Specialty Corner: Cardiovascular Disease Risk in Youth with Metabolic Syndrome

Case Presentation
A 15-year-old male was referred for dyslipidemia. Initial and follow-up laboratory findings are shown below. Renal and thyroid function were normal. No etiology was found for his elevated liver function tests (LFTs); liver ultrasound demonstrated only fatty infiltration.

Extensive acanthosis nigricans (AN) of the neck and axillary was noted. His body mass index (BMI) was > 99 percent and his blood pressure (BP) was elevated (systolic blood pressure [SBP] 98 percent; diastolic blood pressure [DBP] 68 percent). Numerous maternal and paternal family members have type 2 diabetes mellitus (T2D), many with complications including renal failure and a history of amputation of a lower extremity.

An oral glucose tolerance test (OGTT) revealed a fasting blood glucose (FBG) of 129 mg/dL; two-hour glucose 188 mg/dL. Recommendations were made for ways to achieve a heart-healthy lifestyle with specific focus on weight management. Because of “pre-diabetes,” he was started on metformin 1,000 mg per os (p.o.) twice daily with meals.

Implementation of lifestyle changes resulted in an 8 kg weight loss within three months. Fasting laboratory results showed improvement (see below). The importance of a heart-healthy lifestyle was re-emphasized, and he was continued on metformin. In addition, he was started on an angiotensin-converting enzyme inhibitor for persistent hypertension.

Within six months of his initial presentation, the patient had returned to his former sedentary lifestyle and increased consumption of refined sugars and fats. His weight increased approximately 10 kgs and his laboratory results deteriorated. (Table 1)

Discussion
This scenario is one that is all too commonly encountered in the pediatric population. In 2010, more than one-third of U.S. children and adolescents were overweight or obese.1 Most continue to be overweight or obese as adults,2 predisposing to premature cardiovascular disease (CVD) and type 2 diabetes as they mature. Obesity and insulin resistance (IR) also predispose to other metabolic abnormalities, such as non-alcoholic fatty liver disease, obstructive sleep apnea and, in females, polycystic ovarian syndrome.³

Independent of obesity, insulin resistance is associated with a greater risk for development of dyslipidemia and hypertension.^4,5  The presence of risk factors at such a young age leads to an earlier onset and a longer duration of disease, as well as an increased risk of premature mortality.

Metabolic Syndrome in Youth
While there are many definitions of the metabolic syndrome (MS) in youth (Figure 1), most include central obesity, impaired glucose metabolism (impaired fasting glucose, impaired glucose tolerance), dyslipidemia (elevated triglyceride [TG] and reduced high-density lipoprotein cholesterol [HDL]), and hypertension. As in adults, the components of metabolic syndrome have been shown to cluster in children. The presence of metabolic syndrome in childhood predicts metabolic syndrome, development of type 2 diabetes, and an increased rate of premature CVD-related events in adulthood.⁶ In the National Health and Nutrition Examination Survey III (NHANES III), the prevalence of the metabolic syndrome in youth ages 12 to 19 years was 4.2 percent and correlated with BMI (0.1 percent for BMI < 85 percent, 6.8 percent for BMI 85 to 95 percent, and 28.7 percent for BMI ≥ 95 percent).⁷  Although several criteria have been proposed (Figure 1), there is no consensus on a definition of metabolic syndrome in youth. The most recent criteria by the International Diabetes Federation are shown below. (Figure 2) Regardless of whether all the criteria are met, it is important to identify at-risk or affected youth early and to address all components of the metabolic syndrome. The goal in youth is to prevent risk-factor development and, when present, to treat all risk factors to reverse or prevent progression of metabolic markers linked to disease outcomes such as premature CVD and type 2 diabetes.

Childhood Predictors of Metabolic Syndrome and CVD
Although the consequences of atherosclerotic cardiovascular disease (ASCVD) are only rarely seen in children, the early pathophysiological changes in arteries begin soon after birth and accelerate during adolescence. The same risk factors associated with disease severity and progression in adults are present in the pediatric population, and the degree to which these risk factors are present in childhood is predictive of their prevalence in adulthood.^8,9 Visceral obesity and insulin resistance appear to be pivotal in the development of the metabolic syndrome in youth.¹⁰ Studies have identified characteristics in childhood that may predict metabolic syndrome and help identify individuals who may benefit from early intervention.

Using BMI as a measure of obesity, the Princeton Lipid Research Clinics Follow-up Study included youth ages 5 to 19 years. Twenty-five years after the initial evaluation, the study found that pediatric metabolic syndrome, age at follow-up, and changes in age-specific BMI percentiles were significant predictors of metabolic syndrome during adulthood.¹¹

The Muscatine Study Longitudinal Adult Cohort found that adults with metabolic syndrome had higher BMI, systolic blood pressure, and triglycerides at the time participants initially completed the school examination survey.⁷ Of all measures, BMI was the strongest predictor of adult metabolic syndrome. In the Muscatine study, adolescents with an elevated BMI were found to have higher rates of carotid intima-media thickness (cIMT) as young adults.¹²

These studies have notable limitations, including variable definitions of metabolic syndrome and CVD. Extrapolation of such studies to the entire pediatric population should be done with caution. Further studies with longer follow-up are needed to determine the age range and frequency with which CVD events occur as a consequence of childhood obesity.

Etiology of Metabolic Syndrome and Atherogenic Dyslipidemia
Atherogenic dyslipidemia is the predominant lipid profile seen in childhood metabolic syndrome, with moderate to severe elevation in TG and non-HDL-C, low HDL-C, and increased small dense low-density lipoprotein (sdLDL).¹³ Elevated sdLDL particles facilitate entrapment of LDL in the arterial sub-endothelial matrix, and reduced levels of large HDL particles decrease cholesterol efflux, leading to a highly atherogenic phenotype.

There is currently no consensus on a single cause of metabolic syndrome. However, an increase in BMI in genetically susceptible individuals and the development of insulin resistance appear to be essential. Many believe that weight gain alone may be insufficient, since metabolic syndrome also may occur in those who are not obese. Fat distribution appears to be important, excess visceral fat leading to more insulin resistance than subcutaneous fat.10 Atherogenic dyslipidemia in MS can be seen in > 40 percent of adolescents with a BMI > 95 percent.¹⁴  Studies have shown that both HDL-C and non-HDL-C are the best lipoprotein predictors of atherosclerotic lesions.¹⁵ However, there are no longitudinal studies demonstrating that the atherogenic dyslipidemia seen in metabolic syndrome children and adolescents leads to early vascular injury in affected youth.¹⁶

T2D and Early Development of Complications and Comorbidities
With the increase in childhood obesity, the prevalence of type 2 diabetes has increased dramatically in youth, with the greatest increases seen in ethnic minorities. Type 2 diabetes accounts for 3 percent of all diabetes in white youth. However, it accounts for 23 percent of all diabetes in Hispanic youth, 25 percent in non-Hispanic black youth, and 64 percent in Native American youth.¹⁷ Type 2 diabetes in youth has been shown to potentially be a more aggressive disease than in adults. In the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) cohort, time to treatment failure occurred in 45.6 percent of the participants over an average follow-up period of 3.86 years.¹⁸

The TODAY study also found an increased prevalence of high-risk LDL (> 130 mg/ dL), hypertension, and microalbuminuria in participants by the end of the study as compared to baseline.18 These findings raise the concern that even though T2D- related complications and comorbidities are similar in adults and youth, they may occur at a more accelerated rate in youth. Further, in individuals with onset of diabetes in their youth (15 to 30 years), those with type 2 diabetes have been shown to have greater mortality and shorter disease duration and to have more CVD-related deaths than in individuals with type 1 diabetes mellitus.¹⁹

Clinical Management of the Metabolic Syndrome in Youth
According to the National Heart, Lung and Blood Institute (NHLBI), metabolic syndrome should not be considered an independent risk factor in children and adolescents since there is no agreement on the definition in youth; and also because there are a lack of intervention/outcome studies.¹³ However, since it has been shown that obesity increases the risk of adult metabolic syndrome, prevention of obesity in children is an important goal. According to the U.S. Preventive Services Task Force recommendations, obese children 6 years and older need to be referred for intensive counseling and behavioral interventions to help achieve and maintain a healthy weight.²⁰

The presence of obesity in youth should prompt evaluation of other CVD risk factors, including family history of premature CVD, tobacco use or secondary exposure, hypertension, dyslipidemia, and insulin resistance. Identification of one or more CVD risk factors in an obese youth should prompt more aggressive therapy with the goal of improving those that are modifiable (e.g. decreasing body weight, increasing physical activity, smoking avoidance/cessation, and reducing consumption of fats and refined sugars).¹⁶ Studies have shown that modest degrees of weight loss in children can improve the atherogenic profile and insulin resistance.²¹

Whether to treat youth with dyslipidemia with lipid-lowering medication remains an ongoing debate. Most randomized, placebo-controlled trials in the pediatric population have focused on the use of statins for elevated LDL-C in familial hypercholesterolemia (FH). Results have shown that statins are safe and help decrease atherosclerotic changes in this population. It is tempting, therefore, to apply the same rationale to youth with metabolic syndrome. In addition to a lack of evidence, use of lipid-lowering medication should be used with caution in this population, which commonly has preexisting impaired liver function and is prone to diabetes. Despite these concerns, given the prevalence of risk factors (Figure 3) in pediatric patients with components of the metabolic syndrome, it has been suggested that statin therapy for an LDL-C ≥ 160 mg/dL may be reasonable depending on the risk factors.^13,16

Conclusions
Metabolic syndrome is common in obese, IR youth and is associated with increased risk of T2D and premature CVD during adulthood. Avoidance of excessive weight gain, starting in youth, is critical in the prevention of MS and its consequences. For youth who are already overweight or obese, aggressive lifestyle management is imperative. Medical management may be indicated in those at highest risk and for those who are unable or unwilling to follow recommendations for a heart-healthy lifestyle.

Acknowledgement: The authors would like to thank Karen Keller, Dena Hanson, and Lynn Harmon for their assistance in preparing and editing this manuscript.

Disclosure statement: Alejandro De La Torre has no disclosures to report. Dr. Wilson is a speaker for the Osler Institute, participated on an advisory board of Aegerion Pharmaceuticals, participated on an advisory board of and as an educational speaker for Synageva Biopharma Corp., and received research funding from Merck Sharp & Dohme and Novo Nordisk Inc.

References are listed on page 38 of the PDF.