The American lifestyle is becoming increasingly unhealthy. “Supersizing” is now a household term. For a number of reasons, cardiovascular disease (CVD) is the number one killer of Americans today.1 While most of the clinical burden of CVD lies in adulthood, research is making it clear that the atherosclerotic process (i.e., the building up of plaque on artery walls) begins early and is progressive throughout life.1 Therefore, a new urgency should be placed on early detection and aggressive treatment of risk factors in order to head off the epidemic of CVD in America.2 The American Heart Association (AHA) and the American Academy of Pediatrics (AAP) have issued recent policies regarding this important matter.3 This article will discuss the strongest risk factors for CVD and the screening for and treatment of lipid abnormalities in childhood and adolescence in order to lower the lifelong risk of death and morbidity from the disease.
Risk Factors for Cardiovascular Disease
The strongest risk factors for CVD include elevated low-density lipoprotein cholesterol (LDL-C or “bad” cholesterol), decreased high-density lipoprotein cholesterol (HDL-C or “good” cholesterol), high blood pressure, diabetes (type 1 or 2), cigarette smoking, and obesity.1 Some of these risk factors may be present at young ages, and research has shown that they should be addressed early.1,2 Children and adolescents are becoming increasingly overweight and obese. A recent study reported that the prevalence of overweight 12- to 19-year olds is 15.5%.3 The childhood obesity epidemic has increased the need for pediatric health care professionals to become more knowledgeable about the risk factors for CVD and to begin implementing lifestyle changes in patients.1
Along with the rise of obesity in children has come the increased incidence of pediatric metabolic syndrome (also referred to as insulin resistance syndrome),2,3 another risk factor for adult-onset CVD.1 Metabolic syndrome is a group of risk factors for CVD and diabetes that seems to be associated with obesity and insulin resistance.1 Obesity and the metabolic syndrome are strongly linked to lipid abnormalities. Research has found that overweight schoolchildren are between 2.4 and 7.1 times more likely to have high total cholesterol, LDL-C, and triglyceride levels than children with normal weight.3 There are a number of mechanisms by which insulin resistance can cause dyslipidemias. Hepatic synthesis of very low-density lipoprotein (VLDL) cholesterol, leading to increased triglycerides and LDL-C, is increased by the presence of excess insulin in the blood. Triglycerides and LDL-C can also be increased by insulin’s effects on lipoprotein lipase, an enzyme that breaks down lipoproteins. Additionally, HDL-C is sometimes degraded more rapidly in patients with metabolic syndrome.2 There is currently no accepted definition for metabolic syndrome in children and adolescents. It has been proposed that the adult definition be used, with percentile values used for cut points in the pediatric population.1
While overweight and obesity clearly contribute to dyslipidemias and CVD, there is also an important genetic component to the process.1 Family history positive for CVD clearly puts children and adolescents at risk for developing CVD at some point in their lifetimes. This could include a parent or grandparent less than 55 years of age who has coronary atherosclerosis, peripheral vascular disease, or cerebrovascular disease, or who has had a coronary artery procedure or suffered a myocardial infarction (MI) or sudden cardiac death. Children with parents who have high blood cholesterol levels or who themselves have high cholesterol are also considered at risk.3 Screening is recommended for these individuals.
The Atherosclerotic Process
The atherosclerotic process in children begins in childhood and is progressive. This knowledge provides the strongest evidence for aggressive treatment of risk factors for those individuals who may be at greater risk for CVD at an early age.3 The fatty streak is thought to be the earliest pathologic finding in atherosclerosis. This is characterized by the accumulation of lipid-filled macrophages within the intima (innermost lining) of the arteries. Lipids continue to accumulate here with age. The migration of macrophages and smooth muscle cells into the intima and media of the artery then form a fibrous plaque lesion. It is this lesion that is the site of rupture, initiating a cascade of events that ultimately lead to thrombus formation and ischemia. Adverse outcomes such as stroke and MI begin with the fatty streak.1,3 Pathologic evidence found in autopsy studies in youth (who were victims of accidental trauma, suicide, or homicide) has demonstrated that the fatty streak can be seen well before adulthood.1 These studies also show that the rate of atherosclerotic progression is greatly increased by lipid abnormalities and also by their severity.3 At the time these studies were conducted, there was no childhood obesity epidemic. It is likely that if they were repeated today, an even more aggressive atherosclerotic process would be seen.1
Studies also show that risk factors for CVD present in childhood and adolescence are directly correlated to subclinical measures of atherosclerosis in adulthood.1 With the prevalence of lipid abnormalities in children rising, it is not unreasonable to believe that we could soon see an epidemic of premature CVD. Effective population-based strategies for identifying individuals at risk are crucial.3 Identifying these children could lead to interventions or treatments that could prevent or at least delay adult dyslipidemia and CVD.1,4 While lifestyle changes such as diet and exercise are helpful in many instances, they may not be the answer for all patients.
Screening for Lipid Disorders in Children
Universal screening of children and adolescents for cholesterol abnormalities is not recommended. The best approach to cholesterol screening would be to identify those who are most at risk for CVD in adulthood. Currently there are no noninvasive clinical tools available to effectively assess the progression of atherosclerosis in children. Therefore, as in adults, cholesterol concentrations must be used as a surrogate marker. This approach led to the adoption of the Framingham risk score to evaluate adult patients at a 10-year risk of CVD who would benefit from more aggressive treatment. No similar risk score is currently accepted for children, nor is there any particular level of childhood cholesterol that might predict the risk of adult CVD. Firm, evidence-based recommendations for cholesterol screening for children are therefore elusive.1
Children at high risk because of a family history of premature CVD and/or hypercholesterolemia in their parents should be targeted. Children with unknown family history should also be screened, as should those with other risk factors for CVD such as hypertension and diabetes.1 Additionally, overweight and obese children are now recommended to be screened with a fasting lipid profile and also checked for other aspects of the metabolic syndrome.
Lipid levels are generally understood to increase in young children and reach concentrations seen in young adults by approximately 2 years of age.1 It is not necessary to check cholesterol levels before age 2, as they may not reflect values in successive years of childhood and adulthood.1 Children identified at risk should have levels measured no earlier than age 2 and no later than age 10. If levels are found to be normal, they should be rechecked every three to five years.2
New guidelines for cholesterol screening will target between 36% and 46% of children and adolescents.3 Cholesterol screening is therefore recommended for select individuals as part of well-child care. However, only two-thirds of pediatricians report that they test children for high cholesterol based on family history. Furthermore, one study found that only 70% of parents chose to have their child screened when it was offered by their pediatrician’s office.4 Multiple blood draws in children and multiple visits to see their practitioner are both barriers to compliance with guidelines.3
Cut Points
It is estimated that the prevalence of children with high cholesterol is 15.6% of girls and 11.1% of boys.1 Children and adolescents who have elevated LDL-C are recommended to begin interventions.3 Elevated LDL-C is the most common clinically significant marker of dyslipidemia in children.4
Lipid concentrations are variable during different periods of childhood. Typically, total cholesterol concentrations decline during puberty and increase thereafter. Gender also affects cholesterol levels, with females usually having higher total cholesterol and LDL-C, as well as higher HDL-C, after puberty. Ethnicity also complicates patterns.1,2 Abnormal concentrations of cholesterol in children should be identified using percentile values. This takes into consideration the variability of lipids by age and sexual differences. These values are outlined in TABLE 1. LDL-C concentrations greater than the 95th percentile and HDL-C concentrations less than the 5th percentile would be considered abnormal. This would be particularly true if the value was outlying over repeated measurements. LDL-C concentrations between the 90th and 95th percentiles and HDL-C concentrations between the 5th and 10th percentiles would be deemed borderline.1
Treatment
Current guidelines for lowering cholesterol in children recommend a two-pronged strategy. First, there is the population approach, which promotes a healthy lifestyle for all children. Recommendations state that all healthy children over 2 years of age adopt a fat- and cholesterol-restricted diet with the appropriate number of calories to support growth and development and to maintain a desirable body weight.2,3 Children younger than 2 years should not be placed on this type of diet, as their rapid growth and development requires sufficient fat and cholesterol intake.4 Age-appropriate physical activity levels are also encouraged in the population approach.1
Next, there is the high-risk individual approach, in which children who themselves have high cholesterol or who are at high risk because of a parental history of premature CVD and/or hypercholesterolemia are targeted. Lifestyle modifications are first-line. Exercise not only helps to lower LDL-C, but can also significantly increase HDL-C. Weight loss is recommended for overweight children, which may include maintenance of weight during growth in height.1,4 Changes in diet are important. The AHA Step I diet is one example of a low-fat, low-cholesterol diet.4 It is also important to limit saturated and trans fats.1 One shortcoming of the recommended fat- and cholesterol-restricted diet is that by default it increases carbohydrate intake, which may in fact contribute to overweight and obesity. Additionally, only limited effects on LDL-C are usually seen, while HDL-C may actually be decreased and triglycerides increased. The patient may then be at risk for mixed dyslipidemia.3
In addition to diet and exercise, dietary supplements may be introduced. Dietary fiber, plant sterols and stanols, and omega-3 fatty acids are available as dosage forms, but can also be incorporated into a patient’s nutrition.4 Fiber can be increased by taking in more fruits and vegetables. Plant sterols and stanols can be found in some margarines.4 Fish and nuts are good sources of omega-3 fatty acids.
While lifestyle modification is the mainstay of therapy, sometimes it is not sufficient to achieve desired cholesterol levels in patients. Drug therapy may be warranted.2 Although there has been a general reluctance to use lipid-lowering drugs in the pediatric population, evidence is becoming increasingly available that suggests effectiveness and at least short-term safety quite similar to that in adults.3
Pharmacologic Intervention
The AHA recommended in July of 2007 that children 10 years of age or older whose LDL-C remains extremely elevated after a six- to 12-month trial of diet be started on LDL-C–lowering drug therapy.3 The AAP states that it is difficult to articulate the specific age at which pharmacologic treatment should be implemented, as evidence-based data are lacking.1 More recent studies of children and adolescents have established the effectiveness and safety of the available agents, including their use in prepubertal children and those between the ages of 8 and 10 years.1 In July 2008, the AAP stated that children age 8 years or older are candidates, and even younger children may be considered for drug therapy if they have such dramatic elevations in LDL-C as seen with homozygous familial hypercholesterolemia (>500 mg/dL).1 The recommended cut points for pharmacologic treatment based on LDL-C concentrations are delineated in TABLE 2. The five different classes of lipid-lowering drugs are outlined in TABLE 3.
Bile Acid–Binding Resins: Older recommendations stated that in patients for whom lifestyle modifications were insufficient, bile acid–binding resins should be started.1 Bile acid–binding resins work to bind cholesterol in bile acids in the intestinal lumen, preventing their reuptake into the enterohepatic circulation and thereby decreasing the formation of new cholesterol. These resins are not absorbed systemically and for that reason have few side effects.1 However, this class of drugs is poorly tolerated in children, resulting in poor compliance and effectiveness. Gastrointestinal (GI) complaints are most common. Only modest decreases in LDL-C are therefore seen, and patients will not likely reach their target levels.3 However, bile acid–binding resins are the only class of lipid-lowering drugs that are approved for treatment of dyslipidemia in children younger than 8 years.4
Statins: The 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors, or statins, are a class of drugs that show promise in studies for children with high cholesterol.4 Statins work to lower cholesterol by inhibiting the rate-limiting enzyme in the synthesis of cholesterol. They are currently approved for use in older children with heterozygous familial hypercholesterolemia.4 This class of drugs is preferred because statins are much more effective in lowering LDL-C and total cholesterol and better tolerated than the bile acid–binding resins. Patients may experience cholesterol lowering of 20% to 50% below baseline.1 The HMG CoA reductase inhibitors have led to significant reductions in cardiovascular and all-cause mortality in adults who are at risk for or who have manifested atherosclerotic CVD.3 Early statin therapy has been shown to reverse vessel damage.1 There have been a number of well-performed clinical trials of statins in children and adolescents, which continue to show safety and efficacy similar to that in adults.1-3 While these studies are generally short term, results are promising. Lovastatin is the oldest drug in the class and has been on the market for only about 20 years.2 The ultra-long-term effects of the statins remain of concern for all patients, regardless of age.2,3
Statins should be initiated in pediatric patients requiring drug therapy first line.1-3 The lowest dose is preferred and is usually associated with the most dramatic change in LDL-C concentrations.3 Each time the dose of a statin is doubled, the resulting decrease in LDL-C is only 6%. This is known as the Rule of Six. Statins are dosed once daily, usually at bedtime. Atorvastatin, simvastatin, fluvastatin, and lovastatin are approved for use in children aged 10 years and up.2 Pravastatin has been FDA approved for ages 8 and up, regardless of pubertal status.1,2 Rosuvastatin is not currently recommended in children, but the drug is in trials.2,3
Other Drugs: Three other classes of cholesterol-lowering drugs are available for use in adults. These include niacin, fibrates, and cholesterol-absorption inhibitors. Niacin is not routinely recommended for use in the pediatric population due to its high incidence of adverse effects.3 Fibric acid derivatives, or fibrates, have not been extensively studied in children, but may be used in extreme cases of hypertriglyceridemia under the care of a pediatric lipid specialist.1,2 Cholesterol-absorption inhibitors are a new class of drugs and represent a potentially important new first-line treatment for children.1 There are currently no published trials evaluating the safety and efficacy of ezetimibe in children or adolescents.2
The Role of the Pharmacist
Patients young and old must be counseled on their medications. Young patients with newly prescribed therapies for lowering cholesterol should be counseled on the importance of medication adherence. Patients on statin therapy should be made aware of the possibility for developing muscle pain or weakness.3 Care should be taken to prevent rhabdomyolysis caused by drug–drug interactions with concomitant use of statins with erythromycin, cyclosporine, and gemfibrozil.3 Girls of childbearing age should be counseled on the need for effective contraception, due to the possibility of teratogenicity (Pregnancy Category X).2,3 The most common side effect of statins is infrequent GI upset. Use of creatine kinase and liver transaminases should be monitored regularly.3
It is becoming very clear that CVD is a major problem in adults and children alike. While the prevalence of CVD is increasing, there are effective therapies available that are proven to save or prolong lives. It is the responsibility of the health care professional to encourage screening for patients who may be at risk. The new recommendations discussed in this article will increase the number of pediatric patients that should be screened. The community pharmacist is at a unique advantage for identifying these individuals. The pharmacist often develops relationships with entire families and is aware, through knowledge of drug therapy, which disease states are present in the family history and which ones can be passed on to the next generations. Children of patients with prescriptions for lipid-lowering therapies should be encouraged by their pharmacist to get checked. The pharmacist should reassure nervous parents that by giving their children this treatment now, they may be adding invaluable healthy years to their lives.
REFERENCES
1. Daniels SR, Greer FR; Committee on Nutrition. Lipid screening and cardiovascular health in childhood. Pediatrics. 2008;122:198-208.
2. Treatment of hyperlipidemia in children and adolescents. Pharm Lett/Prescr Lett. 2008;24:240803.
3. McCrindle BW, Urbina EM, Dennison BA, et al. Drug therapy of high-risk lipid abnormalities in children and adolescents: scientific statement from the American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee, Council of Cardiovascular Disease in the Young, with the Council on Cardiovascular Nursing. Circulation. 2007;115:1948-1967.
4. Haney EM, Huffman LH, Bougatsos C, et al. Screening and treatment for lipid disorders in children and adolescents: systematic evidence review for the US Preventive Services Task Force. Pediatrics.
2007;120:e189-e214.
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