Journal of Hypertension:
ORIGINAL PAPERS: Obesity
Obesity phenotype and incident hypertension: a prospective community-based cohort study
Lee, Seung Kua; Kim, Seong Hwanb; Cho, Goo-Yeongc; Baik, Inkyungd; Lim, Hong Euye; Park, Chang Gyue; Lee, Jung Bokf; Kim, Yong Hyunb; Lim, Sang Yupb; Kim, Hyuna; Shin, Chola
aInstitute of Human Genomic Study
bDivision of Cardiology, Department of Internal Medicine, Korea University Ansan Hospital, Ansan
cDivision of Cardiology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam
dDepartment of Foods and Nutrition, College of Natural Sciences, Kookmin University
eDivision of Cardiology, Department of Internal Medicine, Korea University Guro Hospital
fDepartment of Clinical Epidemiology and Biostatistics, Asan Medical Center, Seoul, Korea
Correspondence to Seong Hwan Kim, MD, PhD, Division of Cardiology, Department of Medicine, Korea University Ansan Hospital, 516 Gojan-1-dong, Danwon-gu, Ansan-si, Gyeonggi-do 425-707, Korea. Tel: +82 31 412 5546; fax: +82 31 412 5594; e-mail: firstname.lastname@example.org
Abbreviations: CI, confidence interval; CRP, C-reactive protein; CVD, cardiovascular disease; HDL, high-density lipoprotein; HOMA-IR, homeostasis model assessment insulin resistance; HR, hazard ratio; IMT, intima–media thickness; KoGES, Korean Genome Epidemiology Study; MetS, metabolic syndrome
Received 7 February, 2012
Revised 5 September, 2012
Accepted 7 September, 2012
Objective: The relationship betweens the healthy obese phenotype and the risk of cardiovascular events remains unclear. We prospectively investigated the association between the obesity phenotype and the incidence of hypertension.
Methods: We studied 2352 participants, aged 40–69 years at baseline, with normal blood pressure (BP) from the Ansan cohort and the Ansung cohort of the Korean Genome Epidemiology Study. Participants were divided into six groups based on BMI and the metabolic syndrome (MetS) components: healthy (none of the five MetS components) normal weight (BMI <23 kg/m2), unhealthy (one or more MetS component) normal weight, healthy overweight (BMI 23–24.9 kg/m2), unhealthy overweight, healthy obesity (BMI ≥25 kg/m2), and unhealthy obesity. The incidence of hypertension was identified by biennial health examinations during the 8-year follow-up.
Results: After adjusting for age, sex, cohort, physical activity, smoking, alcohol consumption, and family history of hypertension and cardiovascular diseases, an increased risk for hypertension in combined cohort was observed in the healthy obesity [hazard ratio (HR): 2.20, 95% confidence interval (CI):1.34–3.60], unhealthy overweight (HR: 1.47, 95% CI: 1.00–2.14), and unhealthy obesity (HR: 2.45, 95% CI: 1.79–3.37), compared with the healthy normal weight group. In each cohort, the healthy obesity was still associated with a higher incidence of hypertension (HR 2.20, 95% CI 1.11–4.36 for the Ansan cohort and HR 2.21, 95% CI 1.01–4.83 for the Ansung cohort).
Conclusion: These findings provide evidence that the metabolically healthy obese phenotype may not be a benign condition.
Obesity has become a major issue in both developing and developed countries, with 502 million adults globally being reported as obese [1,2]. The growing obesity epidemic is associated with a sharp increase in obesity-related cardiovascular disease (CVD), such as hypertension and type 2 diabetes mellitus, and consequently increases the risk of all-cause, coronary artery disease, and CVD mortality [3–5]. Even though obesity is a well established risk factor for CVD, recent studies have introduced a unique obesity phenotype known as ‘healthy obesity’ or ‘metabolically normal obesity’ based on data showing that some obese individuals with relatively favorable cardiometabolic profiles do not have increased risk of CVD morbidity and mortality compared with normal weight individuals [6–8]. The metabolic characteristics of healthy obese individuals including higher levels of insulin sensitivity and high-density lipoprotein (HDL) cholesterol as well as lower levels of fasting triglycerides and fasting glucose have been suggested as possible explanations for why healthy obesity may be a harmless condition. In contrast, more recent studies refute the existence of healthy obesity by demonstrating that healthy obesity is associated with all-cause and CVD mortality in longitudinal studies [9,10] as well as with target organ changes in cross-sectional studies [11,12].
As the development of hypertension is a strong predictor of all-cause and CVD mortality, clarifying whether healthy obesity is associated with an increased risk of hypertension would be an essential step to solving the controversial issues related to mortality. However, no epidemiologic data up to this point has explored the association of the healthy obese phenotype with hypertension. Therefore, we investigated the risk of hypertension according to the obesity phenotype, based on BMI and metabolic syndrome (MetS) components, from a large ethnically homogenous prospective cohort study.
Two independent prospective cohort studies embedded within the Korean Genome Epidemiology Study (KoGES) began in 2001 in two different cities: Ansan, which is an urban community with 555 000 residents, and Ansung, which is a rural community with a population of 133 000 (based on the 2000 census). Each cohort consists of a population-sample of Korean men and women 40–69 years of age with the same ethnic background. Detailed information on the sampling plan and the selection criteria for these ongoing prospective studies have been published previously [13,14]. From 2001 to 2002, we identified 10 957 eligible participants in Ansan and 7129 eligible participants in Ansung. In total, 5020 (2523 men and 2497 women) participants from Ansan and 5018 (2239 men and 2779 women) participants from Ansung completed a baseline examination at their respective cities. Cohort participants were examined again at 2-year intervals in 2003–2004 (1st follow-up examination), 2005–2006 (2nd follow-up examination), 2007–2008 (3rd follow-up examination), and 2009–2010 (4th follow-up examination). Follow-up rates were 80, 71, 65, and 65%, respectively, in the Ansan cohort and 91, 81, 68, and 68%, respectively, in the Ansung cohort.
Among the 10 038 participants from the Ansan and Ansung cohorts, we excluded 3996 with hypertension defined as SBP at least 140 mmHg and/or DBP at least 90 mmHg and/or antihypertensive medication use, diabetes mellitus or antidiabetic medication use, preexisting CVD, serum creatinine at least 2.0 mg/dl, lipid-lowering drug use, missing data in any of covariates, or BMI less than 18.5 kg/m2 at the baseline examination. For longitudinal analysis, 1916 who did not attend the fourth follow-up examination and 54 lacking one or more additional follow-up examinations (other than the 4th follow-up examination) were also excluded from the participant pool, and 1720 prehypertensives were finally excluded. The remaining 2352 participants were eligible for analysis.
This study was approved by the Human Subjects Review Committee at the Korea University Ansan Hospital and the Ajou University Medical Center, and written informed consent was obtained from all participants.
All participants completed a comprehensive health examination and interviews according to a site visit schedule. The health examination included the evaluation of anthropometric indexes and the collection of biological specimens for assessment. Participants also completed interviewer-administered questionnaires on demographic information (age and sex), medical history including medication use, family disease history, and lifestyle factors (smoking status and alcohol intake). All examinations were administered by health professionals trained to follow a standardized protocol. BMI (kg/m2) was calculated from height (cm) and body weight (kg), which were measured to the nearest 0.1 cm or 0.1 kg. Similarly, waist circumference (cm) was measured at the narrowest point between the lower rib and the iliac crest. After all participants had fasted for at least 8 h, venous blood samples were collected and delivered to the Seoul Clinical Laboratories (Seoul, Korea) for assays of plasma glucose and insulin, C-reactive protein (CRP), serum total cholesterol, HDL cholesterol, and triglyceride concentrations. The homeostasis model assessment insulin resistance (HOMA-IR) index was calculated as fasting serum insulin (μU/ml) × fasting plasma glucose (mg/dl)/405.
Definition of body size phenotype
Body-size phenotypes were defined based on the combination of BMI categories and the absence or presence of MetS components proposed by a modified version of the National Cholesterol Education Program Adult Treatment Panel III . The MetS components for this study included the following criteria: central obesity based on ethnicity-specific values (waist circumference ≥90 cm for men and ≥80 cm for women) , hypertriglyceridemia (≥150 mg/dl), low HDL cholesterol (<40 mg/dl for men and <50 mg/dl for women), BP at least 130/85 mmHg, and fasting glucose at least 100 mg/dl. By defining BMI cutoffs for normal weight (<23 kg/m2), overweight (23–24.9 kg/m2), and obese (≥25 kg/m2) , the study population was divided into six groups: healthy (none of the five MetS components) normal weight, unhealthy (one or more MetS component) normal weight, healthy overweight, unhealthy overweight, healthy obesity, and unhealthy obesity. To examine the status of the obesity phenotype upon diagnosis of newly developed hypertension among the healthy obese individuals at baseline, we considered four MetS components excluding BP to define the healthy and unhealthy status.
Blood pressure measurement and hypertension incidence
At baseline and biennial follow-up visits, BP was measured by trained examiners according to a standardized protocol after a rest period of at least 5-min in the sitting position using an appropriate-sized cuff and a mercury sphygmomanometer . The first and the fifth phases of Korotkoff sounds were used for SBP and DBP. BP measurements were repeated after a 30-s interval and were recorded to the nearest 2 mmHg. The average value of the two readings was used for analysis. The use of antihypertensive medication was assessed by an interviewer-administered questionnaire at baseline and at every visit in both the Ansan and Ansung cohorts. Incident hypertension was defined as the first occurrence at any follow-up examination if the participants had SBP at least 140 mmHg, DBP at least 90 mmHg, or were being treated with antihypertensive medication. A participant was classified as having hypertension at the next follow-up examination if criteria had been met at any previous follow-up examination.
Baseline characteristics of KoGES participants were calculated using means for continuous variables and frequencies or percentages for categorical variables. The analyses of continuous and categorical variables to assess differences among six groups according to different combinations of BMI categories and the absence or presence of the MetS components were determined by one-way analysis of variance using the Scheffe posthoc test for comparison or the χ2 test. The crude 8-year incidence rates of hypertension were calculated as the number of risk cases per 1000 person-years based on the BMI categories and MetS components. The crude 8-year cumulative hypertension incidence was also compared with 2-year interval incidences. Thereafter, hazard ratios (HRs) and 95% confidence intervals (CIs) from Cox proportional hazards regression models with fixed covariates (with the healthy normal weight group as the reference category) were used to estimate relative risks for 8-year cumulative hypertension incidence based on baseline BMI categories and MetS components. Model 1 was adjusted for age and sex, and model 2 added physical activity, alcohol consumption, smoking status, and family history of hypertension and CVD to model 1. A similar subgroup analysis was performed in each cohort. A two-sided P < 0.05 was considered statistically significant. All statistical analyses were performed using SAS statistical software (SAS 9.1.3, SAS Institute, Cary, North Carolina, USA).
Baseline data of the 2352 normotensive participants including five MetS components are presented in Table 1. The mean age of participants was 48.7 years, and 59.7% of participants were women. In our middle-aged Korean cohort, the prevalence of healthy obesity in all participants and among obese individuals was 5.7 and 18.1% at baseline, respectively. Compared with the healthy normal weight group, the participants with unhealthy metabolic profiles, regardless of BMI status, had unfavorable values for all MetS variables except for BP component. In spite of the fact that the healthy obese group did not meet any criteria of the five MetS components, significant differences in waist circumference, DBP, and HDL cholesterol were found between the healthy normal weight and healthy obesity groups. On the contrary, the inflammatory marker and insulin sensitivity index were similar between the two groups.
Hypertension incidence before adjustment
During the 8-year follow-up, 352 participants developed incident hypertension. The hypertension incidence rates (per 1000 person-years) were affected by the presence of obesity more than by the presence of MetS components (Fig. 1). The cumulative 8-year hypertension incidence was higher in obese individuals, irrespective of the presence of MetS components, compared with healthy normal weight individuals (Fig. 2). The healthy obese participants had the second highest incidence of hypertension after the unhealthy obese individuals. By year four, those in the healthy groups, regardless of BMI category, had similar hypertension incidences. However, hypertension incidence in the healthy obese group increased more rapidly from year 4 to year 8 (Fig. 2a).
Hypertension incidence after adjustment
Table 2 shows the multivariable-adjusted HRs for hypertension incidence when compared with healthy normal weight individuals. After adjusting for age, sex, and cohort (model 1) in the combined data, the risk for hypertension incidence was significantly higher in the healthy and unhealthy obese groups than in the healthy normal weight individuals, irrespective of the presence of MetS components. Additional adjustment for physical activity, current smoking, alcohol consumption, family history of hypertension, and family history of CVD (model 2) did not significantly affect the HRs of healthy and unhealthy obese groups, even though participants with unhealthy overweight were at risk of developing hypertension in the combined data. These patterns were still seen in subgroup analyses conducted in each cohort. In this study population, healthy obesity displayed the second highest HR for incident hypertension after unhealthy obesity, whereas unhealthy normal weight was not associated with an increased risk of hypertension incidence.
Change in baseline phenotype
The biennial changes in each baseline phenotype are shown in Figure 3. During the 8-year follow-up, there were no significant phenotype transitions in baseline unhealthy groups irrespective of BMI categories, whereas a number of healthy individuals moved to unhealthy groups within the same BMI categories. This trend was also evident at the second examination. To determine whether hypertension developed with the healthy obese phenotype or after transition to other phenotypes, we assessed the phenotype status of 23 newly developed hypertensive individuals among 135 initially healthy obese participants (Fig. 4). Thirteen participants of the 23 were transitioned to unhealthy overweight and obese individuals before the diagnosis of hypertension. On the contrary, nine participants of the 23 initially healthy obese individuals developed hypertension without changing into other phenotypes during the 8-year follow-up.
In this prospective cohort study, we observed that obesity is associated with an increased risk of hypertension during an 8-year period, regardless of the presence of MetS components. As expected, unhealthy obesity showed the highest risk, and being overweight in combination with MetS components also showed significant association with an increased risk of hypertension. Interestingly, healthy obese patients with favorable metabolic profiles were not at an increased risk of hypertension for the first 4-year follow-up period, when they were compared with the healthy normal weight individuals. However, the cumulative hypertension incidence line for the healthy obese group began to diverge significantly from the line of healthy normal weight participants in the last 4 years, from the third follow-up. As a whole, the status of healthy obesity does not appear to have a protective effect against the development of hypertension, implying that healthy obese patients could be at an increased risk for CVD in clinical settings.
Until recently, the effects of healthy obesity based on the level of insulin resistance or the number of cardiometabolic risk factors on target organs, CVD events, and mortality remained unclear. Only a small number of studies have evaluated the effect of obesity on target organs [11,12,18]. One study found that intima–media thickness (IMT) in the healthy obese group was not statistically different from that of the normal weight group , whereas another study that used insulin resistance as the grouping factor in lieu of the MetS definition revealed that carotid IMT was thicker in the healthy obese group . The latter group also demonstrated that healthy obesity is associated with subclinical impairment in other target organs when assessed by forearm blood flow, brachial artery ultrasound, and echocardiography . On the contrary, our previous study  showed that metabolically healthy participants with excess weight demonstrated subtle changes in left ventricular structure and function, although the carotid IMT and arterial stiffness in healthy obese individuals were comparable with those of healthy normal weight participants, suggesting that the prognosis for healthy obesity may not be completely benign. These contradictory results may be explained by differences in the definition of the obesity phenotype and differences in age, sex, ethnicity, and size of the study samples.
Besides the changes in target organs, previous studies that investigated the effects of healthy obesity on CVD events or mortality are not in agreement. Some longitudinal studies reported that metabolically healthy overweight or obese participants were not at an increased risk for type 2 diabetes mellitus or CVD mortality [6–8]. On the contrary, others have shown that overweight and obese men without MetS have an increased risk of CVD mortality [9–11]. Interestingly, one of the main differences among these studies was the follow-up duration. The increased risk for CVD events or mortality in healthy obese individuals could be seen after a 10-year lag time , indicating that some major risk factors that typically require years or decades to advance to CVD events or mortality were present at baseline or developed during the follow-up period in metabolically healthy obese participants. Although cross-sectional or longitudinal studies have shown that being obese is associated with an increased risk of hypertension in both men and women [19–23], the association of the obese phenotype based on metabolic status with hypertension has not yet been evaluated. Considering that one of the most important predictors of CVD mortality is hypertension, identification of an increased risk of hypertension in the metabolically healthy obese phenotype may partially explain previous inconsistent results regarding the risk of CVD events or mortality.
It is still unknown whether healthy obesity alone can induce CVD or whether the transition to the other obesity phenotype is required during the follow-up period. When we re-examined their obesity phenotypes upon diagnosis of hypertension among the healthy obese participants at baseline, we found that hypertension could be eventually developed in healthy obese participants, although many healthy obese individuals developed hypertension after transitioning to the unhealthy obese phenotype. To the best of our knowledge, these results showing an increased risk of hypertension in the healthy obese phenotype and changes in the obesity phenotype associated with the diagnosis of hypertension have not been previously reported.
The mechanism that links obesity and increased risk of hypertension still remains unclear. Based on recent studies, metabolic and neurohormonal pathways including insulin resistance, the renin–angiotensin–aldosterone system, and the sympathetic nervous systems play important roles in the development of hypertension among obese individuals [24–26]. In this study, because scores of HOMA-IR as an index of insulin resistance were comparable between the healthy obesity and healthy normal weight groups at baseline, it is likely that other unexamined pathways or inflammatory cytokines, such as interleukin-6 and tumor necrosis factor-α, might contribute to BP increase in the healthy obese phenotype.
Although the present study included a large general population sample, prospective design, biennial follow-up measurements, exclusion of prehypertensive individuals, and a stringent definition of healthy obesity, it has the following limitations. First, the BP measurement was obtained during a single day, which could result in inaccuracies. However, we have assessed inter-observer and intra-observer variability every 3 months to partially minimize this problem, and other epidemiological studies of the same nature have used the similar BP measurements as a standardized methodology. Second, the use of different levels of BMI and waist circumferences for diagnosis of obesity in the Asian population, which are modified by the WHO Western Pacific Region, cannot be generalized to other ethnic groups. Accordingly, the effect of healthy obesity on the development of hypertension should be validated in other ethnic populations. Finally, unmeasured information such as dietary sodium and phosphorus intake, which are closely related to the development of hypertension, should be accounted for.
In summary, although recent studies have identified the healthy obese phenotype with favorable cardiometabolic profiles, data that examines the effects of healthy obesity on the development of hypertension does not exist. In this large population-based prospective study, we found that obese individuals in a metabolically healthy status are at an increased risk for hypertension compared with metabolically healthy normal weight participants. Our study results, combined with recent data on obese individuals without MetS or insulin resistance who also had early changes in specific organs as well as an increased risk for CVD events and mortality, provide additional evidence that the diagnosis of healthy obesity is not a benign condition in clinical practice. Because the beneficial effects of weight loss in this subgroup have been questioned [27,28], further longitudinal studies on whether intentional weight loss in metabolically healthy obese population improves or prevents the development of hypertension are required.
This study was supported by grants (2001-347-6111-221, 2002-347-6111-221, 2003-347-6111-221, 2004-E71001-00, 2005- E71001-00, 2006-E71005-00, 2007-4854-300, 2008-E00169-00, 2009-E00454–00, and 2010-E71001-00) from the Korean Centers for Disease Control and Prevention, Ministry for Health and Welfare and was partially supported by a grant (R0903121) from the Korea University Medical Center.
Conflicts of interest
There are no conflicts of interest.
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