Development of metabolic syndrome components in adults with a healthy obese phenotype: A 3-year follow-up†
Disclosure: The authors declared no conflict of interest.
There is a lack of data on the progression from a healthy obese phenotype toward an unhealthy obese phenotype and the development of metabolic syndrome (MetS). Our aim was to assess the development of MetS 3 years after screening in centrally obese individuals with a healthy obese phenotype and to evaluate the usefulness of repeated screening.
Design and Methods:
Eighty-eight individuals (mean age 47 years, 88% female) with central obesity as their only MetS component (ATP III criteria) at baseline screening were re-evaluated for MetS status after 3 years.
At follow-up, the cardiometabolic risk profile in centrally obese individuals with a healthy phenotype showed a tendency toward deterioration. Thirty-two percent developed at least one additional MetS component, 7% had developed MetS. Nobody had developed type 2 diabetes. An increased triglyceride level (n = 16) and an increased blood pressure (n = 18) were the components most often present at follow-up. The people developing additional MetS components had a lower education level compared with the group that preserved the healthy centrally obese phenotype (80 vs. 71% lower educated, P = 0.35). They also had slightly worse baseline levels of the risk factors.
The number of centrally obese individuals developing an unhealthy phenotype in this relatively short follow-up period emphasizes the need for a regular surveillance of cardiometabolic parameters in centrally obese individuals. However, it is questionable whether a repeated screening for type 2 diabetes every 3 years, as recommended by the American Diabetes Association, in this category of patients is appropriate.
Cardiometabolic risk factors often tend to cluster. The term “Metabolic Syndrome” (MetS) refers to this clustering. The National Cholesterol Education Program's Adult Treatment Panel III (NCEP ATP III) report defines this syndrome as the presence of at least three of the following five components: an increased waist circumference, increased triglycerides, an increased blood pressure, an increased fasting glucose, or a decreased HDL cholesterol level (1). MetS is associated with an increased risk of developing both type 2 diabetes and cardiovascular disease (2-5). Patients with MetS have an up to fourfold increased risk of mortality from cardiovascular disease (3, 4). Early detection and adequate treatment can modify or even abolish the risk factors associated with MetS and thus prevent cardiovascular disease (6-9). We could demonstrate that a population-based screening among apparently healthy individuals, with self-measurement of waist circumference as a first step, is a feasible and reliable method to identify individuals with MetS (10, 11). During this screening, also people were diagnosed with no other additional MetS components than an increased waist circumference, so called “healthy obese people” (12, 13). However, an increased waist circumference, or abdominal obesity, is associated with an increased risk of developing cardiovascular disease (14, 15) and type 2 diabetes (16-18). Individuals with abdominal obesity also have an increased risk of developing additional risk factors, such as hypertension and dyslipidemia, which further increases the risk of developing cardiovascular disease (18, 19). Therefore, we hypothesize that people identified as “healthy centrally obese” at screening, are likely to develop additional cardiometabolic risk factors in the near future. Because screening must be an ongoing process, instead of a once and for all action, intervals for repeating the screening should be determined (20). The centrally obese individuals without any other MetS component at screening are the ones eligible for a following screening round. There is lack of data on the progression from a healthy obese phenotype toward an unhealthy obese phenotype and the development of MetS. Based on expert consensus, the American Diabetes Association recommends repeated screening for type 2 diabetes in asymptomatic overweight and obese people above the age of 45 without additional risk factors for diabetes to be carried out at least at 3-year intervals (21). Three years after our initial screening, we invited a random sample of the screening participants whose only MetS component at the time of screening was an increased waist circumference. Our aim was to assess the development of MetS 3 years after screening in centrally obese individuals and to evaluate whether a screening interval of 3 years is appropriate.
Methods and Procedures
Setting and participants
Between October 2006 and May 2007 the study “IJsselstein Screening for Central Obesity to detect metabolic syndrome” was conducted in the city of IJsselstein (the Netherlands) among 12,000 individuals (10, 11). Participants were aged 20-70 years and not known with diabetes, hypertension, dyslipidemia, or cardiovascular disease at the time of screening. All people were invited to measure their own waist circumference at home, with a mailed tape measure. People with a self-measured increased waist circumference (≥102 cm for men, ≥88 cm in women) were invited for further examinations. A total of 1,721 individuals had a self-measured increased waist circumference and underwent a subsequent physical examination and laboratory assessment. They were advised to contact their general practice for the results of their screening. Four hundred seventy-three of the 1,721 participants (27%) fulfilled the MetS criteria, whereas 247 participants were diagnosed with central obesity without any other MetS component. A random selection (n = 144) from the latter group, the so called metabolically healthy obese were invited for follow-up measurements, 3 years after screening. The selection procedure was as follows: the patient identification numbers of the 247 patients with central obesity as their only MetS component were entered into an electronic data file (Statistical Package of Social Sciences version 17.0 (SPSS (IBM), Chicago, IL). We asked the program to randomly select 144 of the 247 cases. The study was approved by the medical ethics committee of the University Medical Center Utrecht, the Netherlands. Written informed consent was obtained from all participants.
Follow-up measurements took place 3 years after screening. Both at screening and 3 years later, the same measurements were performed. In a physical examination, body weight, height, waist circumference, and blood pressure were measured. Body weight and height (to the nearest 0.5 kg and 0.5 cm, respectively) were measured without shoes with an analogue balance (Seca) and wall-mounted tape measure (Seca). Waist circumference was measured twice (to the nearest 0.5 cm) after a normal expiration halfway between the lowest rib and the top of the pelvis. The mean of the 2 measurements was calculated. Blood pressure was measured with an automatic tonometer (Microlife BP 3AC1-2) after participants had been sitting down for at least 5 minutes. A pause of 2 minutes was taken between the 2 measurements. If there was a difference in systolic blood pressure of >20 mmHg, a third measurement was performed. The mean of 2 measurements was calculated. In case of three measurements, the last 2 measurements were taken.
Venous blood samples were drawn after an overnight fast to determine serum concentrations of fasting blood glucose, triglycerides, and HDL cholesterol.
At baseline, participants had completed a questionnaire to determine ethnicity, education level, and lifestyle factors such as smoking. Education level was dichotomized: completing at least a higher level of secondary education was defined as “higher education level.” Smoking was regarded positive when the participant was currently smoking; in case of former or never smoking, it was regarded negative. Smoking status was re-evaluated at follow-up. Physical activity was assessed using the validated SQUASH questionnaire, which measures habitual activities with respect to occupation, leisure time, household tasks, transportation means, and other daily activities (22). The results were dichotomized based on the Dutch Standard Healthy Movement: a minimum of 30 minutes of moderately intensive exercise at least 5 days a week (23).
For determining the development of new MetS components, the threshold levels according to the redefined NCEP ATP III criteria were used (1): increased waist circumference (≥102 cm for men, ≥88 cm in women), elevated blood pressure (systolic ≥130 and/or diastolic ≥85 mmHg), elevated triglycerides (≥1.7 mmol/L), elevated fasting glucose (≥6.1 mmol/L), and reduced HDL cholesterol (≥1.0 mmol/L in men, ≥1.3 mmol/L in women).
MetS is present when at least three of the five aforementioned components are present. Participants who used medication for either high blood pressure or high fasting glucose or a reduced HDL cholesterol or elevated triglycerides were defined as having the respective MetS component.
Categorical variables are reported as numbers and percentages, continuous variables as means with standard deviations (SD).
We checked for selection bias by testing for differences in baseline variables between screening participants who were invited for follow-up measurements and those who were not invited, and by testing for differences in baseline characteristics between participants and nonparticipants among those invited for follow-up examinations. Chi-square tests were used for categorical variables, independent t-tests for continuous variables. A P-value > 0.05 was considered significant. Chi-square tests and independent t-tests were also used to test for baseline differences between the participants that maintained the healthy obese phenotype (≤1 MetS component at follow-up) and those who developed additional risk factors (≥2 MetS components at follow-up). To test for a significant change in mean risk factor levels between screening and follow-up, we used paired-sample t-tests.
To evaluate whether the development of new MetS components should have had consequences with regard to drug treatment, we calculated the 10-year risk for cardiovascular disease mortality by using the Dutch version (24) of the SCORE risk function (25). According to the guideline “Cardiovascular Risk Management” of the Dutch College of General Practitioners (24), antihypertensive and/or lipid lowering treatment are indicated if the 10-year cardiovascular mortality risk exceeds the 10% threshold in combination with a systolic blood pressure ≥140 mmHg and/or a LDL cholesterol ≥2.5 mmol/L. Analyses were performed using SPSS version 17.0 (SPSS (IBM), Chicago, IL).
A random sample of 144 of the 247 individuals with an increased waist circumference without any other MetS components at screening were invited for follow-up examinations. There were no significant differences in age, gender, smoking status, education level, ethnicity, or baseline levels of MetS components between the invited and noninvited individuals. Eighty-eight of the 144 (61%) invited individuals participated. Their descriptive characteristics are presented in Table 1. There were no significant differences in baseline variables between the invited individuals who participated and those who did not, except for ethnicity: one of the 88 participants was non-Western European, whereas 11 of the 56 nonparticipants were non-Western European.
Table 1. Baseline characteristics of the people invited for follow-up examinations
|Age (years)||46.7 ± 9.3||44.6 ± 10.2||0.22|
|Gender (% female)||88||88||1.00|
|Physical activity meeting Dutch Standard Healthy Movementa (%)||58||52||0.47|
|Higher education level (%)||26||39||0.10|
|Western European origin (%)||99||82||< 0.001|
Mean follow-up duration was 3.0 years (SD 0.1 year). The mean risk factor levels at baseline and follow-up are shown in Table 2. Mean levels for the total group remained the same or showed a slight deterioration, but remained within the normal range. Two of the 11 participants who were smoking at baseline stopped smoking, whereas 2 others not smoking at baseline started smoking.
Table 2. Risk factor levels at baseline and follow-up and mean change from baseline (n = 88)
|BMI (kg/m2)||28.4 ± 3.0||28.4 ± 3.5||0.1 ± 1.9||−0.3;0.5||0.78|
|Waist circumference (cm)|| || || || || |
| ♂||105.3 ± 2.4||106.6 ± 4.6||1.3 ± 4.5||−1.7;4.3||0.34|
| ♀||95.7 ± 7.1||94.2 ± 8.2||−1.4 ± 6.9||−3.0;0.1||0.07|
|Blood pressure (mmHg)|| || || || || |
| Systolic||119.2 ± 6.3||121.5 ± 9.3||2.2 ± 8.6||0.4;4.1||0.02|
| Diastolic||75.1 ± 4.9||75.3 ± 7.3||0.2 ± 6.7||−1.3;1.6||0.82|
|Triglycerides (mmol/L)||1.0 ± 0.3||1.3 ± 0.4||0.3 ± 0.4||0.2;0.4||< 0.001|
|HDL cholesterol (mmol/L)|| || || || || |
| ♂||1.3 ± 0.2||1.3 ± 0.2||0.0 ± 0.2||−0.1;0.1||1.0|
| ♀||1.7 ± 0.3||1.6 ± 0.3||−0.1 ± 0.2||−0.2;−0.1||< 0.001|
|Fasting glucose (mmol/L)||4.7 ± 0.4||5.0 ± 0.4||0.3 ± 0.4||0.2;0.4||< 0.001|
Five patients were on antihypertensive drug treatment at follow-up; there was no medication prescribed for elevated fasting glucose, elevated triglyceride, or reduced HDL cholesterol levels.
Table 3 shows the development of new MetS components. An increased triglyceride level (n = 16) and an increased blood pressure (n = 18) were the MetS components most often present at follow-up. Only one participant developed an impaired fasting glucose level (fasting glucose 6.7 mmol/L).
Table 3. Presence of metabolic syndrome (MetS) components at baseline and follow-up
|Waist circumference|| || || |
|≥102 cm in men||100%||78%||(n = 69)|
|≥88 cm in women|
|Blood pressure|| || || |
|Systolic ≥130 mmHg or||0%||20%||(n = 18)|
|Diastolic ≥85 mmHg or|
|Antihypertensive drug treatment|
|Triglycerides|| || || |
|≥1.7 mmol/L or||0%||18%||(n = 16)|
|Drug treatment for elevated triglycerides|
|HDL cholesterol|| || || |
|1.0 mmol/L in men||0%||11%||(n = 10)|
|1.3 mmol/L in women or|
|Drug treatment for reduced HDL cholesterol|
|Fasting glucose|| || || |
|≥6.1 mmol/L or||0%||1%||(n = 1)|
|Blood glucose lowering drug treatment|
|Number of components|| || || |
|0|| ||11%||n = 10|
|1|| ||55%||n = 48a|
|2|| ||27%||n = 24|
|≥3|| ||7%||n = 6|
In 43 of the 48 individuals with one MetS component at follow-up, this component still was an increased waist circumference. Thirty individuals developed additional MetS components, whereas 6 individuals fulfilled the MetS criteria.
Baseline characteristics of the group that did not develop additional MetS components (n = 58) and the group that did develop additional components (n = 30) are shown in Table 4. With regard to age, gender, ethnicity, and physical activity, there were no differences between both groups. The percentage of higher educated individuals was slightly higher in the group that did not develop additional MetS components (29 vs. 20%, P = 0.35). With regard to baseline levels of the MetS components, the group developing additional components during follow-up had slightly less favorable levels compared with the group that did not develop additional risk factors, though mean levels in both groups were well within normal range at baseline. Of the 30 participants developing additional MetS components, 3 were on antihypertensive treatment and one participant used a statin. None of the remaining 26 participants without cardiovascular medication had an indication for drug treatment according to the aforementioned guideline “Cardiovascular Risk Management” of the Dutch College of General Practitioners (24).
Table 4. Baseline characteristics according to the number of metabolic syndrome (MetS) components at follow-up
|Age (years)||46.0 ± 9.1||48.0 ± 9.7||0.35|
|Gender (% female)||88%||87%||0.87|
|Physical activity meeting Dutch Standard Healthy Movementa (%)||59%||57%||0.86|
|Higher education level (%)||29%||20%||0.35|
|Western European origin (%)||98%||100%||0.47|
|BMI (kg/m2)||28.1 ± 3.1||28.8 ± 3.0||0.29|
|Waist circumference (cm)|| || || |
| ♂||104.9 ± 2.3||106.1 ± 2.7||0.45|
| ♀||94.9 ± 7.4||97.2 ± 6.5||0.12|
|Blood pressure (mmHg)|| || || |
| Systolic||118.6 ± 6.2||120.5 ± 6.4||0.19|
| Diastolic||74.4 ± 4.8||76.5 ± 4.8||0.05|
|Triglycerides (mmol/L)||0.9 ± 0.3||1.1 ± 0.3||0.01|
|HDL cholesterol (mmol/L)|| || || |
| ♂||1.3 ± 0.2||1.2 ± 0.2||0.44|
| ♀||1.8 ± 0.4||1.6 ± 0.3||0.15|
|Fasting glucose (mmol/L)||4.7 ± 0.3||4.8 ± 0.4||0.09|
This is to the best of our knowledge the first prospective study describing the development of additional MetS components in an adult population with a healthy centrally obese phenotype. Within a 3 years' time period, the cardiometabolic risk profile in centrally obese individuals with a healthy phenotype showed a tendency toward deterioration. Thirty-two percent developed at least one additional MetS component and 7% had developed MetS. However, only one person was diagnosed with an impaired fasting glucose and nobody had developed type 2 diabetes.
Little prospective data exist on the development of MetS components in healthy centrally obese individuals. There are some studies with comparable follow-up times that describe the incidence of MetS in individuals who are at baseline free of MetS. Incidence rates vary from 19% after 3 years to 13-20% after 5 years follow-up (26-29). These rates are higher than the 7% we observed in our population. An important reason for this discrepancy might be the difference in baseline characteristics. The other studies included individuals free of MetS at baseline, which means that individuals with 2 MetS components at baseline were eligible as well. As a result, baseline levels of blood pressure, fasting glucose, and triglycerides were higher—or in case of HDL cholesterol lower—than the mean levels in our study population, which was selected on the absence of other MetS components. Only one study provides incidence rates for the subgroup of its population without any MetS components at baseline, the ones we could call the “healthy nonobese.” This is a population of male Koreans, aged 30–39 years. 1,645 of them had zero MetS components at baseline. Given the increased risk of developing additional cardiometabolic risk factors among people with central obesity, one would expect a higher MetS incidence among the “healthy obese” compared with the “healthy nonobese.” After a mean follow-up duration of 2.1 years, 6.4% of them developed MetS, which is comparable with the 7% in our population. They used, however, the NCEP ATP III definition, with an adapted abdominal obesity criterion, overall obesity being defined as a BMI ≥25 kg/m2) (30). Therefore, we do not know which percentage of them was nonobese with regard to both BMI and waist circumference at baseline. A definite answer on whether or not the development of additional MetS components differs between healthy centrally obese and nonobese people remains uncertain. Individuals who preserved their healthy centrally obese phenotype tended to be higher educated than those who developed additional MetS components. A higher education level might prevent the transition toward an unhealthy obese phenotype. In cross-sectional studies, a lower level of education was strongly associated with the presence of MetS and its separate components (31, 32). Indeed, the healthier lifestyle with regard to diet (33, 34) and physical activity (35, 36) often accompanying a higher education level might help preventing the development of additional MetS components. In our study, the percentages of people adhering to the Dutch Standard Healthy Movement were comparable between the individuals who maintained their healthy obese phenotype and those who developed additional MetS components (59 vs. 57%). Either this could be the result of our dichotomized physical activity measure, which does not provide information on mean absolute levels of physical activity, or physical activity indeed does not influence the development of additional MetS components in this population.
The people who developed additional MetS components were a little older, although this difference was not significant (48 vs. 46 years, P = 0.35). They also had slightly worse baseline levels of BMI and the MetS components. For them, less deterioration was needed to fulfil the MetS criteria. These results underline the idea that obesity is not just a diagnosis based on body mass index or waist circumference. It is merely the visible sign of a cardiometabolic disease range which runs from healthy obesity, via the development of obesity-related cardiometabolic risk factors such as hypertension and dyslipidemia, to manifest obesity-related diseases such as type 2 diabetes and myocardial infarction on the other end of the spectrum. The patient's position in this spectrum seems to change with aging, mostly toward the manifest disease side of the spectrum. Therefore, obesity should always be evaluated in the context of its concomitant cardiometabolic risk factors and diseases. This is in agreement with the recently developed Edmonton Obesity Staging System, which ranks people with excess adiposity on a 5-point ordinal scale, incorporating not only obesity-related comorbidities but also functional status into the assessment (37). The Edmonton Obesity Staging System independently predicted increased mortality even after adjustment for contemporary methods of classifying adiposity. Although this system may offer improved clinical utility in assessing obesity-related risk and prioritizing treatment, assessment requests additional data with regard to disease history, comorbidities, and functional status. MetS on the contrary only needs measurement of blood pressure and blood examination and, therefore, seems to be a more practical tool to evaluate obesity-related risk in a population-broad setting.
Some limitations of this study have to be discussed. We invited a random sample of the 247 participants who were defined as metabolically healthy centrally obese at screening. Of these 90% were female, whereas 68% of all centrally obese participants were female. Apparently, more women than men with central obesity had the healthy phenotype in our screening population. Other studies support this finding that a healthy obese phenotype is more common in women than in men (38, 39).
Gender distribution and the other baseline characteristics of the people we invited were comparable with those of the noninvited people. Also the participants and nonparticipants among those invited did not differ significantly. Therefore, selection bias seems unlikely and the participants are a representative sample of a metabolically healthy centrally obese population. However, metabolically healthy individuals with central obesity may not represent metabolically healthy obese individuals overall (with pear-shaped adiposity, for example); therefore, our results cannot be generalized to all healthy obese individuals. Because our population consisted almost completely of individuals of Western European origin, our results cannot be generalized to individuals of non-Western European origin.
As a consequence of the relatively small number of study participants, we could not demonstrate significant differences in baseline characteristics between the people that did not develop additional MetS components and the group that did develop additional components.
To conclude, our data suggest that a regular surveillance of cardiometabolic parameters in all obese individuals should be applied. We did not perform a cost-effectiveness study and the decision on when an increase in the percentage of MetS components makes screening efficient may be more or less arbitrary. However, the combined screening for type 2 diabetes as well as for hypertension and dyslipidemia is likely to improve the cost per quality-adjusted life-year (40).
Based on expert consensus, the American Diabetes Association recommends repeated screening for type 2 diabetes in asymptomatic overweight and obese people above the age of 45 without additional risk factors for diabetes to be carried out at least at 3-year intervals (21). In our population, however, after a 3-year follow-up period, only one participant developed an impaired fasting glucose and no cases of type 2 diabetes occurred. The rate of development of new MetS components with indications for treatment does not support repeated screening measurements after a 3-year time period in healthy centrally obese individuals. A longer time interval between subsequent screening rounds seems appropriate, which makes it more attractive to implement such a screening.
The IJsselstein Study of Central Obesity to detect metabolic syndrome was supported in part by a research grant from the Investigator Initiated Studies Program of Merck Sharp & Dohme Corp. The opinions expressed in this article are those of the authors and do not necessarily represent those of Merck Sharp & Dohme Corp.