Abstract
Lipid abnormalities in youth pose place patients at risk for the early development of atherosclerotic cardiovascular disease (ASCVD). A growing body of evidence supports early detection and treatment of dyslipidemia in youth. While lifestyle modifications remain the cornerstone of treatment, there are a growing number of safe and effective lipid-lowering therapies that providers can feel comfortable initiating in their patients with the appropriate patient selection and monitoring.
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Introduction
Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death in the United States and worldwide [1,2,3]. While the consequences of ASCVD typically occur in the fifth and sixth decades of life, its antecedents are found in youth. Autopsy reports have demonstrated the development of atherosclerotic fatty streaks in youth, and risk factors for future CVD have been found to track from youth to adulthood [4,5,6,7,8,9,10,11]. While hypertension, diabetes mellitus, tobacco use, and a family history of early ASCVD contribute to an increased risk of ASCVD, the development of atherosclerosis likely requires the introduction of atherogenic apolipoprotein B (apoB) into the vascular endothelium. It is well-established that LDL cholesterol values, a surrogate marker for apoB levels, are associated with CVD [12, 13].
Further, trials have consistently demonstrated that the degree to which low-density lipoprotein (LDL) cholesterol is lowered correlates with ASCVD event incidence [13,14,15]. Conditions that lead to an increased LDL cholesterol in both adults and youth, such as familial hypercholesterolemia, place patients at an increased risk for ASCVD. Therefore, early intervention to encourage health behavior changes or initiate pharmacotherapy has consistently been shown to reduce the risk of ASCVD associated with these risk factors [14, 16,17,18,19]. In this review, we will discuss the options for treating hypercholesterolemia in youth.
Diet and Physical Activity
Physical Activity
The cornerstone of treatment for patients with hypercholesterolemia is optimizing the patient’s health behaviors [20, 21]. These include a (1) healthy diet, (2) sufficient physical activity, (3) low amounts of sedentary time, (4) avoiding tobacco, (5) maintaining a healthy body mass index, (6) optimizing blood glucose, (7) lowering blood pressure, and (8) obtaining sufficient sleep [22,23,24]. While the efficacy of interventions varies widely, it is generally considered that lifestyle changes can reduce LDL cholesterol levels by about 10% [24]. In addition, consistent epidemiologic evidence suggests an association between a healthy diet and the risk of CVD [25,26,27,28].
For children over five years old, at least one hour per day of moderate-to-vigorous activity is recommended, along with having less than two hours per day of recreational screen time [23]. However, the effect of sufficient physical activity on the LDL cholesterol of children and adolescents is minor. Studies generally demonstrate variable, but positive, effects of increased physical activity on the lipid profile of youth. Several recent meta-analyses have found that increased physical activity results in lower LDL cholesterol, higher high-density lipoprotein (HDL) cholesterol, and an improved total cholesterol-to-HDL ratio [29,30,31,32,33,34,35,36,37]. Indeed, the effects of physical activity are not uniform but depend on genetics [38] and the intensity and duration of intervention. In general, the most pronounced effects occur in those with higher risk profiles, such as those with obesity, [31, 39, 40] and a more modest impact on the lipid profiles of children without obesity or dyslipidemia [35, 41].
There is more consistent evidence that diet can lead to a positive impact on LDL cholesterol. The Cardiovascular Health Integrated Lifestyle Diet (CHILD-1) supports a diet relatively low in saturated and sugar-sweetened beverages. It emphasizes the intake of fiber (from fruits and vegetables), whole grains, and lean protein [24]. Lower fat diets are not associated with reduced nutritional measures or adverse effects on growth during puberty [42]. For children, low-fat and low-cholesterol diets, like the CHILD diets, have been found to be safe and effective in normalizing serum lipids. In the Dietary Intervention Study in Children (DISC), pre-pubertal boys and girls with elevated LDL cholesterol who did not meet the criteria for medications were randomized into a diet intervention or usual care. The intervention group received counseling that promoted a diet with reduced total fat, saturated fat, polyunsaturated fat, and cholesterol. Although there were only minor differences between the two groups, those considered to be most adherent to the intervention had a clinically significant decline in LDL cholesterol [43]. Similarly, the Special Turku Coronary Risk Factor Intervention Project (STRIP) found that in a cohort of families of newborns who received counseling to reduce fat intake, there was a 3–6% reduction in total cholesterol and non-HDL cholesterol without any effect on growth [44, 45].
Recently, guidelines have moved away from recommendations concerning specific nutrients because of the limited evidence for limitations of particular substances (e.g., cholesterol). Instead, recommendations focus on promoting various diet patterns, such as the healthy American diet, the Mediterranean diet, and the vegetarian diet [23, 25, 46]. These diets are rich in vegetables, fruits, legumes, nuts, whole grains, and fish, while servings of red meat (fresh or processed), processed foods, and foods and drinks with added sugar are limited.
Initiation of Pharmacotherapy
For patients who either have a genetic predisposition to hypercholesterolemia or who have not been able to reach treatment goals after a 6-month trial of lifestyle changes, there is a growing number of lipid-lowering therapies that can lower LDL cholesterol to unprecedented. Baseline cholesterol panels should be checked at least two weeks apart (but no longer than three months) and averaged for decision purposes in starting pharmacological treatment. For any patient with LDL cholesterol greater than or equal to 190 mg/dL, statin initiation is recommended (Fig. 1). Additional risk factors should be considered for levels ranging from 160 to 190 mg/dL (Table 1). For those with high-risk conditions, such as diabetes mellitus, treatment is often initiated at LDL cholesterol levels above 130 mg/dL. Treatment should be up-titrated as tolerated for target LDL cholesterol < 130 mg/dL for most patients and < 100 mg/dL for patients with high-risk conditions [22, 23].
Simplified Algorithm for Management of Elevated LDL Cholesterol (LDL, low density lipoprotein)
Statins
Statins are currently the first-line treatment for most patients with hypercholesterolemia. Currently, six statins have been approved by the Federal Drug Administration (FDA) for use in youth. Except for pravastatin (approved for youth over eight years old and older), they are approved for patients starting at age ten. Statins work by inhibiting mevalonate synthesis by β-hydroxy-β-methylglutaryl-coenzyme A reductase. With decreased intrahepatic cholesterol levels, there is an increase in LDL cholesterol receptor production and clearance of circulating LDL cholesterol [47]. Statins reduce LDL cholesterol by 30–60%, depending on the statin chosen and its dose [48].
McCrindle et al. compared atorvastatin to placebo in patients aged 10–17 after 26 weeks of follow-up. The authors found a 40% reduction in LDL cholesterol, a 3% increase in HDL cholesterol, and a 12% decrease in triglycerides [17]. In a long-term follow-up study, Luirink et al. demonstrated a reduction in cardiovascular events from 26 to 1% and death from CVD from 7% to zero in patients with heterozygous familial hypercholesterolemia treated with statins as compared to their similarly affected parents after 20 years of follow-up [49].
Statins are generally well-tolerated in youth. However, routine monitoring is still recommended after starting a patient on a statin (Table 2). While statin-related muscle symptoms are commonly reported in adults (10–60% of patients), [50] they are rare in youth [51]. Further, rates of rhabdomyolysis leading to severe renal impairment are very low (< 0.1%) and have not been described in pediatric studies. Creatinine kinase levels are monitored in most studies, though elevation of 10 times the upper limit of normal has been rarely reported. Therefore, while concerns about muscle aches should be investigated, routine creatine kinase levels are unnecessary [52]. It should be noted that genetic polymorphisms in solute carrier organic anion transporter family member 1B1 gene (SLCO1B1) are associated with an increased risk of myalgias [53].
Transaminases have traditionally been obtained when starting patients on a statin and with dose increases. However, transaminases greater than three times the upper limit of normal rarely occur (< 1%) [50], and severe liver damage is rare [54].
Randomized clinical trials of statins, Mendelian randomization studies, [13] and several meta-analyses [55,56,57,58,59] have suggested a small but clinically significant increased risk of diabetes mellitus in those taking a statin. This risk varies based on the statin, its dose, and patient-related factors. For instance, the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial found that the risk was highest in those with a family history of diabetes mellitus or who had evidence of glucose intolerance at baseline [60].
Since cholesterol is a component of testosterone and estrogen, there has been concern about its effect on growth and puberty. However, several trials have demonstrated no effect on these parameters [52]. Clauss et al. found no difference in various sex hormones in adolescent females started on lovastatin [61]. Similarly, in a study in younger children, there was no effect of statins on sex hormones or measures of puberty (e.g., Tanner staging or testicular volume) [19]. In general, statins are not recommended during pregnancy. Although animal models have suggested that statin medications should not be taken during pregnancy, one recent study did not find an association between congenital anomalies and statin use, though this study was observational [62].
Statins also may interact with a number of medications, and it is recommended that providers check for interactions when starting a new medication. Typically, interactions are related to interactions with OATP1B1, an enzyme that transports medications into the cell. Clarithromycin, ritonavir, indinavir, saquinavir, and cyclosporine are dependent on OATP1B1 and can lead to increased statin concentrations when taken concurrently with a statin. In addition, statin concentrations are affected by the P-glycoprotein efflux transporter, cytochrome P450 in enterocytes, and the ATP-binding cassette sub-family G member 2 gene, which encodes for Breast Cancer Resistance Protein and is responsible for excreting statins back into the intestinal lumen [53].
Ezetimibe
Ezetimibe inhibits intestinal cholesterol absorption in the intestine by blocking the NPC1L1 transporter [63]. It is often used in conjunction with statins in patients whose statin monotherapy is ineffective or not well-tolerated. Although it has not been studied widely in pediatric populations, ezetimibe 10 mg daily has been shown to reduce LDL cholesterol levels in adults by 15–20% [22, 64,65,66,67] and an additional 20% in patients taking a statin [68]. Higher doses of ezetimibe have not been found to be more potent. The IMPROVE-IT (Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes) compared a combination of simvastatin and ezetimibe to simvastatin alone and showed an additional reduction in LDL cholesterol of 24% compared to statin monotherapy. This difference in LDL cholesterol levels was also present at long-term follow-up one year later [69]. Recent studies demonstrate a significant reduction in LDL cholesterol in adolescents with familial hypercholesterolemia, both with ezetimibe added to statins or as monotherapy [70, 71]. With the publication of IMPROVE-IT, [69] the benefits of LDL cholesterol lowering were demonstrated to occur in patients taking lipid-lowering therapy other than statins. This landmark trial provided the most substantial evidence that it is the amount of LDL cholesterol reduction that is important, rather than some specific mechanism unique to statins.
In patients with familial hypercholesterolemia, ezetimibe is expected to decrease LDL cholesterol by 26–42% [64,65,66,67]. In general, studies have found either little or no change in triglyceride levels or HDL cholesterol using ezetimibe [63]. Significantly, ezetimibe does not block the absorption of triglycerides or fat-soluble vitamins [67, 72, 73]. Ezetimibe should be considered in patients who are intolerant of statins or who fail to reach goal LDL cholesterol levels on a maximally tolerated statin.
Ezetimibe is generally well-tolerated and has standard daily dosing, making it an appealing treatment in patients with hypercholesterolemia [66, 67]. Of the adverse effects reported, the most common reason for discontinuation is gastrointestinal distress [74]. When added to a statin, there is no further increase in liver enzymes, serum creatinine, or myalgias [73, 75]. Further, ezetimibe is not metabolized by the P450 enzyme system and has minimal interactions with other medications [76].
Ezetimibe is also the first-line treatment for patients with sitosterolemia. In sitosterolemia, patients have mutations in ATP-binding cassette (ABC) subfamily G member 5 or member 8 (ABCG5 or ABCG8), which prevents the efficient removal of plant sterols from the body, leading to their accumulation [77]. Ezetimibe blocks the absorption of dietary cholesterol and plant sterols, leading to at least a 20% reduction in sterol levels, although some trials have suggested reductions reaching 50% [78, 79].
Bempedoic Acid
Bempedoic acid is a more recent addition to the armamentarium of lipid-lowering therapy. Like statins, it inhibits cholesterol production but targets a downstream enzyme, adenosine triphosphate-citrate lyase. However, it is a prodrug that is activated in the liver, not in muscles, which is expected to reduce the risk of muscle-associated adverse effects [80]. The Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients (CLEAR) trial showed that those treated with bempedoic acid had a decrease in LDL cholesterol levels by 18% and fewer reports of myalgias and muscular weakness as compared to placebo in patients who were intolerant of statins [81]. Bempedoic acid should be considered in patients intolerant of statins.
PCSK9 Inhibitors
Proprotein convertase subtilisin-kexin type 9 (PCSK9) is an enzyme produced by the liver that is involved in LDL cholesterol receptor degradation. The LDL cholesterol receptor typically is recycled up to 150 times before eventual degradation in the lysosome. By binding to the LDL receptor, PCSK9 “redirects” the LDL cholesterol to the lysosome [82]. Two PCSK9 inhibitor medications are fully humanized monoclonal antibodies against PCSK9 (evolucumab and alirocumab), and one, inclisiran, is a small interfering messenger ribonucleic acid.
FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) demonstrated a reduction of LDL cholesterol levels of 56 mg/dL at one-year follow-up. At two years of follow-up, a significant decrease in cardiovascular death, stroke, and myocardial infarction was found [83]. In ODYSSEY (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment with Alirocumab), LDL cholesterol was reduced by 48 mg/dL at one year, along with a decrease in cardiovascular death and cardiovascular events at nearly three years of follow-up. Adverse events for both drugs were similar for placebo and study populations, aside from injection site reactions, which were higher in patients receiving the medication in both trials [84]. In one pediatric studies of evolocumab, LDL cholesterol levels decreased by 69 mg/dL at 24 weeks follow-up. In this pediatric trial, there were similar rates of adverse events in both the treatment and placebo groups, and no major adverse effects were observed from evolocumab [85].
Lomitapide and Mipomersen
While the previously mentioned medications improve LDL cholesterol via upregulation of the LDL receptor, lomitapide and mipomersen do not. Lomitapide inhibits the microsomal triglyceride transfer protein (MTP) from transferring triglycerides to apoB to produce very low-density lipoproteins (liver) and chylomicrons (enterocytes). This leads to prematurely degrading the apolipoprotein. Clinical trials suggest lomitapide can reduce LDL cholesterol by as much as 50% [86, 87]. While effective in lowering LDL cholesterol, its side effect profile limits its use in clinical practice. Because of its mechanism of action, it should be given at least two hours after a meal for maximum effectiveness and to reduce the incidence and severity of adverse effects. Patients must follow a fat-restricted diet to avoid gastrointestinal adverse effects, which can be difficult in youth. Further, as the apolipoprotein B is not excreted, triglycerides accumulate in the liver, leading to increases in transaminases and eventually non-alcoholic fatty liver disease. Drug-drug interactions with lomitapide are common, including with statins [87].
Mipomersen is a single-stranded antisense oligonucleotide that disrupts the production of the apoB-100 lipoprotein. It decreases LDL cholesterol by approximately 60% [88]. Interestingly, it lowers lipoprotein(a) by 23%, which lomitapide does not affect. Studies in youth have shown a more modest decrease in LDL cholesterol, ranging from 26 to 42% [89]. In addition, drug-drug interactions are rarer with mipomersen compared to lomitapide as it is not metabolized by the p450 system [90]. However, adverse effects are common and are associated with poor compliance [89]. The most common side effects include injection site reactions, influenza-like symptoms, and liver toxicity. As with lomitapide, a low-fat diet is recommended in these patients.
Evinacumab
Evinacumab is a fully human monoclonal antibody that inhibits Angiopoietin-like 3 (ANGPTL3) and reduces LDL cholesterol independent of the LDL receptor. Currently, it is FDA-approved in those with homozygous hypercholesterolemia. Evinacumab has been shown to decrease LDL cholesterol by 48% in youth with homozygous familial hypercholesterolemia [91]. This reduction is seen even in patients without functioning LDL receptors. The most common adverse effects include sore throat, abdominal pain, diarrhea, nausea, vomiting, headache, and nasopharyngitis.
Bile Acid Sequestrants
Bile acid sequestrants (BAS) were one of the first treatments for hypercholesterolemia in youth. BAS interrupt enterohepatic circulation, thereby decreasing the availability of cholesterol available for bile acid synthesis in the liver. Studies suggest that they lower LDL cholesterol by 10–20% and in a similar amount when added to a statin [47, 90, 92]. Further, BAS may be especially beneficial in patients with diabetes mellitus as they may lead to reductions in glycated hemoglobin [93]. Colesevelam is the only FDA-approved bile acid sequestrant currently and has been shown to decrease LDL cholesterol by 6.3 to 12.5%. Unfortunately, the unpalatable solution and frequent gastrointestinal adverse effects limit their clinical use. Symptoms of bloating, abdominal pain, and diarrhea are commonly reported in children and adults [94, 95]. Further, BAS are contraindicated in patients with triglycerides exceeding 300 mg/dL as they raise the triglyceride level [50]. Patients should be aware that they should not be taken within 4 h of several medications because they may inhibit absorption [90].
Nutraceuticals
In addition to the therapies mentioned, supplements and nutraceuticals have been used to treat dyslipidemia. While a full review of the available nutraceuticals with purported benefits is not possible, we will highlight the ones with the most evidence suggesting benefit. For a majority of natural substances, the evidence is too limited to make a conclusion regarding whether a naturally occurring substance is effective at reducing CVD or if it is safe [96].
Red yeast rice extract is used to reduce LDL cholesterol. Its mechanism of action is similar to statins in that it inhibits HMG-CoA reductase. In fact, the extract from red yeast rice, monacolin K, is nearly identical to lovastatin. Depending on the dose, LDL cholesterol is reduced by 15–25% based on the results of meta-analyses. Interestingly, studies in China suggest a moderate reduction in CVD endpoints compared to statins with similar LDL cholesterol lowering [97]. Theoretically, its side effect profile should be similar to statins, but it seems better tolerated than statins in some populations [98]. The primary argument against the recommendation of red yeast rice for LDL cholesterol reduction is that it is not regulated, and there may be more variability in the amount of extract in each “dose” of red yeast rice compared to statins. This can make monitoring the therapeutic response and assessing for adverse effects more difficult. Further, because of its similarity to a statin, there is less reason to think that it would necessarily be safer than the more potent and generally less expensive statins.
Conclusions
The early recognition and treatment of dyslipidemia is necessary for the most effective prevention of ASCVD. Non-pharmacological approaches should be discussed with all patients and should be continued even if medications are needed to reach goal LDL cholesterol levels as they have benefits beyond LDL cholesterol lowering. However, there are a growing number of safe and effective lipid-lowering therapies that providers can feel comfortable initiating in their patients with the appropriate patient selection and monitoring.
Data Availability
No datasets were generated or analysed during the current study.
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Degen, M.G., Hartz, J. The Diagnosis and Treatment of Lipid Abnormalities in Pediatric Patients. Curr Pediatr Rep 12, 52–61 (2024). https://doi.org/10.1007/s40124-024-00323-9
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DOI: https://doi.org/10.1007/s40124-024-00323-9