These data provide further evidence of the potential benefit of the Diabetes Prevention Program interventions beyond diabetes prevention alone and raise the additional possibility of cardiovascular prevention. Although we are unaware of any publications specifically examining the prevalence of the metabolic syndrome in patients with impaired glucose tolerance, a recent analysis of the data set from the Third National Health and Nutrition Examination Survey (NHANES III) suggests that 33% of U.S. adults who are 50 years of age or older and have impaired glucose tolerance also have the metabolic syndrome (4
). Our overall prevalence of 53% is probably higher, even allowing for our additional requirement of a fasting plasma glucose level of at least 5.3 mmol/L (≥95 mg/dL). Several reports have also documented the general prevalence of this syndrome by using either the Adult Treatment Panel III criteria (1
) used in the current report or the WHO definitions (2
). Ford and colleagues (3
) recently estimated from NHANES III that the metabolic syndrome was present in approximately 22% of all U.S. adults age 20 years and older. Of interest, unlike our data, which showed a relatively constant prevalence by age group, the age-specific prevalence of the metabolic syndrome in the general population increased dramatically, from just over 12% among individuals in their thirties to 20% among those in their forties, 35% among those in their fifties, and 45% thereafter. Again, it would seem that our population, as expected, has a higher prevalence of the metabolic syndrome and presumably higher cardiovascular and diabetes risk than the general population. However, it should be noted that our population is highly selected for having impaired glucose tolerance but not diabetes. One might thus anticipate a less marked prevalence relationship with age in the Diabetes Prevention Program, since we would be increasingly eliminating participants with the metabolic syndrome who have also developed diabetes as they age. The NHANES data from Ford and colleagues (3
) also examined prevalence by sex and, as in our population, showed little difference overall. The American Diabetes Association recently redefined prediabetes by using a fasting plasma glucose criterion (15
) of greater than 5.6 mmol/L (>100 mg/dL). As anticipated, this increased the prevalence of the condition but had little effect on the relative impact of the interventions on incidence.
Prevalence studies that have examined the association of the metabolic syndrome with cardiovascular disease generally support the syndrome’s identification and prevention. The Bruneck study (16
), for example, reported that participants with the WHO definition of the metabolic syndrome had an increased risk for both carotid and coronary disease after 5 years of follow-up. Alexander and associates’ analysis of the NHANES III data (4
) also suggests that participants with the metabolic syndrome (with or without diabetes) have an increased prevalence of coronary artery disease, thus further underscoring the potential benefit of preventing or delaying the syndrome. However, these findings should be interpreted in the context of other related states, for example, impaired glucose tolerance itself. The Diabetes Epidemiology: Collaborative analysis Of Diagnostic criteria in Europe (DECODE) study (17
) recently firmly established a strong predictive role for all-cause and cardiovascular mortality. Nonetheless, these interventions, especially the lifestyle intervention, should yield cardiovascular benefit by improving glucose tolerance and the metabolic syndrome, no matter how the risk is attributed between the two.
Our data, although derived from a volunteer population with impaired glucose tolerance but not diabetes, provide potentially important clinical information concerning the metabolic syndrome and its prevention. Although the population studied had moderately severe impaired glucose tolerance (fasting plasma glucose level ≥5.3 mmol/L [≥95 mg/dL]), only 53% overall had the metabolic syndrome, suggesting that this high-risk state is far from omnipresent even in impaired glucose tolerance. Of particular note is the variation by age group of the components contributing to the diagnosis. Waist circumference and low HDL cholesterol level appear to be particular features of the younger participants with the metabolic syndrome, while blood pressure is particularly important for the older participants. Triglyceride levels, on the other hand, appear fairly constant for all ages. It is interesting to speculate whether this age difference relates to the increasing conversion to diabetes (and thus study ineligibility) with age or differences in perceived diabetes risk leading to Diabetes Prevention Program screening. Similarly, the difference between the sexes is interesting: Waist circumference and low HDL cholesterol level predominate in women and high fasting glucose level and high blood pressure are more noticeable in men. Because the criteria for entry varied by ethnic group to some degree, meaningful interpretation of ethnicity-specific data is limited, although it is important to note that no heterogeneity was seen for treatment effects by ethnic group.
Because the metabolic syndrome is not consistent over age groups, these findings could be interpreted as an argument for treating the individual risk factors themselves and not limiting intervention to the syndrome. These findings also raise the issue recently addressed by Stern and colleagues (19
) that cardiovascular risk prediction is probably better addressed by multivariable models than by categorizing participants by glucose tolerance status. Of interest, waist circumference and low HDL cholesterol levels were the best predictors in the San Antonio Heart Study (12
Particularly encouraging is the dramatic effect of life-style on both the incidence of new metabolic syndrome (and its components) and on participants who had the syndrome at baseline. The beneficial effect of lifestyle intervention on components other than glucose level is particularly encouraging and provides important evidence of the value of this approach to those with blood pressure, weight, and lipid disturbances in general. The intermediary effect of metformin, which closely mirrors the pattern of results for the overall trial in terms of diabetes prevention or delay, further underscores the preferential value of life-style as the initial approach to prevention of the metabolic syndrome and its cardiovascular complications.
The complete lack of effect of metformin in women is surprising, given its overall effect on diabetes prevention. This finding can be only partly related to the smaller sample available for prevention of the metabolic syndrome. Sex differences in the prediction of the metabolic syndrome have, however, been noted before. For example, Han and colleagues (20
) reported that C-reactive protein level predicted the metabolic syndrome in women but not men. It has also been observed that metformin decreases basal testosterone levels in men (21
) but not women (22
). In addition, the sex-specific criteria for the syndrome may play a role. These criteria are somewhat arbitrary and may not effectively represent underlying metabolic differences between the sexes. The reduced efficacy of metformin in participants with higher baseline insulin levels also deserves further investigation, although it probably reflects a relatively weaker effect of metformin on insulin resistance than that seen for lifestyle.
The dramatic effect of lifestyle on both the prevention of incident metabolic syndrome and reduction of its overall prevalence appears to be most strongly related to a reduction in waist circumference and in blood pressure and not, as might have been anticipated, through a correction of the lipid abnormalities of triglycerides and HDL cholesterol. The incidence of abnormal HDL cholesterol level was virtually identical by treatment group, while waist circumference and frequency of hypertension were both significantly reduced by intensive lifestyle intervention. It is interesting to speculate why lifestyle should have relatively little effect on HDL cholesterol level but such a marked effect on blood pressure. Similar results have been reported by the Finnish Diabetes Prevention Study (23
). One possibility may be that although total calories were reduced in the lifestyle group, the relatively greater focus on fat content may have altered the ratio of polyunsaturated to saturated fats, which is related to HDL cholesterol levels (24
Although we were not able to determine the best way to define the metabolic syndrome as an intervention target, or even whether to define it at all, future follow-up of the cohort will enable us to determine whether this particular combination of risk factors or some other variation better predicts cardiovascular outcomes. Naturally, our intervention results apply primarily to persons with impaired glucose tolerance and cannot be immediately translated to other groups.
These data provide an extensive and detailed description of the metabolic syndrome in a high-risk population and reveal important differences in composition of the syndrome by age and sex. They also demonstrate the value of lifestyle intervention, in particular, in both the prevention and treatment of this condition, above and beyond improvement in glycemia alone. Lifestyle intervention may reduce cardiovascular risk in persons with impaired glucose tolerance.