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Transition from metabolically healthy to unhealthy overweight/obesity and risk of cardiovascular disease incidence: A systematic review and meta-analysis

      Highlights

      • Transition from metabolically healthy to unhealthy state throughout follow-up elevated the risk of cardiovascular disease in both male and female.
      • The association between metabolically healthy obesity and incidence of cardiovascular events was observed especially with longer follow up period.
      • The findings propose the importance of monitoring metabolic health, regardless of body weight, when recommending strategies for preventing cardiovascular disease risks.

      Abstract

      Aims

      Discrepant results have been demonstrated regarding the cardiovascular (CV) risk of populations with metabolically healthy overweight/obesity (MHO) who were transitioned into metabolically unhealthy states. So, the objective of this systematic review and meta-analysis was to estimate the risk of cardiovascular diseases (CVD) incidence in individuals with transitional MHO phenotype.

      Data synthesis

      A literature review was done in PubMed, Scopus, EMBASE, and google scholar databases. Pooled HRs for all fatal and nonfatal CV events were computed using random-effect models for transitional MHOs in general as well as for each sex subgroup separately.
      This systematic review and meta-analysis included a total of 7 prospective observational studies with a total of 7,720,165 participants, published between 2018 and 2020. The mean follow-up duration of participants was 11.7 (5.5) years. Overall, the transitional MHO individuals had a significant risk of CVD incidence [HR = 1.42, 95% CI (1.24–1.60)]. In addition, in both male and female subgroups, unstable MHO phenotype demonstrated a significant CVD risk and HRs for incident CVD in males and females were 1.51 (1.07–1.96) and 1.71 (1.08–2.34), respectively.

      Conclusion

      Transition from MHO to unhealthy state throughout follow-up elevated the risk of CVD in both male and female groups. This can explain the association between MHO and incidence of CV events especially with longer follow up period.

      Registration code in prospero

      CRD42021270225.

      Keywords

      1. Introduction

      The prevalence of obesity worldwide has reached epidemic levels, contributing greatly to the burden of diseases [
      • Haslam D.W.
      • James W.P.
      Obesity.
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      • World Health Organization Global Health Observatory Data
      Risk factors.
      ,
      • Ng M.
      • Fleming T.
      • Robinson M.
      • et al.
      Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013.
      ]. The link between obesity and metabolic abnormalities and chronic diseases is well understood. Obesity-related metabolic disorders, including hyperglycaemia, dyslipidemia, or hypertension, contribute to an elevated risk of cardiovascular diseases (CVDs) [
      • Yusuf S.
      • Hawken S.
      • Ounpuu S.
      • et al.
      Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study.
      ]. Furthermore, novel data indicate that obesity and impaired metabolic health are important risk factors for severe coronavirus disease 2019 (COVID-19) [
      • Stefan N.
      • Birkenfeld A.L.
      • Schulze M.B.
      Global pandemics interconnected - obesity, impaired metabolic health and COVID-19.
      ,
      • Stefan N.
      Metabolic disorders, COVID-19 and vaccine-breakthrough infections.
      ].
      Various obesity phenotypes result from different distributions of metabolic risk factors across body mass index (BMI) spectrum. Metabolically healthy overweight/obesity (MHO) is a subgroup of people that does not co-occur with obesity-related metabolic abnormalities; however, a standard definition has not been developed [
      • Hosseinpanah F.
      • Barzin M.
      • Sheikholeslami F.
      • Azizi F.
      Effect of different obesity phenotypes on cardiovascular events in Tehran Lipid and Glucose Study (TLGS).
      ,
      • Bobbioni-Harsch E.
      • Pataky Z.
      • Makoundou V.
      • Laville M.
      • Disse E.
      • Anderwald C.
      • et al.
      From metabolic normality to cardiometabolic risk factors in subjects with obesity.
      ]. Thus, a more rigorous and universally accepted definition of MHO is required to determine true prevalence and long-term consequences of MHO, as well as to investigate the mechanisms that contribute to some people with obesity being protected from the adverse metabolic effects caused by excess body fat [
      • Smith G.I.
      • Mittendorfer B.
      • Klein S.
      Metabolically healthy obesity: facts and fantasies.
      ]. Such a definition of metabolic health might include the absence of any cardiometabolic disease, having a healthy cardiometabolic profile, and lack of insulin resistance and fatty liver. Moreover, measurement of body fat mass could be an important predictor of cardiometabolic diseases [
      • Stefan N.
      Causes, consequences, and treatment of metabolically unhealthy fat distribution.
      ].
      Compared to individuals with the metabolic consequences of obesity known as metabolically unhealthy overweight/obesity (MUHO), MHO patients have a relatively favourable metabolic profile [
      • Mongraw-Chaffin M.
      • Foster M.C.
      • Anderson C.A.M.
      • Burke G.L.
      • Haq N.
      • Kalyani R.R.
      • Ouyang P.
      • Sibley C.T.
      • Tracy R.
      • Woodward M.
      • Vaidya D.
      Metabolically healthy obesity, transition to metabolic syndrome, and cardiovascular risk.
      ]. The mechanisms responsible for the divergent impacts of obesity on metabolic health are unclear, but rodent models indicate that differences in adipose tissue biology during or after weight gain can cause or prevent systemic metabolic dysfunction [
      • Smith G.I.
      • Mittendorfer B.
      • Klein S.
      Metabolically healthy obesity: facts and fantasies.
      ].
      A large number of prospective studies have shown inconsistent results in relation to increased risk of cardiovascular (CV) events and mortality in patients with MHO phenotype [
      • Appleton S.L.
      • Seaborn C.J.
      • Visvanathan R.
      • Hill C.L.
      • Gill T.K.
      • Taylor A.W.
      • et al.
      Diabetes and cardiovascular disease outcomes in the metabolically healthy obese phenotype: a cohort study.
      ,
      • Ortega F.B.
      • Lee D.-C.
      • Katzmarzyk P.T.
      • Ruiz J.R.
      • Sui X.
      • Church T.S.
      • et al.
      The intriguing metabolically healthy but obese phenotype: cardiovascular prognosis and role of fitness.
      ,
      • Zheng R.
      • Zhou D.
      • Zhu Y.
      The long-term prognosis of cardiovascular disease and all-cause mortality for metabolically healthy obesity: a systematic review and meta-analysis.
      ,
      • Roberson L.L.
      • Aneni E.C.
      • Maziak W.
      • Agatston A.
      • Feldman T.
      • Rouseff M.
      • et al.
      Beyond BMI: the “Metabolically healthy obese” phenotype & its association with clinical/subclinical cardiovascular disease and all-cause mortality—a systematic review.
      ,
      • Bell J.A.
      • Hamer M.
      • Sabia S.
      • Singh-Manoux A.
      • Batty G.D.
      • Kivimaki M.
      The natural course of healthy obesity over 20 years.
      ]. Variable follow-up lengths appear to contribute to this discrepancy, since a previous meta-analysis reported that MHO individuals had increased risk for CV events compared with metabolically healthy normal-weight (MHNW) individuals when only studies with 10 or more years of follow-up were considered [
      • Kramer C.K.
      • Zinman B.
      • Retnakaran R.
      Are metabolically healthy overweight and obesity benign conditions?: a systematic review and meta-analysis.
      ]. In fact, about half of the participants lost their metabolic health over the 10 years taken to follow them up, so it can be considered a dynamic or transient phenotype [
      • Appleton S.L.
      • Seaborn C.J.
      • Visvanathan R.
      • Hill C.L.
      • Gill T.K.
      • Taylor A.W.
      • et al.
      Diabetes and cardiovascular disease outcomes in the metabolically healthy obese phenotype: a cohort study.
      ,
      • Eshtiaghi R.
      • Keihani S.
      • Hosseinpanah F.
      • Barzin M.
      • Azizi F.
      Natural course of metabolically healthy abdominal obese adults after 10 years of follow-up: the Tehran Lipid and Glucose Study.
      ]. The dynamic characteristic of MHO may contribute to its heterogeneity from transitional to persistent subgroups of this phenotype. Hence, long-term studies are more likely to detect transitional MHO subgroups [
      • Appleton S.L.
      • Seaborn C.J.
      • Visvanathan R.
      • Hill C.L.
      • Gill T.K.
      • Taylor A.W.
      • et al.
      Diabetes and cardiovascular disease outcomes in the metabolically healthy obese phenotype: a cohort study.
      ,
      • Kramer C.K.
      • Zinman B.
      • Retnakaran R.
      Are metabolically healthy overweight and obesity benign conditions?: a systematic review and meta-analysis.
      ]. Additionally, in a recent study by Zembic et al. [
      • Zembic A.
      • Eckel N.
      • Stefan N.
      • Baudry J.
      • Schulze M.B.
      An empirically derived definition of metabolically healthy obesity based on risk of cardiovascular and total mortality.
      ], a new, empirically derived definition of MHO, based on risk of cardiovascular and total mortality in the two large cohort studies (NHANES-III and UK Biobank), it was revealed that MHO, diagnosed by this new definition, was not associated with an increased risk of CVD and total mortality, compared with metabolically healthy normal weight people.
      Specifically, few studies have conducted to evaluate the risk of CVDs incidence in individuals with transitional MHO phenotype, and the estimates they report are inconsistent. So, there is an urgent need to evaluate documents systematically to determine more precise estimates of the association between the MHO condition and prognosis for patients. Hence, we conducted a meta-analysis to examine the link between the transition from MHO to MUHO and CVD incidence.

      2. Methods

      2.1 Search strategy

      We reviewed the literature in PubMed, Scopus, EMBASE, and google scholar databases, until October 2021, with no restrictions on language and date. The keywords used for the search were: “body mass index”, “overweight”, “obesity”, “metabolically”, “healthy”, “metabolic syndrome”, “transition”, “cardiovascular disease”, “cardiovascular events”, CVD”, “risk”. In order to find further research, a bibliographic analysis of relevant papers was also carried manually. All included articles were published in English. The process of study selection is presented in Fig. 1. The systematic review was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISM) Statement [
      • Page M.J.
      • McKenzie J.E.
      • Bossuyt P.M.
      • Boutron I.
      • Hoffmann T.C.
      • Mulrow C.D.
      • et al.
      The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.
      ]. Code of registration of the systematic review and meta-analysis protocols in PROSPERO is CRD42021270225.
      Figure 1
      Figure 1PRISMA flow diagram for selection process of the studies.

      2.2 Eligibility criteria

      Observational studies with prospective designs were eligible if they were conducted in adults at baseline; reported original prospective longitudinal data; assessed subjects based on 3 categories of BMI, defined as normal weight (BMI: 18–25 kg/m2), overweight (BMI: 25.0–30 kg/m2), and obesity (BMI ≥30 kg/m2); investigated subjects within these BMI categories based on metabolic condition (healthy/unhealthy); and fatal or non-fatal cardiovascular (CV) events, and baseline characteristics.
      Studies that were literature reviews, retrospective, cross-sectional, and case-control studies, animal or genetic variation studies, as well as studies that excluded participants who were not stratified into the mentioned subgroups, and studies without reporting CV events in the subgroups were excluded.

      2.3 Study selection

      Following the elimination of duplicates, titles and abstracts collected in the initial search were evaluated separately by two authors (BA and FH). Full-text articles were assessed by these two authors to be assured they matched the eligible inclusion and exclusion criteria. Any disagreements were reassessed by a third author.

      2.4 Data extraction and quality assessment

      We extracted information about the first author, year of publication, country, study design, the number and age of participants, follow-up duration, metabolically healthy/unhealthy definitions, outcomes, adjustment, and main findings of the studies. Adjusted estimates were extracted.
      The Newcastle–Ottawa Scale (NOS), a method for evaluating nonrandomized studies in systematic reviews and meta-analyses, was used [

      Wells GA, Shea B, O'Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa Hospital Research Institute. Accessed at www.ohri.ca/programs/clinical_epidemiology/oxford.asp on 2 December 2012.

      ]. Eight items are included in the NOS, separated into three aspects: selection, comparability, and exposure. Response options are offered in each item. The star system is used for evaluating study quality semi-quantitatively, with the highest quality studies being awarded a maximum of 1 star per item; the only exception is when assessing comparability, which is given 2 stars. Therefore, the NOS is a scale from 0 to 9 stars [
      • Stang A.
      Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses.
      ]. Details of data extraction and quality assessment are demonstrated in Table 1.
      Table 1Characteristics of the studies on the association between transition from healthy to unhealthy overweight/obesity and risk of cardiovascular disease incidence.
      First author (Reference No)Year of publication, countryNo of participants (sex)Age of participantsFollow-up durationDefinition of metabolically healthyOutcomeAdjustmentMain findingStudy quality (NOS)
      Hosseinpanah [
      • Hosseinpanah F.
      • Tasdighi E.
      • Barzin M.
      • Mahdavi M.
      • Ghanbarian A.
      • Valizadeh M.
      • Azizi F.
      The association between transition from metabolically healthy obesity to metabolic syndrome, and incidence of cardiovascular disease: tehran lipid and glucose study.
      ]
      2020, Iran6758 (2812 males and 3946 females)≥20 years (males: 43.5 ± 14.5; females: 42.3 ± 13.1 years)15.9 years (11.6–16.4)Metabolic health was defined using the JIS criteria as follows: FBS ≥100 mg/dl or 2-h blood glucose ≥140 mg/dl or drug treatment; fasting TGs ≥150 mg/dl or drug treatment; fasting HDL-C <50 mg/dl in women and <40 mg/dl in men or drug treatment; raised BP as SBP≥ 130 mmHg, DBP≥ 85 mmHg or drug treatment; WC ≥ 89/91 cm in men/women. Metabolically healthy state was recognized as having ≤2 of the JIS elements, and those with ≥3 criteria were metabolically unhealthy.CVD was defined as any CHD, stroke (a new neurological deficit that has lasted for 24 h), or CVD death (fatal CHD or fatal stroke).Age, physical activity, total cholesterol, education, smoking, family history CVDTransition from MHO to MUO status during follow-up elevated the CVD risk just in male individuals.6
      Guo [
      • Guo X.
      • Li Z.
      • Zhou Y.
      • Yu S.
      • Yang H.
      • Sun G.
      • Zheng L.
      • Afzal J.
      • Liu Y.
      • Sun Y.
      The effects of transitions in metabolic health and obesity status on incident cardiovascular disease: insights from a general Chinese population.
      ]
      2020, China7472 (3483 males and 3989 females)≥35 years4.66 yearsMetS was investigated by the following items: WC ≥ 85 cm for males and ≥80 cm for females, BP ≥ 130/85 mm Hg or current use of drugs, serum glucose ≥5.6 mmol/l or current use of drugs, serum TGs ≥1.7 mmol/l, and serum HDL-C<1.0 mmol/l for males and <1.3 mmol/l for females. Metabolically healthy status was defined as score <3 points, and those with ≥3 criteria were considered metabolically unhealthy.Incident CVD was defined as fatal and nonfatal stroke and CHD.Age, sex, ethnicity, smoking, current drinking, education, family income, exercise, amily history of CVD, eGFR, LDL, uric acid, statin use, aspirin use.Transition from metabolically healthy obesity to metabolically unhealthy obesity was associated with elevated cardiovascular disease risk compared with metabolically healthy non-obesity.4
      Lee [
      • Lee Y.B.
      • Kim D.H.
      • Kim S.M.
      • et al.
      Hospitalization for heart failure incidence according to the transition in metabolic health and obesity status: a nationwide population-based study.
      ]
      2020, Korea7148763 (4041534 males and 3107229 females)≥20 years4 yearsMetS was defined using the IDF criteria, using the cutoffs for abdominal obesity set by the Korean Society for the Study of Obesity (WC ≥ 90 cm for men and ≥85 cm for woman. Individuals without MetS were considered metabolically healthy, whereas those with MetS were considered metabolically unhealthy.Incidence of hHF was defined as the first hospitalization under a primary diagnosis of ICD-10 code I50.Age, sex, smoking history, alcohol consumption, regular exercise, eGFR, SBP, LDL, household income.Loss of metabolic health was significantly associated with an increased hazard of hHF. Even if metabolic health was maintained, persistent obesity remained as a risk factor for hHF.8
      Gao [
      • Gao M.
      • Lv J.
      • Yu C.
      • Guo Y.
      • Bian Z.
      • Yang R.
      • Du H.
      • Yang L.
      • Chen Y.
      • Li Z.
      • Zhang X.
      • Chen J.
      • Qi L.
      • Chen Z.
      • Huang T.
      • Li L.
      China Kadoorie Biobank (CKB) Collaborative Group. Metabolically healthy obesity, transition to unhealthy metabolic status, and vascular disease in Chinese adults: a cohort study.
      ]
      2020, China458246 (186964 males and 271282 females)50.9 (10.4) yearsMedian 10.0 yearsMetabolic health was defined based on a modified definition of the MetS, as described by the joint statement in 2009. Metabolic health was defined as meeting less than 2 of the following 4 criteria (elevated waist circumference, hypertension, elevated plasma glucose level, and dyslipidemia).CVD, including major vascular events, major coronary events, ischemic heart disease, and stroke.Study region, age, sex, Education, household income, marital status, smoking, alcohol use, intakes of red meat, fruits and vegetables, family history of heart attack or stroke, exercise.MHO individuals have elevated risks of major vascular events. Obesity remains a risk factor for CVD independent of major metabolic factors.7
      Kouvari [
      • Kouvari M.
      • Panagiotakos D.B.
      • Yannakoulia M.
      • Georgousopoulou E.
      • Critselis E.
      • Chrysohoou C.
      • Tousoulis D.
      • Pitsavos C.
      ATTICA Study Investigators
      Transition from metabolically benign to metabolically unhealthy obesity and 10-year cardiovascular disease incidence: the ATTICA cohort study.
      ]
      2019, Greece1890 (937 males and 953 females)>18 years10 yearsMetabolic status was defined using the criteria suggested by Lavie et al. In particular, healthy metabolic status was defined as absence of hypertension, dyslipidemia and glycemic abnormalities.A CVD event was defined as the development of acute myocardial infarction, or unstable angina, or other identified forms of ischemia, or heart failure of different types and chronic arrhythmias.Age, gender, life style, clinical and biochemical markersMHO status is a dynamic condition and weight management is needed to prevent the establishment of unhealthy cardiometabolic features.5
      Mongraw-Chaffin [
      • Mongraw-Chaffin M.
      • Foster M.C.
      • Anderson C.A.M.
      • Burke G.L.
      • Haq N.
      • Kalyani R.R.
      • Ouyang P.
      • Sibley C.T.
      • Tracy R.
      • Woodward M.
      • Vaidya D.
      Metabolically healthy obesity, transition to metabolic syndrome, and cardiovascular risk.
      ]
      2018, United States5005 (male and female)45–84 years12.2 yearsMetS was defined using the IDF criteria for MetS: ≥3 of the following components: TG ≥ 150 mg/dl, HDL <40 mg/dl in men and <50 mg/dl in women, SBP ≥130 mm Hg or DBP ≥85 mm Hg or BP medications, FBS ≥100 mg/dl or medications for diabetes, WC > 102 cm in men and >88 cm in women. Individuals with MetS were considered metabolically unhealthy, and those without MetS were considered metabolically healthy.Incident coronary heart disease (fatal and nonfatal), stroke (fatal and nonfatal), heart failure, combined cardiovascular disease (CVD; coronary heart disease, stroke, and heart failure)Age, sex, race/ethnicity, education, income, smoking, LDL cholesterol, statin useMHO is not a stable indicator of future risk for CVD. Weight loss and lifestyle management for CVD risk factors should be recommended to all individuals with obesity.6
      Eckel [
      • Eckel N.
      • Li Y.
      • Kuxhaus O.
      • Stefan N.
      • Hu F.B.
      • Schulze M.B.
      Transition from metabolic healthy to unhealthy phenotypes and association with cardiovascular disease risk across BMI categories in 90 257 women (the Nurses' Health Study): 30 year follow-up from a prospective cohort study.
      ]
      2018, USA90257 female nurses30–55 yearsMedian: 24 yearsMetabolic disorders including hypertension, diabetes, and hypercholesterolaemia for the definition of metabolic health.

      Individuals with none of these disorders were considered as metabolically healthy, whereas metabolically unhealthy individuals were defined as those showing at least one of these disorders.
      Fatal and non-fatal myocardial infarction and stroke as well as their combination as total cardiovascular disease.Age, race, educational degree, alcohol consumption, smoking status, post-menopausal status, post-menopausal hormone use, physical examinations for screening purposes, aspirin use, family history of myocardial infarction and diabetes, and physical activity.A large proportion of metabolically healthy women transitioned to an unhealthy phenotype over time across all BMI categories, which is related to an elevated cardiovascular disease risk.8
      Abbreviations: JIS, joint interim statement; BP, blood pressure; SBP, systolic blood pressure; DBP, diastolic blood pressure; FBS, fasting blood sugar; WC, waist circumference; CVD, cardiovascular disease; CHD, coronary heart disease; eGFR, glomerular filtration rate; MetS, metabolic syndrome; hHF, hospitalization for heart failure, IDF, international diabetes federation; ICD, international classification of diseases; NOS, Newcastle–Ottawa Scale.

      3. Statistical analysis

      Meta-analysis was done by STATA software (version 13.0; StataCorp, College Station, TX, USA).
      An overall HR was computed to assess the risk of all fatal and nonfatal CV events. The hazard for CVD among individuals with transitional MHO phenotype was determined. In the subgroup analysis, according to sex, the risk was estimated, as well.
      A random-effects model was used to compute pooled estimates of HR. To account for the measured variance between study inaccuracies, the likelihood approach was used with random effects [
      • Hardy R.J.
      • Thompson S.G.
      A likelihood approach to meta-analysis with random effects.
      ]. I2 testing was conducted to assess the magnitude of heterogeneity among studies. This percentage of heterogeneity between studies was derived using the I2 statistic. The I2 indicates the percent of total variation across studies, which is because of heterogeneity rather than sampling error. It ranges from 0% (no heterogeneity) to 100% (high heterogeneity), with 25, 50, and 75% representing low, moderate, and high heterogeneity, respectively [
      • Higgins J.P.
      • Thompson S.G.
      • Deeks J.J.
      • et al.
      Measuring inconsistency in meta-analyses.
      ]. Additionally, for more investigation of the effects of studies, the sensitivity analysis was conducted. Egger's linear regression test was used to determine whether there is publication bias.

      4. Results

      4.1 Characteristics of included studies

      Initially, 2511 studies were found in a systematic database search. Of which, after excluding 1201 duplicate articles, 1272 were removed after scanning the titles/abstracts since they were not relevant to the present systematic review and meta-analysis. Following carefully screening of 38 full texts, we also removed 31 more studies since they did not assess MHO transition as the exposure or CVD risk as the outcome, or were editorial, and reviews. Finally, seven prospective observational studies [
      • Eckel N.
      • Li Y.
      • Kuxhaus O.
      • Stefan N.
      • Hu F.B.
      • Schulze M.B.
      Transition from metabolic healthy to unhealthy phenotypes and association with cardiovascular disease risk across BMI categories in 90 257 women (the Nurses' Health Study): 30 year follow-up from a prospective cohort study.
      ,
      • Mongraw-Chaffin M.
      • Foster M.C.
      • Anderson C.A.M.
      • Burke G.L.
      • Haq N.
      • Kalyani R.R.
      • Ouyang P.
      • Sibley C.T.
      • Tracy R.
      • Woodward M.
      • Vaidya D.
      Metabolically healthy obesity, transition to metabolic syndrome, and cardiovascular risk.
      ,
      • Kouvari M.
      • Panagiotakos D.B.
      • Yannakoulia M.
      • Georgousopoulou E.
      • Critselis E.
      • Chrysohoou C.
      • Tousoulis D.
      • Pitsavos C.
      ATTICA Study Investigators
      Transition from metabolically benign to metabolically unhealthy obesity and 10-year cardiovascular disease incidence: the ATTICA cohort study.
      ,
      • Hosseinpanah F.
      • Tasdighi E.
      • Barzin M.
      • Mahdavi M.
      • Ghanbarian A.
      • Valizadeh M.
      • Azizi F.
      The association between transition from metabolically healthy obesity to metabolic syndrome, and incidence of cardiovascular disease: tehran lipid and glucose study.
      ,
      • Guo X.
      • Li Z.
      • Zhou Y.
      • Yu S.
      • Yang H.
      • Sun G.
      • Zheng L.
      • Afzal J.
      • Liu Y.
      • Sun Y.
      The effects of transitions in metabolic health and obesity status on incident cardiovascular disease: insights from a general Chinese population.
      ,
      • Lee Y.B.
      • Kim D.H.
      • Kim S.M.
      • et al.
      Hospitalization for heart failure incidence according to the transition in metabolic health and obesity status: a nationwide population-based study.
      ,
      • Gao M.
      • Lv J.
      • Yu C.
      • Guo Y.
      • Bian Z.
      • Yang R.
      • Du H.
      • Yang L.
      • Chen Y.
      • Li Z.
      • Zhang X.
      • Chen J.
      • Qi L.
      • Chen Z.
      • Huang T.
      • Li L.
      China Kadoorie Biobank (CKB) Collaborative Group. Metabolically healthy obesity, transition to unhealthy metabolic status, and vascular disease in Chinese adults: a cohort study.
      ] with a total of 7,720,165 participants, published between 2018 and 2020, were included in the systematic review and meta-analysis.
      The flow diagram of study selection is demonstrated in Fig. 1. There was geographical diversity among the populations studied in the meta-analysis (Iran, Greece, USA [two cohorts], China [two cohorts], and Korea); but ethnic composition was not explicitly mentioned in any of the studies.
      The sample size of the studies in pooled analysis ranged between 1860 and 7,148,763 subjects and the total number of participants included in the meta-analysis was 7,720,165. The mean follow-up duration of participants was 11.7 (5.5) years. All included studies included both overweight and obese population except Mongraw-Chaffin et al.’s study [
      • Mongraw-Chaffin M.
      • Foster M.C.
      • Anderson C.A.M.
      • Burke G.L.
      • Haq N.
      • Kalyani R.R.
      • Ouyang P.
      • Sibley C.T.
      • Tracy R.
      • Woodward M.
      • Vaidya D.
      Metabolically healthy obesity, transition to metabolic syndrome, and cardiovascular risk.
      ] that involved obese individuals only. In the present meta-analysis cardiovascular diseases were considered as any fatal and non-fatal coronary heart disease (CHD) or stroke, MI, ischemic heart disease, heart failure, and major coronary events.
      For the study conducted by Eckel et al. [
      • Eckel N.
      • Li Y.
      • Kuxhaus O.
      • Stefan N.
      • Hu F.B.
      • Schulze M.B.
      Transition from metabolic healthy to unhealthy phenotypes and association with cardiovascular disease risk across BMI categories in 90 257 women (the Nurses' Health Study): 30 year follow-up from a prospective cohort study.
      ] that reported its results for overweight, obesity and different follow-up durations separately, we considered this study as 4 data sets and at first, we pooled its results then it was included in the meta-analysis.
      All included studies involved both sexes except Eckel et al.‘s study [
      • Eckel N.
      • Li Y.
      • Kuxhaus O.
      • Stefan N.
      • Hu F.B.
      • Schulze M.B.
      Transition from metabolic healthy to unhealthy phenotypes and association with cardiovascular disease risk across BMI categories in 90 257 women (the Nurses' Health Study): 30 year follow-up from a prospective cohort study.
      ] that conducted in women only. Table 1 displays the characteristics of all included studies.

      4.2 Meta-analysis of the association between transition from metabolically benign to unhealthy overweight/obesity state and risk of CVD incidence

      Overall, the transitional MHO phenotype had a significant risk of CVD incidence [HR = 1.42, 95% CI (1.24–1.60)] (Fig. 2). In addition, in both male and female subgroups, unstable MHO individuals demonstrated a significant CVD risk and HRs for CVD incidence in males and females were 1.51 (1.07–1.96) and 1.71 (1.08–2.34), respectively (Fig. 3).
      Figure 2
      Figure 2Forest plot of the association between transitional MHO status and risk of CVD incidence.
      Figure 3
      Figure 3Forest plot of the association between transitional MHO status and risk of CVD incidence in male and female subgroups.
      A pooled analysis of all the studies found no significant heterogeneity between them (I2 = 52.0%, P = 0.052) (Fig. 2), as well as between male (I2 = 0.0%, P = 0.763), and female (I2 = 48.9%, P = 0.118) subgroups (Fig. 3).
      In order to evaluate if any study had a dominating impact on the meta-analysis, we excluded the study conducted by Guo et al. [
      • Guo X.
      • Li Z.
      • Zhou Y.
      • Yu S.
      • Yang H.
      • Sun G.
      • Zheng L.
      • Afzal J.
      • Liu Y.
      • Sun Y.
      The effects of transitions in metabolic health and obesity status on incident cardiovascular disease: insights from a general Chinese population.
      ], with lowest weight (0.74%), at a time and analyzed its impact on the main summary estimate. Based on this analysis, a single study had no significant influence on the heterogeneity or outcomes.

      4.3 Publication bias

      Egger's linear regression test did not demonstrate any evidence that the CVD incidence risk was influenced by publication bias in studies evaluating individuals with transitional MHO phenotype (P = 0.731) (Fig. 4).
      Figure 4
      Figure 4Egger's publication bias plot of the studies on the association between transitional MHO status and risk of CVD incidence.

      5. Discussion

      Based on the current systematic review and meta-analysis of prospective cohort studies, participants with a transitional MHO phenotype have a higher CVD risk [HR = 1.42, 95% CI (1.24–1.60)] than those with a stable MHO phenotype, both in men [HR = 1.51, 95% CI (1.07–1.96)] and women [HR = 1.71, 95% CI (1.08–2.34)].
      Metabolically healthy obesity state and its related CVD risk has been a controversial issue. Much evidence reported that MHO state is not fully a benign phenotype [
      • Eckel N.
      • Meidtner K.
      • Kalle-Uhlmann T.
      • Stefan N.
      • Schulze M.B.
      Metabolically healthy obesity and cardiovascular events: a systematic review and meta-analysis.
      ,
      • Kramer C.K.
      • Zinman B.
      • Retnakaran R.
      Are metabolically healthy overweight and obesity benign conditions?: a systematic review and meta-analysis.
      ], although few investigations have revealed otherwise [
      • Appleton S.L.
      • Seaborn C.J.
      • Visvanathan R.
      • Hill C.L.
      • Gill T.K.
      • Taylor A.W.
      • et al.
      Diabetes and cardiovascular disease outcomes in the metabolically healthy obese phenotype: a cohort study.
      ,
      • Ortega F.B.
      • Lee D.-C.
      • Katzmarzyk P.T.
      • Ruiz J.R.
      • Sui X.
      • Church T.S.
      • et al.
      The intriguing metabolically healthy but obese phenotype: cardiovascular prognosis and role of fitness.
      ]. The dynamic characteristic of MHO and its transition to the MUHO state might be a cause of these discrepant findings, and this feature divides MHO phenotype into transitional and persistent groups [
      • Hosseinpanah F.
      • Tasdighi E.
      • Barzin M.
      • Mahdavi M.
      • Ghanbarian A.
      • Valizadeh M.
      • Azizi F.
      The association between transition from metabolically healthy obesity to metabolic syndrome, and incidence of cardiovascular disease: tehran lipid and glucose study.
      ]. After 10 years of follow-up, a study [
      • Eshtiaghi R.
      • Keihani S.
      • Hosseinpanah F.
      • et al.
      Natural course of metabolically healthy abdominal obese adults after 10 years of follow-up: the Tehran Lipid and Glucose Study.
      ] found that almost half of the MHO participants had lost their metabolic health. In the meta-analysis by Kramer et al. [
      • Kramer C.K.
      • Zinman B.
      • Retnakaran R.
      Are metabolically healthy overweight and obesity benign conditions?: a systematic review and meta-analysis.
      ], it was reported that MHO individuals had elevated hazard for CV events (RR, 1.24; 95% CI, 1.02 to 1.55) compared to individuals with metabolically healthy normal weight (MHNW) phenotype when only investigations with ≥10 years of follow-up were pooled. There was an increased risk in all groups with metabolically unhealthy states: normal weight (RR, 3.14; CI, 2.36 to 3.93), overweight (RR, 2.70; CI, 2.08 to 3.30), and obese (RR, 2.65; CI, 2.18 to 3.12). According to another meta-analysis of 43 studies, MHO phenotype was associated with a higher adjusted CVD risk as well as all-cause mortality, while positive dose-response correlation was demonstrated between BMI and CVD risk among those with metabolically healthy status [
      • Yeh T.L.
      • Chen H.H.
      • Tsai S.Y.
      • et al.
      The relationship between metabolically healthy obesity and the risk of cardiovascular disease: a systematic review and metaanalysis.
      ], indicating that MHO is not entirely benign state.
      Research into the transition from MHO to MUHO and its impact on CVD has revealed various findings. A number of issues vary across these studies, including follow-up length, sample size, definition of healthy state, adjustments and outcome verification. In assessing low-risk populations for future outcomes, follow-up duration is crucially important. An elevated CVD incidence in MHO participants was seen only after about 10 years of follow-up in one study [
      • Arnlöv J.
      • Ingelsson E.
      • Sundström J.
      • Lind L.
      Impact of body mass index and the metabolic syndrome on the risk of cardiovascular disease and death in middleaged men.
      ] with a long follow-up period (30 years). Furthermore, the risk of hypertension was not observed immediately after diagnosis in individuals with an MHO phenotype, however after 8 years of follow-up, the risk was strongly associated with this phenotype [
      • Lee S.K.
      • Kim S.H.
      • Cho G.Y.
      • Baik I.
      • Lim H.E.
      • Park C.G.
      • et al.
      Obesity phenotype and incident hypertension: a prospective community-based cohort study.
      ]. The study noted a correlation between a longer time spent in a metabolically unhealthy state and a greater chance of developing CVD [
      • Eckel N.
      • Li Y.
      • Kuxhaus O.
      • Stefan N.
      • Hu F.B.
      • Schulze M.B.
      Transition from metabolic healthy to unhealthy phenotypes and association with cardiovascular disease risk across BMI categories in 90 257 women (the Nurses' Health Study): 30 year follow-up from a prospective cohort study.
      ]. Moreover, because metabolic syndrome (MetS) and metabolic health were not defined precisely, the reported high discrepancy could be the result of the lack of a defined measure and also the fact that the contribution of each metabolic component to CV events was diverse [
      • Guo X.
      • Li Z.
      • Zhou Y.
      • Yu S.
      • Yang H.
      • Sun G.
      • Zheng L.
      • Afzal J.
      • Liu Y.
      • Sun Y.
      The effects of transitions in metabolic health and obesity status on incident cardiovascular disease: insights from a general Chinese population.
      ]. In the investigations conducted by Eckel et al. [
      • Eckel N.
      • Li Y.
      • Kuxhaus O.
      • Stefan N.
      • Hu F.B.
      • Schulze M.B.
      Transition from metabolic healthy to unhealthy phenotypes and association with cardiovascular disease risk across BMI categories in 90 257 women (the Nurses' Health Study): 30 year follow-up from a prospective cohort study.
      ] and Kouvari et al. [
      • Kouvari M.
      • Panagiotakos D.B.
      • Yannakoulia M.
      • Georgousopoulou E.
      • Critselis E.
      • Chrysohoou C.
      • Tousoulis D.
      • Pitsavos C.
      ATTICA Study Investigators
      Transition from metabolically benign to metabolically unhealthy obesity and 10-year cardiovascular disease incidence: the ATTICA cohort study.
      ] a metabolically healthy condition was characterized by the absence of hypertension, dyslipidemia, and dysglycemia. Mongraw-Chaffin et al. [
      • Mongraw-Chaffin M.
      • Foster M.C.
      • Anderson C.A.M.
      • Burke G.L.
      • Haq N.
      • Kalyani R.R.
      • Ouyang P.
      • Sibley C.T.
      • Tracy R.
      • Woodward M.
      • Vaidya D.
      Metabolically healthy obesity, transition to metabolic syndrome, and cardiovascular risk.
      ] and Lee et al. [
      • Lee Y.B.
      • Kim D.H.
      • Kim S.M.
      • et al.
      Hospitalization for heart failure incidence according to the transition in metabolic health and obesity status: a nationwide population-based study.
      ] defined MetS using the IDF criteria. As defined by Gao et al. [
      • Gao M.
      • Lv J.
      • Yu C.
      • Guo Y.
      • Bian Z.
      • Yang R.
      • Du H.
      • Yang L.
      • Chen Y.
      • Li Z.
      • Zhang X.
      • Chen J.
      • Qi L.
      • Chen Z.
      • Huang T.
      • Li L.
      China Kadoorie Biobank (CKB) Collaborative Group. Metabolically healthy obesity, transition to unhealthy metabolic status, and vascular disease in Chinese adults: a cohort study.
      ] the metabolic health is the absence of more than two of these four indicators: elevated waist circumference (WC), hypertension, hyperglycemia, and dyslipidemia. In the study by Hosseinpanah et al. [
      • Hosseinpanah F.
      • Tasdighi E.
      • Barzin M.
      • Mahdavi M.
      • Ghanbarian A.
      • Valizadeh M.
      • Azizi F.
      The association between transition from metabolically healthy obesity to metabolic syndrome, and incidence of cardiovascular disease: tehran lipid and glucose study.
      ] metabolic health was recognized using the Joint Interim Statement (JIS) criteria and metabolically healthy state was defined as meeting ≤2 of the JIS elements, and those with ≥3 criteria were defined as metabolically unhealthful. It should be noted that some studies included in this meta-analysis (e.g. Mongraw-Chaffin et al. [
      • Mongraw-Chaffin M.
      • Foster M.C.
      • Anderson C.A.M.
      • Burke G.L.
      • Haq N.
      • Kalyani R.R.
      • Ouyang P.
      • Sibley C.T.
      • Tracy R.
      • Woodward M.
      • Vaidya D.
      Metabolically healthy obesity, transition to metabolic syndrome, and cardiovascular risk.
      ], Guo et al. [
      • Guo X.
      • Li Z.
      • Zhou Y.
      • Yu S.
      • Yang H.
      • Sun G.
      • Zheng L.
      • Afzal J.
      • Liu Y.
      • Sun Y.
      The effects of transitions in metabolic health and obesity status on incident cardiovascular disease: insights from a general Chinese population.
      ] and Hosseinpanah et al. [
      • Hosseinpanah F.
      • Tasdighi E.
      • Barzin M.
      • Mahdavi M.
      • Ghanbarian A.
      • Valizadeh M.
      • Azizi F.
      The association between transition from metabolically healthy obesity to metabolic syndrome, and incidence of cardiovascular disease: tehran lipid and glucose study.
      ]) used a problematic definition of metabolic health. They considered subjects being metabolically healthy when up to 2 risk parameters were present, which definitively is not acceptable as considering a person as healthy. In addition, Mongraw-Chaffin et al. [
      • Mongraw-Chaffin M.
      • Foster M.C.
      • Anderson C.A.M.
      • Burke G.L.
      • Haq N.
      • Kalyani R.R.
      • Ouyang P.
      • Sibley C.T.
      • Tracy R.
      • Woodward M.
      • Vaidya D.
      Metabolically healthy obesity, transition to metabolic syndrome, and cardiovascular risk.
      ], Guo et al. [
      • Guo X.
      • Li Z.
      • Zhou Y.
      • Yu S.
      • Yang H.
      • Sun G.
      • Zheng L.
      • Afzal J.
      • Liu Y.
      • Sun Y.
      The effects of transitions in metabolic health and obesity status on incident cardiovascular disease: insights from a general Chinese population.
      ], Gao et al. [
      • Gao M.
      • Lv J.
      • Yu C.
      • Guo Y.
      • Bian Z.
      • Yang R.
      • Du H.
      • Yang L.
      • Chen Y.
      • Li Z.
      • Zhang X.
      • Chen J.
      • Qi L.
      • Chen Z.
      • Huang T.
      • Li L.
      China Kadoorie Biobank (CKB) Collaborative Group. Metabolically healthy obesity, transition to unhealthy metabolic status, and vascular disease in Chinese adults: a cohort study.
      ] and Hosseinpanah et al. [
      • Hosseinpanah F.
      • Tasdighi E.
      • Barzin M.
      • Mahdavi M.
      • Ghanbarian A.
      • Valizadeh M.
      • Azizi F.
      The association between transition from metabolically healthy obesity to metabolic syndrome, and incidence of cardiovascular disease: tehran lipid and glucose study.
      ] used WC cut-offs to define metabolic health, which is not appropriate [
      • Schulze M.B.
      Metabolic health in normal-weight and obese individuals.
      ]. The absence of the metabolic syndrome in obesity has most commonly been used to define MHO [
      • Schulze M.B.
      Metabolic health in normal-weight and obese individuals.
      ].
      Our study has several strengths. As far as we know, the present systematic review and meta-analysis is the first one that evaluated the relationship between transitional MHO phenotype and CVDs incidence risk, and suggests the elevated risk of CVDs, relative to stable MHO subjects, in both male and females. There was no evidence of publication bias, which was another strength of the study. There was no recall bias or selection bias in any of the original studies included in this analysis because they were all prospective studies. It should be noted, however, that there are some limitations. The development of metabolic disturbances was linked to weight gain. However, no studies revealed weight alterations when follow-up was performed.

      6. Conclusion

      Both men and women are at increased risk of CVD if they transition from MHO to an unhealthy state while being followed up. Our study proposes the importance of monitoring metabolic health, regardless of body weight, when recommending strategies for preventing CVD risks. To prevent the transition from metabolically healthy to unhealthy, and then to cardiometabolic disease, healthy lifestyle interventions should be promoted in high-risk populations [
      • Stefan N.
      • Häring H.U.
      • Schulze M.B.
      Metabolically healthy obesity: the low-hanging fruit in obesity treatment?.
      ]. There is substantial evidence [
      • Micha R.
      • Peñalvo J.L.
      • Cudhea F.
      • Imamura F.
      • Rehm C.D.
      • Mozaffarian D.
      Association between dietary factors and mortality from heart disease, stroke, and type 2 diabetes in the United States.
      ,
      • Estruch R.
      • Ros E.
      • Salas-Salvadó J.
      • et al.
      Primary prevention of cardiovascular disease with a Mediterranean diet.
      ,
      • Estruch R.
      • Martínez-González M.A.
      • et al.
      Effect of a high-fat Mediterranean diet on bodyweight and waist circumference: a prespecified secondary outcomes analysis of the PREDIMED randomised controlled trial.
      ,
      • Abiri B.
      • Valizadeh M.
      • Nasreddine L.
      • Hosseinpanah F.
      Dietary determinants of healthy/unhealthy metabolic phenotype in individuals with normal weight or overweight/obesity: a systematic review.
      ] that a healthy lifestyle can reduce the risk of cardiometabolic morbidity and mortality, independent of the effects on bodyweight.

      Statements

      Conflict of interest statement

      No conflict of interest.

      Ethical approval statement

      For this type of study formal consent is not required.

      Informed consent statement

      Informed Consent does not apply.

      Funding

      None.

      Acknowledgements

      None.

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