There is compelling evidence that the elevated plasma lipoprotein(a) [Lp(a)] levels increase the risk of atherosclerotic cardiovascular disease (ASCVD) in the general population. Like low‐density lipoprotein (LDL) particles, Lp(a) particles contain cholesterol and promote atherosclerosis. In addition, Lp(a) particles contain strongly proinflammatory oxidized phospholipids and a unique apoprotein, apo(a), which promotes the growth of an arterial thrombus. At least one in 250 individuals worldwide suffer from the heterozygous form of familial hypercholesterolemia (HeFH), a condition in which LDL‐cholesterol (LDL‐C) is significantly elevated since birth. FH‐causing mutations in the LDL receptor gene demonstrate a clear gene‐dosage effect on Lp(a) plasma concentrations and elevated Lp(a) levels are present in 30‐50% of patients with HeFH. The cumulative burden of two genetically determined pro‐atherogenic lipoproteins, LDL and Lp(a), is a potent driver of ASCVD in HeFH patients. Statins are the cornerstone of treatment of HeFH, but they do not lower the plasma concentrations of Lp(a). Emerging therapies effectively lower Lp(a) by as much as 90% using RNA‐based approaches that target the transcriptional product of the LPA gene. We are now approaching the dawn of an era, in which permanent and significant lowering of the high cholesterol burden of HeFH patients can be achieved. If outcome trials of novel Lp(a)‐lowering therapies prove to be safe and cost‐effective, they will provide additional risk reduction needed to effectively treat HeFH and potentially lower the CVD risk in these high‐risk patients even more than currently achieved with LDL‐C lowering alone.

—In heterozygous familial hypercholesterolemia (FH), serum low density lipoprotein (LDL) cholesterol levels are already elevated at birth. Premature coronary heart disease occurs in ≈30% of heterozygous untreated adult patients. Accordingly, to retard development of atherosclerosis, preventive measures for lowering cholesterol should be started even in childhood. To this end, 19 FH families consumed dietary stanol ester for 3 months. Stanol ester margarine lowers the serum cholesterol level by inhibiting cholesterol absorption. Each individual in the study replaced part of his or her daily dietary fat with 25 g of 80% rapeseed oil margarine containing stanol esters (2.24 g/d stanols, mainly sitostanol). The families who consumed this margarine for 12 weeks included 24 children, aged 3 to 13 years, with the North Karelia variant of FH (FH-NK), 4 FH-NK parents, and 16 healthy family members, and a separate group of 12 FH-NK adults who consumed the margarine for 6 weeks and who were on simvastatin therapy (20 or 40 mg/d). Fat-soluble vitamins were measured by high-pressure liquid chromatography, and cholesterol precursor sterols (indexes of cholesterol synthesis) and cholestanol and plant sterols (indexes of cholesterol absorption efficiency) were assayed by gas-liquid chromatography. No side effects occurred. Serum LDL cholesterol levels were reduced by 18% ( P <0.001), 11%, 12% ( P <0.001), and 20% ( P <0.001) in the 4 groups, respectively. The serum campesterol-to-cholesterol ratios fell by 31% ( P <0.001), 29%, 23% ( P <0.001), and 36% ( P <0.001), respectively, suggesting that cholesterol absorption efficiency was inhibited. Serum lathosterol ratios were elevated by 38% ( P <0.001), 11%, 15% ( P <0.001), and 19% ( P <0.001), respectively, suggesting that cholesterol synthesis was compensatorily upregulated. The FH-NK children increased their serum lathosterol ratio more than did the FH-NK adults treated with stanol ester margarine and simvastatin ( P <0.01). In the FH-NK children, serum retinol concentration and α-tocopherol–to-cholesterol ratios were unchanged by stanol ester margarine, but α- and β-carotene concentrations and ratios were decreased. As assayed in a genetically defined population of FH patients, a dietary regimen with stanol ester margarine proved to be a safe and effective hypolipidemic treatment for children and adults. In FH-NK adults on simvastatin therapy, serum LDL cholesterol levels could be reduced even further by including a stanol ester margarine in the regimen.

Background Familial hypercholesterolemia is one of the most common inherited metabolic diseases and is an autosomal dominant disorder meaning heterozygotes, or carriers, are affected. Those who are homozygous have severe disease. The average worldwide prevalence of heterozygous familial hypercholesterolemia is at least 1 in 500, although recent genetic epidemiological data from Denmark and next generation sequencing data suggest the frequency may be closer to 1 in 250. Diagnosis of familial hypercholesterolemia in children is based on elevated total cholesterol and low‐density lipoprotein cholesterol levels or DNA‐based analysis, or both. Coronary atherosclerosis has been detected in men with heterozygous familial hypercholesterolemia as young as 17 years old and in women with heterozygous familial hypercholesterolemia at 25 years old. Since the clinical complications of atherosclerosis occur prematurely, especially in men, lifelong treatment, started in childhood, is needed to reduce the risk of cardiovascular disease. In children with the disease, diet was the cornerstone of treatment but the addition of lipid‐lowering medications has resulted in a significant improvement in treatment. Anion exchange resins, such as cholestyramine and colestipol, were found to be effective, but they are poorly tolerated. Since the 1990s studies carried out on children aged 6 to 17 years with heterozygous familial hypercholesterolemia have demonstrated significant reductions in their serum total and low‐density lipoprotein cholesterol levels. While statins seem to be safe and well‐tolerated in children, their long‐term safety in this age group is not firmly established. This is an update of a previously published version of this Cochane Review. Objectives To assess the effectiveness and safety of statins in children with heterozygous familial hypercholesterolemia. Search methods Relevant studies were identified from the Group's Inborn Errors and Metabolism Trials Register and Medline. Date of most recent search: 04 November 2019. Selection criteria Randomized and controlled clinical studies including participants up to 18 years old, comparing a statin to placebo or to diet alone. Data collection and analysis Two authors independently assessed studies for inclusion and extracted data. Main results We found 26 potentially eligible studies, of which we included nine randomized placebo‐controlled studies (1177 participants). In general, the intervention and follow‐up time was short (median 24 weeks; range from six weeks to two years). Statins reduced the mean low‐density lipoprotein cholesterol concentration at all time points (high‐quality evidence). There may be little or no difference in liver function (serum aspartate and alanine aminotransferase, as well as creatinine kinase concentrations) between treated and placebo groups at any time point (low‐quality evidence). There may be little or no difference in myopathy (as measured in change in creatinine levels) (low‐quality evidence) or clinical adverse events (moderate‐quality evidence) with statins compared to placebo. One study on simvastatin showed that this may slightly improve flow‐mediated dilatation of the brachial artery (low‐quality evidence), and on pravastatin for two years may have induced a regression in carotid intima media thickness (low‐quality evidence). No studies reported rhabdomyolysis (degeneration of skeletal muscle tissue) or death due to rhabdomyolysis, quality of life or compliance to study medication. Authors' conclusions Statin treatment is an effective lipid‐lowering therapy in children with familial hypercholesterolemia. Few or no safety issues were identified. Statin treatment seems to be safe in the short term, but long‐term safety remains unknown. Children treated with statins should be carefully monitored and followed up by their pediatricians and their care transferred to an adult lipidologist once they reach 18 years of age. Large long‐term randomized controlled trials are needed to establish the long‐term safety issues of statins.