Obesity among children and adolescents has become a major public health challenge in the twenty-first century. Over the past decade, the prevalence of pediatric obesity in the United States increased from 17.7% to 21.5% (1). Pediatric obesity leads to a significant increase in cardiometabolic morbidity, including type 2 diabetes, hypertension, dyslipidemia, fatty liver, and cardiovascular complications (2–4). Screening tests for children with obesity include fasting lipids, glycated hemoglobin (HbA1c), fasting or random plasma glucose, and liver enzymes (5).

The clustering of cardiometabolic risk factors (CMRFs) in early childhood is of particular concern, given that the majority of children remain obese in adulthood (3). Skinner et al., using National Health and Nutrition Examination Survey (NHANES) data, demonstrated that severe obesity in children and adolescents was associated with increased prevalence of CMRFs, particularly among males (6). They also showed that, as expected, subjects with Class 1 obesity, defined as having a BMI ≥95th percentile to <120% of the 95th percentile for age and sex, had a higher risk of having most risk factors as compared to those with overweight (6, 7).

Each 10% increase in BMI above the 95th percentile is equivalent to an average increase of 2.1 kg/m² and 2.7 kg/m² in BMI among male children and adolescents, respectively; and of 2.2 kg/m² and 2.8 kg/m² among female children and adolescents, respectively ( Table S1 ) (8). Such increments in BMI may be clinically significant. For example, the Princeton Follow-up Study demonstrated that the risk of metabolic syndrome in adulthood increased by 24% for each 10% increase in age-specific BMI in children and youth (9).

The question of whether the increment in BMI above 109% of the 95th percentile translates into a significant difference in the risk of cardiometabolic morbidity within the Class 1 obesity group has not yet been addressed. Therefore, in the present study, we aimed at assessing the prevalence and clustering of CMRFs in Israeli children and adolescents with a BMI of 110%-119% of the 95th BMI percentile, as compared to those with overweight and Class 1obesity.

Among 7211 children and adolescents with a BMI at the 85th percentile or higher, 40.2% were classified as overweight, 50.3% as obesity-A, and 9.5% as obesity-B ( Table 2 ). Figure S2 depicts median BMI values classified by weight categories and age. No significant correlation was found between SES and severity of obesity ( Table S3 ).

Table S4 shows the mean values for each cardiometabolic variable for all subjects. These values increased with the severity of obesity, except for HDL cholesterol.

Table 3 and Figure 1 show the prevalence of CMRFs among children and adolescents, classified by weight category. Except for total cholesterol, diastolic blood pressure, and diabetes, the prevalence of CMRFs (including prediabetes) consistently increased with the severity of obesity in adolescents ( Tables 3 , S5 ). This trend was evident albeit to a lesser extent among children for whom only systolic blood pressure and ALT levels differed significantly between weight groups ( Tables 3 , S6 ).

Table 4 shows a direct comparison of CMRFs between weight groups of children and adolescents in multivariable generalized linear models that adjusted for age and sex. Children and adolescents in the obesity-B group had greater odds for higher triglycerides, LDL cholesterol, and ALT and lower HDL cholesterol levels, as compared to the obesity-A group. These differences were significant in females except for the difference in ALT levels, the only observation that was significant in males. The odds of prediabetes tended to be higher in the obesity-B group but did not reach significance. Overweight children and adolescents had lower odds for most of the CMRFs.

The number of CMRFs increased with the severity of obesity in children and adolescents ( Table S7 ; Figure 2 ). The prevalence of clustering of ≥2 and ≥3 CMRFs were 12.1% and 6.3%, respectively; and 19.8% and 6.7% among children and adolescents from the obesity-B group, respectively ( Figure 2 ). Table 5 shows the adjusted odds ratios for the number of CMRFs across weight groups of children and adolescents. Compared with the obesity-A group, subjects from the obesity-B group were at 52% and 76% higher risk of clustering of ≥ 2 and ≥3 CMRFs, respectively ( Table 5 ).

The present study shows a higher prevalence of most of the cardiovascular risk factors in children and adolescents with a BMI between 110%-119% of the 95th BMI percentile (obesity-B group) as compared to individuals with lower degree of obesity. This ten percent increment in BMI within the Class 1 obesity group translates into significantly higher odds for clustering of CMRFs.

Severe obesity in childhood is associated with significant metabolic and cardiovascular morbidity (14). In our study, we aimed at assessing children and adolescents with lower degrees of obesity. Class 1 obesity reflects a wide spectrum of BMI values. Each 10% increase in BMI above the 95th percentile is equivalent to an average increase of 2.15 kg/m² and 2.75 kg/m² in BMI among children and adolescents, respectively ( Table S1 ) (8). Such increments may be of high clinical importance. For example, the Princeton Follow-up Study demonstrated that the risk of metabolic syndrome in adulthood increased by 24% for each 10% increase in age-specific BMI in childhood (9). In young adults, each 1-kg/m² increase in BMI was associated with a 6% higher risk of developing type 2 diabetes before the age of 45 years (15). In a cohort of Danish and Finnish subjects, each z-score increase in BMI at 7 years of age (equivalent to a 1.5 to 2.5 kg/m² increment) was associated with a 5%-10% greater risk of coronary heart disease in adulthood (16). Moreover, the risk of mortality increases significantly throughout the overweight and obesity range. In adults younger than 50 years of age, every five units higher BMI above 25 kg/m² was associated with an approximate 52% higher risk of premature death (17). These findings emphasize the importance of losing relative weight at a young age.

We subclassified Class 1 obesity into two groups to “zoom in” and better understand the cardiometabolic morbidity associated with lower degrees of obesity in childhood.

In our study, the prevalence of most CMRFs increased with the severity of obesity, except for diastolic blood pressure, diabetes, and total cholesterol ( Table 3 ).

Our results are in line with Sorof et al. that showed a progressive increase in systolic blood pressure with each increase in BMI percentile, whereas diastolic blood pressure showed no association (18). In our study, the prevalence of prediabetes was higher in the obesity groups as expected. However, the prevalence of diabetes was low with no difference seen between the groups. These registry-derived diagnoses include patients with all forms of diabetes, including type 1 diabetes, which might explain the higher (though insignificant) trend of having diabetes in the overweight group ( Table 4 ). However, Twig et al. showed that the cumulative incidence of early-onset type 2 diabetes was more than 2-fold higher among adolescents with severe obesity than among those with Class 1 obesity (4). This relationship should be regarded as a continuum in which each increment above the 95th BMI increases the risk of prediabetes and the transition toward type 2 diabetes.

Obesity is associated with elevated ALT levels. We defined abnormal serum ALT concentrations as >25 U/L for boys and >22U/L for girls (11). This is because liver biopsy specimens from children with normal or mildly elevated ALT (≥26 to 50 U/L for boys and ≥23 to 44 U/L for girls) were histologically abnormal, including advanced fibrosis (19). In our study, an increment in BMI above 109% of the 95th percentile more than doubled the risk for abnormal ALT values in children and adolescents as compared to those with overweight ( Table S5 , S6 ). Despite being nonspecific when used alone, the increased plasma concentrations of ALT with higher severity of obesity might reflect the presence of nonalcoholic fatty liver disease (NAFLD) in a substantial proportion of these children.

There were differences observed between children and adolescents in terms of their lipid and glucose profiles, with children showing nonsignificant differences across the weight groups ( Table 3 ). This suggests that the duration of obesity may play a stronger role than BMI alone.

There were important differences between male and female subjects in our study. It should be noted that girls constitute 60% of the study sample, although the prevalence of obesity in the general population is greater among boys (20, 21). Given the cross-sectional nature of the study and the eligibility for inclusion based on available data, this gender disparity may have occurred by chance. The present study demonstrates clearly that an increment in BMI above 109% of the 95th percentile is clinically significant, particularly among females. This increment increases the odds of higher triglycerides and LDL cholesterol and lower HDL cholesterol levels as compared to in females with lower degree of obesity ( Table 4 ). This markedly unfavorable lipid profile relative to weight gain in girls has been reported in a previous study which demonstrated slightly stronger indirect effects of weight gain, through childhood adiposity, in girls as compared with boys (22). There was a nonsignificant trend towards increased odds for prediabetes and higher ALT levels in females with a BMI above 109% of the 95th percentile as compared to those with lower degree of obesity. In males, an increment above 109% of the 95th BMI percentile was associated with increased odds for higher ALT levels. This result is in line with previous studies showing that prevalence was generally higher in boys as compared with girls and increased incrementally with greater BMI (23, 24).

Our findings differ from those in other reports. Some studies showed minimal differences between boys and girls and another study (in which 16.7% of the sample had severe obesity) showed a higher prevalence of risk factors in males (6, 25–27).

The clustering of CMRFs in childhood is of high concern, taking into account the fact that around 80% of them remain obese in adulthood (3). Indeed, this observation justifies the evaluation of cardiometabolic variables at a young age, especially among those who are overweight or obese.

Several definitions of metabolic syndrome in children and adolescents have been proposed (28–33). These definitions are diverse and lack uniformity, and there is no clear consensus on which to use. The American Academy of Pediatrics recommends shifting the focus to the concept of clustering of CMRFs rather than defining metabolic syndrome in children and adolescents (34).

In the Bogalusa Heart Study, the clustering of CMRFs was associated with increased severity of asymptomatic coronary atherosclerotic lesions in young people (35). Since the clustering of risk factors is present in childhood and continues into young adulthood, the presence of multiple risk factors such as hyperglycemia, hypertension, and abnormal lipid profile may indicate a faster progression of atherosclerosis in young people.

Using conservative thresholds for prediabetes, dyslipidemia, and hypertension, a large multi-ancestral cohort demonstrated a direct correlation between the severity of obesity and prevalence of CMRFs, whereby each half-unit increase in the BMI z score increased the risk of having cardiovascular risk factors’ clustering by 55% (29). Skinner et al. showed that values for some, but not all, CMRFs were higher with increased severity of obesity in children and adolescents, and demonstrated that greater severity of obesity is associated with a higher risk of lower HDL-cholesterol levels, elevated plasma triglycerides, and high systolic and diastolic blood pressure (6).

In our study, subjects with BMI between 110%-120% of the 95th BMI percentile had a higher prevalence of CMRFs clustering (17.8% and 6.6% for clustering of ≥2 and ≥3 risk factors, respectively) ( Table S7 ). They exhibited a substantially higher risk for CMRFs clustering as compared to those with lower degree of obesity ( Table 5 ). This highlights the need for further stratification of weight groups at a young age to better reflect the risk for metabolic and cardiovascular morbidity.

Previous research has shown that a lower SES during childhood is linked to a higher risk of developing metabolic syndrome in adulthood, even when controlling for other childhood risk factors (36). However, our study did not find a significant association between SES and the level of obesity, thus it cannot be considered a confounding factor.

There are several limitations to our study that should be considered. First, this is a cross-sectional study, which cannot prove the causality between obesity and CMRFs. In addition, we cannot exclude any secondary causes of obesity, such as genetic or hormonal factors. Second, we lacked data on lifestyle, physical activity, and other indicators of obesity such as waist circumference. The latter may be more sensitive than BMI in the context of this study and better define cardiovascular risk in the long term. Third, our sample might differ from the general population in terms of gender representation, as obesity is more common in boys (20). A considerable difference was observed in the number of individuals with obesity-A and obesity-B (50.3% compared to 9.5%). It should be noted that our sample was limited to individuals with available lipid profile data. This limitation, combined with the observational nature of the study, raises the possibility that the representation of obesity-B in our sample may not accurately reflect its prevalence in the general population. Finally, the sample size was relatively small in weight subgroups of children younger than 12 years old, which resulted in some estimates with wide confidence intervals, deeming them insignificant. Thus, some of these estimates should be interpreted with caution.

Our study has certain strengths. The study was based on a relatively large sample of children and adolescents. This permitted the evaluation of a wide variety of CMRFs and the exploration of their clustering among weight subgroups. In conclusion, among children and adolescents with Class 1 obesity, a BMI ≥ 110% of the 95th percentile was associated with a higher prevalence of and greater clustering of CMRFs. The consideration of this group (obesity-B group) in the standard obesity classification may assist in the identification of children and adolescents who could be at a greater risk for abnormal lipid profile, hyperglycemia, and abnormal ALT levels.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Maccabi Healthcare Services institutional review board and ethics committee. Approval number 0183-20-MHS. Written informed consent from the participants’ legal guardian/next of kin was not required to participate in this study in accordance with the national legislation and the institutional requirements.

AN and RS were responsible for the design of the study and data acquisition. AN and RS contributed to the analysis and the interpretation of data, drafted the manuscript and revised it critically for important intellectual content. NS and EF contributed to the analysis and the interpretation of data and revised the manuscript critically for important intellectual content. All authors contributed to the article and approved the submitted version.