Author + information
- Received August 24, 2005
- Revision received December 1, 2005
- Accepted December 5, 2005
- Published online April 18, 2006.
- Javed Butler, MD, MPH, FACC⁎,⁎ (, )
- Nicolas Rodondi, MD, MAS∥,
- Yuwei Zhu, PhD†,
- Kathleen Figaro, MD, MS‡,
- Sergio Fazio, MD, PhD⁎,
- Douglas E. Vaughan, MD, FACC⁎,
- Suzanne Satterfield, MD§,
- Anne B. Newman, MD, MPH#,
- Bret Goodpaster, PhD#,
- Douglas C. Bauer, MD∥,
- Paul Holvoet, PhD⁎⁎,
- Tamara B. Harris, MD, MS††,
- Nathalie de Rekeneire, MD††,
- Susan Rubin, MPH¶,
- Jingzhong Ding, PhD‡‡,
- Stephen B. Kritchevsky, PhD‡‡,
- Health ABC Study
- ↵⁎Reprint requests and correspondence:
Dr. Javed Butler, Cardiology Division, 383-PRB, Vanderbilt University Medical Center, Nashville, Tennessee 37232
Objectives The purpose of this study was to assess whether metabolic syndrome (MetSyn) predicts a higher risk for cardiovascular events in older adults.
Background The importance of MetSyn as a risk factor has not previously focused on older adults and deserves further study.
Methods We studied the impact of MetSyn (38% prevalence) on outcomes in 3,035 participants in the Health, Aging, and Body Composition (Health ABC) study (51% women, 42% black, ages 70 to 79 years).
Results During a 6-year follow-up, there were 434 deaths overall, 472 coronary events (CE), 213 myocardial infarctions (MI), and 231 heart failure (HF) hospital stays; 59% of the subjects had at least one hospital stay. Coronary events, MI, HF, and overall hospital stays occurred significantly more in subjects with MetSyn (19.9% vs. 12.9% for CE, 9.1% vs. 5.7% for MI, 10.0% vs. 6.1% for HF, and 63.1% vs. 56.1% for overall hospital stay; all p < 0.001). No significant differences in overall mortality was seen; however, there was a trend toward higher cardiovascular mortality (5.1% vs. 3.8%, p = 0.067) and coronary mortality (4.5% vs. 3.2%, p = 0.051) in patients with MetSyn. After adjusting for baseline characteristics, patients with MetSyn were at a significantly higher risk for CE (hazard ratio [HR] 1.56, 95% confidence interval [CI] 1.28 to 1.91), MI (HR 1.51, 95% CI 1.12 to 2.05), and HF hospital stay (HR 1.49, 95% CI 1.10 to 2.00). Women and whites with MetSyn had a higher coronary mortality rate. The CE rate was higher among subjects with diabetes and with MetSyn; those with both had the highest risk.
Conclusions Overall, subjects over 70 years are at high risk for cardiovascular events; MetSyn in this group is associated with a significantly greater risk.
Metabolic syndrome (MetSyn) has recently been acknowledged as a risk factor for cardiovascular disease and mortality (1–4). The third report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III) specifically underscores the importance of the MetSyn and provides a working definition of this syndrome (5). Findings from the third National Health and Nutrition Examination Survey showed that the MetSyn is highly prevalent within the U.S. (6); however, most of the data regarding MetSyn and cardiovascular outcomes are derived from populations consisting mostly of middle-aged and younger subjects. Although elderly subjects might have been included in some of these studies, to date there are no large studies that have primarily focused on MetSyn in the elderly population exclusively. Therefore, whether MetSyn is as strong a cardiovascular risk factor in older adults as it is in younger populations has not been established. Some differences in the risk factors and their importance among the geriatric versus the broader adult patient population have been described previously, and the predictive power of many traditional cardiovascular risk factors diminishes with increasing age (7–9). This is an important issue, because the proportion of older adults in the population is increasing and the trend is projected to continue (10). This becomes even more important when considering that older adults are not treated as aggressively as younger subjects (11–13).
The Health, Aging, and Body Composition Study (Health ABC) was designed to investigate the impact of changes in body composition and health conditions on age-related physiological and functional status among adults from 70 to 79 years of age. In this cohort, we assessed the relationship between MetSyn, cardiovascular outcomes, and mortality in older adults.
Study subjects for this investigation included participants in the Health ABC study, a population-based cohort of 3,075 healthy, well-functioning, community-dwelling men and women ages 70 to 79 years. To be eligible for participation in Health ABC study, subjects had to report no difficulty in walking one-quarter mile or climbing 10 stairs without resting. Participants were identified from a random sample of white Medicare beneficiaries and all age-eligible black community residents in designated zip code areas surrounding Pittsburgh and Memphis. Exclusion criteria included: difficulties with activities of daily living, obvious cognitive impairment, inability to communicate with the interviewer, intention of moving within three years, or participation in a trial involving a lifestyle intervention. All participants gave written informed consent: the institutional review boards at both study sites approved the protocol. Forty subjects from this cohort were excluded, owing to missing data needed to define MetSyn; thus a total of 3,035 subjects were studied. Baseline data were collected in 1997 to 1998, and these results represent the outcomes during the first six years of follow-up.
Subjects were classified with the baseline data into those who did and did not have MetSyn, using the ATP III guidelines (any three of the following risk factors: increased waist circumference [men >101.6 cm and women >88.9 cm], triglycerides ≥150 mg/dl, low high-density lipoprotein cholesterol [men <40 mg/dl, women <50 mg/dl], blood pressure ≥130/≥85 mm Hg, and fasting glucose >110 mg/dl) (5). Diabetes was defined in Health ABC study as self-reported diagnosis and/or as using any anti-hyperglycemic medication at baseline. Participants taking anti-hyperglycemic medications were counted as meeting the glucose criterion, and participants taking antihypertensive medication were counted as meeting the blood pressure criterion. Smoking status was defined as current, past use (if the participant had stopped smoking, but smoked at least 100 cigarettes in his/her life), or never.
Participants were asked to report any hospital stays, and every 6 months they were asked direct questions to elicit information about interim cardiovascular event. When an event was reported, hospital stay records were collected and the diagnosis was verified by a Health ABC Disease Adjudication Committee, and only confirmed events were included. Coronary event (CE) was defined as admission to the hospital for myocardial infarction (MI), angina, or either percutaneous or surgical revascularization. Myocardial infarction was defined by coronary death or any overnight hospital stay for acute MI. Similarly, all hospital admissions that were confirmed as related to decompensated heart failure (HF) were studied. Events and diagnoses were adjudicated on the basis of hospital stay records and death records. Date of death was taken from the death certificate and hospital stay records. Underlying causes of death were determined by central adjudication. Coronary heart death was defined as any death where the underlying cause of death was ascertained as atherosclerotic cardiovascular disease, which included definite fatal MI, definite fatal coronary heart disease (CHD), and possible fatal CHD. Cardiovascular death was defined as any death classified as coronary death or death due to HF.
Descriptive and exploratory analyses were used to evaluate demographic characteristics stratified by MetSyn status at baseline. Bivariate analyses were performed to assess the associations between MetSyn and risk for MI, HF hospital stay, CE, overall hospital stay, and coronary, cardiovascular, and overall mortality, stratified by race and gender. Furthermore, a sub-group analysis of 2,249 patients without any past history of CHD or HF was constructed to assess the importance of MetSyn in predicting new onset events. For this analysis, we excluded participants with baseline cardiovascular disease, defined as CHD (angina, MI, angioplasty of coronary arteries, or coronary artery surgery) or HF. The presence of clinical disease at baseline was determined on the basis of the International Classification of Diseases 9th Revision-Clinical Modification (ICD9-CM) codes reported by Medicare and Medicaid Services for the years 1995 to 1998, self-reported history, and the use of selected drugs, and ascertained by use of algorithms mirroring adjudicated diagnoses in the Cardiovascular Health Study (14). To assess the importance of diabetes, similar outcomes were assessed in the entire cohort stratified by the presence or absence of diabetes. All comparisons were done with chi-square test for categorical and ttest for continuous variables. The patients were divided into six groups on the basis of the presence of zero to all five of the MetSyn risk factors in order to assess the importance of multiple MetSyn risk factors. Similar analyses were performed with chi-square test for trend.
Finally, we constructed a proportional hazard model (Cox regression) to determine the adjusted likelihood of first coronary death, first cardiovascular death, first any-cause death, first MI or MI death (other deaths censored), first HF hospital stay (all deaths censored), first CE (all death censored), or first any-cause hospital stay (all death censored) before six years (2,190 days) between two MetSyn groups. Subjects who didn’t have events or who had events that happened six years after enrollment were censored. Potential confounders included in the regression were age, race (white and black), gender (male and female), smoking (never, past, and current), marital status (married, widow, and other), site (Memphis and Pittsburgh), and the presence of diabetes at baseline. We then chose clinically relevant interaction terms to develop our model. This included the interaction between race and gender and the interaction between MetSyn and race. The effects of such interaction terms were tested and were found not to be statistically significant. They were therefore not incorporated into the final model. Hazard ratio (HR) and 95% confidence interval (CI) were estimated. Survival function plots were generated for first MI or MI death, first HF hospital stay, first CE, and first any-cause death. All analyses were done with PC-SAS version 9.1 (SAS Institute, Inc., Cary, North Carolina).
Table 1describes the baseline characteristics of the study population. Subjects with MetSyn were more likely to be women (57% vs. 48%, p < 0.001), widowed (33.1% vs. 29.4%, p = 0.03), and white (60.7% vs. 57.0%, p = 0.04). Common cardiovascular comorbidities assessed were all more prevalent among subjects with MetSyn (Table 1). The study population comprised primarily moderate to high-risk individuals with only 6% of the population with none of the five MetSyn risk factors.
As shown in Table 2,patients with MetSyn were at a significantly higher risk of MI (9.1% vs. 5.7%), CE (19.9% vs. 12.9%), HF hospital stay (10.0% vs. 6.1%), any-cause hospital stay (63.1% vs. 56.1%) (all p values < 0.001). The overall mortality was not different between the two groups (14.5% vs. 14.2%, p = 0.85); however, there was a trend toward higher coronary mortality (4.5% vs. 3.2%, p = 0.51) and cardiovascular mortality (5.1% vs. 3.8%, p = 0.067) among patients with MetSyn. Higher risk for MI, HF hospital stay, and any-cause hospital stay was seen in both whites and blacks and in both genders.
When stratified by the presence of history of CHD or HF at baseline, the risk for CE, MI, and HF hospital stay was significantly higher among those with a positive past history and MetSyn at baseline. The overall event rates were lower among those with no past history of CHD or HF. Among these older adults also, the rate of CE was significantly higher among subjects with MetSyn (14.5% vs. 9.1%, p < 0.001). Yet the proportion of MI (6.1% vs. 4.8%, p = 0.18) and HF hospital stay (5.6% vs. 4.3%, p = 0.17), although higher among those with MetSyn without past history of CHD or HF, did not reach statistical significance.
As shown in Table 3,patients with diabetes were at a significantly higher risk of events irrespective of MetSyn status; and among patients who did not have diabetes, presence of MetSyn was associated with a higher risk for CE, MI, or HF hospital stay. Overall, presence of either diabetes or MetSyn increased CE rate; subjects having both diabetes and MetSyn had higher risk compared with either alone.
Women with MetSyn were at a significantly higher risk for overall mortality (13.4% vs. 9.0%, p = 0.007), coronary mortality (3.9% vs. 1.5%, p = 0.002), and cardiovascular mortality (4.4% vs. 1.9%, p = 0.005) as compared with those without MetSyn. This relationship was not observed among men. Similarly, white subjects with MetSyn were at a higher risk for coronary mortality (4.2% vs. 2.5%, p = 0.048) and had a trend toward higher cardiovascular mortality (4.7% vs. 2.9%, p = 0.06) as compared with those without MetSyn.
Figure 1shows the significance of MetSyn when the risks are adjusted for age, gender, race, smoking, marital status, enrollment site, and presence of diabetes. Coronary event (HR 1.56, 95% CI 1.28 to 1.91), MI (HR 1.51, 95% CI 1.12 to 2.05), HF hospital stay (HR 1.49, 95% CI 1.10 to 2.00), and any-cause hospital stay (HR 1.19, 95% CI 1.07 to 1.32) were all significantly more common among patients with MetSyn even after adjusting for these factors. Figure 2shows Kaplan-Meier curves for time to event-free survival among patients with and without MetSyn with respect to MI, CE, HF, and any-cause hospital stay; patients without MetSyn had longer event-free survival for all end points.
Multiple risk factors
Table 4shows the outcomes among the entire cohort with respect to presence of multiple risk factors, irrespective of MetSyn status. Except for all-cause mortality, there was a linear increase in worse outcomes with increasing number of risk factors for coronary or cardiovascular death, CE, MI, HF, and any-cause hospital stay for patients with risk factors zero to five, respectively.
Metabolic syndrome, a common clinical problem with a high prevalence, has been associated with adverse cardiovascular risk and mortality in data consisting primarily of middle-aged populations with no special focus on older adults (1–4,15). In this study we sought to assess the impact of MetSyn on cardiovascular outcomes among older adults and found that it was associated was a significantly higher risk of CE, MI, HF hospital stay, all-cause hospital stay, and cardiovascular and coronary mortality among subjects older than 70 years. These associations were clearer in those with prevalent CHD or HF than those without. These results underscore the importance of aggressive treatment of risk factors in older adults, because MI significantly impacts on mortality, morbidity, and quality of life in these patients (16,17). Similarly, diabetes, impaired glucose tolerance, and impaired fasting glucose increase risk for cardiovascular events (18–20). The overall hospital stay rate was also substantially higher among patients with MetSyn, confirming that patients with MetSyn are also at a higher risk for multiple other diseases along with cardiovascular risk leading to worsening outcomes and need for hospital stay.
Our results also show a strong trend toward an increased risk for coronary and cardiovascular mortality but not overall mortality with MetSyn in older adults. This is in contrast to the recent study in adult population in 30- to 74-year-old subjects that showed that MetSyn was not only associated with cardiovascular risk but also with overall mortality risk (4). There could be several reasons for this. In older adults, weight loss is associated with elevated mortality risk. Because the MetSyn criteria are sensitive to weight change, it might be that participants without MetSyn include a significant proportion of weight-losing subjects who also experience a high mortality rate. There are competing risks for mortality in older adults and therefore even if cardiovascular risk is attenuated, mortality reduction might be difficult to attain because other diseases (e.g., cancer) might terminate life. Also, this is a 6-year follow-up study as opposed to the study cited previously, which had a 13-year follow-up and higher proportion of events. Thus, further data are needed to assess the all-cause mortality relationship with MetSyn in older adults. Even if the main effect of managing MetSyn in older adults would be only a reduction in cardiovascular morbidity, disability, and hospital stays, this would translate to tremendous improvements in quality of life.
The definition of MetSyn includes elevated fasting glucose, which might be due to impaired fasting glucose or diabetes. To assess the significance of MetSyn without diabetes, we performed a sub-group analysis of patients with and without overt diabetes. Patients with diabetes were a small sub-group with a higher risk of events irrespective of whether or not they met the criteria for MetSyn. This contrasts with data from the National Health and Nutrition Examination Survey (NHANES)-III showing that MetSyn modifies cardiovascular risk predictivity in diabetic subjects, although this was a much larger, cross sectional study with a different age range (21). When patients with MetSyn without diabetes were studied specifically in our study, however, the higher risk of CE, MI, HF, and any-cause hospital stay was still evident. These results support both the importance of MetSyn irrespective of diabetes and the overwhelming effect of diabetes on the vasculature in older adults. Overall, presence of either diabetes or MetSyn increased CE rate; subjects having both diabetes and MetSyn had higher risk compared with either alone.
We also assess the importance of MetSyn in both men and women and among whites versus blacks. Metabolic syndrome was associated with worse outcomes in all four racial and gender-based groups. An interesting observation was that women seemed to have the strongest relationship between MetSyn and adverse outcomes, and theirs was the only sub-group where MetSyn was also associated with higher all-cause mortality (13.4% vs. 9.0%, p = 0.007). Although one should be cautious in interpreting smaller subgroups with lower event rates, these data are intriguing in light of recent studies delineating the gender differences with respect to cardiovascular diseases and merit further investigation (22). Similarly, white subjects as compared with black subjects seemed to have a higher risk of coronary and cardiovascular mortality in the presence of MetSyn.
We also assessed the importance of having multiple risk factors irrespective of the presence or absence of MetSyn. As shown in Table 4, there was a positive relationship with worsening cardiovascular risk among older adults even when subjects had one or two risk factors but did not quality for MetSyn. These data would suggest that all risk factors should be managed aggressively. Table 4also shows that having three elements of MetSyn does not maximize cardiovascular risk, because outcome rates were highest among subjects with all five elements Further research is needed to assess the relative importance of one risk factor versus another and the impact of different combinations of risk factors on outcomes.
There are several limitations to our study. The study included only well-functioning older adults, and therefore the sicker and disabled subjects were excluded. The HF outcomes studied were limited to HF hospital stays. Many patients who might have developed HF might not have required a hospital stay. Similarly, we did not prospectively collect data on ejection fraction on all subjects. These data only represent the white and black races and might not be generalizable to other races. Finally, MetSyn was defined on the basis of the ATP III original criteria, which included a fasting glucose of >110 mg/dl; however, this criteria has recently been changed to >100 mg/dl on the basis of American Diabetes Association/European Association for the Study of Diabetes revised criteria for impaired fasting glucose level (23). The impact of this change in the definition of MetSyn in older adults needs further study.
In summary, our study shows that elderly subjects with MetSyn are at a higher risk for CE, MI, HF, and all-cause hospital stay. Further studies are needed to assess the feasibility of risk factor modification and its impact on outcomes in older adults. Age should not be a deterrent to aggressive medical care.
This work is supported in part by Grants N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106; the National Institute of Aging, National Institutes of Health, Bethesda, Maryland; and the Clinical Nutrition Research Unit, Vanderbilt University; and in part by Grant NIH-DK26657-24.
- Abbreviations and Acronyms
- coronary event
- coronary heart disease
- confidence interval
- Health ABC
- Health, Aging, and Body Composition study
- heart failure
- hazard ratio
- metabolic syndrome
- myocardial infarction
- Received August 24, 2005.
- Revision received December 1, 2005.
- Accepted December 5, 2005.
- American College of Cardiology Foundation
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