diabetes research and clinical practice 107 (2015) 407–414

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Diabetes Research and Clinical Practice journ al h ome pa ge : www .elsevier.co m/lo cate/diabres

Clinical associations between metabolic syndrome and the development of microalbuminuria in Korean men Jae-Hong Ryoo a, Hyejin Chun b, Hong-Soo Lee c, Eunkyung Suh d, Joong-Myung Choi a, Min-Gi Kim e, HoCheol Shin f, Sung Keun Park a,g,*, Chang-Mo Oh h, Taeg Su Ko i a

Department of Preventive Medicine, School of Medicine, Kyung Hee University, Seoul, Republic of Korea Health Promotion Center, Ewha Womans University Mokdong Hospital, Ewha Womans University School of Medicine, Seoul, Republic of Korea c Department of Family Medicine, Ewha Womans University Mokdong Hospital, Ewha Womans University School of Medicine, Seoul, Republic of Korea d Department of Family Medicine, CHAUM, CHA University School of Medicine, Pocheon, Republic of Korea e Department of Occupational and Environmental Medicine, Dongguk University, Gyeongju Hospital, Seoul, Republic of Korea f Department of Family Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University, School of Medicine, Seoul, Republic of Korea g Total Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University, School of Medicine, Seoul, Republic of Korea h Korea Institute of Drug Safety and Risk Management, Seoul, Republic of Korea i Department of Orthopaedic Surgery, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea b

article info

abstract

Article history:

Aims: There have been several studies on the association between metabolic syndrome

Received 9 April 2014

(MetS) and microalbuminuria. However, none has examined whether MetS is associated

Received in revised form

with the prospective development of microalbuminuria. Accordingly, we performed a

7 October 2014

prospective study to evaluate the longitudinal effects of baseline number of MetS traits

Accepted 25 December 2014

on the development of microalbuminuria in Korean men.

Available online 15 January 2015

Methods: 1649 Korean men without microalbuminuria in 2005 were included and followed prospectively until 2010 with the endpoint being the development of microalbuminuria.

Keywords:

MetS was defined according to the joint interim statement of the International Diabetes

Metabolic syndrome

Federation Task Force on Epidemiology and Prevention. Microalbuminuria was evaluated by

Microalbuminuria

urine albumin creatinine ratio (UACR). Risk estimations for development of microalbumi-

Urine albumin creatinine ratio

nuria were analyzed according to the number of MetS traits using multivariate adjusted Cox proportional hazards model.

* Corresponding author at: Total Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University, School of Medicine, 78 Saemunan-gil, Jongro-Gu, Seoul, Korea 110-746. Tel.: +82 10 3377 6314; fax: +82 2 2001 2626. E-mail address: [email protected] (S.K. Park). Abbreviations: UACR, urine albumin creatinine ratio; MetS, metabolic syndrome; BP, blood pressure; LDL, low-density lipoprotein; HDL, high-density lipoprotein; BMI, body mass index; HOMA-IR, homeostasis model assessment of insulin resistance; AST, aspartate aminotransferase; ALT, alanine aminotransferase; GGT, g-glutamyltransferase; eGFR, estimated glomerular filtration rate; SCr, serum creatinine; CVD, cardiovascular disease; CKD, chronic kidney disease; CRP, C-reactive protein; ACE i, angiotensin-converting-enzyme inhibitor; ARB, angiotensin II receptor blocker. http://dx.doi.org/10.1016/j.diabres.2014.12.005 0168-8227/# 2015 Elsevier Ireland Ltd. All rights reserved.

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diabetes research and clinical practice 107 (2015) 407–414

Results: During 5611.8 person-years of follow-up (median 3.40  1.46 years), microalbuminuria developed in 91 (5.5%) participants between 2006 and 2010. After adjusting for multiple covariates, the hazard ratios (95% confidence interval) for development of microalbuminuria comparing 1, 2 and 3–5 MetS traits vs 0 were 2.57 (0.97–6.82), 2.94 (1.09–7.98) and 3.85 (1.37–10.86), respectively. Conclusions: The number of MetS traits independently associated with the future development of microalbuminuria during the 5-year follow-up period, and MetS per se was an independent risk factor for microalbuminuria. # 2015 Elsevier Ireland Ltd. All rights reserved.

1.

Introduction

Metabolic syndrome (MetS) is defined as the presence of at least three of the following traits, with or without diabetes: abdominal obesity, elevated triglyceride, decreased HDL cholesterol, elevated fasting glucose (insulin resistance) and elevated blood pressure [1]. The prevalence of MetS is increasing in many countries. With an increasingly sedentary lifestyle and high rates of obesity exceeding 30% in most age and gender groups, the prevalence of MetS in Korea increased from 24.9% in 1998 to 31.3% in 2007 [2]. The central feature of MetS is insulin resistance, which results in hyperglycemia and hyperinsulinemia, and may eventually leads to the development of diabetes [3]. MetS, a cluster of several cardiovascular risk factors linked to obesity and insulin resistance, has received increasing attention as a risk factor for cardiovascular disease (CVD) and mortality [4] and maybe used as a predictive tool of future CVD risk. However, others have stated that MetS does not predict more than the sum of its traits, and a major criticism has been raised that MetS is neither associated with CVD nor all-cause mortality [5]. A recent meta-analysis concluded that the ability of currently used definitions of MetS to predict CVD and mortality may be limited [6]. The term ‘microalbuminuria’, which is defined as the urine albumin creatinine ratio (UACR) range within 30–300 mg/g, first appeared in a medical document written by Svendsen et al. [7]. Microalbuminuria was initially used in the evaluation and management of diabetic nephropathy [8]. Microalbuminuria is highly predictive of future overt proteinuria in diabetic patients. Recently however, studies have shown that microalbuminuria is not only a renal risk factor but is also a powerful predictor of CVD in both diabetic and non-diabetic subjects [7,8]. It has also been shown to be an indicative marker of asymptomatic cerebral ischemic lacunar infarcts observed on neuroimaging [9]. More recently microalbuminuria has been extensively regarded as a marker of generalized vascular endothelial impairment even in non-diabetic populations [10] and is reported to have a close association with CVD. The HOPE study indicated that there was no evident threshold of UACR for the risk of CVD [11] and showed a graded relationship between UACR and cardiovascular events, indicating that patients are at increased risk even before UACR reaches the currently accepted thresholds for microalbuminuria. The risk of major cardiovascular events was increased by 5.9% for each increment of 3.01 mg/g (equivalent to 0.4 mg/mmol) in microalbuminuria. The relationship between MetS and microalbuminuria or proteinuria and chronic kidney disease (CKD) has been

investigated in several cross-sectional studies [12–18]. Microalbuminuria in patients with MetS in the absence of diabetes would cause a pro-inflammatory milieu that would result in a greater prevalence of subclinical atherosclerosis and development of CVD [19]. An increasing body of evidence supports the contributory role of microalbuminuria in the prediction of CVD and all-cause mortality. Microalbuminuria represents an important intermediate endpoint of CVD risk in patients with MetS. Thus, considering the inclusion of microalbuminuria as a MetS component or testing microalbuminuria in the followup of MetS patients has been debated. It is still controversial whether MetS components directly influence microalbuminuria in healthy men. In other words, it is unclear whether MetS is a cause or a consequence of microalbuminuria. To our knowledge there are little data available on whether MetS traits directly influence microalbuminuria. For this reason we performed a prospective study to assess whether MetS was associated with the risk of developing microalbuminuria. We also aimed to assess whether the risk of developing microalbuminuria increase progressively with the number of MetS traits.

2.

Materials and methods

2.1.

Study design

A prospective cohort study was conducted in order to investigate the association baseline number of MetS traits and the development of microalbuminuria. Study participants consisted of Korean men undergoing a medical health check-up program at the Health Promotion Center of Kangbuk Samsung Hospital, Sungkyunkwan University, Seoul, Korea. The study methods have been described in detail previously [20]. The purpose of the medical health check-up program is to promote health of the employees and to enhance early detection of existing diseases. All employees participate in either annual or biennial health check-up, as required by the Industrial Safety and Health law in Korea. Most of the study population is the employees and family members of various companies from all around the country. Costs of the medical examinations are largely paid by their employers. We took advantage of this opportunity to conduct a follow-up study.

2.2.

Study population

A total of 4802 men who had an UACR measurement as part of a medical check-up in 2005 participated in this study. Among

diabetes research and clinical practice 107 (2015) 407–414

the 4802 participants, 1109 men were excluded based on the following exclusion criteria: 35 had a past history of malignancy; 78 had a past history of cardiovascular disease; 404 were receiving medication for lipid-lowering agents; 438 had baseline missing data of MetS; 237 had microalbuminuria (30  UACR < 300 mg/mg) and 26 had overt albuminuria (UACR 300  mg/mg) at initial examinations. Because some participants had more than one exclusion criteria, the total number of men who were eligible for the study was 3693. We further excluded 2044 participants who did not attend any follow-up visits between 2006 and 2010. Without the follow-up visit, we could not identify the development of microalbuminuria and could not calculate individual person year. Accordingly, 1649 participants were included in the final analysis and were observed for the development of microalbuminuria (Fig. 1). The total follow-up period was 5611.8 person year and average follow-up period was 3.40 (standard deviation [SD], 1.46) person year. Ethics approval for the study protocol and analysis of the data were obtained from the institutional review board of Kangbuk Samsung Hospital.

2.3.

Clinical and laboratory measurements

Study data included medical history, physical examination, information provided by questionnaire, anthropometric measurements and laboratory measurements. Medical history and history of drug prescription were assessed by the examining physicians. All participants were asked to respond to a questionnaire on health-related behavior. Questions about alcohol intake included frequency of alcohol consumption on a weekly basis and usual consumption amount on a daily basis (20 g/day). Persons who reported smoking at the time were considered to be current smokers. In addition, participants were asked about their physical activity on a weekly basis, such as jogging, bicycling and swimming that lasted long enough to produce perspiration (1 time/week). Diabetes mellitus was defined as fasting serum glucose of at least 126 mg/dL or current use of blood glucose—lowering agents at initial examinations. Hypertension was defined as Initial participants enrolled in 2005 (n=4,802)

Exclusion Criteria in 2005 (n= 1,109) (n=404)

Medication of lipid lowering agentf Past history of cardiovascular disease g

(n=78)

Past history of malignancy

(n=35)

Existence of metabolic syndrome

n(n=438) n(n=51)

Existence of microalbuminuria Existence of overtalbuminuria

n

(n=26)

Initial cohort in 2005 (n=3,693)

Follow-up loss between 2006 and 2010 (n=2,044)

Final sample size (n=1,649)

Fig. 1 – Flow chart of enrolled study participants.

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taking antihypertensive medication or having blood pressure (BP) 140/90 mmHg at initial examinations. Trained nurses obtained sitting BP levels with a standard mercury sphygmomanometer. The first and fifth Korotkoff sounds were utilized in order to estimate systolic and diastolic BP. Blood samples were collected after more than 12 h of fasting and were drawn from the antecubital vein. Serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and g-glutamyltransferase (GGT) were measured using Bayer Reagent Packs (Bayer HealthCare, Tarrytown, NY) by an automated chemistry analyzer (ADVIA 1650 Autoanalyzer; Bayer Diagnostics, Leverkusen, Germany). Insulin level was measured with immunoradiometric assay (Biosource, Nivelles, Belgium). Insulin resistance was calculated with the homeostasis model assessment of insulin resistance (HOMA-IR) as described by Matthews et al.: fasting serum insulin (mU/dL)  fasting serum glucose (mmol/L)/22.5 [21]. Serum creatinine (SCr) level was measured by means of the alkaline picrate (Jaffe) method. Kidney function was measured with estimated glomerular filtration rate (eGFR), calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation: eGFR = 141  min(SCr/K, 1)a  max(SCr/K, 1) 1.209  0.993age  1.018 [if female]  1.159 [if Black], where SCr is serum creatinine, K is 0.7 for females and 0.9 for males, a is 0.329 for females and 0.411 for males, min indicates the minimum of SCr/K or 1 and max indicates the maximum of SCr/K or 1 [22]. A single morning voided urine sample at baseline was used to measure UACR. Urinary albumin concentration was determined by immunoradiometry (radioimmunological competition assay, Immunotech Co. Prague, Czech Republic), and urinary creatinine concentration was measured by the modified Jaffe method. The UACR measured in spot urine sample is known to be highly correlated with the 24-h urine albumin excretion [23]. The development of microalbuminuria was assessed from annual records of all participants and was defined as UACR between 30 and 300 mg/mg. The presence of overt albuminuria was routinely defined as UACR more than 300 mg/mg. Fasting serum glucose was measured with the hexokinase method. Total cholesterol and triglyceride were measured with enzymatic colorimetric tests, low-density lipoprotein (LDL) cholesterol was measured with the homogeneous enzymatic colorimetric test, and HDL cholesterol was measured with the selective inhibition method (Bayer Diagnostics; Leverkusen, Germany). The clinical laboratory has been accredited by the Korean Association of Quality Assurance for Clinical Laboratories and participates annually in inspections and surveys. The presence of MetS was determined according to the joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention [1]. Elevated BP was defined as systolic or diastolic BP of 130/85 mmHg or higher; elevated fasting serum glucose level was defined as 100 mg/dL or greater; high serum triglyceride levels were defined as 150 mg/dL or greater; low HDL-cholesterol levels were defined as less than 40 mg/dL and elevated waist circumference (WC) was defined as more than 90 cm. MetS was defined as the presence of three or more of the above components [24,25]. Body mass index (BMI) was calculated as the weight (kg) divided by the square of the height (m). Height and weight

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diabetes research and clinical practice 107 (2015) 407–414

were measured after an overnight fast with the participants wearing a lightweight hospital gown and without shoes. The WC was measured in a standing position, at the level of umbilicus by a single examiner.

2.4.

Statistical analyses

Data were expressed as means  (standard deviation) or medians (interquartile range) for continuous variables and percentages of the number for categorical variables. The independent t-test and X2-test were used to analyze the statistical differences between baseline non-MetS and MetS. One-way ANOVA and X2-test were used to analyze the statistical differences among the characteristics of the study participants at the time of enrollment in relation to the number of MetS traits. Participants were categorized according to the number of existing MetS traits: 0–2 and 3–5. Participants with 3 components (N = 252, 15.28%), 4 components (N = 105, 6.37%) and 5 components (N = 7, 0.42%) were combined into the 3–5 category for analyses. Because the time of incident microalbuminuria could not be identified exactly, the time of incident microalbuminuria was assumed to be the midpoint between the baseline visit (2005) and the visit at which microalbuminuria was first diagnosed. Person years were calculated as the sum of follow-up times from baseline until the assumed time of microalbuminuria development or until the final examination. We calculated the adjusted hazard ratios (HRs) and 95% confidence intervals (CI) for incident microalbuminuria using the Cox proportional hazards model.

In the multivariate models, we included variables that might confound the relationship between baseline MetS traits and incident microalbuminuria, which include age, LDLcholesterol, eGFR, GGT, HOMA-IR, recent smoking status, regular exercise, alcohol intake, diabetes mellitus and hypertension. For the linear trends of risk, the number of MetS traits was used as a continuous variable and was tested on each model. To use the Cox proportional hazards models, we checked the validity of the proportional hazards assumption. Two approaches were used to assess the validity of the proportional hazards assumption. First, the assumption was assessed by log-minus-log survival function and was found to graphically hold. Second, to confirm the validity of the proportional hazards assumption, time-dependent covariate analysis was used. The time-dependent covariate of the number of MetS traits was not statistically significant, suggesting that the proportional hazards assumption was not violated (P = 0.602). P values

Clinical associations between metabolic syndrome and the development of microalbuminuria in Korean men.

There have been several studies on the association between metabolic syndrome (MetS) and microalbuminuria. However, none has examined whether MetS is ...
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