Influence of Metabolic Syndrome and General Obesity on the Risk of Ischemic Stroke
Background and Purpose— In 2005, the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) guideline lowered the fasting glucose cut point used to define metabolic syndrome (MS). This study investigated the influence of MS on ischemic stroke (IS) risk using both the original and revised definitions. In addition, because abdominal obesity is the measure of obesity used in the guideline to define MS, we also investigated whether general obesity (GOB) should be considered in the definition of MS.
Methods— Baseline data from 3453 adults (≥20 years of age) in the Cardiovascular Diseases Risk Factor Two-Township Study were linked to insurance claim and death certificate records. The 2001 and 2005 NCEP-ATP III definitions were used with Asian and Taiwanese specific cut-off values for waist circumference and body mass index. Hazard ratios of MS and GOB on IS were calculated using Cox models, and the Kaplan–Meier method was used to derive free-of-IS survival curves.
Results— During 10.4 years of follow-up, 132 persons developed IS. Hazard ratios of subjects with 1 to 2 and ≥3 MS component disorders were 2.69 and 4.30, respectively, under the 2001 definition, and 3.16 and 5.15, respectively, under the 2005 definition (all P values <0.05). MS subjects with GOB had reduced survival at a borderline significance level. Adding GOB in the MS definition did not significantly alter the number of subjects with MS nor the ability to predict stroke risk. Replacing abdominal obesity with GOB in MS definition reduced the number slightly and increased the hazard ratio.
Conclusion— MS predicted IS and the 2005 NCEP definition showed a stronger dose-response relationship with IS. Adding GOB to the existing MS definition had limited benefit.
The metabolic syndrome (MS) has attracted tremendous attention in recent years, and ≥5 definitions of MS have been proposed by various medical societies.1 The most recent definition proposed by the International Diabetes Federation in 20052 emphasizes abdominal obesity (AOB), a lowered cut point for fasting glucose, and ethnic-specific cut points for waist circumference.
Obesity is defined by waist circumference in the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) guideline as well as in several other MS definitions. However, the World Health Organization definition uses both waist-to-hip ratio and body mass index (BMI).1 It is important to evaluate whether incorporating BMI in the MS definition improves prediction of future cardiovascular disease.
The ATP III definition has been used widely in recent studies. The American Heart Association (AHA) and the National Heart, Lung, and Blood Institute (NHLBI) have recently issued new guidelines for the diagnosis and management of MS.1 The new NCEP-ATP III guideline uses a lower glucose cut point and ethnic-specific waist measures. In the present study, we investigate whether general obesity (GOB) can improve prediction of ischemic stroke (IS) risk in addition to MS, using both the original and newly modified ATP III definitions.
Materials and Methods
The CardioVascular Disease risk FACtors Two-township Study (CVDFACTS) is a community-based follow-up study focusing on cardiovascular diseases and their risk factors in Taiwan. During 1991 to 1993, all residents ≥3 years of age in 5 villages in Chu-Dung and 5 villages in Pu-Tzu were invited to participate in the baseline examination. A total of 6312 people participated (2902 males and 3410 females), corresponding to a 20% participation rate,3 and 5040 participants were ≥20 years of age. Three follow-up examinations have been performed in 1994 to 1997, 1997 to 1999, and 1999 to 2001. Although the information collected in the follow-up examinations varied, measurements of anthropometric, biochemical, and hemodynamic variables as well as subjects’ self-reported disease status were all included. Subjects were excluded if they reported a history of stroke at baseline (n=103), had fasted for <8 hours (n=344), were not covered by National Health Insurance (NHI; n=30), or had missing or extreme values of BMI, or 1 of the 5 MS-defining components (n=1110). There were 3453 adult subjects eligible for analysis in this study. Further details about sampling and data collection are described previously.3 All participants gave informed consent at baseline and follow-up.
Examinations were performed in the study clinics set up in the 2 townships. While lightly clothed, the participants’ weight, height, and waist circumference were measured.4 Blood pressure was measured 3 times after the subject had been seated for ≥5 minutes, and the mean of the last 2 readings was used for analysis. All subjects were asked to fast overnight for ≥8 hours before blood specimen collection. Fasting glucose and triglyceride were measured on −70°C stored specimen soon after blood collection (<1 month). High-density lipoprotein cholesterol (HDL-C) measurement using the homogeneous method5 was left until 2001. Individuals attending the baseline examination also completed a questionnaire-based interview. The questionnaire contained items on demographic data (birth date and sex), lifestyle (smoking, alcohol consumption, physical activity), socioeconomic status (education level, occupation), self-reported health conditions (disease status or on antihypertensives, diabetes, cardiovascular diseases, cancers), and family history of disease.
Definition of First-Ever IS
Both fatal and nonfatal IS end points were included in the analysis. Three sources of information were used to determine whether a subject experienced first-ever IS after the baseline examination, including death certificate data, insurance claim records in the NHI database, and subject’s self-reported disease history. A total of 99.5% of our studied subjects were covered by NHI (loss to follow-up rate=0.5%), and their medical history could be obtained from the claim data. Validated rules were established to determine whether the subjects had experienced a first-ever IS and the timing of this event during follow-up. A first-ever stroke was defined by any 1 of the following conditions in those with no history of stroke at baseline: (1) hospitalization claim for >1 day with International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes of 430 to 438 followed by claims for various neurological imaging technology (computed tomography, MRI, transcranial or carotid Doppler sonography) or claims for rehabilitation and long-term prescriptions customarily used for IS; (2) records of emergency room service with the above codes followed by claim data for imaging, rehabilitation, and long-term medication as described in (1); or (3) records of >3 consecutive outpatient visits to a teaching hospital with the above codes and claims for examinations, services, or prescriptions as described in (1). IS was defined by the ICD-9-CM code 432, 433, or 436. If claim data with relevant codes did not match any of the above rules, or if claim data contained different stroke subtypes, the patient’s stroke status was evaluated independently by 3 neurologists blind to the patient’s profile. Consensus was reached after discussion in cases of disagreement. Subjects who had an incident IS or died from any cause were censored on the date of the event. The remaining subjects were censored in December 2002 because their medical claim data indicated that they were free from stroke up to that time.
ATP III6 defines MS as the presence of ≥3 defining component disorders: AOB (waist circumference ≥102 cm for men and ≥88 cm for women), high fasting triglycerides (≥1.7 mmol/L [150 mg/dL]), low HDL-C (HDL-C <1.04 mmol/L [40 mg/dL] for men and <1.30 mmol/L [50 mg/dL] for women), high fasting glucose (≥6.1 mmol/L [110 mg/dL] or taking antihyperglycemics), and high blood pressure (systolic blood pressure ≥130 mm Hg or diastolic blood pressure ≥85 mm Hg or taking antihypertensives). The cut points for waist circumference are lower for Asians (≥90 cm for men and ≥80 cm for women).7 The modified definition recommended by AHA/NHLBI, which lowered the cut point of fasting glucose to 5.6 mmol/L (100 mg/dL),1 was also used in the present study. GOB for Taiwanese was defined as BMI ≥27 kg/m2, corresponding to a similar degree of fat composition to whites with a BMI of 30.8 When evaluating the effect of incorporating GOB in the MS definition on the prediction of IS, we used 2 alternative MS definitions, one with GOB replacing AOB, and the other using AOB or GOB to define obesity.
To estimate the contribution of MS and its related variables to the development of stroke, we calculated hazard ratios (HRs) by applying Cox proportional hazard models, adjusted for age, age squared, residential township, smoking, alcohol intake, physical activity level, parental history of stroke, and education level. Four IS-free survival curves were calculated using the Kaplan–Meier method for: MS with GOB (or excess BMI), MS without GOB, non-MS with GOB, and non-MS without GOB. The log-rank test was used to examine whether these curves were significantly different. All analyses were performed using SAS 8.02.
Baseline characteristics of the subjects are shown in Table 1. Those who developed IS during follow-up were significantly more likely to be elderly, less educated, and have AOB, high blood pressure, high fasting glucose, and more MS component disorders at baseline. Women with incident IS were significantly more likely to have high fasting triglycerides, and men with incident IS were more likely to have low HDL-C. The prevalence of high fasting glucose increased from 20.5% to 43.8% in men and 16.7% to 35.0% in women when the cut point was lowered from 110 to 100 mg/dL. Nevertheless, the prevalence of MS only changed from 22.0% to 27.8% in men and from 20.7% to 24.9% in women after switching to the new definition.
During a mean follow-up time of 10.4 years, there were 174 incident strokes identified, 132 of which were IS. Risk of IS increased with the number of MS component disorders. Compared with men without any component disorders at baseline, HRs of IS for men with 1 to 2, and ≥3 component disorders were 3.4 (95% CI, 1.2 to 9.5) and 5.8 (2.0 to 16.5), respectively. This trend was also demonstrated in women: 1.7 (0.5 to 5.9) and 2.5 (0.7 to 8.4). Using the AHA/NHLBI-modified definition, the corresponding HRs were 4.1 (1.0 to 17.3) and 8.2 (2.0 to 34.3) in men and 2.0 (0.5 to 8.6) and 2.6 (0.6 to 11.3) in women. The first column in Table 2 shows the dose-response effect of MS component disorders for men and women combined. We observed a stronger HR trend under the 2005 definition.
GOB was more prevalent in people with more MS component disorders. Only a few people (8 and 5, respectively) had GOB without any MS component disorders under either definition. Because of the small sample size and the lack of incident IS cases, this group was not included in the Cox models (Table 2). Taking people without any MS component disorders and without GOB as the referent group, the dose-response effect of MS disorders on IS was stronger in men and women with GOB at baseline. The degree of additional risk contributed by GOB was more marked in women. GOB increased the IS risk in women with MS by 73% and 95% using the 2001 and 2005 definitions, respectively. GOB increased the risk in men with MS by 25% and 41%, respectively. The Figure shows the Kaplan–Meier IS-free survival curves. For both people with or without MS, the survival curves were steeper in the groups with GOB, although the difference had only borderline significance (P=0.0605) for people with MS and was not significant for people without MS.
If the obesity component of MS was defined by having either GOB or AOB, the HR of MS did not differ greatly from that of MS using AOB only. The HR of MS was slightly higher when defined solely by GOB; however, fewer subjects satisfied this alternative definition (Table 3).
MS has been associated with a higher risk of coronary artery disease9 and all-cause and cardiovascular mortality.10,11 In a large sample size of people with a history of coronary heart disease, Koren-Morag et al showed that the risk of IS was highest in men with 4 or 5 MS component disorders, whereas in women, the risk was highest in those with 5 component disorders.12 In a case-control study, Milionis et al demonstrated that elderly patients with MS had higher odds for a first-ever ischemic nonembolic stroke.13 However, these 2 studies did not examine the role of GOB in conjunction with MS in the development of IS. This is the first community-based cohort study that examines the relationship between GOB, MS and IS. Similar to previous studies, we found that the number of MS component disorders was associated with IS risk in a dose-response fashion.
We found that MS subjects with GOB exhibited a greater risk of IS. Our findings differed from those of another study exploring the relationships between GOB, MS, and incident overall cardiovascular events in women with suspected myocardial ischemia, which found a strong association between cardiovascular diseases and MS but not with excess BMI.14 Our community-based study on cardiovascular disease–free individuals with >10 years of follow-up provides temporal evidence toward the effect of excess BMI on IS risk. Although this effect showed only borderline statistical significance in this study of moderate sample size, it is potentially plausible. The risk of IS attributed to GOB in addition to MS may result from other factors in the etiologic pathway of IS that are not included in the syndrome definition. Adverse affects of circulating coagulation factors,15,16 inflammatory factors,9,17 and cardiac physiological variables18 are among the possible candidates. Despite our finding of the additional effect of elevated BMI, we do not advocate the inclusion of GOB in the definition of MS because incorporating AOB already accounted for most of the subjects with GOB. Including GOB will only include 0.4% to 0.5% more people as having MS. Nonetheless, our results are pertinent to IS risk in those of Chinese ethnicity. Further studies are needed to explore this issue in other ethnic groups, particularly in relation to coronary artery disease.
There is growing evidence that intervention to reduce insulin resistance delays the onset of type 2 diabetes and reduces cardiovascular disease risk in people with impaired glucose tolerance.19,20 The relationship between fasting glucose and cardiovascular risk is a continuous one, and therefore it is often hard to decide on cut points to use for screening. The relationship between the 2 definitions of MS and IS was examined in our study and showed that the dose-response effect was stronger when a lower glucose cut point was chosen. This result suggests that lowering the glucose threshold improves the classification of MS and non-MS individuals with regard to IS risk.
In conclusion, MS is associated with higher incidence of IS. Our data indicate that the new ATP III definition shows a stronger dose-response relationship between MS and IS risk. GOB contributed to the risk of IS with only borderline significance when used in addition to MS with AOB. However, the predictive power of MS on IS remained the same after incorporating GOB into the MS definition.
The present study was funded by the National Health Research Institutes in Taiwan (NHRI-EX93-9225PP, NHRI-EX94-9225PP). Data collection was supported by the Department of Health in Taiwan (DOH80-27, DOH81-021, DOH8202-1027, DOH83-TD-015, and DOH84-TD-006). The authors would like to express their gratitude to neurologists in Shin Kong WHS Memorial Hospital who helped review medical charts of stroke patients and provided consultation for the development of decision rules to identify new stroke cases from national health insurance data. Appreciation should also go to Dr Hsing-Yi Chang for her guidance on the Kaplan–Meier method.
- Received September 26, 2005.
- Revision received December 2, 2005.
- Accepted January 13, 2006.
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