Weight Change and Development of Subclinical Carotid Atherosclerosis Among Metabolically Healthy Adults: A Cohort Study (original) (raw)

Journal Article

Dong Hyun Sinn ,

Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine

, Seoul, Gangnam-gu,

South Korea

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Danbee Kang ,

Department of Clinical Research Design and Evaluation, SAIHST, Sungkyunkwan University

, Seoul, Gangnam-gu,

South Korea

Center for Clinical Epidemiology, Samsung Medical Center

, Seoul, Gangnam-gu,

South Korea

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Soo Jin Cho ,

Center for Health Promotion, Samsung Medical Center

, Seoul, Gangnam-gu,

South Korea

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Yoosoo Chang ,

Center for Total Health Studies, Kangbuk Samsung Hospital

, Seoul, Jongro-gu,

South Korea

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Seungho Ryu ,

Center for Total Health Studies, Kangbuk Samsung Hospital

, Seoul, Jongro-gu,

South Korea

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Young Bin Song ,

Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine

, Seoul, Gangnam-gu,

South Korea

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Seung Woon Paik ,

Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine

, Seoul, Gangnam-gu,

South Korea

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Yun Soo Hong ,

Departments of Epidemiology and Medicine and Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Medical Institutions

, Baltimore, Maryland,

USA

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Di Zhao ,

Departments of Epidemiology and Medicine and Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Medical Institutions

, Baltimore, Maryland,

USA

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Eliseo Guallar

Center for Clinical Epidemiology, Samsung Medical Center

, Seoul, Gangnam-gu,

South Korea

Departments of Epidemiology and Medicine and Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Medical Institutions

, Baltimore, Maryland,

USA

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Contributed equally to this study as co-first authors.

Author Notes

Accepted:

20 September 2019

Published:

23 September 2019

Corrected and typeset:

08 February 2020

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Dong Hyun Sinn, Danbee Kang, Soo Jin Cho, Yoosoo Chang, Seungho Ryu, Young Bin Song, Seung Woon Paik, Yun Soo Hong, Di Zhao, Eliseo Guallar, Juhee Cho, Geum-Youn Gwak, Weight Change and Development of Subclinical Carotid Atherosclerosis Among Metabolically Healthy Adults: A Cohort Study, The Journal of Clinical Endocrinology & Metabolism, Volume 105, Issue 3, March 2020, Pages e410–e416, https://doi.org/10.1210/clinem/dgz040
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Abstract

Background

The benefit of weight loss for reducing cardiovascular disease (CVD) risk in metabolically healthy obese people is unknown.

Objectives

We evaluated the association between weight change and incident subclinical carotid atherosclerosis (SCA) in metabolically healthy but overweight or obese subjects.

Methods

Cohort study of 3117 metabolically healthy overweight or obese adults who did not have any metabolic syndrome components or insulin resistance at baseline. SCA was assessed using carotid artery ultrasonography. The study outcome was the development of incident SCA among participants free of the disease at baseline.

Results

During 12 248 person-years of follow-up (median 3.42 years), 747 participants developed SCA. The proportions of participants with no reduction or increased weight, reduction in weight from 0.1% to 4.9%, and reduction in weight ≥ 5% during follow-up were 47.0%, 44.4%, and 8.6%, respectively. The fully-adjusted hazard ratios (HRs) for incident SCA in participants with a reduction in weight of 0.1% to 4.9% and ≥ 5% compared with those with no reduction or increased weight were 0.84 (95% CI, 0.72–0.98) and 0.66 (95% CI, 0.50–0.87), respectively.

Conclusions

In a large cohort study of metabolically healthy but overweight or obese adult men and women, weight reduction was associated with a lower incidence of SCA. Our findings suggest that metabolically healthy overweight or obese subjects may benefit from weight reduction in terms of CVD risk.

Obesity is an established risk factor for cardiovascular disease (CVD) (1). Obesity is associated with multiple metabolic disturbances, including insulin resistance, adipose tissue dysfunction, and inflammation, which partially mediate the increase in CVD risk (1, 2). Nevertheless, the risk profile of a subset of obese individuals with normal metabolic profiles, the so-called metabolically healthy obese (MHO) (3), has generated substantial controversy (4). In systematic reviews and meta-analyses, MHO was associated with a higher risk of cardiovascular events, including new-onset angina, myocardial infarction, sudden cardiac death, heart failure, stroke, and CVD mortality (5, 6). In cross-sectional studies, MHO was also associated with an increased prevalence of subclinical atherosclerosis, including carotid atherosclerosis (7), and coronary artery calcification (8).

The impact of weight change on the development of subclinical atherosclerosis in MHO individuals, however, is still unknown. Therefore, we conducted a longitudinal cohort study in a large sample of metabolically healthy overweight or obese men and women to evaluate the association between weight change and the development of incident subclinical carotid atherosclerosis (SCA).

Methods

Study population

We conducted a retrospective cohort study of men and women 18 years of age or older who underwent at least 2 comprehensive health check-up examinations, including carotid ultrasonography, at the Health Promotion Center of the Samsung Medical Center in Seoul, South Korea, from March 1, 2005 to December 31, 2013. We restricted our analysis to participants free of carotid atherosclerosis at baseline (N = 18 357; Fig. 1). Since the objective of the study was to evaluate weight change in metabolically healthy overweight or obese subjects, we further excluded 12 240 subjects with any of the following metabolic abnormalities (9): 1) fasting blood glucose ≥ 100 mg/dL or current use of blood glucose-lowering agents (N = 4812); 2) blood pressure ≥ 130/85 mm Hg or current use of blood pressure–lowering agents (N = 5060); 3) triglyceride levels ≥ 150 mg/dL or current use of lipid-lowering agents (N = 6003); 4) high-density lipoprotein cholesterol (HDL-C) < 40 mg/dL in men or < 50 mg/dL in women (N = 3262); or 5) homeostasis model assessment of insulin resistance (HOMA-IR) ≥ 2.5 (N = 4063) (10). In addition, we excluded participants who were underweight or had normal weight at baseline (N = 2755), as well as those with a history of CVD (N = 139) or cancer (N = 89), use of aspirin (N = 238), or use of antithrombotic medications (N = 9). Finally, we excluded participants with missing data on diabetes, dyslipidemia, hypertension, and body mass index (BMI) (N = 12), resulting in a final sample of 3117 participants (Fig. 1).

Figure 1.

Flow chart of study participants.

The study was approved by the Institutional Review Board of the Samsung Medical Center. Informed consent was waived because the study was based on de-identified existing administrative and clinical data routinely collected for screening purposes.

Data collection

During each screening visit, study participants completed a self-administered questionnaire with questions on medical history and lifestyle habits, including smoking, alcohol use, and medication use. Weight and height were measured by trained nurses, with the participants wearing a lightweight hospital gown and no shoes. BMI was calculated as weight in kilograms divided by height in meters squared and was classified according to Asian-specific criteria (underweight, BMI < 18.5 kg/m2; normal weight, BMI 18.5 to 22.9 kg/m2; overweight, BMI 23 to 24.9 kg/m2; and obese, BMI ≥ 25 kg/m2) (11). Blood pressure was measured using a mercury sphygmomanometer after the subject had been seated for at least 10 minutes.

Blood specimens were sampled after at least a 12-hour fast. Serum levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), HDL-C, triglycerides, glucose, and C-reactive protein were measured as part of the health check-up examination at Samsung Medical Center’s Department of Laboratory Medicine, which participates in several proficiency testing programs operated by the Korean Association of Quality Assurance for Clinical Laboratory, the Asian Network of Clinical Laboratory Standardization and Harmonization, and the College of American Pathologists.

Subclinical carotid atherosclerosis

Carotid artery ultrasonography was performed using a B-mode ultrasound system (Logiq 7, GE Medical System, Milwaukee, WI, USA) with a 9-MHz linear array transducer. The examination included bilateral scans of the common, internal, and external carotid arteries, including the bifurcation site. Abnormal carotid-intima media thickness was defined as a carotid intima-media thickness > 1.2 mm (12, 13). Carotid plaque was defined as a focal wall thickening that was at least 0.5 mm or 50% greater than the surrounding carotid intima-media thickness, or a focal region with carotid intima-media thickness > 1.5 mm that protrudes into the lumen in any carotid segment (14). The study endpoint was the development of SCA, defined as the development of abnormal carotid intima-media thickness or carotid plaque.

Statistical analyses

Participants were followed from the baseline visit until the visit in which they developed SCA or until the last available visit in participants who did not develop SCA. The main exposure variable was percent weight change, calculated as the difference in weight from baseline until the visit in which a participant developed SCA or until the last available visit until divided by the baseline weight × 100. Participants were classified into 3 categories: no reduction or increased weight, reduction in weight of 0.1% to 4.9%, and reduction in weight of ≥ 5% during follow-up.

We used a proportional hazards regression model to estimate the hazard ratios (HRs) with 95% CIs for the development of SCA comparing participants with 0.1% to 4.9% reduction in weight and those with ≥ 5% reduction in weight versus those who had no reduction or increased weight during follow-up. In addition, we modeled weight change as a continuous variable using restricted cubic splines with knots at the 5th, 35th, 65th, and 95th percentiles of the sample distribution to provide a flexible estimate of the dose-response relationship between weight change and incidence of SCA.

We used 3 models with increasing degrees of adjustment to account for potential confounding factors at baseline. Model 1 was adjusted for age, sex, and year of visit. Model 2 was further adjusted for smoking (never, former, current, and missing), and alcohol intake. Model 3 was further adjusted for potential metabolic mediators of the association between weight change and SCA: systolic blood pressure, fasting serum glucose, triglycerides, HDL-C, total cholesterol, and C-reactive protein.

In subgroup analysis, we examined the association between percent weight change and incident SCA separately in participants who were overweight and those who were obese at baseline. Statistical analyses were performed with Stata version 14.0 (StataCorp LP, College Station, Texas) and R 3.2.1 (Vienna, Austria; http://www.R-project.org/). All reported P values are 2-tailed, and comparisons with P < 0.05 were considered statistically significant.

Results

The mean (SD) age and BMI of study participants (N = 3117) were 50.4 (7.6) years and 25.0 (1.6) kg/m2, respectively (BMI range: 23.0 to 36.4 kg/m2). The proportion of participants with no reduction or increased weight, reduction in weight from 0.1% to 4.9%, and reduction in weight ≥ 5% during follow-up were 47.0%, 44.4%, and 8.6%, respectively (Table 1). Among the 3 groups, the group with no reduction or increased weight was on average younger, had a higher prevalence of current smokers, and higher total and LDL-cholesterol levels, as well as lower BMI, percent body fat, and waist circumference.

Table 1.

Baseline Characteristics of Study Participants

Values are number (%), mean (SD), or median (IQR). Abbreviations: LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol.

Table 1.

Baseline Characteristics of Study Participants

Values are number (%), mean (SD), or median (IQR). Abbreviations: LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol.

During 12 248 person-years of follow-up (median 3.42 years; range, 0.5-8.7 years), 747 participants developed SCA. After adjusting for confounding factors, the HRs for incident SCA in participants with a reduction in weight of 0.1% to 4.9% and ≥ 5% compared with those who had no reduction or increased weight were 0.84 (95% CI, 0.72–0.98) and 0.66 (95% CI, 0.50–0.87), respectively (Table 2). In spline regression models, the association between percent weight change and incident SCA was approximately linear (P value for nonlinear spline terms 0.16; Fig. 2).

Table 2.

Multivariable-Adjusted Hazard Ratios (95% CI) for Incident Subclinical Carotid Atherosclerosis by Percent Weight Change Category (N = 3117)

Model 1: Adjusted for baseline age, sex, and year of visit. Model 2: Further adjusted for smoking (never, former, current, and missing), and alcohol use (none, modest, heavy, and missing). Model 3: Further adjusted for systolic blood pressure, fasting glucose, high-density lipoprotein cholesterol, triglycerides (loge-transformed), total cholesterol and C-reactive protein. Abbreviations: IQR, interquartile range.

Table 2.

Multivariable-Adjusted Hazard Ratios (95% CI) for Incident Subclinical Carotid Atherosclerosis by Percent Weight Change Category (N = 3117)

Model 1: Adjusted for baseline age, sex, and year of visit. Model 2: Further adjusted for smoking (never, former, current, and missing), and alcohol use (none, modest, heavy, and missing). Model 3: Further adjusted for systolic blood pressure, fasting glucose, high-density lipoprotein cholesterol, triglycerides (loge-transformed), total cholesterol and C-reactive protein. Abbreviations: IQR, interquartile range.

Figure 2.

Multivariable-adjusted hazard ratios (95% CI) for incident subclinical carotid atherosclerosis by percent weight change. The curves represent multivariable-adjusted hazard ratios (solid line) and their 95% CIs (dashed lines) for subclinical carotid atherosclerosis based on restricted cubic splines for percent weight change with knots at the 5th, 35th, 65th, and 95th percentiles of their sample distribution. The reference value (diamond dot) was set at no weight change. The model was adjusted for age, sex, year of visit, smoking (never, former, current, and missing), alcohol (none, modest, heavy, and missing), blood pressure, fasting blood glucose, high-density lipoprotein cholesterol, triglycerides (loge-transformed), total cholesterol, and C-reactive protein.

In subgroup analysis, the fully adjusted HRs for incident SCA in participants with a reduction in weight of 0.1% to 4.9% and ≥ 5% compared with those who had no reduction or increased weight were 0.91 (95% CI, 0.74–1.12) and 0.73 (95% CI, 0.49–1.07), respectively, in overweight participants, and 0.74 (95% CI, 0.60–0.94) and 0.59 (95% CI, 0.39–0.87), respectively, in obese participants (Table 3). The P value for interaction of baseline weight by weight change categories was 0.42.

Table 3.

Multivariable-Adjusted Hazard Ratios (95% CI) for Incident Subclinical Carotid Atherosclerosis by Percent Weight Change Category in Metabolically Healthy Overweight or Obese Participants (N = 3117)

Adjusted for baseline age, sex, year of visit, smoking (never, former, current, and missing), alcohol (none, modest, heavy, and missing), systolic blood pressure, fasting glucose, high-density lipoprotein cholesterol, triglycerides (loge-transformed), total cholesterol and C-reactive protein. The P value for interaction of baseline weight by weight change categories was 0.42. Abbreviation: IQR, interquartile range.

Table 3.

Multivariable-Adjusted Hazard Ratios (95% CI) for Incident Subclinical Carotid Atherosclerosis by Percent Weight Change Category in Metabolically Healthy Overweight or Obese Participants (N = 3117)

Adjusted for baseline age, sex, year of visit, smoking (never, former, current, and missing), alcohol (none, modest, heavy, and missing), systolic blood pressure, fasting glucose, high-density lipoprotein cholesterol, triglycerides (loge-transformed), total cholesterol and C-reactive protein. The P value for interaction of baseline weight by weight change categories was 0.42. Abbreviation: IQR, interquartile range.

Discussion

In this large study of metabolically healthy but overweight or obese adult men and women, participants who lost weight showed a lower risk of incident SCA compared to those who did not lose weight during follow-up. The risk reduction in incident SCA was proportional to the proportion of weight loss. The reduction in risk was evident both in overweight and obese participants. Our findings suggest that, even in metabolically healthy overweight or obese individuals, weight loss may prevent the development of subclinical atherosclerosis and reduce CVD risk.

By definition, metabolically-healthy overweight or obese subjects do not have metabolic abnormalities. However, the cutoffs for identifying metabolic abnormalities are arbitrary, and the association between cardio-metabolic risk factors and CVD risk is continuous, without clear thresholds (8, 15). Furthermore, there is disagreement on which and how many metabolic abnormalities should be included in the definition of metabolic health (16, 17). In our study, we defined metabolic health as the absence of any component of the metabolic syndrome and the absence of insulin resistance. Other factors that may be used to define metabolic health include inflammatory markers (18), the presence of fatty liver (19, 20), or hyperinsulinemic-euglycemic clamp findings (4). Indeed, obesity is a complex, multifactorial chronic disease with many different phenotypes (21), but our findings suggest that, even after using a relatively strict definition of metabolic health, metabolically healthy overweight and obese individuals may benefit from weight reduction.

The mechanisms underlying a reduction in CVD risk by weight reduction in metabolically healthy overweight or obese people is unknown. Adipose tissue is an active endocrine organ that produces and releases adipokines with pro-inflammatory and other adverse effects (22). Adipokines may affect endothelial function, vascular homeostasis, and atherogenesis, independently of their effect on glucose and fat metabolism (23). Weight reduction may thus reduce these adverse effects. Furthermore, metabolically healthy overweight and obese individuals may progressively develop adverse metabolic changes over time (24), but weight reduction may prevent this progression. Finally, lifestyle changes that determine weight reduction may have multiple physiological effects and may further prevent the development of atherosclerosis (25, 26).

The strengths of our data included the availability of a large cohort of apparently healthy middle-aged men and women and the availability of repeated measurements of multiple cardiovascular and metabolic risk factors. Our data, however, had several limitations. First, BMI, a simple index of weight-for-height, is an imperfect measure of excess adiposity and obesity, and reflects only overall adiposity (11). Second, metabolic markers are subject to within-person variability and laboratory error, and we cannot exclude the possibility of residual confounding by unmeasured factors. Third, we did not have information on the reasons for weight reduction over follow-up, and we could not know if it was intentional due to dieting and/or increased physical activity, or unintentional due to a chronic condition that may itself be associated with the risk of carotid atherosclerosis. Fourth, we used 2 time points to assess weight change during follow-up period, however, weight change might not have been linear during the entire follow-up period. Finally, our study was based on a cohort of apparently healthy middle-aged Korean men and women attending health check-up visits, and thus our findings may not be generalizable to other race/ethnicity groups or to other settings.

In conclusion, we found that in metabolically healthy but overweight or obese adult men and women, weight reduction was associated with a lower incidence of SCA. Our findings suggest that metabolically healthy overweight or obese subjects may benefit from weight reduction, and adds to the growing literature showing that MHO is not a benign condition. Prospective interventional studies are warranted to validate whether weight reduction reduced CVD risk in metabolically healthy overweight or obese men and women and to understand the mechanisms underlying this association.

Abbreviations

Abbreviations

• BMI
• BP
• CI
• CIMT
  carotid intima-media thickness
• CVD
• HDL-C
  high-density lipoprotein cholesterol
• HOMA-IR
  homeostasis model assessment of insulin resistance
• HR
• IQR
• LDL-C
  low-density lipoprotein cholesterol
• MHO
  metabolically healthy obesity
• SCA
  subclinical carotid atherosclerosis

Acknowledgments

Financial Support: Authors confirm no funding was received for this article.

Author Contributions: Sinn DH, study design, statistical analysis, drafting of manuscript; Kang D, data collection, statistical analysis, drafting of manuscript; Cho SJ, data collection, critical revision of the manuscript; Chang Y, Ryu S, Song YB, Paik SW, Hong YS, and Zhao D, critical revision of the manuscript; Guallar E, statistical analysis, critical revision of the manuscript, study supervision; Cho J, statistical analysis, critical revision of the manuscript, study supervision; Gwak GY, study design, critical revision of the manuscript, study supervision. All authors approved the final submission.

Additional Information

Disclosure Summary: The authors have nothing to disclose.

Data Availability: The datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

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Author notes

Contributed equally to this study as co-first authors.

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