Abstract & Commentary
The metabolic syndrome (tms), also known as the deadly quartet, Reaven’s syndrome, the insulin resistance syndrome, etc, has attracted considerable attention over the past few years, as it has been suspected that individuals with TMS are at increased risk for vascular disease, as well as the development of type 2 diabetes. Major concern has been raised by the increasing prevalence of TMS, which accompanies obesity and sedentary lifestyle in many individuals. As the world population is becoming more overweight and obese, the potential public health implications of TMS are enormous. This report is of considerable importance, as it clearly documents the increased burden of all-cause and cardiovascular mortality in men with TMS who have no overt coronary artery disease (CAD) at baseline. Mortality increases of 2- to 3-fold are documented during long-term follow-up using 2 different definitions of TMS.
The Kuopio Ischemic Heart Disease Risk Factor study is a prospective observational report of a random sample of 2700 men from Eastern Finland, who were entered into the protocol at age 42-60 years, between 1984 and 1989. Of the entire cohort, 1123 were excluded because of a history of cardiovascular disease, cancer, or diabetes; others were excluded because of absence of certain study lab tests. Thus, a population of 1209 men was available for a subsequent analysis. Major components of TMS included blood pressure, body mass index, waist circumference, waist-hip ratio, fasting blood glucose, LDL and HDL cholesterol, and white blood cell count. Two definitions of TMS were used: the National Cholesterol Education Program (NCEP)—ATP III version—and a World Health Organization (WHO) definition emphasing hyperinsulinema, elevated fasting glycemia, and at least 2 additional factors, including abdominal obesity, dyslipidemia, or hypertension. Insulin resistance (IR) was calculated; a hyperinsulinemic group was defined, which represented the upper quartile of baseline IR. Impaired glycemia was defined as a blood glucose of 101-109 mg/dL, with diabetes defined as a blood glucose of > 110 mg/dL. Thus, the WHO criteria excluded many patients who would be considered to have TMS by the NCEP criteria.
All deaths were accounted for over the follow-up period ending December 1998. Sophisticated statistical analyses were carried out, including several proportionate hazard regression models, a factor analysis of various components of TMS, and a technique called principle component analysis. Men in the highest quartile of any variety of the components of TMS were likely to have TMS. Cardiovascular and all-cause death were treated as dependent variables.
The median follow-up was 11.6 years (range, 9.1-13.7). There were 109 deaths, of which 46 were cardiovascular disease and 27 CAD. Univariate analyses indicated that blood pressure, BMI, waist circumference, smoking, blood glucose, and serum insulin levels were associated with cardiovascular and all-cause mortality. Overall, Kaplan-Meier survival at 13.7 years for men with TMS vs those without was 79% vs 90%, using the NCEP waist measurement of 40 inches or more; 83% vs 90% for NCEP criteria with waist size of > 35 inches; and 84% vs. 90% for WHO based on waist-hip ratio or waist circumference. Age-adjusted Cox proportional hazard regression models indicated that TMS was associated with a 2.4- to 3.4-fold higher mortality from CAD, which rose to a 2.9- to 4.2-fold increase when LDL cholesterol, smoking, or family history were taken into account. Cardiovascular death was 2.5-2.8 times greater in individuals with TMS using WHO criteria, but was not significant using the NCEP criteria. In general, the risk ratios for the WHO definition of TMS appeared to be higher than those for the NCEP definitions. All-cause mortality was increased by 2-fold using the WHO TMS definition but was not significant using NCEP definition. In men who had no impaired glycemia at baseline, comparable results were noted. Total mortality was also related to metabolic syndrome, but less strongly than CAD mortality.
Lakka and colleagues concluded, "This is the first prospective population-based cohort study reporting the association of the metabolic syndrome using recently proposed definitions with cardiovascular and overall mortality; the mortality was independent of other important factors, such as smoking, alcohol intake, and LDL cholesterol." In the Finnish Study, the overall prevalence of TMS at baseline was low at 9-14% and far less than the approximate 30% prevalence of TMS in the United States estimated by the NHANES III survey. However, Lakka et al point out that with increasing obesity and overall abdominal adiposity, TnMS will be more frequent as will be vascular disease burden and diabetes. Most of the risk of TMS in this study was modulated through CAD mortality (3- to 4.3-fold), which comprised the bulk of cardiovascular disease mortality and overall mortality. Nevertheless, overall mortality was substantially increased even in the absence of cardiovascular deaths. Lakka et al stress that this analysis excluded individuals with diabetes or known CV disease, and thus it represents an earlier stage of TMS. Waist circumference was a particularly important factor, with increased mortality in individuals with the waist cutoff of > 40 inches. WHO criteria using waist-hip ratio appear to be more sensitive in detecting individuals who will develop diabetes; the NCEP definition readily defined individuals with an increased risk for all-cause and CVD mortality. Finally, Lakka et al stress that 2 major published diabetes prevention studies, one from Finland and one from the United States, have indicated that relatively modest lifestyle interventions can have a major positive effect on decreasing risk of subsequent diabetes in TMS individuals. Thus, weight loss, diet, and physical activity favorably alter many of the components of TMS, at least in the short term; the Kuopio group has previously shown that men engaged in regular moderate to vigorous physical activity are less likely to develop TMS. Lakka et al suggest an increased emphasis on "early identification, treatment, and prevention of the metabolic syndrome" as a means of decreasing cardiovascular and overall mortality as well as diabetes and cardiovascular disease (Lakka HM, et al. JAMA. 2002;288:2709-2716).
This important observational study serves as a "smoking gun" with respect to the serious risks of the phenomenon of the metabolic syndrome and insulin resistance. The interrelationships between glycemic control, insulin sensitivity, inflammation, cytokine activation, hypertension, and dyslipidemia are complex, plus TMS probably has a genetic basis as well. The recently published Botnia study1 indicates that high-risk TMS individuals are those with a family history of diabetes or who have known vascular disease; the present report underscores the risk for men with TMS at earlier stages, which represent a large and increasing percentage of the population. The Diabetes Prevention Program, a randomized trial comparing healthy lifestyle of diet and regular exercise to usual care, demonstrated that the development of diabetes could be substantially reduced over a relatively short period. In addition to dietary changes as well as regular physical activity, there is increasing evidence that agents activating nuclear transcription factors may also improve the metabolic syndrome. No randomized clinical trials are available to show a decrease in clinical events or increased survival in TMS, but it is likely that the substantial increase in mortality found in the Kuopio study can be abrogated with vigorous lifestyle interventions. It behooves the practicing physician-cardiologist, internist, or family practitioners to focus on the concatenation of abdominal or visceral (male pattern) obesity, hypertension, dyslipidemia, and/or elevated plasma glucose not yet in the diabetic range; these factors represent a particularly lethal phenomenon, deserving of aggressive and vigorous risk factor and lifestyle changes. The recent recognition that more than 50% of Americans are overweight or obese underscores the need for urgency in the recognition of the metabolic syndrome, as well as an aggressive therapeutic strategy of lifestyle and even pharmacologic therapy for these individuals.
Reference
1. Isomaa B, et al. Diabetes Care. 2001;24:683-689.
The metabolic syndrome (tms), also known as the deadly quartet, Reavens syndrome, the insulin resistance syndrome, etc, has attracted considerable attention over the past few years, as it has been suspected that individuals with TMS are at increased risk for vascular disease, as well as the development of type 2 diabetes.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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