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Published online September 11, 2007
Diabetes Care 30:3099-3104, 2007
DOI: 10.2337/dc07-0985
© 2007 by the American Diabetes Association
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Cardiovascular and Metabolic Risk
Original Research

Metabolic Syndrome and Incident End-Stage Peripheral Vascular Disease

A 14-year follow-up study in elderly Finns

Jianjun Wang, MD, Sanna Ruotsalainen, MD, Leena Moilanen, MD, Päivi Lepistö, MD, Markku Laakso, MD and Johanna Kuusisto, MD

From the Department of Medicine, Kuopio University Hospital, Kuopio, Finland

Address correspondence and reprint requests to Johanna Kuusisto, MD, Medicine, Cardiology Unit, Kuopio University Hospital, P.O. Box 1777, 70211 Kuopio, Finland. E-mail: johanna.kuusisto{at}kuh.fi


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
 References
 
OBJECTIVE—We investigated the relationship of the metabolic syndrome and its single components, defined by four different criteria, with peripheral vascular disease (PVD) in a prospective population-based study.

RESEARCH DESIGN AND METHODS—The metabolic syndrome was defined according to the World Health Organization (WHO), the National Cholesterol Education Program (NCEP), the International Diabetes Federation (IDF), and the American Heart Association (updated NCEP) criteria. We investigated the relationship of the metabolic syndrome defined by the aforementioned four criteria with PVD (revacularization and amputation) by Cox regression analyses in a Finnish population of 1,212 subjects, aged 65–74 years, with and without diabetes during a 14-year follow-up.

RESULTS—The metabolic syndrome defined by the WHO, NCEP, and updated NCEP criteria was associated with a statistically significant risk for incident PVD (n = 57) with adjustment for all confounding variables except for prevalent diabetes (hazard ratios [HRs] from 1.91 to 2.62). After adjustment for prevalent diabetes or after the exclusion of subjects with prevalent diabetes, there was no association between the metabolic syndrome by any criteria and incident PVD. Of the single components of the metabolic syndrome, elevated fasting glucose by the WHO and NCEP criteria (HR 2.35) and microalbuminuria by the WHO definition (2.56) predicted PVD in multivariable models (prevalent diabetes included).

CONCLUSIONS—The metabolic syndrome defined by the WHO, NCEP, and updated NCEP criteria predicted incident end-stage PVD in elderly Finns but only when not adjusted for diabetes status. Two of the single components of the metabolic syndrome, elevated fasting plasma glucose and microalbuminuria, predicted PVD. We conclude that the metabolic syndrome predicts PVD but not above and beyond the risk associated with diabetes and microalbuminuria.

Abbreviations: ACR, ratio of urinary albumin to urinary creatinine • CHD, coronary heart disease • CVD, cardiovascular disease • FPG, fasting plasma glucose • IDF, International Diabetes Federation • IGT, impaired glucose tolerance • NCEP, National Cholesterol Education Program • PVD, peripheral vascular disease • WHO, World Health Organization


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
 References
 
Peripheral vascular disease (PVD) refers to the atherosclerotic disease of peripheral arteries, most commonly in the lower extremities. Smoking and diabetes are considered to be main risks of lower extremity PVD (1), but it is unclear whether other risk factors for coronary heart disease (CHD) are also risk factors for PVD. The metabolic syndrome, a clustering of cardiovascular risk factors that confers an increased risk of cardiovascular disease (CVD), has been defined by a variety of groups, including the World Health Organization (WHO) in 1999 (2), the European Group for the Study of Insulin Resistance (EGIR) in 1999 (3), the National Cholesterol Education Program (NCEP) Expert Panel in 2001 (4), the American College of Endocrinology (ACE) in 2003 (5), the International Diabetes Federation (IDF) in 2005 (6), and the American Heart Association and the National Heart, Lung, and Blood Institute (updated the NCEP criteria) in 2005 (7). Since these different definitions were published, various prospective studies have reported that the metabolic syndrome defined by the criteria is associated with incidence or mortality of CHD and CVD and stroke (8–17). However, there are limited data on the effect of the metabolic syndrome on PVD (18). In particular, it is unknown whether the metabolic syndrome predicts PVD above and beyond diabetes. Therefore, the aim of the present study was to investigate the relationship of the metabolic syndrome and its single components, defined by the WHO, NCEP, IDF, and updated NCEP criteria, with the risk of end-stage lower extremity PVD in an elderly cohort of Finnish subjects during a 14-year follow-up.


   RESEARCH DESIGN AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
RESULTS
 CONCLUSIONS
 References
 
Baseline study
The formation (19) and representativeness (20) of the study population have been described in detail previously. Briefly, the study was conducted in Kuopio, east Finland, between 1986 and 1988. Altogether, 1,910 subjects born between 1912 and 1921 were randomly selected from the population register including all inhabitants of Kuopio. This random sample covered 35% of all residents in the age-group of 65–74 years. The overall participation rate was 71%. All subjects with intermittent claudication and gangrene diagnosed by physicians at the baseline examination or with a previous history of leg amputation and peripheral revascularization surgery were excluded from the statistical analyses for incident PVD. The WHO criteria (2) for impaired glucose tolerance (IGT) and diabetes were used in the classification of subjects without previously known diabetes based on fasting plasma glucose (FPG) and 2-h postload glucose values at baseline. The diagnosis of previously known diabetes was based on drug treatment for diabetes or a history of a diagnosis of diabetes made by a physician. A total of 1,212 subjects aged 65–74 years were included in the current study. Among them, 962 were nondiabetic, 122 had known diabetes, and 128 had newly diagnosed diabetes at baseline.

Previous verified definite and possible myocardial infarctions before the baseline study were defined according to the WHO Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) project criteria (21) as modified by the FINMONICA Acute Myocardial Infarction (AMI) Register Study Group (22).

Weight, height, waist and hip circumference, and blood pressure were measured. Waist-to-hip ratio was defined as the ratio of waist circumference to hip circumference. BMI was calculated as weight in kilograms divided by the square of height in meters. Smoking status was defined as current smoking. With respect to alcohol consumption, subjects were classified as alcohol users or nonusers. Physical activity during leisure time was classified as physically inactive (little and occasional activity) and physically active (regular exercise at least once a week and at least 30 min per time). Physical activity at work was classified as light physical work (sedentary; standing, and walking a little) and heavy physical work (exhausting workload or heavy manual work).

Blood samples were taken in the morning after a 12-h overnight fast. All subjects, except for those receiving insulin, underwent an oral glucose tolerance test (75 g glucose). Plasma glucose and insulin, serum lipids and lipoproteins, and urinary albumin were determined as described previously (19,23). The ratio of urinary albumin (milligrams per liter) to urinary creatinine (millimoles per liter) (ACR) was used as a measure of albumin excretion.

The study complies with the Declaration of Helsinki and was approved by the Ethics Committee of Kuopio University Hospital. All study subjects gave informed consent.

Follow-up study
Medical records of all study subjects who participated in the baseline study in 1986–1988 were reviewed by two of the authors (S.R. and J.K.). Clinical records for individuals who developed end-stage PVD during the 14-year follow-up were obtained from the medical records of the Kuopio University Hospital where all patients with PVD are treated (S.R. and J.K.). PVD was defined as lower extremity amputation (n = 26) due to ischemic vascular disease or peripheral revascularization (angioplasty or surgery) (n = 31), recorded until the end of June 2001.

Definitions of the metabolic syndrome
The WHO, NCEP, IDF, and updated NCEP definitions include diabetic individuals, and, therefore, the present study was based on these definitions. Each component of the four definitions was defined according to the original criteria. Criteria for the four definitions of the metabolic syndrome are shown in Table 1.


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  		Table 1— Definitions of the metabolic syndrome by the WHO, NCEP, IDF, and updated NCEP criteria

 
Statistical analyses
All statistical analyses were performed with SPSS 14.0 statistical programs. Because of the skewed distribution of fasting insulin, triglyceride concentrations, and ACR, these variables were log transformed for statistical analyses. Differences in baseline characteristics between subjects with and without incident PVD were tested by a {chi}2 test and univariate ANOVA adjusted for age and sex. The baseline variables not included in the definitions of metabolic syndrome but showing a statistically significant association with incident PVD were added into the multivariable Cox regression models as covariates. The multivariable Cox regression analyses were applied to investigate the association of the metabolic syndrome defined by the four criteria with incident PVD in adjusted models (model 1: adjusted for age and sex; model 2: adjusted for age, sex, history of myocardial infarction, and physical activity of work; and model 3: adjusted for age, sex, history of myocardial infarction, physical activity of work, and prevalent diabetes). A product term of sex x each of four definitions was added to the model to represent interaction. The null hypothesis of no interaction was tested using the change in –2 log likelihoods between Cox models with and without the product term. The effect of the single components of the metabolic syndrome on incident PVD was tested by the multivariable Cox regression models adjusted for other risk factors. P < 0.05 (two sided) was considered to be statistically significant. Exact P values and 95% CIs are given in the tables.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
CONCLUSIONS
 References
 
The median follow-up for incident PVD (nondiabetic subjects: 24 revascularizations and 2 amputations; diabetic subjects: 9 revascularizations and 22 amputations) was 14.0 years (the 25th and the 75th quartiles were 13.6 and 14.7 years, respectively). Of the 57 subjects with PVD during the follow-up, 31 had diabetes. Compared with subjects without incident PVD, more subjects with incident PVD had previous myocardial infarctions and diabetes and were physically active at work. Subjects with PVD had also higher levels of systolic blood pressure, ACR, triglycerides, FPG, and 2-h postload glucose and lower levels of HDL cholesterol (Table 2). Although there was a trend that more subjects with incident PVD were current smokers compared with those without PVD (12.3 vs. 7.9%), no statistically significant difference in smoking was found.


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  		Table 2— Baseline characteristics of subjects with and without incident PVD during the 14-year follow-up in 1,212 elderly subjects

 
Table 3 shows hazard ratios (HRs) of the metabolic syndrome defined by the four different criteria to predict PVD during the 14-year follow-up among all subjects. The prevalence of the metabolic syndrome at baseline varied from 51.1% (WHO criteria) to 61.1% (IDF criteria), depending on the metabolic syndrome criteria. The metabolic syndrome by the WHO, NCEP, IDF, and updated NCEP criteria was associated with a 1.84- to 2.74-fold risk for incident PVD when adjusted for age and sex (model 1). After further adjustment for history of myocardial infarction and physical activity at work (model 2), the metabolic syndrome defined by the WHO, NCEP, and the updated NCEP criteria was associated with a statistically significant 1.91- to 2.62-fold risk for future PVD. However, the metabolic syndrome by the IDF criteria did not predict PVD when adjusted for all of aforementioned factors in model 2. When prevalent diabetes was added into model 2, none of the four definitions predicted future PVD (model 3). Interaction terms between sex and the metabolic syndrome by the four definitions were not significant for PVD (P > 0.50).


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  		Table 3— HRs (95% CIs) of the metabolic syndrome defined by the WHO, NCEP, IDF, and updated NCEP criteria for incident PVD during the 14-year follow-up in 1,212 nondiabetic and diabetic subjects

 
We also repeated statistical analyses by excluding subjects with prevalent diabetes (n = 250), with previous myocardial infarction (n = 107), and with microalbuminuria (n = 277), respectively. None of the four definitions predicted incident PVD in nondiabetic subjects and in subjects without microalbuminuria (data not shown). When 107 subjects with previous myocardial infarction were excluded, results similar to those given in Table 3 were obtained. When analyses were done separately in diabetic and nondiabetic subjects, the metabolic syndrome was not a predictor of incident PVD because of a small number of events.

Table 4 shows HRs for the single components of the metabolic syndrome definitions for risk of PVD in multivariable Cox regression models after adjustment for other risk factors in all subjects. In all subjects, the following single components of the metabolic syndrome predicted PVD after the adjustment for age, sex, history of myocardial infarction, and physical activity at work (model 1): elevated FPG (FPG ≥6.1 mmol, HR 4.03) according to the WHO and NCEP criteria and elevated FPG (FPG ≥5.6 mmol, HR 2.55) according to the updated NCEP criteria, low HDL cholesterol (HDL cholesterol <1.03 mmol/l in men or <1.29 mmol/l in women, HR 1.90) according to the NCEP criteria, and microalbuminuria (ACR ≥3.39 mg/mmol, HR 3.23) according to the WHO definition. After further adjustment for prevalent diabetes (model 2), the following single components of the metabolic syndrome still predicted PVD: elevated FPG (FPG ≥6.1 mmol, HR 2.35) and microalbuminuria (ACR ≥3.39 mg/mmol, HR 2.56). Of the single components, only low HDL cholesterol (HDL cholesterol <1.03 mmol/l in men or <1.29 mmol/l in women) according to the NCEP criteria predicted PVD risk in model 2 (HR 3.02) among nondiabetic subjects.


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  		Table 4— HRs (95% CIs) of individual components of the metabolic syndrome based on the WHO, NCEP, IDF and updated NCEP definitions for incident PVD in 1,212 subjects

 

   CONCLUSIONS
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
References
 
To our knowledge, this is the first study investigating the role of the metabolic syndrome, defined by the WHO, NCEP, IDF, and updated NCEP criteria, to predict incident end-stage PVD. In the present study, the metabolic syndrome defined by the WHO, NCEP, and updated NCEP criteria predicted PVD in the elderly population. After the diabetes status was taken into account, none of the metabolic syndrome definitions predicted incident PVD.

Only one previous prospective study (Dutch) has reported that the modified NCEP definition predicted PVD in subjects with familial hypercholesterolemia (18). However, the original definition of the metabolic syndrome was not used in this study because of the lack of waist circumference measurement. Moreover, the authors did not investigate whether the metabolic syndrome predicted PVD when diabetes status and CHD were taken into account or whether all risk factors included in the definition of the metabolic syndrome are equally important in predicting PVD. In our study, we investigated the relationship between PVD and the metabolic syndrome defined by the four originally proposed criteria and included all components of each definition. Given the fact that the risk of PVD is increased by the presence of CHD and diabetes (24,25), we also controlled for diabetes status and previous myocardial infarction in statistical analyses.

We also investigated whether all single components of the metabolic syndrome were equally important in predicting PVD and whether the single components were better predictors of PVD than was the metabolic syndrome. We found that of the single components of the metabolic syndrome, elevated FPG (FPG ≥6.1mmol/l) and microalbuminuria, were predictive of PVD with higher HRs compared with the metabolic syndrome definitions. Although epidemiological and experimental data show that microalbuminuria is associated with an increased risk for all-cause and CVD mortality, hypertension, and diabetes, there is a little information on the relationship between microalbumin and PVD (26,27). In this study, we found that the metabolic syndrome did not predict PVD when subjects with microalbuminuria were excluded, supporting the findings of previous studies (26–28), which have shown that microalbuminuria is associated with PVD and diabetes. Accordingly, the WHO and NCEP criteria for the metabolic syndrome, which include FPG ≥6.1mmol/l and microalbuminuria in their definitions, had the highest HRs in different statistical models. However, with adjustment for diabetes status, the predictive powers of elevated FPG and microalbuminuria were significantly attenuated. Furthermore, low HDL cholesterol predicted PVD risk only without adjustment for diabetes status. IGT was not a predictor of incident PVD in any model.

In the present study, the metabolic syndrome was not a statistically significant risk factor for PVD in nondiabetic and diabetic subjects when it was analyzed separately. In contrast, our previous study showed that the metabolic syndrome was a predictor of CVD mortality in subjects without diabetes, although not above and beyond the risk associated with its individual components, such as impaired fasting glucose, IGT, low HDL cholesterol, and microalbuminuria (17). The relationship between the metabolic syndrome and PVD may be different from that of the metabolic syndrome and CVD (17), but it is also possible that the number of cases of PVD in subgroups was too small (26 in nondiabetic subjects and 31 in diabetic subjects) to demonstrate a statistically significant effect of the metabolic syndrome on the risk of PVD.

Although smoking is probably the most important risk factor for the development of PVD in middle-aged men (29), we did not find this association in our study. A low percentage of smokers and a low number of PVD events (n = 57) as well as the elderly population may explain the results.

A major limitation of our study is a relatively low number of PVD events, even though the follow-up time was long. We restricted our analysis to end-stage PVD, and, thus, milder cases of PVD (claudication and limb ischemia) were not included. Therefore, our findings may apply only to severe cases of PVD. The diagnosis of PVD was determined by strict clinically relevant criteria at both baseline and follow-up examinations similarly in diabetic and nondiabetic subjects, and the proportion of revascularizations of all cases of PVD was >50%. However, amputations do not necessarily result from atherosclerosis alone, because in diabetic subjects, neuropathy and concurrent infections may contribute to gangrene. Furthermore, the absence of middle-aged individuals in the cohort may lead to bias in the incidence of PVD. Finally, because of several definitions of the metabolic syndrome, multiple testing increases the likelihood of false-positive P values.

In summary, the metabolic syndrome defined by the WHO, NCEP, and updated NCEP criteria predicts incident end-stage PVD in elderly subjects but only when not adjusted for diabetes status. Two single components of the metabolic syndrome, namely elevated FPG and microalbuminuria, predicted PVD with higher HRs than those for the metabolic syndrome. Therefore, the metabolic syndrome is a risk factor for PVD, but not above and beyond the risk associated with diabetes and microalbuminuria.


   Acknowledgments
 
This work was supported by a grant from the Academy of Finland to M.L.


   Footnotes
 
Published ahead of print at http://care.diabetesjournals.org on 11 September 2007. DOI: 10.2337/dc07-0985.

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C Section 1734 solely to indicate this fact.

Received for publication May 22, 2007. Accepted for publication September 1, 2007.


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TOP
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 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
 References
 

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