Waist-to-height ratio as a clinical predictor for cardiovascular risks and insulin resistance in children and adolescents with exogenous obesity

Obesity is one of the most challenging clinical syndromes associated with deleterious health problems. Waist-to-height ratio (WHtR), a newer index for abdominal fat assessment, can be a superior tool in the evaluation of cardiometabolic risk. This study aimed to determine the relation between WHtR and lipid cardiovascular risk ratios and insulin resistance (IR) in children and adolescents with exogenous obesity. This analytical cross-sectional study included 80 children and adolescents with exogenous obesity, compared to 80 age- and sex-matched healthy non-overweight non-obese controls. Fasting lipid profile (total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL) and low-density lipoprotein (LDL)), fasting insulin, and fasting blood glucose were done and lipoprotein risk ratios were calculated; TC/HDL, LDL/HDL, non-HDL/HDL, and TG/HDL). In addition, homeostatic model assessment for IR (HOMA IR), triglyceride glucose index (TyG), TyG-BMI, and TyG-WC were calculated. The study group included 55 (34.4%) males and 105 (65.6%) females with a mean age of 13.6 ± 2.22 years. Obese group had significantly higher TC, TG, LDL, non-HDL, LDL/HDL, TC/HDL, non-HDL/HDL, and TG/HDL, with significantly lower HDL. In addition, they had significantly higher FBG, HOMA IR, TyG, TyG-BMI, and TyG-WC indices compared to the control group. There were statistically significant correlations between WHtR and lipid profile, lipid risk ratios and indices of IR. WHtR was found to be an independent predictor of IR by linear regression analysis. WHtR can be an excellent, easy, and reliable clinical predictor for cardiovascular risk and IR in children and adolescents with exogenous obesity.


Background
Obesity represents one of the most serious public health problems of the twenty-first century and can be defined as a state of excessive body adiposity occurring when energy intake chronically exceeds energy expenditure [1]. Moreover, obesity is one of the most complex and challenging clinical syndromes worldwide that can affect children and adults and has an association with numerous deleterious health outcomes as type 2 diabetes mellitus (T2DM), dyslipidemia, hyperinsulinemia, polycystic ovary syndrome, hypertension, coronary heart diseases, as well as many psychosocial and social problems [2][3][4][5].
Anthropometric measures such as weight, height, and circumferences are often used in clinical practice due to their low cost and high convenience. Anthropometric measures of abdominal obesity (as waist circumference (WC), Waist-to-hip ratio (WHR)) appear to be strongly associated with metabolic and cardiovascular risk

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Egyptian Pediatric Association Gazette factors [6,7]. However, waist-to-height ratio (WHtR), a newer index for abdominal fat assessment, has emerged to be a superior tool in the evaluation of cardiometabolic risks [8].
Coronary risk assessment based exclusively on lowdensity lipoprotein (LDL) cholesterol is not optimal. Several lipoprotein ratios or "atherogenic indices" were identified and proved to be better predictors for cardiovascular disease (CVD) than conventional lipid parameters [9,10]. Total cholesterol/high-density lipoprotein cholesterol ratio (TC/HDL); known as the atherogenic or Castelli index and LDL/HDL ratio can be also used [9,11]. In addition, the use of a simple non-HDL calculation in a lipid profile testing, with determination of the new risk factors, can provide a better assessment of the CVD risk [12][13][14].
Insulin resistance (IR) or impaired insulin sensitivity is considered an important risk factor for metabolic syndrome, T2DM, and CVD. Thus, early detection of IR can help to prevent the manifestation of clinical diseases. Currently, there are various indirect and direct methods to assess IR; the standard method was the euglycemichyperinsulinemic clamp technique, originally developed by Defronzo. However, it is a complex, costly, and timeconsuming method, making it difficult to be used for routine clinical practice. Therefore, a number of indices for the measurement of IR have been suggested. Triglyceride glucose index (TyG) and TyG-related indices (TyG-BMI and TyG-WC) were found to be excellent surrogate markers of IR [15][16][17].
The aim of this study is to determine the relation between WHtR and lipid cardiovascular risk ratios (LDL/ HDL, TC/HDL, non-HDL/HDL, and TG/HDL ratios) and IR (measured by homeostatic model assessment for IR (HOMA-IR), TyG index, TyG-BMI, and TyG-WC) in children and adolescents with exogenous obesity.

Study population
This cross-sectional study included 80 children and adolescents with exogenous obesity. Patients were recruited from the Pediatric Endocrine Unit, in the period from May 2018 to May 2019. Subjects were eligible if they had exogenous obesity, were between 10 and 19 years, had a body mass index more than or equal to 95% for age and sex plotted on Egyption growth charts [18] and showing pubertal signs; Tanner stage 2 or more. Subjects with a history of diabetes mellitus, hypothyroidism or other endocrinal disorders, or prepubertal, or those taking any lipid altering drugs or corticosteroids or having obesity due to any endocrinal or syndromic etiology were excluded from the study. Eighty healthy non-overweight non-obese age-and sex-matched controls were recruited from the general outpatient clinics.
All procedures performed in this study, involving human participants were in accordance with the ethical standards of Cairo University and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from every individual participant or their legal guardians included.

Data collection
All patients and controls were subjected to full history taking laying stress on age, gender, the presence of any associated conditions or complications.
Thorough clinical examination and the following measurements were carried out: height, weight, BMI, waist circumference (WC-measured in centimeters to the nearest 0.1 cm, with a flexible tape, at the level of umbilicus, at the end of expiration with person breathing silently. Hip circumference (HC-measured in centimeters to the nearest 0.1 cm at the level of the greater trochanters, using a flexible tape), waist-hip ratio (WC/HC-calculated as WC divided by HC), and waist-to-height ratio (WHtR-calculated by dividing WC/height).
Regarding the laboratory findings; the obese group has significantly higher TC, TG, LDL, non-HDL, LDL/ HDL, TC/HDL, non-HDL/HDL, and TG/HDL, with significantly lower HDL. In addition, they had significantly higher FBG, HOMA-IR, TyG, TyG-BMI, and TyG-WC indices compared to the control group (Table 2). Moreover, all obese subjects had high HOMA-IR values, however, only 22.5% (18 out of 80) of the control group had their HOMA-IR values above the cut-off point (≥ 3.12).
There was significantly positive correlation between waist-height ratio and BMI, WC, WHR, TC, TG, LDL, non-HDL, LDL/HDL ratio, TC/HDL ratio, non-HDL/ HDL ratio, and TG/HDL ratio in addition to, FBG, and HOMA-IR, TyG index, TyG-BMI, and TyG-WC.  However, there was a significant negative correlation with HDL (Table 3). Linear regression analysis was done and proved that WHtR is an independent predictor of IR assessed by HOMA-IR in this study (adjusted R 2 = 0.65, p< 0.001) (Fig. 1)

Discussion
Obesity in childhood and adolescence is associated with well-known comorbidities. Moreover, regional body fat distribution has an important influence on metabolic and cardiovascular risk factors. Increased visceral fat accumulation is considered a risk factor for CVD, dyslipidemia, hypertension, stroke, and T2DM [23,24].
In the current study, the measures of visceral obesity (WC, WHR, and WHtR) were significantly higher in obese patients compared to the control group. Moreover, obese children had significantly higher TC, TG, LDL, and non-HDL compared to the control group. This is in line with other studies that found that obesity especially the central obesity was associated with unfavorable lipid profile [25][26][27][28].
Estimation of cardiovascular risk is the cornerstone of cardiovascular prevention. Many lipoprotein ratios were defined in an attempt to optimize the predictive capacity of the lipid profile [9]. In our study, lipoprotein risk ratios (LDL/HDL, TC/HDL, non-HDL/HDL, and TG/ HDL ratio) were significantly higher in obese children and adolescents compared to the control group. This in agreement with other authors who found that obesity is associated with increased risk for CVD and these ratios had greater predictive value for CVD than conventional lipid parameters used independently [9,10,28].
There is a well-known association between obesity and T2DM especially the visceral obesity [29][30][31]. Visceral obesity plays an important role in the development of T2DM by mobilizing free fatty acids and certain inflammatory cytokines causing IR [30]. Studies have shown that IR is a risk factor for the development of T2DM and CVD in children and adolescents [32,33].
In this work, fasting blood glucose (FBG), IR assessed by HOMA-IR, TyG index, TyG-BMI, and TyG-WC were significantly higher in the obese group compared to the control group. This is in line with Hussain et al. [30] who found increased incidence of T2DM in obese patients. Also, Hajian-Tilaki and Heidari [34] found a significant correlation between FBG and WHR and explained this by central obesity which correlates with the development of subsequent metabolic abnormalities and cardiovascular morbidity.
In the current study, there were significantly positive correlations between WHtR and BMI, WC, WHR, TC, TG, LDL, non-HDL, LDL/HDL ratio, TC/HDL ratio, non-HDL/HDL ratio, and TG/HDL ratio in addition to, FBG, HOMA-IR, TyG index, TyG-BMI, and TyG-WC. However, there was significant negative correlation with HDL. This agrees with Miralles et al. [8] who analyzed the correlation of WHtR with the other anthropometric variables, and observed a positive significant correlation with BMI, WC, BF%, lipid profile and TG/HDL and significant negative correlation with HDL. Moreover, Jamar et al. [35] found that among anthropometric obesity indicators, WHtR was most closely associated with occurrences of IR and predicted the onset of diabetes in obese individuals as compared with other parameters (BMI, WC, WHR, neck circumference, and body shape index).
Several studies have been recently conducted to demonstrate the accuracy of WHtR in identifying the risks for CVD in obese children and adolescents from healthy youth population; defining cut-offs and centiles for this easily calculated parameter [36][37][38]. It is also ideal and non-invasive tool in terms of interpretation and measurement to be used in clinical practice.
Potential limitations of our study must be considered. First, this is a cross-sectional rather than a populationbased study, which may lead to over-estimation of the prevalence of insulin resistance in obese children Moreover, this work was a cross-sectional study and might lack adequate evidence of the predictive values of WHtR. Although, this value is not diagnostic; it can be predictor for the screening for IR among obese children and adolescents. Additionally, being based on convenient consecutive sampling this study may lack clear generalizability, however, while applying consecutive sampling, each consecutive eligible patient who presents for care within the defined study time period is approached for enrollment, thus, consecutive sampling provides some structure and additional rigor that reduces the bias in sampling. Finally, blood pressure measurements for the studied subjects were not included in the study.

Conclusion
Waist-to-height ratio (WHtR) can be an excellent, easy and reliable clinical predictor for cardiovascular risk and insulin resistance in children and adolescents with exogenous obesity.