted a community‐based, large study in China to determine and family medical history (hypertension, diabetes mellitus, stroke,
1) the effect of metabolic status on the risk of atherosclerosis in atrial fibrillation, etc.), and current medications (antihypertensive
individuals with normal weight, overweight, and obesity and 2) the therapy, lipoprotein‐lowering therapy, and hypoglycemic therapy) at
association of these metabolic‐BMI phenotype transitions with the screening point by trained technicians using calibrated in-
atherosclerosis. struments with standard protocols. All participants were invited to
HUANG ET AL.
- 3 of 15
participate in the physical measurements. Height, weight, Waist Individuals who met <3 of the following five criteria were considered
circumference (WC), and blood pressure were measured according to metabolically healthy: (1) systolic blood pressure ,SBP ≥130 mmHg
the standard protocols. Waist circumference was determined using a or diastolic blood pressure (DBP) ≥85 mmHg or self‐reported hy-
measuring tape positioned midway between the lowest rib and the pertension or using antihypertensive drugs; (2) fasting blood glucose
superior border of the iliac crest as the participant exhaled normally. ≥5.6 mmol/L or self‐reported diabetes or medications for diabetes;
Body mass index was calculated as body weight (kg) divided by t (3) reduced plasma high‐density lipoprotein cholesterol (HDL‐C)
height squared (m). Blood pressure was measured after a 5‐min rest (<1.3 mmol/L for women and <1.0 mmol/L for men); (4) elevated
period using a random‐zero sphygmomanometer, and the average of plasma TG (≥1.7 mmol/L); (5) WC ≥85 cm for women and ≥90 cm for
the last two of three consecutive measurements was used for the men. Obesity was classified by BMI criteria based on Chinese
analysis. Fasting blood glucose levels were measured using the guidelines23: normal weight (18.5 to < 24 kg/m2), overweight (24
glucose assay. Overnight fasting blood samples were collected to test to < 28 kg/m2), and obesity (≥28 kg/m2).
the triglyceride (TG), high‐density lipoprotein, low‐density lipopro- Transitions in metabolic health status across BMI categories
tein, and total cholesterol (TC) levels using an HP‐AFS/3 automatic were examined from baseline (2017–2018) to the second resurvey
immunoassay system A3 Specific Protein Analyser with supporting (2019–2020) in 4733 participants with information on obesity and
reagents (Shijiazhuang Hebo Biotechnology Co., Ltd., Shijiazhuang, metabolic health at both time points. Individuals with MHOW or
China). obesity (MHOO) at baseline examination were categorised into four
Patients with AF included self‐reported patients and those with subgroups: stable MHOO, MHOO to MHN, MHOO to MUN, and
arrhythmia detected on on‐site screening and confirmed by electro- MHOO to metabolically unhealthy overweight or obese (MUOO),
cardiography. The diagnosis of stroke requires the investigator to with a combination of overweight and obesity for small sample sizes.
provide a diagnostic or image certificate from a secondary or higher
medical unit and be interviewed by trained neurologists. Diabetes
mellitus was defined as self‐reported diabetes mellitus, insulin in- 2.4 | Assessment of carotid atherosclerosis
jections, or use of oral hypoglycemic agents. Hypertension was
defined as self‐reported hypertension or the use of antihypertensive Carotid atherosclerosis was measured using ultrasound systems (S
medications. Family history, including stroke, hypertension, diabetes 2000 [Siemens Medical Solutions], iU22 [Philips Healthcare], and
mellitus, and coronary heart disease, was defined as the occurrence Logiq 9 [GE Healthcare]) in the supine position. The transmission
in ≥1 of the participant's parents or siblings. Physical activity (PA) frequency of ultrasound images was 6–10 MHz. The common carotid
was defined according to the World Health Organization recom- external carotid, internal carotid, bulb, subclavian and vertebral ar-
mendation standard (75 min of vigorous‐intensity PA per week, at teries were measured and recorded for the presence of atheroscle-
least 150 min of moderate‐intensity PA, or any equivalent combi- rotic plaques. Two qualified sonographers with uniform training who
nation of the two). The consumption of vegetable and fruits (300 g of were unaware of the baseline characteristics and laboratory findings
vegetables and 200 g of fruits per day) was classified as follows: of the participants measured each participant separately and dis-
insufficient intake (frequency: ≤4 days per week) and sufficient crepancies in the measurement data were resolved by consensus.
intake (frequency: ≥5 days per week). Meat and vegetarian diets According to the 2016 European guidelines on CVD prevention in
were divided into balanced and unbalanced (partial meat and partial clinical practice or the Mannheim carotid intima–media thickness ,
vegetarian). Taste preferences were classified as salty, oily, light, or CIMT Consensus,24 increased CIMT, carotid plaque, or carotid ste-
moderate. Smoking status was divided into three categories: no nosis were defined in a standardised manner as follows: Increased
smoking, current smoking (continuous or cumulative smoking for CIMT was defined as a thickness of 1.0 mm or more in either the
>6 months), and former smoking (continuous smoking for >6 months right or left carotid artery. Carotid plaque was defined as a focal
but no smoking at the time of the survey). Alcohol consumption was CIMT of 1.5 mm or focal narrowing of the vessel wall of >50%
classified into alcohol and non‐alcohol consumption. Educational relative to the adjacent segments. Carotid stenosis was defined as
level was categorised as less than high school, high school, or higher. 50% or more stenosis, including occlusion. Participants with
increased CIMT, plaques, or stenosis were defined as having CA.
2.3 | Definition of BMI categories and metabolic

health status and their transitions 2.5 | Statistical analysis
Participants were divided into six groups based on their metabolic Continuous variables are expressed as mean � standard deviation
health and obesity status: MHN, metabolically healthy overweight (SD). Categorical variables were expressed as numbers (percentages).
(MHOW), MHO, metabolically unhealthy normal weight (MUN), Logistic regression models were used to estimate the odds ratios
metabolically unhealthy overweight (MUOW), and metabolically un- (ORs) and 95% confidence intervals (CIs) for the risks of CA based on
healthy obese (MUO). We used the harmonised International Dia- BMI‐metabolic health status, with the MHN phenotype as the
22
betes Federation criteria for the metabolic health status. reference. The association between the transitions in metabolic
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- HUANG ET AL.
health from to 2017–2018 to 2019–2020 and the risk of CA during than in older people. Subjects with MHO were characterised by
follow‐up (after 2019–2020) was assessed using Cox proportional worse lipid profiles than healthy and lean populations. However, in-
hazards regression models with age as the time‐scale. The multi- dividuals with MHO exhibited more favourable metabolic profiles
variate model was adjusted for age, sex, alcohol consumption, than those with MUN, MUOW, or MUO. Mean WC and age were
smoking, education, PA, medical history (stroke, diabetes, hyperten- higher among metabolically unhealthy individuals than among their
sion, AF, transient ischemic attack, TIA), family history (stroke, CHD, healthy counterparts across all BMI categories. The levels of fasting
diabetes, hypertension), taste preferences (salty or oily), meat and plasma glucose (FPG), blood pressure (BP), TG, and TC were higher,
vegetarian balance (balanced or unbalanced), and fruit or vegetable and HDL‐C was lower in metabolically unhealthy individuals, irre-
intake (sufficient or insufficient). The joint effects of BMI‐metabolic spective of obesity. The estimates of the indicators of events,
health status with sex (male, female) or age (≤60 years, >60 years) including CA, increased CIMT, carotid plaques, and carotid stenosis,
were examined to estimate the age‐ and sex‐specific associations. exhibited a similar pattern (Figure S3).
Restricted cubic splines with knots at the 5th, 35th, 65th, and 95th
percentiles were used to explore the shape of the dose‐response
relationship between the aforementioned risk factors of metabolic 3.2 | Associations of BMI‐metabolic health status
health (blood pressure, WC, and fasting glucose) and CA in meta- with carotid atherosclerosis
bolically healthy and unhealthy participants The association between
the number of participants with metabolic disorders and the preva- Table 2 and Figure 1 present the risk of CA in participants cross‐
lence of CA was examined. classified according to BMI categories and metabolic health. The in-
Several sensitivity analyses were performed to examine the dividuals with MHO status had a 10% higher risk of developing CA
robustness of our findings: excluding cases with the history of stroke; (odd ratio [OR], 1.10; 95% CI 1.02–1.21) as compared with MHN
excluding subjects older than 70 years; using waist‐height ratio individuals; the corresponding OR for MUO was 1.54 (95% CI 1.44–
(≥0.50) instead of the WC criterion defined metabolic health status; 1.64). For increased CIMT (early stage of CA), the adjusted ORs for
additionally adjusting for SBP, DBP and fasting plasma glucose to the MHO and MUO individuals were 1.18 (95% CI 1.07–1.29) and
report whether the relationship was caused by difference of blood 1.53 (95% CI 1.44–1.63), respectively. For carotid plaques (middle
pressure and fasting plasma glucose; additionally adjusting for low‐ and late stage of CA), the adjusted ORs for the MHO and MUO in-
density lipoprotein cholesterol ,LDL‐C and lipoprotein‐lowing ther- dividuals were 0.97 (95% CI 0.88–1.07) and 1.25 (95% CI 1.17–1.33),
apy to investigate whether the associations was caused by the levels respectively. However, we did not find an association between ca-
of LDL‐C and hypolipidemic effects; using an alternative definition of rotid stenosis and MHO phenotype (OR 0.86, 95% CI 0.53–1.41).
metabolic health that <2 of the following criteria: elevated blood Notably, individuals with a metabolically unhealthy phenotype have a
pressure, elevated plasma glucose, high triacylglycerols, low HDL‐C, higher risk of CA than those with a metabolically healthy phenotype,
and excluding WC criterion for high correlation with BMI.22 All the irrespective of obesity. To further explore the non‐linear relation-
sensitivity analyses were performed using the final adjustment ships, we fitted restricted cubic spline models. The SBP levels with
model. All statistical analyses were performed using SPSS (version the lowest OR were 128.25 mmHg in metabolically healthy and
25.0; IBM Corp., Armonk, NY, USA) and R version 4.2.1 (R Devel- 138.23 mmHg in metabolically unhealthy populations. The reference
opment Core Team, Vienna, Austria). Statistical significance was DBP levels were set at 82.68 mmHg in metabolically healthy and
defined as p < 0.05. 82.01 mmHg in metabolically unhealthy populations for OR estima-
tion. The fasting blood glucose levels associated with the lowest ORs
were 5.91 mmol/L in the metabolically healthy population and
3 | RESULTS 5.76 mmol/L in the metabolically unhealthy population. These models
also suggested a positive association between CA at higher levels of
3.1 | Baseline characteristics of participants by WC in both metabolically healthy and unhealthy populations
BMI‐metabolic health status (Figure 2). Moreover, the higher risk of CA was accompanied by an
increase in the number of metabolic disorders (Figure S4).
Baseline characteristics of the study population, as cross‐classified The sex‐ and age‐specific associations are presented in Table 3
according to metabolic health and obesity status, are shown in and Table S1. As compared with male participants who were in MHN
Table 1. Among these 50,885 study participants, the mean age of the status, the risk of CA (OR 1.15, 95% CI 1.01–1.31) and increased
participants was 60.7 (standard deviation [SD], 10.9) years; 26,978 CIMT (OR 1.20, 95% CI 1.06–1.36) was higher among males with
(53.0%) participants were female. The prevalence of MHO was the MHO status. By contrast, we did not find an association between CA
lowest among all metabolic health statuses; 2372 (4.7%) participants and MHO phenotype in females (OR 0.99, 95% CI 0.86–1.13), as well
were defined as having the MHO phenotype according to the BMI as increased CIMT and MHO status (OR 1.10, 95% CI 0.96–1.26).
categories (Figure S2). The sex‐ and age‐specific prevalence of BMI‐ Compared with males in MHN status, the risks in MUO men for CA,
metabolic health status is presented in Figure S2. The prevalence of increased CIMT, carotid plaques and stenosis was 1.49 (95% CI 1.36–
MHO was higher in male than in female participants and younger 1.63), 1.43 (95% CI 1.31–1.57), 1.24 (95% CI 1.13–1.36), and 0.82
HUANG ET AL.
- 5 of 15
TABLE 1 Baseline characteristics of the study population.
Normal weight Overweight Obese
Metabolically Metabolically Metabolically Metabolically Metabolically Metabolically

Characteristics healthy unhealthy healthy unhealthy healthy unhealthy
N 16,142 6672 9179 10,409 2372 6111
Female (n, %) 8704(53.9) 4395(65.9) 4033(43.9) 5567(53.5) 1108(46.7) 3171(51.9)
Age (years) 60.68(11.54) 63.37(10.56) 59.19(10.79) 61.51(10.32) 58.64(10.42) 59.62(10.18)
Exercise habits (n, %)
Regular exercise 10,153(62.9) 4091(61.3) 5860(63.8) 6419(61.7) 1422(59.9) 3780(61.9)
Lack of exercise 5989(37.1) 2581(38.7) 3319(36.2) 3990(38.3) 950(40.1) 2331(38.1)
Education (n, %)
Less than high school 11,365(70.4) 4981(74.7) 6330(69.0) 7304(70.2) 1708(72.0) 4394(71.9)
High school or above 4777(29.6) 1691(25.3) 2849(31.0) 3105(29.8) 664(28.0) 1717(28.1)
Cigarette smoking (n, %)
Non‐smoker 11,649(72.2) 5301(79.5) 6421(70.0) 7476(71.8) 1669(70.4) 4427(72.4)
Past smoker 485(3.0) 180(2.7) 312(3.4) 339(3.3) 90(3.8) 259(4.2)
Current smoker 4008(24.8) 1191(17.9) 2446(26.6) 2594(24.9) 613(25.8) 1425(23.3)
Current drinking (n, %) 2911(18.0) 948(14.2) 2118(23.1) 2209(21.2) 541(22.8) 1457(23.8)
Taste preferences (n, %)
Salty 2536(15.7) 1165(17.5) 1629(17.7) 1994(19.2) 460(19.4) 1361(22.3)
Oily 2460(15.2) 1153(17.3) 1287(14.0) 1652(15.9) 335(14.1) 900(14.7)
Meat and vegetarian (n, %)
Balanced 1127(7.0) 459(6.9) 785(8.6) 916(8.8) 231(9.7) 672(11.0)
unbalanced 15,015(93.0) 6213(93.1) 8394(91.4) 9493(91.2) 2141(90.3) 5439(89.0)
Fruit or vegetables per day

(n, %)
Sufficient intake 9727(60.3) 4118(61.7) 5332(58.1) 6561(63.0) 1395(58.8) 3826(62.6)
Insufficient intake 6415(39.7) 2554(38.3) 3847(41.9) 3848(37.0) 977(41.2) 2285(37.4)
Medical history (n, %)
Diabetes 2808(17.4) 3324(49.8) 1347(14.7) 4644(44.6) 248(10.5) 2374(38.8)
Hypertension 6587(40.8) 4929(73.9) 4109(44.8) 7909(76.0) 1193(50.3) 4707(77.0)
Stroke 1105(6.8) 623(9.3) 664(7.2) 924(8.9) 90(3.8) 358(5.9)
TIA 233(1.4) 84(1.3) 138(1.5) 135(1.3) 23(1.0) 72(1.2)
AF 196(1.2) 82(1.2) 91(1.0) 124(1.2) 24(1.0) 75(1.2)
Family history (n, %)
Diabetes 1331(8.2) 784(11.8) 816(8.9) 1388(13.3) 241(10.2) 777(12.7)
Hypertension 3958(24.5) 1866(28.0) 2570(28.0) 3481(33.4) 670(28.2) 2154(35.2)
Stroke 2296(14.2) 1137(17.0) 1449(15.8) 1896(18.2) 345(14.5) 982(16.1)
Coronary heart disease 1625(10.1) 749(11.2) 974(10.6) 1336(12.8) 266(11.2) 856(14.0)

2
BMI (kg/m ) 21.80(1.49) 22.40(1.59) 25.52(1.07) 25.86(1.10) 30.37(3.39) 31.36(2.54)
WC (cm) 78.00(6.68) 82.01(7.68) 83.75(6.83) 88.29(6.96) 88.38(9.63) 94.14(7.93)
FPG (mmol/L) 5.22(1.27) 6.15(1.53) 5.10(1.16) 5.99(1.52) 5.03(1.07) 5.87(1.46)
SBP (mmHg) 128.78(18.23) 138.73(17.45) 129.99(17.97) 138.66(17.83) 131.11(18.08) 138.76(18.02)
(Continues)
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- HUANG ET AL.
T A B L E 1 (Continued)
Normal weight Overweight Obese
Metabolically Metabolically Metabolically Metabolically Metabolically Metabolically

Characteristics healthy unhealthy healthy unhealthy healthy unhealthy
DBP (mmHg) 77.55(9.95) 81.37(10.12) 79.07(9.85) 82.76(10.33) 80.08(10.14) 83.76(10.54)
TC (mmol/L) 4.69(1.01) 4.73(1.03) 4.67(0.99) 4.73(1.00) 4.70(0.99) 4.70(0.97)
HDL‐C (mmol/L) 1.52(0.44) 1.23(0.40) 1.42(0.42) 1.20(0.36) 1.42(0.39) 1.18(0.35)
TG (mmol/L) 1.42(0.66) 2.14(0.82) 1.52(0.68) 2.16(0.82) 1.49(0.66) 2.12(0.81)
LDL‐C (mmol/L) 2.65(0.87) 2.67(0.92) 2.68(0.87) 2.66(0.89) 2.71(0.85) 2.63(0.88)
Antihypertensive therapy 2938(18.2) 2623(39.3) 2009(21.9) 4520(43.4) 620(26.1) 2857(46.8)

(n, %)
Lipoprotein‐lowing therapy 387(2.4) 649(9.7) 264(2.9) 934(9.0) 49(2.1) 571(9.3)

(n, %)
Hypoglycemic therapy (n, %) 1317(8.5) 1885(28.3) 698(7.6) 2558(24.6) 135(5.7) 1218(19.9)
CA (n, %)
No 8491(52.6) 2882(43.2) 5019(54.7) 4448(42.7) 1284(54.1) 2711(44.4)
Yes 7651(47.4) 3790(56.8) 4160(45.3) 5961(57.3) 1088(45.9) 3400(55.6)
Increased CIMT (n, %)
No 10,182(63.1) 3710(55.6) 5881(64.1) 5671(54.5) 1488(62.7) 3356(54.9)
Yes 5960(36.9) 2960(44.4) 3298(35.9) 4738(45.5) 884(37.3) 2755(45.1)
Plaques (n, %)
No 10,447(64.7) 3817(57.2) 6179(67.3) 6005(57.7) 1628(68.6) 3764(61.6)
Yes 5695(35.3) 2855(42.8) 3000(32.7) 4404(42.3) 744(31.4) 2347(38.4)
Stenosis (n, %)
No 15,969(98.9) 6560(98.3) 9094(99.1) 10,275(98.7) 2325(99.2) 6045(98.9)
Yes 173(1.1) 112(1.7) 85(0.9) 134(1.3) 18(0.8) 66(1.1)
Note: Values are presented as n (percentage) or mean (standard deviation).

Abbreviations: AF, atrial fibrillation; BMI, body mass index; CA, carotid atherosclerosis; CIMT, carotid intima–media thickness; DBP, diastolic blood
pressure; FPG, Fasting plasma glucose; HDL‐C, high‐density lipoprotein cholesterol; LDL‐C, low‐density lipoprotein cholesterol; SBP, systolic blood
pressure; TC, total cholesterol; TG, triglyceride; TIA, transient ischemic attack; WC, Waist circumference.
(95% CI 0.54–1.24), respectively. The risks for CA (OR 1.52, 95% CI 95% CI 1.14–1.48; for subjects aged >60 years, OR 1.01, 95% CI
1.39–1.66), increased CIMT (OR 1.58, 95% CI 1.45–1.73), carotid 0.88–1.15). Although predominantly non‐significant, the same trend
plaques (OR 1.24, 95% CI 1.13–1.36) and stenosis (OR 1.92, 95% CI was observed for the association of carotid plaques and stenosis with
1.25–2.96) were all statistically significant in female with MUO than age. Interaction analysis revealed a significant interaction effect of
MHN status. However, no statistically significant differences in ca- age on these associations (p < 0.05), except for carotid stenosis
rotid plaques or stenosis were found between females and males (p < 0.139).
with MHO (Table 3 and Figure 3). The risk of CA was particularly high When participants aged ≥70 years were excluded, the risk of CA
in all metabolically unhealthy male and female participants (Table 3 for metabolically unhealthy participants was especially high (Table-
and Figure 3). Significant interactions between metabolic health‐ S2). The associations between MHO and CA were not materially
obesity phenotypes, sex, and the risk of CA were detected (Table- altered when further adjusted for SBP, DBP, and fasting plasma
3, all p < 0.05). glucose, although these relationships were relatively attenuated.
The analyses stratified by age are presented in Table S1. The Other sensitivity analyses, such as the exclusion of cases with a
associations between MHO and CA were significantly stronger in history of stroke, use of waist‐height ratio instead of WC, further
participants <60 years (OR 1.26, 95% CI 1.11–1.42) than in their adjustment for LDL‐C and lipoprotein‐lowering therapy, and using an
counterparts (OR 0.89, 95% CI 0.77–1.02). Similar associations were alternative definition excluding the WC criterion did not change the
observed for increased CIMT (for subjects aged ≤60 years, OR 1.30, results (Table S2).
HUANG ET AL.
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TABLE 2 Adjusted ORs for carotid atherosclerosis by BMI‐metabolic health status.
OR (95% CI)
Metabolic health‐obesity status Cases, No. (%) Model 1 Model 2 Model 3
Carotid atherosclerosis
Metabolically healthy Normal weight 7651/16,142(47.40) 1[reference] 1[reference] 1[reference]
Overweight 4160/9179(45.32) 0.92(0.87,0.97) 0.98(0.93,1.04) 0.98(0.93,1.04)
Obese 1088/2372(45.87) 0.94(0.86,1.03) 1.06(0.97,1.16) 1.10(1.02,1.21)
Metabolically unhealthy Normal weight 3790/6672(56.80) 1.46(1.38,1.55) 1.31(1.23,1.39) 1.27(1.19,1.35)
Overweight 5961/10,409(57.27) 1.49(1.42,1.56) 1.47(1.40,1.55) 1.41(1.33,1.48)
Obese 3400/6111(55.64) 1.39(1.31,1.48) 1.55(1.46,1.65) 1.54(1.44,1.64)
Increased carotid intima–media thickness
Overweight 3298/9179(35.93) 0.96(0.91,1.01) 1.02(0.96,1.08) 1.01(0.96,1.07)
Obese 884/2372(37.27) 1.02(0.93,1.11) 1.13(1.03,1.24) 1.18(1.07,1.29)
Overweight 4738/10,409(45.52) 1.43(1.36,1.50) 1.42(1.35,1.49) 1.36(1.29,1.43)
Obese 2755/6111(45.08) 1.40(1.32,1.49) 1.54(1.44,1.63) 1.53(1.44,1.63)
Carotid plaques
Overweight 3000/9179(32.68) 0.89(0.84,0.94) 0.96(0.91,1.02) 0.96(0.91,1.02)
Obese 744/2372(31.37) 0.84(0.76,0.92) 0.95(0.86,1.05) 0.97(0.88,1.07)
Overweight 4404/10,409(42.31) 1.35(1.28,1.42) 1.35(1.27,1.42) 1.28(1.22,1.36)
Obese 2347/6111(38.41) 1.14(1.08,1.22) 1.28(1.20,1.37) 1.25(1.17,1.33)
Carotid stenosis
Overweight 85/9179(0.92) 0.86(0.67,1.12) 0.95(0.73,1.24) 0.96(0.73,1.24)
Obese 18/2372(0.76) 0.71(0.43,1.15) 0.84(0.52,1.38) 0.86(0.53,1.41)
Overweight 134/10,409(1.29) 1.20(0.96,1.51) 1.27(1.01,1.60) 1.23(0.98,1.55)
Obese 66/6111(1.08) 1.01(0.76,1.34) 1.21(0.91,1.62) 1.19(0.89,1.59)
Note: Model 1 was not adjusted. Model 2 was adjusted for age and sex. Model 3 was adjusted for age, sex, alcohol consumption, smoking, education,
physical activity, medical history (stroke, diabetes, and hypertension, AF, TIA), family history (stroke, CHD, diabetes, and hypertension), taste
preferences (salty, oily), meat and vegetarian balance (balanced, unbalanced), fruit or vegetables intake (sufficient, insufficient).
Abbreviations: BMI, body mass index; CI, confidence interval.; OR, odds ratio.
3.3 | Transition of metabolic health status and converted to MUOO status, while 47.8% (n = 493) were uncon-
carotid atherosclerosis verted. According to the survey data, 29.76% of the 803 participants
who had MHOW at baseline switched to the MHOO phenotypes,
Next, we investigated whether CA risk was modified by changes in while 45.95% did not. Of the 228 participants with MHO, 46.05%
metabolic health status. The second survey characteristics of the converted to MUOO and 35.53% failed to convert (data not shown).
study population according to BMI‐metabolic health status are The majority of MUOO cases (70.7%, n = 1229) were unconverted
shown in Table S3, which are similar to the characteristics of the from the first to the second survey.
subjects at baseline (Table 1). In total, 9.2% (n = 119) of MHN in- As compared with participants in stable MHN status, MHOO
dividuals transitioned to a MHOW or obese (MHOO) phenotype individuals who transitioned to metabolically unhealthy phenotype
(Table 4). Among participants with MHOO, 33.4% (n = 344) were at an increased risk of CA (Figure 4, HR 1.21, 95% CI 1.02–
8 of 15
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F I G U R E 1 Adjusted ORs for carotid atherosclerosis by BMI‐metabolic health status. Values shown are the OR (95% CI) for (A) CA,
(B) Increased carotid intima–media thickness, (C) Carotid plaques, and (D) Carotid stenosis, by BMI‐metabolic health status. ORs were
adjusted for age, sex, alcohol consumption, smoking, education, physical activity, medical history (stroke, diabetes, and hypertension, AF, TIA),
family history (stroke, CHD, diabetes, and hypertension), taste preferences (salty, oily), meat and vegetarian balance (balanced, unbalanced),
and fruit or vegetable intake (sufficient, insufficient). The values above the squares indicate ORs and the values under the squares indicate the
number of cases in each category. The vertical lines indicate 95% CIs. BMI, body mass index; CI, confidence interval; OR, odd ratio; MHN,
metabolically healthy normal weight; MHO, metabolically healthy obesity; MHOW, metabolically healthy overweight; MUN, metabolically
unhealthy normal weight; MUO, metabolically unhealthy obesity; MUOW, metabolically unhealthy overweight; TIA, transient ischemic attack.
1.43). The cumulative incidence of CA for stable MUOO participants in participants who changed from MHOO to MUOO status than in-
was the highest among all groups (HR 1.32, 95% 1.17–1.48), similar dividuals with stable MHOO status (data not shown).
to that for increased CIMT (HR 1.27, 95% CI 1.12–1.46) and carotid
plaques or stenosis (HR 1.36, 95% CI 1.19–1.56). The risk of partic-
ipants who changed from MHN to MHOO status was not significant 4 | DISCUSSION
but substantially lower than that of the subjects who transferred
from MHOO to MUOO and who stayed in the MUOO status Our findings showed that metabolically healthy participants had a
(Figure 4). In contrast to people who consistently sustained MHO substantially lower risk of CA than participants with pre‐existing
status, those who shifted from MHO to MUOO status exhibited an metabolic disorders across all BMI groups. However, participants
adjusted Hazard Ratio (HR) for CA of 1.26 (95% CI 1.00–1.58) (data with MHO were at an increased risk of CA compared with those with
not shown). However, the risks for CA (HR 1.20, 95% CI 0.98–1.46), MHN (shown in Figure 5). Furthermore, metabolic health was tran-
increased CIMT (HR 1.20, 95% CI 0.96–1.50), and carotid plaques or sient in a large proportion of participants with obesity. The transition
stenosis (HR 1.15, 95% CI 0.92–1.46) were not statistically significant from MHO to metabolically unhealthy status increases the risk of CA
HUANG ET AL.
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F I G U R E 2 Dose‐response relationship between risk factors of metabolic health and carotid atherosclerosis among metabolically healthy
and unhealthy participants. The association between risk factors (blood pressure, waist circumference, fasting glucose) of metabolic health and
CA among metabolically healthy (A) and unhealthy (B) participants. The solid lines and shaded areas represent the ORs and corresponding 95%
CIs. The models were adjusted for age, sex, alcohol consumption, smoking, education, physical activity, medical history (stroke, diabetes, and
hypertension, AF, TIA), family history (stroke, CHD, diabetes, and hypertension), taste preferences (salty, oily), meat and vegetarian balance
(balanced, unbalanced), fruit or vegetables intake (sufficient, insufficient). CI, confidence interval; OR, odd ratio; TIA, transient ischemic attack.
*p < 0.05, significant nonlinear relationship.
in the community population. Our findings suggest that individuals a benign condition and has an unfavourable impact on CA progres-
with a metabolically healthy status may benefit from early manage- sion, especially in the early stages of CA. Consistent with previous
ment focusing on preventing progression to a metabolically un- findings,12,33 our results showed that obesity remains a risk factor
healthy status. independent of common metabolic disorders. In contrast to BMI,
The association with an increased risk of atherosclerosis is anthropometric indices representing abdominal obesity, such as WC
believed to be driven mainly by the coexistence of obesity and and the waist‐to‐height ratio, are directly associated with athero-
metabolic disorders.25–27 However, whether MHO is an innocuous sclerosis.34 When we used another definition that excluded the WC
low‐risk condition remains controversial. A prospective study based criterion for a high correlation with BMI to define metabolic health or
on 6220 Chinese adults showed that as compared with those in the when we used the waist‐to‐height ratio instead of BMI to define
metabolically healthy non‐obesity reference group, those with tran- obesity, the results were largely similar, suggesting that MHO is not a
sient MHO had an increased risk of composite subclinical athero- benign condition.
sclerosis.27 In contrast, a cross‐sectional study based on 980 Korean Most recently, MHO status was believed to be transient.35
men, the Cardiovascular and Metabolic Diseases Aetiology Research Approximately half of the initial participants with MHO converted
Centre Cohort based on 7824 community‐dwelling adults, and a to MUO within 20 years in the Whitehall cohort study.36 The rate
cross‐sectional study based on 3467 steelworkers in North China of transitioning from MHO to MUO over a follow‐up period of 4–
showed that the presence of CA was not associated with MHO 10 years was reported to vary between 30% and 60%.37 In the
subtypes.28–30 The remaining inconsistencies may be attributed to present study, we showed a transition rate of 33.4% in MHOW
the transient nature of the MHO phenotype, different criteria used to individuals or individuals with MUOO over 2 years. We calculated
define MHO, heterogeneity of study populations, and different stages the transition rate by combining overweight and obese subjects
of subclinical atherosclerosis. Furthermore, an array of studies con- with a small sample size. The proportion of overweight or obese
ducted over the years have consistently demonstrated an association subjects and metabolic health at baseline was relatively high in the
31,32
between obesity and low‐grade inflammation. A study examining present study (approximately 37%), which may explain the higher
the interplay between increased adiposity and inflammatory pro- conversion rates observed. Furthermore, our participants were
cesses, especially C‐reactive protein (CRP), concluded that circulating middle‐aged and elderly, and hence more vulnerable to metabolic
CRP may interact with the effects of body fat on mortality in coro- abnormalities than younger people. Correspondingly, we observed a
31
nary heart disease. Given the complex interactions among CRP, significantly higher risk of CA in participants with a change from
obesity and cardiovascular events, the metabolic perturbations MHOO to MUOO status. Therefore, individuals with obesity, even
observed in individuals with obesity may also be partly explained by those without metabolic disorders, should not be considered to
interindividual variability in the inflammatory profile associated with harbour a benign phenotype, but rather to exhibit an earlier stage
excess weight. Our findings from a relatively large cohort study of of metabolic unhealthy, which is also correlated with a high risk of
approximately 50,000 Chinese participants showed that MHO is not atherosclerosis.
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TABLE 3 Carotid atherosclerosis stratified by BMI‐metabolic health status and sex.
Metabolic health‐obesity status Male Female p for interaction

a a
Carotid atherosclerosis Case, NO (%) OR (95% CI) Case, NO (%) OR (95% CI) p < 0.001
MHN 3993(53.7) 1[reference] 3658(42.0) 1[reference]
MHOW 2533(49.2) 0.99(0.92,1.07) 1627(40.3) 0.96(0.89,1.05)
MHO 634(50.2) 1.15(1.01,1.31) 454(41.0) 0.99(0.86,1.13)
MUN 1326(58.2) 1.16(1.05,1.28) 2464(56.1) 1.30(1.20,1.41)
MUOW 2865(59.2) 1.40(1.30,1.52) 3096(55.6) 1.38(1.28,1.49)
MUO 1665(56.6) 1.49(1.36,1.63) 1735(54.7) 1.52(1.39,1.66)

a
Increased carotid intima–media thickness Case, NO (%) OR (95% CI) Case, NO (%) OR (95% CI)a p < 0.001
MHOW 2004(38.9) 1.00(0.93,1.08) 1294(32.1) 1.02(0.93,1.11)
MHO 516(40.8) 1.20(1.06,1.36) 368(33.2) 1.10(0.96,1.26)
MUN 1073(47.1) 1.18(1.07,1.30) 1889(43.0) 1.23(1.14,1.33)
MUOW 2326(48.0) 1.37(1.27,1.48) 2412(43.3) 1.34(1.24,1.44)
MUO 1342(45.6) 1.43(1.31,1.57) 1413(44.6) 1.58(1.45,1.73)

a
Carotid plaques Case, NO (%) OR (95% CI) Case, NO (%) OR (95% CI)a p < 0.001
MHOW 1863(36.2) 0.95(0.88,1.03) 1137(28.2) 0.95(0.87,1.04)
MHO 442(35.0) 1.01(0.88,1.15) 302(27.3) 0.89(0.77,1.04)
MUN 999(43.9) 1.08(0.97,1.19) 1856(42.2) 1.27(1.17,1.38)
MUOW 2153(44.5) 1.30(1.20,1.40) 2251(40.4) 1.27(1.17,1.37)
MUO 1166(39.7) 1.24(1.13,1.36) 1181(37.2) 1.24(1.13,1.36)

a
Carotid stenosis Case, NO (%) OR (95% CI) Case, NO (%) OR (95% CI)a p < 0.001
MHOW 61(1.2) 0.87(0.64,1.19) 24(0.6) 1.14(0.70,1.87)
MHO 10(0.8) 0.65(0.34,1.25) 8(0.7) 1.36(0.64,2.89)
MUN 50(2.2) 1.31(0.94,1.83) 62(1.4) 1.95(1.34,2.86)
MUOW 81(1.7) 1.17(0.88,1.56) 53(1.0) 1.42(0.96,2.10)
MUO 29(1.0) 0.82(0.54,1.24) 37(1.2) 1.92(1.25,2.96)
Note: Data are n or OR (95% CI).

Abbreviations: CI, confidence interval; MHN, metabolically healthy normal weight; MHO, metabolically healthy obesity; MHOW, metabolically healthy
overweight; MUN, metabolically unhealthy normal weight; MUO, metabolically unhealthy obesity; MUOW, metabolically unhealthy overweight.; OR,
odds ratio.
a
ORs adjusted for age, alcohol consumption, smoking, education, physical activity, medical history (stroke, diabetes, and hypertension, AF, TIA), family
history (stroke, CHD, diabetes, and hypertension), taste preferences (salty, oily), meat and vegetarian balance (balanced, unbalanced), and fruit or
vegetable intake (sufficient, insufficient).
Micha et al. estimated that almost half of the cardiometabolic reduce atherosclerosis risk in individuals with obesity. Recently, the
deaths were attributable to suboptimal diets, such as diets high in joint association of fitness, especially cardiorespiratory fitness (CRF)
sodium, processed meats, and sugar‐sweetened beverages but low in and PA, with the characterisation and prognosis of the MHO
vegetables and fruits.38 Our findings also showed that participants phenotype,39 CVD,40 and other chronic diseases41 was determined.
with obesity had significantly lower levels of exercise, diets high in The MHO and MUO groups exhibited variations in PA and CRF.42
salt and oil, insufficient intake of fruits or vegetables per day, and This underscores the notion that incorporating assessments of both
unbalanced consumption of meat and vegetarian foods; thus, main- metabolic and CRF statuses in clinical settings could enhance the
taining healthy diets and promoting PA may be a practical method to precision of risk stratification in patients with.39 According to a meta‐
HUANG ET AL.
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F I G U R E 3 Adjusted ORs for carotid atherosclerosis by BMI‐metabolic health status and sex. Values shown are the OR (95% CI) for
(A) CA, (B) Increased carotid intima–media thickness, (C) Carotid plaques, and (D) Carotid stenosis, by BMI‐metabolic health status. ORs
were adjusted for age, sex, alcohol consumption, smoking, education, physical activity, medical history (stroke, diabetes, and hypertension,
AF, TIA), family history (stroke, CHD, diabetes, and hypertension), taste preferences (salty, oily), meat and vegetarian balance (balanced,
unbalanced), and fruit or vegetable intake (sufficient, insufficient). The values above the squares indicate ORs and the values under the
squares indicate the number of cases in each category. The vertical lines indicate 95% CIs. BMI, body mass index; CI, confidence interval;
OR, OR; MHN, metabolically healthy normal weight; MHO, metabolically healthy obesity; MHOW, metabolically healthy overweight; MUN,
metabolically unhealthy normal weight; MUO, metabolically unhealthy obesity; MUOW, metabolically unhealthy overweight; TIA, transient
ischemic attack.
T A B L E 4 Transition of obesity and

Metabolic health status at second resurvey, number of participants (%)
metabolic health status from baseline to Metabolic health
the second resurvey. status at baseline MHN MHOO MUN MUOO Total
MHN 902(68.33) 119(9.02) 232(17.58) 67(5.08) 1320(100)
MHOO 144(13.97) 493(47.82) 50(4.85) 344(33.37) 1031(100)
MUN 206(31.99) 40(6.21) 305(47.36) 93(14.44) 644(100)
MUOO 63(3.62) 320(18.42) 126(7.25) 1229(70.71) 1738(100)
Abbreviations: MHN, metabolically healthy normal weight; MHOO, metabolically healthy

overweight or obesity; MUN, metabolically unhealthy normal weight; MUOO, metabolically
unhealthy overweight or obesity.
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F I G U R E 4 Association of transition from metabolically healthy to unhealthy status with carotid atherosclerosis (HRs and 95% CI) in 4733
participants. Values shown are the HR (95% CI) for (A) CA, (B) Increased carotid intima–media thickness, (C) Carotid plaques or stenosis, by
the transition of BMI‐metabolic health status. HRs were adjusted for age, sex, alcohol consumption, smoking, education, physical activity,
medical history (stroke, diabetes, and hypertension, AF, TIA), family history (stroke, CHD, diabetes, and hypertension), taste preferences (salty,
oily), meat and vegetarian balance (balanced, unbalanced), and fruit or vegetable intake (sufficient, insufficient). The values above the squares
indicate HRs and the values under the squares indicate the number of cases in each category. CI, confidence interval; HR, hazard ratio; MHN,
metabolically healthy normal weight; MHOO, metabolically healthy overweight or obesity; MUOO, metabolically unhealthy overweight or
obesity; TIA, transient ischemic attack.
F I G U R E 5 Structured graphical abstract. Metabolically healthy obesity and its transition to metabolically unhealthy exhibits risk of carotid
atherosclerosis. BMI, body mass index; CI, confidence intervals; HR, hazard ratios; MHOO, metabolically healthy overweight or obesity; MHO,
metabolically healthy obesity; MUOO, metabolically unhealthy overweight or obesity; OR, odd ratio; TIA, transient ischemic attack.
analysis, individuals classified as both obese and physically unfit face more important as these are the key drivers of cardiometabolic dis-
a significantly heightened mortality risk, approximately triple of their eases and adverse outcomes in patients with overweight and
counterparts with normal weight and a high level of fitness. Although obesity.43 In our study, MHO individuals, even those with a markedly
increased BMI was linked to a greater risk of CVD mortality, main- lower risk of atherosclerosis than those with MUO, had a higher risk
taining a high level of fitness almost entirely mitigated this risk of atherosclerosis than (MHN and MHOW) individuals. In the future,
among those who were overweight or obese.40 Focusing on it will be of utmost importance to note the role of CRF and/or PA in
improving CRF, which is largely driven by PA and exercise, may be the prognosis of MHO and the progression of atherosclerosis.
HUANG ET AL.
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Sex‐related dimorphisms in CVDs and atherosclerosis were A U T H O R C O N T R I B U T I O NS

observed more than a decade ago.44 The Tromso Study showed that Qin Huang and Jian Xia designed the study and Qin Huang wrote the
plaque prevalence was greater among men than women in the ma- manuscript. Li Yin and XiaoJun Li contributed to the data curation.
jority of age groups, until the age of 75 years, where more women than Jian Xia and Li Yin critically revised it for important intellectual
men were observed to have CA.45 Consistent with previous findings, content. Jie Feng and Minping Wei performed the data analyses.
in our study, the prevalence rate of CA in the male group was higher Zeyu Liu, Qin Huang and Yunhai Liu contributed to the literature
than that in the female group around overall BMI‐metabolic health search and draft of the manuscript. Li Yin and Jian Xia supervised the
status. This sex difference may be related to a critical determinate of study. Jian Xia and Zunjing Liu are the guarantors of this work, have
body fat distribution and sex steroid oestrogen levels.46,47 However, full access to all the data in the study and take responsibility for the
we found that the association between BMI‐metabolic health status integrity of the data. All authors have read and approved the final
and CA was more prominent in women than in men under metaboli- manuscript.
cally unhealthy conditions. The Atherosclerosis Risk in Communities
study showed that metabolic disorders have higher levels of prog- A CK NO W L E D GE M E NT S
nostic significance for CVD in women than in men,48 a finding that is We acknowledge all researchers and participants of the China Stroke
consistent with the greater impact of the components of metabolic High‐risk Population Screening and Intervention Program. This study
syndrome in women than in men.49 Thus, careful identification of sex‐ was supported by National Key Research and Development Projects
specific risk factors is not a mere formality but a vital cornerstone of (Grant No 2022YFC3602400 and 2022YFC3602401), the Project
full comprehension of atherosclerosis and cardiometabolic diseases. Program of National Clinical Research Center for Geriatric Disorders
This study has some limitations. First, there is no universally (Xiangya Hospital, Grant No. 2020LNJJ16), the Provincial Key Plan
accepted definition of MHO; more than 30 definitions have been for Research and Development of Hunan (Grant No. 2020SK2067),
used in different studies.50 It was impossible to test every MHO and the National Natural Science Foundation of China (Grant No.
definition in this study, and some of the criteria used in the other 82271369).
analyses were not always relevant. However, we found consistent
results using the most common MHO definitions in our study and the CONFLICT OF INTEREST STATEMENT
waist‐to‐height ratio to replace BMI for defining obesity. Second, the All authors declare no competing interests.
transition effects of obesity from a metabolically healthy to an un-
healthy status could not be evaluated with a combination of over- D A T A A V A I LA B I L I T Y S T A T E M E N T
weight and obesity because of the short follow‐up period and The cohort data are not publicly available to researchers currently
relatively small sample size in the second survey. Thus, further large unless on reasonable request. For more information, please contact
prospective study is warranted to confirm our findings Third, this the corresponding author.
study may not be able to fully assess the relationship between carotid
plaques and stenosis and metabolic healthy obesity due to the small E T HI C S S T A T E M E N T
number of events, which may limit the interpretation of results for This study was based on the Stroke Screening and Prevention Project
certain subgroups. Finally, the majority of the participants in the in Hunan Province. Written informed consent was obtained from all
present study were relatively old (mean age 60.7 years) and mainly the participants.
Chinese. Definitions of overweight and obesity vary across ethnic
groups and countries. Asian populations exhibit distinct associations C O N S E N T F OR P U B L I C A T I O N
between BMI, percentage of body fat, and health risks compared with Not applicable.
European populations.51 Therefore, the findings of our study may not
necessarily be generalisable to Western and elderly populations. O R CI D
Jian Xia https://orcid.org/0000-0001-9154-131X
5 | CONCLUSION PE E R R E V I E W
The peer review history for this article is available at https://www.
In conclusion, we observed that obesity, even when maintained with webofscience.com/api/gateway/wos/peer-review/10.1002/dmrr.3766.
a metabolic health status, remains a risk factor for CA. However, the
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Metabolically healthy obesity, transition from metabolic

unhealthy status across all BMI categories. A large proportion of metabolically

2.3 | Definition of BMI categories and metabolic

TABLE 1 Baseline characteristics of the study population.

Normal weight Overweight Obese

Metabolically Metabolically Metabolically Metabolically Metabolically Metabolically

N 16,142 6672 9179 10,409 2372 6111

Female (n, %) 8704(53.9) 4395(65.9) 4033(43.9) 5567(53.5) 1108(46.7) 3171(51.9)

Age (years) 60.68(11.54) 63.37(10.56) 59.19(10.79) 61.51(10.32) 58.64(10.42) 59.62(10.18)

Exercise habits (n, %)

Regular exercise 10,153(62.9) 4091(61.3) 5860(63.8) 6419(61.7) 1422(59.9) 3780(61.9)

Lack of exercise 5989(37.1) 2581(38.7) 3319(36.2) 3990(38.3) 950(40.1) 2331(38.1)

High school or above 4777(29.6) 1691(25.3) 2849(31.0) 3105(29.8) 664(28.0) 1717(28.1)

Cigarette smoking (n, %)

Non‐smoker 11,649(72.2) 5301(79.5) 6421(70.0) 7476(71.8) 1669(70.4) 4427(72.4)

Past smoker 485(3.0) 180(2.7) 312(3.4) 339(3.3) 90(3.8) 259(4.2)

Current smoker 4008(24.8) 1191(17.9) 2446(26.6) 2594(24.9) 613(25.8) 1425(23.3)

Current drinking (n, %) 2911(18.0) 948(14.2) 2118(23.1) 2209(21.2) 541(22.8) 1457(23.8)

Taste preferences (n, %)

Salty 2536(15.7) 1165(17.5) 1629(17.7) 1994(19.2) 460(19.4) 1361(22.3)

Oily 2460(15.2) 1153(17.3) 1287(14.0) 1652(15.9) 335(14.1) 900(14.7)

Meat and vegetarian (n, %)

Balanced 1127(7.0) 459(6.9) 785(8.6) 916(8.8) 231(9.7) 672(11.0)

unbalanced 15,015(93.0) 6213(93.1) 8394(91.4) 9493(91.2) 2141(90.3) 5439(89.0)

Fruit or vegetables per day

Sufficient intake 9727(60.3) 4118(61.7) 5332(58.1) 6561(63.0) 1395(58.8) 3826(62.6)

Insufficient intake 6415(39.7) 2554(38.3) 3847(41.9) 3848(37.0) 977(41.2) 2285(37.4)

Medical history (n, %)

Diabetes 2808(17.4) 3324(49.8) 1347(14.7) 4644(44.6) 248(10.5) 2374(38.8)

Hypertension 6587(40.8) 4929(73.9) 4109(44.8) 7909(76.0) 1193(50.3) 4707(77.0)

Stroke 1105(6.8) 623(9.3) 664(7.2) 924(8.9) 90(3.8) 358(5.9)

TIA 233(1.4) 84(1.3) 138(1.5) 135(1.3) 23(1.0) 72(1.2)

AF 196(1.2) 82(1.2) 91(1.0) 124(1.2) 24(1.0) 75(1.2)

Family history (n, %)

Diabetes 1331(8.2) 784(11.8) 816(8.9) 1388(13.3) 241(10.2) 777(12.7)

Hypertension 3958(24.5) 1866(28.0) 2570(28.0) 3481(33.4) 670(28.2) 2154(35.2)

Stroke 2296(14.2) 1137(17.0) 1449(15.8) 1896(18.2) 345(14.5) 982(16.1)

Coronary heart disease 1625(10.1) 749(11.2) 974(10.6) 1336(12.8) 266(11.2) 856(14.0)

WC (cm) 78.00(6.68) 82.01(7.68) 83.75(6.83) 88.29(6.96) 88.38(9.63) 94.14(7.93)

FPG (mmol/L) 5.22(1.27) 6.15(1.53) 5.10(1.16) 5.99(1.52) 5.03(1.07) 5.87(1.46)

SBP (mmHg) 128.78(18.23) 138.73(17.45) 129.99(17.97) 138.66(17.83) 131.11(18.08) 138.76(18.02)

Normal weight Overweight Obese

Metabolically Metabolically Metabolically Metabolically Metabolically Metabolically

DBP (mmHg) 77.55(9.95) 81.37(10.12) 79.07(9.85) 82.76(10.33) 80.08(10.14) 83.76(10.54)

TC (mmol/L) 4.69(1.01) 4.73(1.03) 4.67(0.99) 4.73(1.00) 4.70(0.99) 4.70(0.97)

HDL‐C (mmol/L) 1.52(0.44) 1.23(0.40) 1.42(0.42) 1.20(0.36) 1.42(0.39) 1.18(0.35)

TG (mmol/L) 1.42(0.66) 2.14(0.82) 1.52(0.68) 2.16(0.82) 1.49(0.66) 2.12(0.81)

LDL‐C (mmol/L) 2.65(0.87) 2.67(0.92) 2.68(0.87) 2.66(0.89) 2.71(0.85) 2.63(0.88)

Antihypertensive therapy 2938(18.2) 2623(39.3) 2009(21.9) 4520(43.4) 620(26.1) 2857(46.8)

Lipoprotein‐lowing therapy 387(2.4) 649(9.7) 264(2.9) 934(9.0) 49(2.1) 571(9.3)

Hypoglycemic therapy (n, %) 1317(8.5) 1885(28.3) 698(7.6) 2558(24.6) 135(5.7) 1218(19.9)

No 8491(52.6) 2882(43.2) 5019(54.7) 4448(42.7) 1284(54.1) 2711(44.4)

Yes 7651(47.4) 3790(56.8) 4160(45.3) 5961(57.3) 1088(45.9) 3400(55.6)

Increased CIMT (n, %)

No 10,182(63.1) 3710(55.6) 5881(64.1) 5671(54.5) 1488(62.7) 3356(54.9)

Yes 5960(36.9) 2960(44.4) 3298(35.9) 4738(45.5) 884(37.3) 2755(45.1)

No 10,447(64.7) 3817(57.2) 6179(67.3) 6005(57.7) 1628(68.6) 3764(61.6)

Yes 5695(35.3) 2855(42.8) 3000(32.7) 4404(42.3) 744(31.4) 2347(38.4)