Dyslipidemia in children and adolescents: Management

INTRODUCTION — 

Dyslipidemias are disorders of lipoprotein metabolism that may result in the following abnormalities (table 1):

●High total cholesterol (TC)

●High low-density lipoprotein cholesterol

●High non-high-density lipoprotein cholesterol (non-HDL-C)

●High triglycerides (TG)

●Low HDL-C

The management of dyslipidemia in children and adolescents will be reviewed here. Related topics include:

●(See "Dyslipidemia in children and adolescents: Definition, screening, and diagnosis".)

●(See "Familial hypercholesterolemia in children".)

●(See "Inherited disorders of LDL-cholesterol metabolism other than familial hypercholesterolemia".)

●(See "Pediatric prevention of adult cardiovascular disease: Promoting a healthy lifestyle and identifying at-risk children".)

●(See "Overview of the management of the child or adolescent at risk for premature atherosclerotic cardiovascular disease (ASCVD)".)

●(See "Overview of pediatric risk factors for premature atherosclerotic cardiovascular disease (ASCVD)".)

●(See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease".)

●(See "Management of low-density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

RATIONALE FOR INTERVENTION — 

The rationale for initiating lipid-lowering therapy during childhood and adolescence is based upon evidence that pediatric dyslipidemia (particularly elevated low-density lipoprotein cholesterol [LDL-C]) contributes to atherosclerosis and the development of premature atherosclerotic cardiovascular disease (ASCVD) [1]. (See "Overview of pediatric risk factors for premature atherosclerotic cardiovascular disease (ASCVD)" and "Dyslipidemia in children and adolescents: Definition, screening, and diagnosis", section on 'Rationale for lipid screening'.)

Evidence establishing the long-term effectiveness of lipid-lowering interventions in children comes largely from studies in children with familial hypercholesterolemia (FH), a group at high risk for morbidity and early mortality. Lipid-lowering therapy in children with FH decelerates the atherosclerosis process, as assessed by subclinical vascular findings (eg, carotid intima-media thickness). Long-term outcome data on cardiovascular morbidity and mortality are not available for the general pediatric population; however, it is reasonable to assume, based on evidence from adult studies and limited pediatric data, that timely intervention to address dyslipidemia in childhood may decelerate the atherosclerotic process, which would prevent or delay the onset of ASCVD. (See "Familial hypercholesterolemia in children".)

The practice of initiating interventions for pediatric dyslipidemia during childhood is supported by several organizations, including the American Heart Association, the American College of Cardiology, the American Academy of Pediatrics, the National Lipid Association, the National Cholesterol Education Program, and an expert panel sponsored by the National Heart, Lung, and Blood Institute [1-5]. Links to these and other society guidelines are provided separately. (See 'Society guideline links' below.)  

Because evidence is lacking to directly link drug treatment with a reduction in ASCVD, some question the risk-benefit of pharmacologic therapy in children with dyslipidemia [6]. (See 'Adverse effects' below and "Dyslipidemia in children and adolescents: Definition, screening, and diagnosis", section on 'Harms of screening'.)

REFERRAL — 

Referral to a pediatric lipid specialist may be warranted in some cases of pediatric dyslipidemia, as described below. A pediatric lipid specialist is typically pediatric cardiologist (or an endocrinologist, gastroenterologist, or general pediatrician), who has completed additional training in lipid disorders through a senior fellowship or via professional societies. If a pediatric lipid specialist is not available locally, referral to an adult lipid specialist may be helpful, particularly for adolescents.

Referral to a pediatric lipid specialist is generally warranted for children and adolescents with any of the following:

●Known primary lipid disorder – Patients with known primary genetic lipid disorders (eg, familial hypercholesterolemia [FH] or other inherited disorder) generally warrant specialty referral (table 2). (See "Familial hypercholesterolemia in children" and "Inherited disorders of LDL-cholesterol metabolism other than familial hypercholesterolemia".)

●Clinical suspicion of FH – Clinical suspicion for FH may arise because (see "Familial hypercholesterolemia in children", section on 'Clinical suspicion'):

•There is a family history of premature atherosclerotic cardiovascular disease (ASCVD), and the child or adolescent's low-density lipoprotein cholesterol (LDL-C) level is ≥160 mg/dL (4.1 mmol/L).

•In the absence of a family history of premature ASCVD, FH should be suspected if the patient's LDL-C level is ≥190 mg/dL (4.9 mmol/L), if confirmed on repeat testing and not responsive lifestyle interventions.

Most patients with FH have heterozygous FH (HeFH), in which untreated LDL-C levels are typically in the range of 160 to <400 mg/dL (4.1 to 10.3 mmol/L). Homozygous FH (HoFH) is rare and is usually associated with untreated LDL-C levels ≥400 mg/dL (10.3 mmol/L). Genetic testing may be helpful, and specialist care will often be beneficial in patients with FH. In particular, patients with HoFH are at risk for ASCVD in early childhood, and they require genetic testing, as well as input from a pediatric cardiologist and a lipid specialist experienced in caring for children with this diagnosis. (See "Familial hypercholesterolemia in children".)

●High-risk conditions – Referral is generally appropriate for patients with conditions that put them at high risk for early ASCVD (table 3) who despite optimal management of the underlying condition have LDL-C levels that warrant pharmacotherapy (ie, LDL-C ≥130 mg/dL [3.4 mmol/L]). (See 'Risk stratification' below.)

●Inadequate response to statin therapy – Patients requiring second-line pharmacologic therapy for treatment of hypercholesterolemia generally warrant specialty referral. (See 'Second-line therapies' below.)

●Extreme hypertriglyceridemia – Patients with extremely elevated triglyceride (TG) levels (>1000 mg/dL [11.3 mmol/L]) should be referred to a lipid specialist, since TG levels in this range suggest the possibility of a primary genetic hypertriglyceridemia. (See 'Hypertriglyceridemia' below.)

HYPERCHOLESTEROLEMIA

Risk stratification — In children, traditional cardiovascular risk factors and other specific conditions are associated with increased risk of early atherosclerotic cardiovascular disease (ASCVD). We agree with the risk stratification schema established by the American Heart Association, based on evidence-informed expert opinion, that categorizes these conditions and risk factors as "high-risk," "moderate-risk," or "at-risk," as summarized in the table and algorithm (table 3 and algorithm 1) [1,7]. Children initially categorized in the at-risk or moderate-risk tier, based on their primary diagnosis, should be moved to a higher tier if they have additional risk factors (algorithm 1). Children with isolated hypercholesterolemia without other ASCVD risk factors or underlying conditions are generally considered "at-risk." High-risk conditions are uncommon in childhood, and most pediatric patients with dyslipidemia will be categorized as moderate- or at-risk.

Risk factors for premature ASCVD in childhood are discussed in greater detail separately. (See "Overview of pediatric risk factors for premature atherosclerotic cardiovascular disease (ASCVD)".)

Risk-based management approach

Extreme hypercholesterolemia (LDL-C >400 mg/dL [10.3 mmol/l]) — Children with low-density lipoprotein cholesterol (LDL-C) ≥400 mg/dL (10.3 mmol/L) should be referred to a pediatric lipid specialist and a pediatric cardiologist as soon as they are identified. LDL-C values in this range indicate that the child likely has a primary severe lipid disorder (eg, homozygous familial hypercholesterolemia [HoFH] or severe heterozygous familial hypercholesterolemia [HeFH]). Children with HoFH are unlikely to respond to dietary and lifestyle modifications alone and require pharmacologic intervention with multiple agents. In addition, children with FH are likely to have affected family members who may benefit from testing and treatment. FH is discussed in detail separately. (See "Familial hypercholesterolemia in children".)

Young children (<10 years old) — For young children (<10 years old) with hypercholesterolemia (defined as LDL-C ≥130 mg/dL [3.4 mmol/L] or total cholesterol [TC] ≥200 mg/dL), management consists mainly of lifestyle changes. (See 'Heart-healthy lifestyle' below.)

Young children with high-risk ASCVD conditions or severe primary hyperlipidemia may benefit from early pharmacotherapy. Patients with any of these conditions should be referred to a pediatric lipid specialist:

●High-risk ASCVD condition (table 3)

●LDL-C levels >400 mg/dL (10.3 mmol/L), which suggest HoFH or severe HeFH (see "Familial hypercholesterolemia in children")

●Strong family history of premature ASCVD

For some patients in these circumstances, early initiation of statin therapy may be warranted depending on the nature of the risk factor(s) and degree of hypercholesterolemia. If the decision is made to start statin therapy, the child should be managed in collaboration with a lipid specialist. (See 'Referral' above.)

Children and adolescents (10 years and older) — Treatment of hypercholesterolemia in older children (>10 years old) and adolescents includes:

●Nonpharmacologic measures (ie, heart-healthy lifestyle changes, including dietary modification, physical activity, weight loss, and avoidance of nicotine), which are appropriate for all patients with hypercholesterolemia (see 'Heart-healthy lifestyle' below)

●Pharmacologic therapy (chiefly with statins), which is reserved for high-risk patients and those who do not achieve adequate response to lifestyle changes (see 'Statin therapy' below)

The decision to initiate lipid-lowering medication depends upon the severity of dyslipidemia and presence of other ASCVD risk factors (table 3 and algorithm 2).  

The LDL-C value used in determining the need for pharmacotherapy should be based on multiple measurements rather than a single measurement. We typically base our management decisions on at least two fasting lipid profiles obtained two weeks to three months apart.

●High-risk patients – For most patients in the high-risk category who have LDL-C ≥130 mg/dL (≥3.4 mmol/L), we suggest management with both lifestyle changes and statin therapy, started simultaneously. The exception is the patient with type 1 or type 2 diabetes mellitus who has poor glycemic control at the time of lipid screening. For such patients, statin therapy is usually deferred for three to six months in attempt to first optimize glycemic control, diet, and exercise. In some patients, LDL-C levels may improve with improved glycemic control and statin therapy may not be required. However, if LDL-C remains elevated despite efforts to improve glycemic control, statin therapy should be initiated. (See "Type 1 diabetes mellitus in children and adolescents: Screening and management of complications and comorbidities", section on 'Dyslipidemia' and "Chronic complications and screening in children and adolescents with type 2 diabetes mellitus", section on 'Dyslipidemia'.)

The treatment target once on statin therapy is LDL-C <100 mg/dL (<2.6 mmol/L). (See 'Treatment goals' below.)

Additional details of lifestyle intervention and statin therapy are provided below. (See 'Heart-healthy lifestyle' below and 'Statin therapy' below.)

●Moderate-risk patients – For patients in the moderate-risk category, initial management consists of lifestyle changes (see 'Heart-healthy lifestyle' below). If the LDL-C remains ≥160 mg/dL (≥4.1 mmol/L) despite three months of lifestyle changes, we suggest initiating statin therapy. The treatment target once on statin therapy is LDL-C <130 mg/dL (<3.4 mmol/L). (See 'Statin therapy' below.)

●At-risk patients (including patients with no other ASCVD risk factors) – For patients in the at-risk category, initial management consists of lifestyle changes (see 'Heart-healthy lifestyle' below). If the LDL-C remains ≥160 mg/dL (≥4.1 mmol/L) despite six months of lifestyle changes, we suggest initiating statin therapy. The treatment target once on statin therapy is LDL-C <130 mg/dL (<3.4 mmol/L). (See 'Statin therapy' below.)

●Persistent LDL-C ≥190 mg/dL (≥4.9 mmol/L) despite initial management – Patients who continue to have severely elevated LDL-C levels (ie, ≥190 mg/dL [4.9 mmol/L]) despite initial lifestyle interventions should be started on statin therapy (if not already initiated) and referred to a pediatric lipid specialist. These patients are likely to have HeFH or a similar genetic lipid disorder that substantially increases the risk of premature ASCVD. (See 'Referral' above and 'Statin therapy' below and "Familial hypercholesterolemia in children".)

Treatment goals — LDL-C goals for the individual patient depend on the presence of associated risk factors and are generally as follows:

●For patients in the high-risk category, the treatment goal is LDL-C <100 mg/dL (<2.6 mmol/L)

●For patients in the moderate-risk and at-risk categories (including those with no additional risk factors or comorbidities), the treatment goal is LDL-C <130 mg/dL (<3.4 mmol/L)

Heart-healthy lifestyle — For all children with hypercholesterolemia, initial management includes heart-healthy lifestyle changes consisting of dietary modification, physical activity, weight loss for children with obesity, maximizing high-quality sleep, and avoidance of nicotine exposure.

For children with comorbidities and risk factors that place them at high risk for early ASCVD (table 3), we typically start statin therapy simultaneously with lifestyle changes (see 'Statin therapy' below). For children in the moderate-risk and at-risk categories (including those with no additional risk factors), lifestyle changes are initiated first, and pharmacotherapy is added if the targeted LDL-C goal is not met by three to six months.

An observational study that tracked blood lipid levels of children starting at age 9, 12, and 15 years through young adulthood demonstrated that adult lipid levels were influenced by lifestyle changes [8]. As an example, weight control and exercise were associated with improved lipid levels in individuals with pediatric dyslipidemia. In contrast, an increase in adiposity and continuation or commencement of smoking from childhood to adulthood were associated with adult dyslipidemia.

Dietary modification — Dietary interventions can modestly improve abnormal lipid levels in healthy children and in those with dyslipidemia [1]. Dietary counseling should be tailored to the patient and their family/caregivers. Behavior modification and motivational interviewing techniques may be helpful. Support and lifestyle modification for the whole family is usually necessary for successful change in the child. (See "Pediatric prevention of adult cardiovascular disease: Promoting a healthy lifestyle and identifying at-risk children", section on 'Heart-healthy diet'.)

The primary dietary modifications for children with elevated LDL-C include reduced intake of saturated fat and cholesterol and increased intake of dietary fiber through fruits, vegetables, and whole grains. Dietary supplements (eg, plant sterols and stanol esters) also appear to modestly reduce LDL-C.

Heart-healthy diet — Dietary modification in children with hypercholesterolemia is carried out in a staged approach [1,3-5,7,9]:

●All children should be encouraged to eat a diet that is high in fiber from fruits, vegetables, and whole grains; high in polyunsaturated and monounsaturated fats; low in saturated fat; and devoid of trans fats (table 4). Ideally, fat comprises approximately 30 percent of total energy intake, and saturated fats is limited to <10 percent of total energy intake. This guidance applies to all children and is particularly important for children with dyslipidemia.  

●For patients with persistent hypercholesterolemia despite appropriate dietary modification, further restricting fat intake may be reasonable (eg, limiting total fat to 25 to 30 percent of total calories and saturated fat to ≤7 percent of total calories). However, adherence to more restrictive diets is difficult and may foster noncompliance and stress between the child and parents/caregivers.

●We emphasize the intake of "healthier" fats (mono- and polyunsaturated fats) as a substitute for saturated and trans fats because of their beneficial effects on cardiovascular health (table 5). Dietary supplementation with plant stanols and sterols can also be considered in this setting, as discussed below. (See 'Dietary supplements' below.)  

Consultation with a registered dietitian is advised for implementation of dietary changes.

Based on the available data, a diet low in saturated fats and high in dietary fiber appears to modestly lower LDL-C levels in children with hypercholesterolemia [10,11]. However, for children with FH or LDL-C >190 mg/dL (4.9 mmol/L), diet modification alone is rarely sufficient to reach target levels for LDL-C. (See "Familial hypercholesterolemia in children", section on 'Management'.)  

In a randomized trial in 663 prepubertal children with LDL-C levels between the 80^th and 98^th percentile for age and sex, those assigned to a restricted diet (total fat intake to 28 percent of total calories, saturated fat <8 percent of total calories, and TC to 75 mg/1000 kcal per day) had a larger reduction of LDL-C levels over a three-year period compared with the control group (15.4 versus 11.9 mg/dL [0.40 versus 0.31 mmol/L]) [11]. There were no statistically significant differences in TC, high-density lipoprotein cholesterol (HDL-C), and TG levels between the two groups. In another study of prepubertal children with FH, following a diet low in total fat (23±5 percent of total calories), saturated fat (8±2 percent of total calories), and cholesterol (67±28 mg/1000 kcal) for one year resulted in reductions in TC and LDL-C levels by 4 and 5.5 percent, respectively [10]. There was no difference in HDL-C or TG levels.

Larger studies in healthy children have also demonstrated that a diet low in saturated fats is associated with improvements in lipid profiles and other cardiovascular measures [12-15]. These data are presented separately. (See "Pediatric prevention of adult cardiovascular disease: Promoting a healthy lifestyle and identifying at-risk children", section on 'Heart-healthy diet'.)  

Dietary supplements — Dietary supplementation with plant stanols and sterols appears to enhance a reduction in LDL-C in conjunction with a low-saturated fat diet [1]. The benefit of other supplements (eg, fiber) to reduce LDL-C is less clear. The following is a summary of these supplements, which are discussed in greater detail separately. (See "Lipid management with diet or dietary supplements".)

●Plant stanols and sterols – These compounds are found naturally in fruits, vegetables, vegetable oils, nuts, and seeds and are additives in a number of other foods, including certain margarines, orange juice, yogurt drinks, cereal bars, and dietary supplements. In adults, supplementation with these compounds has been shown to reduce dietary cholesterol by 5 to 10 percent. One study in healthy children showed that a mean intake of 1.8 g/day of plant sterol contained in a margarine product reduced serum LDL-C by 8 percent [16]. In children with FH, clinical trials have shown that both stanols and sterol esters decrease TC and LDL-C levels [17-19]. Although stanols and sterols reduce serum LDL-C levels, there are no data demonstrating a reduction in the risk of early ASCVD [20,21]. Stanols and sterols decrease absorption of fat-soluble vitamins and beta-carotene. Children taking these supplements should therefore take a daily multivitamin.

●Fiber – It is unclear whether increased fiber intake from supplements reduces serum LDL-C [1,3]. Fiber is thought to bind with cholesterol within bile acids, thus removing it from the enterohepatic circulation. In our practice, we encourage children to consume fiber from dietary sources (eg, fruit, vegetables, whole grains) rather than fiber supplements. Appropriate daily fiber intake in this setting is 6 g for children ages 2 to 12 years and 12 g for children ages 12 years and older.  

●Ineffective supplements – Other supplements, such as garlic, are not effective. Red yeast rice extract, which contains monacolins with statin-like activity, has been shown to lower cholesterol in adults. However, we do not recommend its use, because the amount of monacolins a child would be exposed to is unknown and unregulated. (See "Lipid management with diet or dietary supplements", section on 'Supplements that we do not recommend' and "Statin muscle-related adverse events", section on 'Red yeast rice'.)

Omega-3 fatty acids, as found in fish oil supplements, are not recommended for children with hypercholesterolemia, as they may increase LDL-C levels. However, they are sometimes used to treat patients with hypertriglyceridemia, as discussed below. (See 'Hypertriglyceridemia' below and "Lipid management with diet or dietary supplements", section on 'Supplements that may be of benefit'.)

Physical activity — Studies involving children and adults have shown that engaging in daily moderate or vigorous physical activity and limiting sedentary behavior improve cardiovascular health and reduce the risk of ASCVD in adulthood. Age-based goals for daily physical activity are summarized in the table (table 6) and discussed in greater detail separately. (See "Pediatric prevention of adult cardiovascular disease: Promoting a healthy lifestyle and identifying at-risk children", section on 'Physical activity' and "Prevention and management of childhood obesity in the primary care setting", section on 'Physical activity goals' and "Physical activity and strength training in children and adolescents: An overview", section on 'Benefits of regular physical activity'.)

Weight loss — For children with obesity and dyslipidemia, weight loss can result in substantial improvement in lipid values [22-24]. Management of childhood obesity is discussed separately. (See "Prevention and management of childhood obesity in the primary care setting".)

Avoiding nicotine exposure — Counseling to prevent smoking initiation is an important aspect of routine pediatric primary care for all children and adolescents and particularly important for those with dyslipidemia. For children and adolescents who either are current smokers or have significant secondhand exposure, counseling about smoking cessation should be included in the discussion of heart-healthy lifestyle changes. These issues are discussed in greater detail separately. (See "Prevention of smoking and vaping initiation in children and adolescents" and "Management of smoking and vaping cessation in adolescents" and "Secondhand smoke exposure: Effects in children".)

Statin therapy — The decision to initiate lipid-lowering medication depends upon the age of the child, severity of dyslipidemia, and presence of other ASCVD risk factors, as summarized in the algorithm (algorithm 2) and described above. (See 'Risk-based management approach' above.)

For children and adolescents who meet criteria for lipid-lowering drug therapy, statins are the preferred first-line agents.

Dosing — Several statin agents are available. Atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin are approved by the US Food and Drug Administration for use in children. Dosing guidance for each agent is provided in the table (table 7). Most of these agents are available in generic forms.

The initial choice of agent is generally based on potential drug interactions, price, and patient preference. In our practice, we most commonly use atorvastatin or rosuvastatin. Treatment is initiated at the lowest dose (table 7), which is given once a day, usually at bedtime because most LDL-C synthesis occurs during nighttime hours. If needed, the dose is increased to meet the goals of therapy. (See 'Treatment goals' above and 'Dose titration' below.)

Efficacy — The efficacy of statin therapy in pediatric patients with hypercholesterolemia is supported by multiple clinical trials (most involved children with FH), in which statin therapy, compared with placebo, reduced LDL-C by approximately 25 to 40 percent without significant adverse side effects over many years of follow-up [25,26]. In addition, some studies have shown that statin therapy slows the progression of subclinical atherosclerosis (as assessed by measuring carotid intima-media thickness or flow-mediated dilation). The evidence supporting the efficacy and safety of statins in children with FH is discussed in greater detail separately. (See "Familial hypercholesterolemia in children", section on 'Statin therapy'.)

The efficacy and safety of statin therapy in pediatric patients is also supported by studies of children who have undergone cardiac transplantation [27,28]. In two studies (one retrospective and one a prospective open-label clinical trial), statin therapy was associated with a lower incidence of cardiac transplant vasculopathy and lower mortality. In the prospective study, no severe adverse effects of statin therapy were observed during eight years of follow-up [28].

Statins are the most common agents used in the treatment of hypercholesterolemia in adults and are the class of drugs in which benefits to ASCVD morbidity and mortality have been most consistently demonstrated. (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease".)

Adverse effects — The potential benefits of ASCVD risk reduction with statin therapy must be weighed against the risk of potential adverse effects from the drug itself [6,29,30]. Side effects with statins are rare and include myopathy, new-onset type 2 diabetes mellitus, and hepatic enzyme elevation. In pediatric clinical trials, rates of side effects with statin therapy were low and adherence to statin therapy was generally good [25,31-39]. (See "Statins: Actions, side effects, and administration", section on 'Side effects'.)

Side effects are rare in clinical practice [40]. Side effects of statins are more likely to occur at higher doses and in patients taking other medications, particularly cyclosporine, azole antifungal agents, and other medications and foods (eg, grapefruit) that impact the cytochrome P450 system (table 8). It is important to review drug interactions prior to initiating therapy (specific drug interactions may be determined by using the drug interactions program).

Adolescent females should be counseled about the possibility of drug teratogenicity and appropriate contraceptive methods while receiving statin therapy. In addition, use of statins by breastfeeding mothers is discouraged. (See "Statins: Actions, side effects, and administration", section on 'Risks in pregnancy and breastfeeding' and 'Second-line therapies' below.)

Although data on long-term statin use in adults suggest a safe profile, the long-term safety of statin therapy initiated in childhood is uncertain [6,41]. Concerns have been raised about the theoretical risk of altering the steroid synthesis pathway by using statins in developing children; however, these concerns have not been supported in the literature and must be balanced against risks of early atherosclerotic disease. The results of a 10-year follow-up study of early statin initiation in children with FH found no evidence of adverse effect on growth or development [42,43].

Monitoring

●Pretreatment testing – We suggest the following baseline laboratory evaluation prior to initiating statin therapy:

•Fasting lipid profile

•Serum creatine kinase (CK)

•Serum alanine aminotransferase (ALT)

•Blood glucose and hemoglobin A1C levels

•Pregnancy test, if clinically indicated

●Follow-up testing – At approximately four weeks after starting therapy, we obtain the following tests to determine the response to treatment and to assess for adverse effects (algorithm 3):

•Fasting lipid profile

•Serum ALT

•Blood glucose and hemoglobin AC1

Once on stable therapy, lipid levels, glucose, and hemoglobin A1C are repeated every six months.

Ongoing monitoring of growth and other measures of general and cardiovascular health (eg, blood pressure) should also occur at each visit.

Repeated testing of liver function tests and/or CK levels in asymptomatic patients is generally not necessary. However, testing should be performed if the patient has concerning symptoms (eg, muscle aches or weakness) or other comorbidities (eg, liver disease).

Providers should be aware that estrogen-containing contraceptives can increase lipid levels. We generally recheck a fasting lipid profile approximately one month after starting an estrogen-containing contraceptive to assess its effect.  

Dose titration — Statin therapy is aimed at achieving an LDL-C value <130 mg/dL (3.35 mmol/L) for patients in the moderate- and at-risk categories and a value <100 mg/dL (2.59 mmol/L) for patients in the high-risk category. (See 'Treatment goals' above.)

As the evidence supporting a particular LDL-C goal in youth is scant, decisions about the use of higher-dose statins can be made together with the patient and parents/caregivers, balancing the risk of adverse effects with potential benefits related to the severity of family history, baseline LDL-C levels, and the presence of additional ASCVD risk factors. (See 'Risk stratification' above.)

Titration of statin therapy is accomplished as follows (algorithm 3):

●If the LDL-C goal is met and there are no laboratory abnormalities, therapy is continued at the same dose.

●If the LDL-C goal is not met, the dose is increased (usually by an increment of 10 to 20 mg), and a repeat LDL-C level is obtained in four weeks, including repeat laboratory evaluation.

●If goals are not met after increasing the dose, but the treatment is well tolerated, one of the following options are followed:

•The dose of statin may be increased further until the target is met, the maximum dose is reached (table 7), or there is evidence of toxicity. Laboratory testing is reassessed after each dose change.

•Another drug (eg, ezetimibe or a bile acid sequestrant) may be added to statin therapy under the direction of a pediatric lipid specialist. We advise against adding a fibrate to statin in most cases because this increases the risk of side effects, particularly muscle toxicity. (See 'Adverse effects' above and 'Second-line therapies' below.)

●If laboratory abnormalities develop while on statin therapy, the drug may be stopped and the laboratory testing repeated in two weeks, or sooner depending on the severity. When the abnormalities resolve, the drug may be restarted with close monitoring. For patients with adverse symptoms possibly related to the drug, it is most helpful to obtain laboratory testing while the symptoms are ongoing. If laboratory abnormalities do not appear to be statin-related, it may be reasonable to simply repeat the laboratory tests without stopping the statin.

Patients who fail to achieve goal values of LDL-C despite lifestyle changes and maximally tolerated statin therapy should be referred to a specialist with expertise in managing pediatric dyslipidemia, as other interventions may be warranted. (See 'Second-line therapies' below.)

Second-line therapies — If treatment with the maximally tolerated dose of statin is not successful in achieving the LDL-C goal or if it is not tolerated, a number of other agents are available with varying levels of supporting evidence. Second-line lipid-altering agents encompass several classes of drugs that differ with respect to mechanism of action and to the degree and type of lipid lowering. These include the cholesterol absorption inhibitor ezetimibe, bile acid sequestrants (eg, cholestyramine, colestipol, colesevelam), and fibric acid derivatives (eg, gemfibrozil, fenofibrate) (table 7). Other therapies include proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (eg, evolocumab, alirocumab), evinacumab, lomitapide, bempedoic acid, and LDL apheresis. Nicotinic acid (niacin) is another option, but we do not use it in our practice since there are other equally effective alternatives that are better tolerated.

When a second agent is required, our practice is to use ezetimibe because of its safety profile, demonstrated efficacy in pediatric and adult clinical trials, and because it lacks bothersome side effects, which commonly occur with other second-line agents (eg, bile acid sequestrants). However, the choice of second agent should be individualized to the patient and should generally be done in consultation with a pediatric lipid specialist. (See 'Referral' above.)

●Ezetimibe – Ezetimibe is a lipid-lowering agent that prevents intestinal absorption of cholesterol and plant sterols. Ezetimibe can be useful in children and adolescents with FH or other high-risk factors for premature ASCVD who are not able to reach LDL-C treatment goals on high-intensity statin therapy.

Clinical trials in adults have shown that when ezetimibe is used in combination with a statin, it further lowers serum LDL-C and improves cardiovascular outcomes without altering the side effect profile. These data are discussed separately. (See "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors", section on 'Ezetimibe'.)

Similarly, clinical trials in pediatric patients with FH have demonstrated combination therapy with ezetimibe plus a statin is well tolerated and reduces LDL-C more that statin monotherapy. These data are discussed separately. (See "Familial hypercholesterolemia in children", section on 'Preferred choice for add-on therapy (ezetimibe)'.)

●Bile acid sequestrants – Bile acid sequestrants (eg, cholestyramine, colestipol, colesevelam) are not as effective as statins in lowering LDL-C and have bothersome side effects (eg, constipation and bloating) that result in poor compliance [44]. For these reasons, bile acid sequestrants are used relatively infrequently. However, they may be useful in combination with a statin for patients who fail to meet target LDL-C levels [45]. The sequestrants are extremely safe as they are not absorbed systemically but remain in the gut and are excreted along with the bile-containing cholesterol. For patients with severe LDL-C elevations (eg, HeFH), the sequestrants can effectively lower LDL-C as much as 10 to 20 percent. They can be used in patients who prefer to avoid statins, although they may not achieve sufficient LDL lowering to reach goal. Their use is hampered by bloating, constipation, and altered absorption of other medications, necessitating attention to timing of other medications over the course of the day. (See "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors", section on 'Bile acid sequestrants'.)

●Fibric acid derivatives – Fibric acid derivatives (eg, gemfibrozil, fenofibrate) are used primarily for treating severe hypertriglyceridemia and are discussed in more detail below. (See 'Pharmacotherapy' below.)

●Nicotinic acid (niacin) – Niacin is particularly effective in raising HDL-C, increasing levels by 20 to 30 percent [46]. However, compliance is difficult due to frequent side effects (eg, rash, flushing, and headaches), and adult primary prevention trials have not shown a ASCVD benefit for niacin. Pediatric data are sparse. As a result, niacin is rarely used. Niacin comes in several different formulations, including various over-the-counter preparations, so care should be taken with dosing. The prescription formulation is the most convenient for use. (See "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors", section on 'Nicotinic acid (niacin)'.)  

●Other therapies used primarily in patients with FH – Other lipid-lowing therapies that are sometimes used in pediatric patients with severe or refractory hypercholesterolemia (most commonly HoFH or severe HeFH) include PCSK9 inhibitors (eg, evolocumab and alirocumab), evinacumab, lomitapide, bempedoic acid, and LDL apheresis. Children and adolescents requiring these therapies should be managed by a pediatric lipid specialist. These therapies are discussed in greater detail separately. (See "Familial hypercholesterolemia in children", section on 'Other lipid-lowering therapies' and "PCSK9 inhibitors: Pharmacology, adverse effects, and use" and "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors" and "Treatment of drug-resistant hypercholesterolemia", section on 'LDL apheresis'.)

HYPERTRIGLYCERIDEMIA — 

Hypertriglyceridemia is defined as follows (see "Dyslipidemia in children and adolescents: Definition, screening, and diagnosis", section on 'Definition of pediatric dyslipidemia'):

●Children <10 years: Triglyceride (TG) level ≥100 mg/dL (1.1 mmol/L)

●Children and adolescents 10 to 19 years: TG level ≥130 mg/dL [1.5 mmol/L])

Clinical significance — It is important to recognize that hypertriglyceridemia by itself is not a major risk factor for atherosclerotic cardiovascular disease (ASCVD). Hypertriglyceridemia is associated with other conditions that increase the risk of ASCVD, particularly type 2 diabetes and obesity. In addition, hypertriglyceridemia is often associated with elevated atherosclerotic lipid particles as represented by elevated non-high-density lipoprotein cholesterol (non-HDL-C) or apolipoprotein B (apoB) levels.

Treatment of hypertriglyceridemia primarily focuses on promoting healthy eating habits and encouraging physical activity and weight loss rather than treating the triglyceride (TG) value per se. However, pharmacology may be warranted in patients with very elevated levels to reduce the risk of pancreatitis. (See 'Lifestyle modification' below and 'Pharmacotherapy' below.)

Patients with extremely elevated TG levels (ie, >1000 mg/dL [11.3 mmol/L]) generally warrant specialty care since these levels raise the possibility of a primary genetic hypertriglyceridemia. Pharmacotherapy may or may not be effective at these levels depending on the cause. A fat-restricted diet is often required. (See 'Referral' above.)

Lifestyle modification — Lifestyle interventions for the management of hypertriglyceridemia are aimed primarily at achieving weight loss and diet modification. This includes [1,7]:

●Encouraging physical activity (see 'Physical activity' above and "Pediatric prevention of adult cardiovascular disease: Promoting a healthy lifestyle and identifying at-risk children", section on 'Physical activity' and "Exercise and fitness in the prevention of atherosclerotic cardiovascular disease")

●Dietary changes, including reduced intake of carbohydrates, particularly simple carbohydrates, reduced intake of saturated fats, and, for obese children, calorie restriction

●Other strategies to promote weight loss (see "Prevention and management of childhood obesity in the primary care setting")

Studies in adults and several pediatric reports have shown that a reduction in carbohydrates, particularly simple carbohydrate intake, in conjunction with weight loss and increased physical activity, results in reduced TG levels [47,48]. (See "Hypertriglyceridemia in adults: Management", section on 'Treatment goals'.)

Pharmacotherapy — Pharmacotherapeutic options for children with elevated TG are limited, and the main interventions remain diet modification, increased intake of omega-3 fatty acids, increased physical activity, and weight loss. (See 'Lifestyle modification' above.)

Pharmacologic treatment for pediatric hypertriglyceridemia should be initiated in consultation with a pediatric lipid specialist. We generally use the following indications for initiating pharmacologic treatment [7]:

●Patients with severely elevated TG levels (ie, TG ≥600 to 1000 mg/dL [6.8 to 11.3 mmol/L]) since these levels are associated with risk of pancreatitis. (See "Hypertriglyceridemia-induced acute pancreatitis".)

●Patients who have primary hypertriglyceridemia with average TG levels >400 mg/dL (4.5 mmol/L).

●Patients with both hypertriglyceridemia and hypercholesterolemia (ie, TG 150 to 399 mg/dL [1.7 to 4.5 mmol/L] and non-high-density lipoprotein cholesterol [non-HDL-C] ≥145 mg/dL [≥3.7 mmol/L]) that persists despite appropriate initial therapy (including lifestyle modification and/or optimal statin therapy).

Drug therapy choices include statins, high-dose marine omega-3 fatty acid supplementation, fibrates, or niacin. Niacin is rarely used because of unacceptable side effects and limited evidence of benefit [46].

●Statins – Statins are used if hypertriglyceridemia is accompanied by high levels of atherogenic particles as represented by elevated non-HDL-C, direct LDL-C, or apoB. (See 'Statin therapy' above.)

●Marine omega-3 fatty acids – We use high-dose marine omega-3 fatty acid therapy (2 to 4 g per day) for treating patients with severely elevated TG levels that may lead to pancreatitis (ie, TG >600 to 1000 mg/dL [6.8 to 11.3 mmol/L]). We typically use icosapent ethyl in this setting. It can be given in conjunction with fibrate or statin therapy or as a substitute if fibrates are not tolerated.

Limited data are available on the effectiveness of marine omega-3 fatty acid supplementation in pediatric patients. Two small studies evaluated treatment with an omega-3 fatty acid supplement (omega-3-acid ethyl esters) in adolescents with hypertriglyceridemia and did not find any significant reduction in TG levels compared with placebo [49,50]; however, the studies were likely underpowered.

There are few data on the use of icosapent ethyl for triglyceride lowering in children. Use of this agent is based on evidence from studies in adults with hypertriglyceridemia. Studies in adults have demonstrated that high-dose marine omega-3 fatty acid supplementation lowers serum TG levels and may reduce the risk of ASCVD events in select at-risk populations. These data are discussed separately. (See "Hypertriglyceridemia in adults: Management", section on 'Marine omega-3 fatty acids'.)

●Fibrates – Fibric acid derivatives (eg, gemfibrozil, fenofibrate) are occasionally used in pediatric patients (most often in older adolescents) who have severe or refractory hypertriglyceridemia without concomitant elevated LDL-C or apoB (table 7). These agents raise HDL-C and lower TG levels.

Data are limited on the use of fibric acid derivatives in children [1,51]. In one report from a tertiary center that reviewed its management of 76 children with hypertriglyceridemia (53 patients with primary and 13 with adiposity-related hypertriglyceridemia), TG levels decreased with the use of fibrates, did not change with the use of statins, and increased with the use of bile acid-binding resins [52].

In our experience, fibric acid derivatives are generally well-tolerated. The risk of myopathy and rhabdomyolysis is increased when they are used in combination with statins or in patients with kidney insufficiency. The need for simultaneous use of both statin and fibrate therapy in childhood is rare, and they should be administered under the supervision of a pediatric lipid specialist.

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lipid disorders and atherosclerosis in children".)

SUMMARY AND RECOMMENDATIONS

●Rationale for treatment – Management of dyslipidemia in children and adolescents is based on the rationale that early identification and control of pediatric dyslipidemia will reduce the risk and severity of premature atherosclerotic cardiovascular disease (ASCVD) in adulthood. (See 'Rationale for intervention' above.)

●Heart-healthy lifestyle changes – For all children with dyslipidemia, management includes heart-healthy lifestyle changes, consisting of dietary modification (table 4), physical activity (table 6), weight loss for children with obesity, and avoidance of nicotine exposure. (See 'Heart-healthy lifestyle' above and "Dietary recommendations for toddlers and preschool and school-age children".)  

●Risk-based management – Treatment for hypercholesterolemia (defined as low-density lipoprotein cholesterol [LDL-C] level ≥130 mg/dL [3.4 mmol/L] or total cholesterol [TC] ≥200 mg/dL [5.2 mmol/L]) depends upon the age of the child, severity of dyslipidemia, and presence of other ASCVD risk factors (table 3 and algorithm 2) (see 'Risk-based management approach' above):

•Extreme hypercholesterolemia (eg, LDL-C ≥400 mg/dL [10.3 mmol/L]) – Children with hypercholesterolemia in this range should be referred to a pediatric lipid specialist as it is likely that they have a severe genetic lipid disorder (eg, homozygous familial hypercholesterolemia [HoFH]). (See 'Referral' above and "Familial hypercholesterolemia in children".)

•Children <10 years old – For children <10 years old who are in the moderate- or at-risk categories (table 3), management consists mainly of lifestyle changes (see 'Heart-healthy lifestyle' above). Children <10 years who are in the high-risk category should be referred to a pediatric lipid specialist. Depending on the nature of the risk factor(s) and degree of hypercholesterolemia, pharmacotherapy may be warranted at this age for some patients in the high-risk category; these decisions should be made in collaboration with a lipid specialist. (See 'Referral' above.)

•Children >10 years old and adolescents – Our suggested approach to managing hypercholesterolemia (LDL-C ≥130 mg/dL [3.4 mmol/L]) in pediatric patients ≥10 years old according to their risk category (table 3) is as follows (algorithm 2) (see 'Children and adolescents (10 years and older)' above):

-High-risk – For most patients in the high-risk category who have LDL-C ≥130 mg/dL (3.4 mmol/L), we suggest initial treatment with statin therapy in conjunction with lifestyle changes rather than lifestyle changes alone (Grade 2B). The treatment target once on statin therapy is LDL-C <100 mg/dL (2.6 mmol/L). (See 'Heart-healthy lifestyle' above and 'Statin therapy' above.)

-Moderate-risk – For patients in the moderate-risk category, initial management consists of lifestyle changes (see 'Heart-healthy lifestyle' above). If the LDL-C remains ≥160 mg/dL (4.1 mmol/L) despite three months of lifestyle changes, we suggest initiating statin therapy (Grade 2C). The treatment target once on statin therapy is LDL-C <130 mg/dL (3.4 mmol/L). (See 'Statin therapy' above.)

-At-risk or no other ASCVD risk factors – For patients in these categories, initial management consists of lifestyle changes (see 'Heart-healthy lifestyle' above). If the LDL-C remains ≥160 mg/dL (4.1 mmol/L) despite six months of lifestyle changes, we suggest initiating statin therapy (Grade 2C). The treatment target once on statin therapy is LDL-C <130 mg/dL (3.4 mmol/L). (See 'Statin therapy' above.)

-Persistent severely elevated LDL-C – Patients who continue to have LDL-C ≥190 mg/dL (4.9 mmol/L) despite initial lifestyle interventions should be referred to a pediatric lipid specialist (in addition to starting statin therapy). These patients are likely to have a genetic lipid disorder (eg, familial hypercholesterolemia) that substantially increases the risk of premature ASCVD. (See 'Referral' above.)

●Statin dosing, titration, and monitoring – Several statin agents are available (table 7). The initial choice of agent is generally based on potential drug interactions, price, and patient preference.

Treatment is initiated at the lowest dose and is given once a day, usually at bedtime. The dose is subsequently titrated to achieve the goal LDL-C value according to the child's risk category (<100 mg/dL [2.6 mmol/L] for high-risk patients; <130 mg/dL (3.36 mmol/L) for children in the moderate- and at-risk categories) (algorithm 3). (See 'Dosing' above and 'Dose titration' above and 'Treatment goals' above.)

Side effects with statins are rare and may include myopathy, new-onset type 2 diabetes mellitus, and hepatic enzyme elevation. Side effects are more likely at higher doses and in patients taking other medications. The approach to laboratory monitoring for pediatric patients receiving statin therapy is summarized in the algorithm (algorithm 3). (See 'Adverse effects' above and 'Monitoring' above.)

●Management of hypertriglyceridemia – For children with hypertriglyceridemia, interventions are aimed primarily at achieving weight loss and diet modification. Hypertriglyceridemia by itself is not a major ASCVD risk factor. Drug therapy may be warranted in severe cases to prevent pancreatitis. Statins, high-dose marine omega-3 fatty acid supplementation, and/or fibrates (eg, gemfibrozil, fenofibrate) are typically used in this setting, in conjunction with aggressive lifestyle modification and management of coexisting conditions and risks (eg, diabetes, thyroid disease, kidney insufficiency). (See 'Hypertriglyceridemia' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Jane Newburger, MD, MPH, who contributed to earlier versions of this topic review.