Abstract
Background:
Obesity and metabolic disorders frequently coexist, and both are established risk factors for cardiovascular disease (CVD). Although the phenotype of obesity without metabolic disorders, referred to as metabolically healthy obesity (MHO), is attracting clinical interest, the pathophysiological impact of MHO remains unclear.
Methods and Results:
Using the Japan Medical Data Center database, we studied 802,288 subjects aged ≥20 years without any metabolic disorders or a prior history of CVD. MHO, defined as obesity (body mass index ≥25 kg/m2) with no metabolic disorders, was observed in 9.8% of the study population. The subjects’ mean (±SD) age was 42.8±9.4 years and 44.7% were men. The mean follow-up period was 1,126±849 days. Multivariable Cox regression analysis showed that MHO alone did not significantly increase the risk of any CVD. However, abdominal obesity alone increased the risk of heart failure and atrial fibrillation. Moreover, the coexistence of MHO and abdominal obesity increased the risk of myocardial infarction, angina pectoris, heart failure, and atrial fibrillation. The incidence of stroke was not associated with the presence of MHO and abdominal obesity.
Conclusions:
Among individuals with no metabolic disorders, MHO alone did not significantly increase the subsequent CVD risk. However, individuals with comorbid MHO and abdominal obesity had a higher risk of myocardial infarction, angina pectoris, heart failure, and atrial fibrillation, suggesting the prognostic importance of abdominal obesity in subjects with MHO.
Obesity is known to be associated with metabolic abnormalities such as hypertension, dyslipidemia, and hyperglycemia, and is an established risk factor for cardiovascular disease (CVD).1–5
However, the clustering of concomitant metabolic abnormalities varies widely among the obese population. The subset of obese individuals without metabolic disorders is referred to as metabolically healthy obesity (MHO), and the pathophysiological significance of this condition is currently attracting clinical interest.6–8
However, the definition and diagnostic criteria of MHO have not yet been established in previous investigations,9
and so whether MHO is a benign phenotype remains unclear.10,11
Abdominal obesity is considered an indicator of visceral fat accumulation and may be a key factor linking obesity and various metabolic abnormalities with the development of subsequent CVD. To explore the pathophysiological features of MHO and its prognostic significance, we comprehensively analyzed a nationwide epidemiological database focusing on the role of abdominal obesity in the relationship between MHO and subsequent CVD events.
Methods
Study Design and Data Source
The present retrospective observational study analyzed data recorded between January 2005 and August 2018 in the health claims database of the Japan Medical Data Center (JMDC; Tokyo, Japan), which has >5 million individuals registered.12–14
The JMDC contracts with more than 60 insurers and includes data for health insurance claims on insured individuals who are mostly employees of relatively large Japanese companies.15
The JMDC database includes annual health checkup data regarding subjects’ medical history and the status of medications from questionnaires, laboratory data, and clinical follow-up data from claim records. The incidence of CVD, events such as myocardial infarction (MI), angina pectoris, stroke, heart failure, and atrial fibrillation, was evaluated using the International Classification of Disease, 10th Revision (ICD-10) diagnostic codes from the claim records.16
Ethics
This study was conducted according to the ethical guidelines of the Ethics Committee of The University of Tokyo (2018-10862) and the principles of the Declaration of Helsinki. The requirement for informed consent was waived because all data in the JMDC database were deidentified.
Definitions
MHO was defined as obesity with no metabolic disorders. Obesity was defined as a body mass index (BMI) ≥25 kg/m2. The metabolic disorders were defined as follows: high blood pressure was defined as systolic blood pressure >130 mmHg, diastolic blood pressure >85 mmHg, or the use of antihypertensive medications; hyperglycemia was defined as fasting plasma glucose ≥110 mg/dL or the use of insulin or oral antidiabetic medications; and dyslipidemia was defined as low-density lipoprotein cholesterol ≥140 mg/dL, high-density lipoprotein cholesterol <40 mg/dL, triglyceride ≥150 mg/dL, or the use of lipid-lowering medications according to the Japanese diagnostic criteria.8,17,18
Abdominal obesity was defined as a waist circumference (WC) ≥85 cm in men and ≥90 cm in women.17
Statistical Analysis
Categorical and continuous data for baseline characteristics are presented as numbers and percentages and as the mean±SD, respectively. Categorical and continuous variables were compared between groups using Chi-squared and 1-way analysis of variance, respectively. Multivariable Cox regression analysis was performed to determine the association of MHO and abdominal obesity with the subsequent incidence of CVD events. Using sensitivity analysis, we defined abdominal obesity as a WC ≥90 cm in men and ≥80 cm in women according to the International Diabetes Federation (IDF) criteria for Asians19
and conducted a multivariable Cox regression analysis. The P values for interactions between groups were calculated to assess whether the effect of abdominal obesity on CVD would differ with and without obesity. P<0.05 was considered statistically significant. All statistical analyses were performed using SPSS version 25 (SPSS Inc., Chicago, IL, USA) and STATA (StataCorp, College Station, TX, USA).
Results
Study Population
Among the 875,606 individuals without metabolic disorders enrolled in the JMDC database, those aged <20 years, those with a prior history of MI, angina pectoris, coronary revascularization, stroke, heart failure, atrial fibrillation, or hemodialysis, and those with missing BMI or WC data were excluded from the study. This left data for 802,288 individuals available for analysis in this study (see
Figure).
Characteristics of the Study Population
The characteristics of the study population at the time of enrolment are summarized in
Table 1. The subjects’ mean age was 42.8±9.4 years, and 358,659 (44.7%) were men. MHO was observed in 78,595 subjects (9.8%) and abdominal obesity was seen in 91,311 (11.4%). The study subjects were categorized into 4 groups: (1) those who were not obesity and did not have abdominal obesity (n=686,027; 85.5%); (2) those with abdominal obesity alone (n=37,666; 4.7%); (3) those with MHO alone (n=24,950; 3.1%); and (4) those with MHO and abdominal obesity (n=53,645; 6.7%).
Table 1.
Characteristics of the Study Population
| |
Missing
data (n) |
Metabolically healthy non-obesity |
Metabolically healthy obesity |
P value |
| Abdominal obesity |
Abdominal obesity |
Absent
(n=686,027) |
Present
(n=37,666) |
Absent
(n=24,950) |
Present
(n=53,645) |
| Age (years) |
0 |
42.5±9.5 |
46.1±9.4 |
42.4±8.7 |
43.7±9.0 |
<0.001 |
| Age group (years) |
| 20–29 |
0 |
67,493 (9.8) |
1,516 (4.0) |
2,161 (8.7) |
3,633 (6.8) |
|
| 30–39 |
0 |
146,161 (21.3) |
5,944 (15.8) |
5,055 (20.3) |
10,085 (18.8) |
|
| 40–49 |
0 |
324,756 (47.3) |
17,227 (45.7) |
13,220 (53.0) |
26,989 (50.3) |
|
| 50–59 |
0 |
116,009 (16.9) |
9,432 (25.0) |
3,747 (15.0) |
10,272 (19.1) |
|
| ≥60 |
0 |
31,608 (4.6) |
3,547 (9.4) |
767 (3.1) |
2,666 (5.0) |
|
| Male sex |
0 |
277,200 (40.4) |
34,744 (92.2) |
7,098 (28.4) |
39,617 (73.9) |
<0.001 |
| BMI (kg/m2) |
0 |
20.5±2.0 |
23.6±1.0 |
26.1±1.2 |
27.5±2.4 |
<0.001 |
| Obesity |
0 |
0 (0.0) |
0 (0.0) |
24,950 (100.0) |
53,645 (100.0) |
– |
| WC (cm) |
0 |
74.3±6.1 |
87.9±2.6 |
84.0±3.5 |
93.3±5.8 |
<0.001 |
| Abdominal obesity |
0 |
0 (0.0) |
37,666 (100.0) |
0 (0.0) |
53,645 (100.0) |
– |
| SBP (mmHg) |
0 |
109.1±10.7 |
114.7±9.1 |
113.6±9.6 |
116.4±8.6 |
<0.001 |
| DBP (mmHg) |
0 |
66.8±8.4 |
71.1±7.6 |
69.5±8.0 |
72.0±7.5 |
<0.001 |
| Cigarette smoking |
3,823 |
137,299 (20.1) |
12,253 (32.7) |
4,379 (17.7) |
15,634 (29.3) |
<0.001 |
| Alcohol drinking |
101,531 |
115,391 (19.2) |
11,001 (34.0) |
2,920 (13.4) |
10,086 (21.6) |
<0.001 |
| Laboratory data |
| Glucose (mg/dL) |
0 |
88.6±7.6 |
91.9±7.7 |
90.5±7.5 |
92.1±7.8 |
<0.001 |
| HbA1c (%) |
122,316 |
5.3±0.3 |
5.4±0.3 |
5.4±0.3 |
5.4±0.3 |
<0.001 |
| LDL-C (mg/dL) |
0 |
103.6±20.3 |
112.1±18.4 |
110.3±18.8 |
113.4±17.9 |
<0.001 |
| HDL-C (mg/dL) |
0 |
69.9±15.5 |
59.5±12.8 |
62.9±13.4 |
57.1±12.0 |
<0.001 |
| Triglycerides (mg/dL) |
0 |
66.7±26.0 |
88.5±28.8 |
77.1±28.4 |
89.0±28.9 |
<0.001 |
| ln[Triglycerides] |
0 |
4.1±0.4 |
4.4±0.4 |
4.3±0.4 |
4.4±0.3 |
<0.001 |
Data are expressed as the mean±SD or as n (%). BMI, body mass index; DBP, diastolic blood pressure; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; SBP, systolic blood pressure; WC, waist circumference.
During the mean follow-up period period of 1,126±849 days, MI, angina pectoris, stroke, heart failure, and atrial fibrillation developed in 588 (0.1%), 8,356 (1.0%), 3,357 (0.4%), 7,299 (0.9%), and 2,084 (0.3%) subjects, respectively.
Multivariable Cox regression analysis showed that individuals with MHO did not have a higher risk of MI, angina pectoris, stroke, heart failure, and atrial fibrillation than individuals with neither obesity nor abdominal obesity. However, abdominal obesity alone increased the risk of heart failure (hazard ratio [HR] 1.216, 95% confidence interval [CI] 1.097–1.348, P<0.001) and atrial fibrillation (HR 1.261, 95% CI 1.073–1.482, P=0.005). The coexistence of MHO and abdominal obesity increased the risk of MI (HR 1.496, 95% CI 1.131–1.978, P=0.005), angina pectoris (HR 1.180, 95% CI 1.082–1.287, P<0.001), heart failure (HR 1.342, 95% CI 1.225–1.470, P<0.001), and atrial fibrillation (HR 1.540, 95% CI 1.323–1.793, P<0.001). Meanwhile, the incidence of stroke was not associated with the presence of MHO and abdominal obesity (Table 2). The P values for interaction assessing differences in the association of abdominal obesity with CVD between the MHO and metabolically healthy non-obese groups were 0.889 for MI, 0.202 for angina pectoris, 0.501 for stroke, 0.042 for heart failure, and 0.938 for atrial fibrillation.
Table 2.
Multivariable Cox Regression Analysis
| |
HR (95% CI) |
P value |
| Myocardial infarction |
| Category |
| Non-Ob and Abd Ob(−) |
Reference |
|
| Non-Ob and Abd Ob(+) |
0.985 (0.698–1.390) |
0.932 |
| MHO and Abd Ob(−) |
1.454 (0.922–2.292) |
0.107 |
| MHO and Abd Ob(+) |
1.496 (1.131–1.978) |
0.005 |
| Age |
1.062 (1.051–1.073) |
<0.001 |
| Male sex |
1.449 (1.172–1.792) |
0.001 |
| SBP (per 10 mmHg) |
1.075 (0.985–1.174) |
0.107 |
| Glucose (per SD) |
0.997 (0.913–1.089) |
0.948 |
| LDL-C (per SD) |
1.022 (0.930–1.123) |
0.654 |
| HDL-C (per SD) |
0.985 (0.892–1.088) |
0.771 |
| Triglycerides (per SD) |
1.066 (0.972–1.170) |
0.174 |
| Cigarette smoking |
1.466 (1.206–1.783) |
<0.001 |
| Alcohol drinking |
1.054 (0.861–1.292) |
0.608 |
| Angina pectoris |
| Category |
| Non-Ob and Abd Ob(−) |
Reference |
|
| Non-Ob and Abd Ob(+) |
1.089 (0.987–1.201) |
0.090 |
| MHO and Abd Ob(−) |
1.008 (0.879–1.156) |
0.910 |
| MHO and Abd Ob(+) |
1.180 (1.082–1.287) |
<0.001 |
| Age |
1.047 (1.044–1.050) |
<0.001 |
| Male sex |
1.028 (0.973–1.087) |
0.326 |
| SBP (per 10 mmHg) |
1.048 (1.024–1.072) |
<0.001 |
| Glucose (per SD) |
1.034 (1.009–1.059) |
0.007 |
| LDL-C (per SD) |
0.995 (0.970–1.020) |
0.692 |
| HDL-C (per SD) |
0.988 (0.962–1.014) |
0.349 |
| Triglycerides (per SD) |
1.030 (1.004–1.057) |
0.024 |
| Cigarette smoking |
0.932 (0.878–0.990) |
0.021 |
| Alcohol drinking |
0.984 (0.928–1.043) |
0.591 |
| Stroke |
| Category |
| Non-Ob and Abd Ob(−) |
Reference |
|
| Non-Ob and Abd Ob(+) |
1.132 (0.975–1.313) |
0.103 |
| MHO and Abd Ob(−) |
0.855 (0.678–1.079) |
0.187 |
| MHO and Abd Ob(+) |
1.078 (0.936–1.243) |
0.298 |
| Age |
1.084 (1.079–1.089) |
<0.001 |
| Male sex |
0.839 (0.768–0.916) |
<0.001 |
| SBP (per 10 mmHg) |
1.097 (1.057–1.138) |
<0.001 |
| Glucose (per SD) |
0.984 (0.947–1.022) |
0.398 |
| LDL-C (per SD) |
1.002 (0.962–1.043) |
0.937 |
| HDL-C (per SD) |
0.963 (0.925–1.004) |
0.075 |
| Triglycerides (per SD) |
1.030 (0.989–1.072) |
0.156 |
| Cigarette smoking |
1.043 (0.950–1.145) |
0.376 |
| Alcohol drinking |
1.043 (0.953–1.142) |
0.360 |
| Heart failure |
| Category |
| Non-Ob and Abd Ob(−) |
Reference |
|
| Non-Ob and Abd Ob(+) |
1.216 (1.097–1.348) |
<0.001 |
| MHO and Abd Ob(−) |
1.147 (0.996–1.320) |
0.056 |
| MHO and Abd Ob(+) |
1.342 (1.225–1.470) |
<0.001 |
| Age |
1.057 (1.054–1.060) |
<0.001 |
| Male sex |
0.971 (0.915–1.030) |
0.333 |
| SBP (per 10 mmHg) |
1.055 (1.029–1.081) |
<0.001 |
| Glucose (per SD) |
1.005 (0.979–1.031) |
0.715 |
| LDL-C (per SD) |
0.948 (0.923–0.973) |
<0.001 |
| HDL-C (per SD) |
0.988 (0.961–1.016) |
0.384 |
| Triglycerides (per SD) |
1.003 (0.975–1.031) |
0.846 |
| Cigarette smoking |
0.926 (0.868–0.987) |
0.018 |
| Alcohol drinking |
1.018 (0.957–1.083) |
0.574 |
| Atrial fibrillation |
| Category |
| Non-Ob and Abd Ob(−) |
Reference |
|
| Non-Ob and Abd Ob(+) |
1.261 (1.073–1.482) |
0.005 |
| MHO and Abd Ob(−) |
0.944 (0.680–1.312) |
0.732 |
| MHO and Abd Ob(+) |
1.540 (1.323–1.793) |
<0.001 |
| Age |
1.084 (1.078–1.090) |
<0.001 |
| Male sex |
2.514 (2.231–2.833) |
<0.001 |
| SBP (per 10 mmHg) |
1.024 (0.977–1.075) |
0.321 |
| Glucose (per SD) |
1.052 (1.003–1.104) |
0.037 |
| LDL-C (per SD) |
0.877 (0.835–0.922) |
<0.001 |
| HDL-C (per SD) |
1.024 (0.972–1.078) |
0.378 |
| Triglycerides (per SD) |
0.993 (0.944–1.045) |
0.785 |
| Cigarette smoking |
0.838 (0.750–0.937) |
0.002 |
| Alcohol drinking |
1.147 (1.032–1.275) |
0.011 |
Abd Ob, abdominal obesity; CI, confidence interval; HDL-C, high-density lipoprotein cholesterol; HR, hazard ratio; MHO, metabolically healthy obesity; Ob, obesity; SBP, systolic blood pressure, LDL-C, low-density lipoprotein cholesterol; SD, standard deviation.
The results of the sensitivity analysis based on the IDF criteria for Asians are given in
Table 3. Similar to the results in
Table 2, the coexistence of MHO and abdominal obesity increased the risk of MI (HR 1.457, 95% CI 1.079–1.966, P=0.014), angina pectoris (HR 1.175, 95% CI 1.077–1.284, P<0.001), heart failure (HR 1.353, 95% CI 1.236–1.481, P<0.001), and atrial fibrillation (HR 1.506, 95% CI 1.275–1.779, P<0.001) compared with individuals with neither MHO nor abdominal obesity. Abdominal obesity alone increased the risk of angina pectoris (HR 1.100, 95% CI 1.015–1.191, P=0.020) and atrial fibrillation (HR 1.225, 95% CI 1.013–1.482, P=0.036). MHO alone increased the risk of MI (HR 1.579, 95% CI 1.091–2.285, P=0.016). The incidence of stroke was not associated with the presence of MHO and abdominal obesity.
Table 3.
Multivariable Cox Regression Analysis According to the International Diabetes Federation Criteria for Asian Populations
| |
HR (95% CI) |
P value |
| Myocardial infarction |
| Category |
| Non-Ob and Abd Ob(−) |
Reference |
|
| Non-Ob and Abd Ob(+) |
1.083 (0.775–1.512) |
0.641 |
| MHO and Abd Ob(−) |
1.579 (1.091–2.285) |
0.016 |
| MHO and Abd Ob(+) |
1.457 (1.079–1.966) |
0.014 |
| Age |
1.062 (1.051–1.073) |
<0.001 |
| Male sex |
1.465 (1.173–1.829) |
0.001 |
| SBP (per 10 mmHg) |
1.074 (0.983–1.172) |
0.113 |
| Glucose (per SD) |
0.997 (0.913–1.088) |
0.940 |
| LDL-C (per SD) |
1.021 (0.929–1.122) |
0.668 |
| HDL-C (per SD) |
0.987 (0.894–1.090) |
0.798 |
| Triglycerides (per SD) |
1.065 (0.971–1.169) |
0.179 |
| Cigarette smoking |
1.468 (1.207–1.785) |
<0.001 |
| Alcohol drinking |
1.054 (0.860–1.291) |
0.614 |
| Angina pectoris |
| Category |
| Non-Ob and Abd Ob(−) |
Reference |
|
| Non-Ob and Abd Ob(+) |
1.100 (1.015–1.191) |
0.020 |
| MHO and Abd Ob(−) |
1.038 (0.912–1.181) |
0.575 |
| MHO and Abd Ob(+) |
1.175 (1.077–1.284) |
<0.001 |
| Age |
1.047 (1.044–1.050) |
<0.001 |
| Male sex |
1.068 (1.009–1.131) |
0.024 |
| SBP (per 10 mmHg) |
1.046 (1.022–1.070) |
<0.001 |
| Glucose (per SD) |
1.033 (1.008–1.058) |
0.008 |
| LDL-C (per SD) |
0.994 (0.970–1.020) |
0.656 |
| HDL-C (per SD) |
0.989 (0.963–1.015) |
0.405 |
| Triglycerides (per SD) |
1.030 (1.004–1.057) |
0.024 |
| Cigarette smoking |
0.932 (0.878–0.989) |
0.020 |
| Alcohol drinking |
0.985 (0.929–1.044) |
0.610 |
| Stroke |
| Category |
| Non-Ob and Abd Ob(−) |
Reference |
|
| Non-Ob and Abd Ob(+) |
1.031 (0.912–1.166) |
0.627 |
| MHO and Abd Ob(−) |
1.022 (0.829–1.260) |
0.837 |
| MHO and Abd Ob(+) |
0.992 (0.857–1.148) |
0.909 |
| Age |
1.084 (0.857–1.148) |
<0.001 |
| Male sex |
0.859 (0.784–0.941) |
0.001 |
| SBP (per 10 mmHg) |
1.098 (1.058–1.139) |
<0.001 |
| Glucose (per SD) |
0.985 (0.948–1.023) |
0.425 |
| LDL-C (per SD) |
1.002 (0.963–1.043) |
0.914 |
| HDL-C (per SD) |
0.961 (0.923–1.002) |
0.060 |
| Triglycerides (per SD) |
1.032 (0.991–1.075) |
0.128 |
| Cigarette smoking |
1.042 (0.949–1.143) |
0.390 |
| Alcohol drinking |
1.045 (0.955–1.144) |
0.334 |
| Heart failure |
| Category |
| Non-Ob and Abd Ob(−) |
Reference |
|
| Non-Ob and Abd Ob(+) |
1.070 (0.982–1.166) |
0.124 |
| MHO and Abd Ob(−) |
1.072 (0.932–1.234) |
0.332 |
| MHO and Abd Ob(+) |
1.353 (1.236–1.481) |
<0.001 |
| Age |
1.057 (1.054–1.060) |
<0.001 |
| Male sex |
1.019 (0.958–1.083) |
0.548 |
| SBP (per 10 mmHg) |
1.055 (1.029–1.081) |
<0.001 |
| Glucose (per SD) |
1.005 (0.979–1.031) |
0.717 |
| LDL-C (per SD) |
0.948 (0.923–0.974) |
<0.001 |
| HDL-C (per SD) |
0.986 (0.959–1.014) |
0.329 |
| Triglycerides (per SD) |
1.005 (0.977–1.033) |
0.749 |
| Cigarette smoking |
0.923 (0.866–0.985) |
0.015 |
| Alcohol drinking |
1.021 (0.960–1.087) |
0.506 |
| Atrial fibrillation |
| Category |
| Non-Ob and Abd Ob(−) |
Reference |
|
| Non-Ob and Abd Ob(+) |
1.225 (1.013–1.482) |
0.036 |
| MHO and Abd Ob(−) |
1.185 (0.949–1.479) |
0.133 |
| MHO and Abd Ob(+) |
1.506 (1.275–1.779) |
<0.001 |
| Age |
1.084 (1.078–1.090) |
<0.001 |
| Male sex |
2.737 (2.415–3.103) |
<0.001 |
| SBP (per 10 mmHg) |
1.024 (0.976–1.074) |
0.332 |
| Glucose (per SD) |
1.053 (1.004–1.104) |
0.035 |
| LDL-C (per SD) |
0.878 (0.835–0.923) |
<0.001 |
| HDL-C (per SD) |
1.021 (0.969–1.075) |
0.437 |
| Triglycerides (per SD) |
0.996 (0.947–1.048) |
0.877 |
| Cigarette smoking |
0.835 (0.747–0.934) |
0.002 |
| Alcohol drinking |
1.153 (1.038–1.281) |
0.008 |
Abbreviations as in Table 2.
Discussion
The prevalence of obesity has become increasingly widespread worldwide over the past several decades,20
and obesity-associated metabolic disorders and CVD are major healthcare issues.21–23
In contrast, many obese individuals maintain a metabolically normal status, and this phenotype is known as MHO. We previously studied subjects undergoing voluntary health checkups and found that approximately half the obese individuals did not have metabolic syndrome.8
Therefore, MHO is not a rare condition.
Various studies have investigated the relationship between MHO, metabolic disorders, and CVD. An analysis of 3.5 million adults in the UK showed that obese individuals with no metabolic abnormalities had a higher risk of coronary artery disease, cerebrovascular disease, and heart failure.24
Several meta-analyses also reported the association of MHO with the subsequent risk of CVD events.25–27
However, the relationship between MHO and clinical outcomes is known to vary depending on the definition of MHO used.11
To eliminate the effects of any metabolic disorders as much as possible, we strictly defined MHO as obesity (BMI ≥25 kg/m2) with no metabolic disorders. In this model, the multivariable Cox regression analysis showed that there was no significant difference in the incidence of MI, angina pectoris, stroke, heart failure, and atrial fibrillation between non-obese individuals and individuals with MHO alone. This may suggest that MHO alone may not increase the risk of CVD events if metabolic disorders do not coexist. This result is in line with previous studies showing that the prognostic impact of obesity on CVD risk was attenuated in subjects without metabolic disorders.28,29
In contrast, even after adjusting for covariates, the coexistence of abdominal obesity increased the risk of MI, angina pectoris, heart failure, and atrial fibrillation in obese individuals. Considering the P values for interaction, the effects of abdominal obesity on CVD could differ between those with and without MHO for heart failure, but may not differ between those with and without MHO for other CVDs, including MI, angina pectoris, stroke, and atrial fibrillation.
This study has clinical implications because the results could provide information regarding risk stratification for subsequent CVD and primary CVD prevention among subjects with MHO. The results of this study indicate that if obese individuals have neither metabolic disorders nor abdominal obesity, we may consider them a healthy phenotype and their condition as benign. However, once individuals develop abdominal obesity, they should be considered at a high risk of future CVD, even without any coexisting metabolic disorders. Considering that visceral fat accumulation is a known major risk factor for obesity,30,31
the results of the present study are pathologically reasonable. It should also be noted that abdominal obesity alone was associated with a higher incidence of heart failure and atrial fibrillation, even in non-obese individuals with no metabolic disorders. Overall, abdominal obesity may have a fundamental role in initiating a malignant cycle leading to the development of subsequent CVD events among metabolically healthy individuals regardless of obesity. In addition, further investigations are needed to identify the interaction between MHO, abdominal obesity, and the incidence CVD for secondary prevention.
Further, the diagnostic criteria for abdominal obesity should be reconsidered. In this study, we defined abdominal obesity as WC ≥85 cm in men and ≥90 cm in women according to the Japanese criteria.17
Although the main results did not change, the effects of obesity and abdominal obesity alone were slightly altered in the sensitivity analysis using the IDF criteria for Asians.19
The results using the IDF criteria for Asians for abdominal obesity (WC ≥90 cm in men, ≥80 cm in women) showed that MHO alone could increase the risk of MI, and that abdominal obesity alone could elevate the risk of angina pectoris and atrial fibrillation. These results may suggest the need for further investigations to identify the optimal cut-off values of WC for abdominal obesity from the perspective of the primary prevention of CVD in MHO.
We acknowledge this study has several limitations. First, the data from the JMDC database were mainly obtained from an employed, working-age population. Thus, a “healthy worker” bias should be recognized. Moreover, the entire study population was “metabolically healthy”, and therefore the number of CVD events was relatively small. Consequently, the results of the multivariable Cox regression analyses failed to confirm the association between several established risk factors and incident CVD, such as the association between low-density lipoprotein cholesterol and MI, and that between cigarette smoking and angina pectoris. Second, because we performed multivariable Cox regression analysis, there could be unmeasured confounders and residual bias. Third, the median follow-up period was relatively short to enable us to determine the association of MHO with subsequent CVD. Fan et al reported that compared with healthy normal-weight individuals, individuals with MHO had an elevated risk of subsequent CVD events, which appeared stronger over the course of the long-term observation period of >15 years.26
Therefore, further studies with a longer observation period are required to confirm our results. We have no data on the transition from MHO to metabolically unhealthy obesity, which could affect the results.7
Finally, data on CVD deaths were not available, and therefore we could not assess cardiovascular mortality.
Conclusions
Our comprehensive analysis of a nationwide epidemiological database showed that individuals with MHO alone had a comparable risk of subsequent CVD risk with that of non-obese individuals. Abdominal obesity alone was associated with an increased risk of heart failure and atrial fibrillation. Furthermore, the coexistence of MHO and abdominal obesity increased the subsequent incidence of MI, angina pectoris, heart failure, and atrial fibrillation. The results suggest that MHO alone could be a benign condition, whereas abdominal obesity increases the risk of CVD even in those with metabolically healthy conditions, regardless of obesity. We believe that the results of this study provide valuable information for the risk stratification of subsequent CVD events in individuals with MHO.
Sources of Funding
This work was supported by grants from the Ministry of Health, Labour and Welfare, Japan (19AA2007 and H30-Policy-Designated-004) and the Ministry of Education, Culture, Sports, Science and Technology, Japan (17H04141).
Disclosures
H. Kaneko and K.F. have received research funding and scholarship funds from Medtronic Japan CO., LTD, Abbott Medical Japan CO., LTD, Boston Scientific Japan CO., LTD, and Fukuda Denshi, Central Tokyo CO., LTD. I.K. and H.M. are members of
Circulation Journal’ Editorial Team. The remaining authors have no conflicts of interest to declare.
IRB Information
This study was approved by the Clinical Research Review Board of The University of Tokyo (Reference no. 2018-10862).
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