REVIEW URRENT C OPINION
What is new in familial hypercholesterolemia? Raul D. Santos and Raul C. Maranhao
Purpose of review The purpose of this review is to describe advances in the diagnosis, cause, metabolism, risk factors for atherosclerosis, and treatment of familial hypercholesterolemia. Recent findings Heterozygous familial hypercholesterolemia is almost four-fold more frequent than previously thought and is associated with 10-fold to 13-fold risk of cardiovascular disease comparing with normolipidemics. LDL receptor (LDLR) dysfunction and LDL-cholesterol (LDL-C) accumulation disturb the metabolism of other lipoprotein classes, such as chylomicrons and remnants and HDL. Next-generation sequencing can improve familial hypercholesterolemia molecular diagnosis due to its better performance and lower costs than usual techniques. Despite this, roughly 40% of familial hypercholesterolemia patients do not present mutations on the LDLR, apolipoprotein B, or proprotein convertase subtilisin/kexin type 9 genes. Many individuals with familial hypercholesterolemia phenotype have polygenic instead of monogenic cause of their elevated LDL-C concentrations. Individuals with familial hypercholesterolemia show elevated burden of subclinical atherosclerosis. The intensity of atherosclerosis burden is associated with the severity of LDLR mutation rather than maternal or paternal heritability. Newer-approved and on-development medications that reduce LDL-C hold promise for preventing cardiovascular disease in familial hypercholesterolemia. Summary Familial hypercholesterolemia is frequent and currently underdiagnosed and undertreated, but effective cascade screening programs and early and intensive LDL-C lowering can change this picture and the natural history of the disease. Keywords atherosclerosis, familial hypercholesterolemia, genes, LDL, proprotein convertase subtilisin/kexin type 9
INTRODUCTION Familial hypercholesterolemia is defined as an autosomal dominant disease that is caused by defects in four genes that regulate plasma LDL-cholesterol (LDL-C) concentrations: the LDL receptor (LDLR), apolipoprotein (apo) B, proprotein convertase subtilisin/kexin type 9 (PCSK9), and the adaptor protein [LDLRAP, or autosomal recesive hypercholesterolemia-(ARH) protein] [1]. Defects on the first three causing both homozygous and heterozygous phenotypes, whereas defects on the latter cause only the homozygous phenotype. In most instances, familial hypercholesterolemia is diagnosed by criteria that consider elevated LDL-C plasma levels, family history of early coronary heart disease (CHD) and dyslipidemia, the existence of xanthomas, and, when molecular diagnosis is available, the presence of mutations on the four candidate genes [1]. Familial hypercholesterolemia is characterized by elevated LDL-C levels from birth and is associated with and early onset CHD.
EPIDEMIOLOGY: UNDERDIAGNOSED, NOT UNCOMMON HIGH-RISK CONDITION, AND MOSTLY UNDERTREATED It is usually assumed that heterozygous familial hypercholesterolemia affects 1 of 500 individuals in populations not presenting founder effects [1]. However, the prevalence of heterozygous familial hypercholesterolemia in the general population is apparently higher than previously thought [2 ]. Benn et al. evaluating approximately 70 000 individuals from the Copenhagen General Population &&
Heart Institute (InCor), University of Sao Paulo Medical School Hospital, Sao Paulo, Brazil Correspondence to Raul D. Santos, Heart Institute (InCor), University of Sao Paulo Medical School Hospital, Av Dr Eneas C. Aguiar, 44 Segundo Andar Bloco 2, Sala 4, 05403-900 Sao Paulo, Brazil. Tel: +55 11 26615320; fax: +55 11 26615017; e-mail: [email protected], raul. [email protected] Curr Opin Lipidol 2014, 25:183–188 DOI:10.1097/MOL.0000000000000073
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KEY POINTS Familial hypercholesterolemia is more frequent than previously expected in the general population and is associated with more than 10-fold risk of CHD even in individuals taking statins. In approximately 40% of individuals with familial hypercholesterolemia phenotypes, no mutations on LDLR, apolipoprotein B, or PCSK9 genes are found. A great part of these cases could be explained by a polygenic single nucleotide polymorphism (SNP) score. Statins are a cost-effective and well tolerated treatment for familial hypercholesterolemia. Recently, the antisense oligonucleotide mipomersen and the microsomal triglyceride inhibitor lomitapide were approved for the treatment of homozygous familial hypercholesterolemia. Monoclonal antibodies against PCSK9 are apparently well tolerated and very effective in reducing LDL-C in heterozygous familial hypercholesterolemia.
Study found a prevalence of 1 of 137 of individuals presenting definite/probable familial hypercholesterolemia as defined by a modified Dutch Lipid Clinic Network score. In that study, familial hypercholesterolemia was associated with a 13-fold and 10-fold relative risk of CHD in those individuals receiving or not receiving lipid-lowering therapy, respectively, in comparison with nonfamilial hypercholesterolemia individuals. One can conclude that statin therapy, which reduces cardiovascular events in familial hypercholesterolemia [3], is being underused. Recently, the European Atherosclerosis Society Consensus Panel estimated that less than 10% of familial hypercholesterolemia patients are diagnosed and treated worldwide, showing a tremendous and ominous gap in both diagnosis and treatment [1].
LIPID METABOLISM DISTURBANCES IN FAMILIAL HYPERCHOLESTEROLEMIA The LDLR-mediated endocytic pathway is a key mechanism in the regulation of plasma lipids and body cholesterol homeostasis. The increasing number of more than 1200 mutations and polymorphisms documented to date involving this endocytic pathway occur not only in the lipoproteinbinding domains of the receptor but in domains not directly related to binding, but that can affect the affinity of the receptor for the lipoprotein [1]. They can also affect other steps of the endocytosis, such as the recirculation of LDLR from the cytoplasm back to the cell membrane. The more recent 184
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discoveries of PCSK9 and LDLR adaptor protein (LDLRAP or ARH) functions and mutations add up to the great complexity and the vulnerability of this system to genetic defects, which can compromise the homeostatic function of this endocytic pathway [1]. PCSK9 promotes the LDLR degradation and thereby reduces the efficiency of the LDL endocytic function. Secreted PCSK9 decreases the number of LDLR in mice hepatocytes, and in knockout mice lacking PCSK9, there is an inverse association between PCSK9 expression and LDLR levels [4]. If the numbers of LDLR are reduced, as occurs in heterozygous familial hypercholesterolemia and to a much greater extent in homozygous familial hypercholesterolemia, one would expect PCSK9 levels to be increased [5]. LDLR take up not only LDL but also other products of VLDL and chylomicron degradation [6]. Thus, dysfunction of the LDLR can also impair the removal of chylomicron remnants that may contribute to premature atherosclerosis [7]. Recently, Carneiro et al. [8] showed that the plasma clearance of chylomicron remnants is pronouncedly reduced in heterozygous familial hypercholesterolemia individuals with identified LDLR mutations, using artificial chylomicron-like emulsions to probe this metabolism. The accumulation of LDL in the plasma, with delayed LDL residence time, may also affect the non-LDL fractions. There is evidence that HDL-C concentrations and the reverse cholesterol transport are reduced in familial hypercholesterolemia [9 ]. Exchange of lipids among lipoprotein classes is mediated by the transfer proteins: cholesteryl ester transfer protein and phospholipid transfer protein. Cholesteryl ester transfer protein inhibitors are destined to increase HDL-C concentration, but simultaneously a considerable decrease in LDL-C is also obtained with this treatment, showing that lipid transfer affects not only HDL but also LDL plasma levels [10]. The functional aspects of HDL are, however, partly independent of the HDL-C levels. Recently, an in-vitro assay to assess the simultaneous transfer of the four main lipids to HDL, using an artificial emulsion as lipid donor, was developed [11]. Transfer of unesterified cholesterol to HDL was lower in familial hypercholesterolemia patients than in normolipidemic individuals, whereas the transfer to HDL of triglycerides, and phospholipids, was higher and that of esterified cholesterol was equal [11]. The diminished plasma transfer of unesterified cholesterol to mature HDL particles may also contribute to the defects in reverse cholesterol transport seen in familial hypercholesterolemia [9 ]. This may hamper the antiatherogenic properties of the lipoprotein. &
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What is new in familial hypercholesterolemia? Santos and Maranhao
MOLECULAR DIAGNOSIS: NEXTGENERATION SEQUENCING, MONOGENIC VERSUS POLYGENIC FAMILIAL HYPERCHOLESTEROLEMIA? Guidelines recommend that molecular testing should be offered to individuals with clinical diagnosis of familial hypercholesterolemia and also to their relatives in order to better identify affected individuals and to implement early statin therapy [1,12]. Usually, this is made by direct sequencing, use of arrays when there are a limited number of mutations on the population, or by denaturing high-performance liquid chromatography (DHPLC) and melting analysis [13]. Multiplex ligationdependent probe amplification is used for the detection of large insertions or deletions [14]. Nevertheless, these techniques are generally timeconsuming, not widely available and not practical for screening in large populations. Recently, next-generation sequencing that allows the simultaneous testing of different genes from many patient samples at the same time has been validated in confirmed and suspected familial hypercholesterolemia individuals [14]. These methods have the potential for simplifying and broadening the molecular diagnosis because they present high sensitivities and specificities, allowing the detection not only of single-point LDLR mutations but also of the not so frequent deletions and duplications. In addition, they are less costly than the previously used techniques. However, even with the introduction of these up-to-date methods, mutations were found in only 67 and 26% of UK individuals with definite and possible familial hypercholesterolemia diagnoses, respectively, according to the Simon Broome criteria [14]. Indeed, with the exception of world regions where founder effects are common, mutations on the candidate genes are found in approximately 40% of individuals with a clinical familial hypercholesterolemia phenotype [15]. These data suggest that genes other than the classic ones could cause familial hypercholesterolemia phenotypes. Indeed, Talmud et al. [16 ] found that in many patients with the clinical familial hypercholesterolemia phenotype in whom mutations on LDLR, apoB, and PCSK9 were not found, an elevated polygenic score could account for the hypercholesterolemia. This score consisted of SNPs in 12 LDL-C-raising alleles according to the genome-wide meta-analysis reported by the Global Lipid Genetics Consortium [17]. In those cases, familial hypercholesterolemia had polygenic instead of monogenic cause. The presence of those SNPs explained the variability in cholesterol levels occurring even in familial hypercholesterolemia individuals with proven molecular defects. The authors suggested that &&
individuals without mutations on the three classic genes, but with familial hypercholesterolemia phenotype and high polygenic score, should be classified as polygenic hypercholesterolemia rather than as familial hypercholesterolemia. Interestingly, hypercholesterolemic individuals with high polygenic scores have lesser chance of passing this trait to their offspring since the inheritance of these SNPs is independent of each other [18]. Consequently, the frequency of high LDL-C in relatives of polygenic hypercholesterolemias is lower than that in relatives of individuals with monogenic inheritance. This finding could assist the decision to perform or not molecular cascade screening on families. According to Talmud et al., [16] whenever a monogenic defect is found, molecular cascade screening should be performed, as it is cost-effective. However, when those mutations are not found, family testing should be restricted to those from index cases with a low SNP score, as they have a lower chance of a polygenic cause. In those individuals, a further and more extensive search for monogenic causes should be performed using next-generation sequencing techniques. At any rate, LDL-C at familial hypercholesterolemia-like levels must be treated with statins whatever the genetic background [19].
SUBCLINICAL CARDIOVASCULAR DISEASE IN FAMILIAL HYPERCHOLESTEROLEMIA INDIVIDUALS: DO NOT BLAME THE MOTHERS BUT THE MUTATIONS There is evidence that maternal hypercholesterolemia enhances the future prevalence of atherosclerosis in the offspring [20]. This relationship would be more prominent for the offspring of familial hypercholesterolemia women, as they cannot use statins during pregnancy through which the cholesterol levels raise by 30–50% [21]. Kusters et al. [22] studied 2657 molecularly defined familial hypercholesterolemia individuals and their unaffected siblings evaluated for the presence of subclinical vascular disease by carotid intima-media thickness and separated as offspring of familial hypercholesterolemia mothers or fathers. They found no differences in intima-media thickness or serum lipid levels between maternal versus paternal offspring. This occurred for both familial hypercholesterolemia and their nonaffected siblings. Those data strongly suggest that familial hypercholesterolemia parenthood is not influent concerning the incidence of cardiovascular disease. Subclinical CHD disease can be detected by computed tomography angiography (CTA). The
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cholesterol year score has been associated with coronary atherosclerotic plaque burden in heterozygous familial hypercholesterolemia [23]. LDLR mutations can be classified either as LDLR-negative mutations that lead to the absence of a functional LDLR protein or mutations that generate LDLR proteins with residual function (LDLR-defective mutations) [24]. There is evidence that null mutation alleles lead to more severe hypercholesterolemia and associated clinical consequences [1]. Ten Kate et al. [25] evaluated the cross-sectional association between the severity of LDLR mutation and coronary plaque burden in asymptomatic statin-treated heterozygous familial hypercholesterolemia individuals submitted to coronary CTA. The authors concluded that atherosclerotic plaque burden was greater in patients with LDLRnegative mutational familial hypercholesterolemia. Importantly, differences in plaque burden between LDLR-negative and LDLR-positive mutational familial hypercholesterolemia increased with age. This occurred despite statin treatment. The association between the presence of a LDLR negative mutation and plaque persisted after adjustment for LDL-C levels. The authors also evaluated the severity of plaque burden between those familial hypercholesterolemia individuals presenting defective LDLR or apoB mutations with those in whom a mutation was not found (n ¼ 46). Vessel stenosis severity was greater in those with an identified mutation. Despite the limitations because of its cross-sectional design, this study suggests that more severe mutations implicate in a higher risk of CHD in familial hypercholesterolemia individuals.
NEWER TREATMENTS In 2013, both mipomersen, an apoB antisense oligonucleotide, and lomitapide, a microsomal triglyceride protein inhibitor, were approved for the treatment of homozygous familial hypercholesterolemia in the USA [12]. Lomitapide was also approved in Europe for that purpose.
Mipomersen Raal et al. [26] had previously demonstrated in a double-blind study that after 26 weeks mipomersen 200 mg, as administered once a week subcutaneously on top of maximally tolerated lipid-lowering therapy, reduced apoB, LDL-C, and lipoprotein(a) (Lp(a)) in 21, 24, and 23% versus placebo in homozygous familial hypercholesterolemia. Stein et al. [27] showed that mipomersen reduced LDL-C, apoB, and Lp(a) by 28, 26, and 21% (all P < 0.001 versus placebo) in heterozygous familial 186
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hypercholesterolemia patients, respectively. In both studies, main side-effects of treatment were injection site reactions and flu-like symptoms. Because of reduction of hepatic apoB synthesis, mipomersen leads to liver fat accumulation. Recently, Santos et al. [28 ] reported an up to 104-week open-label evaluation of mipomersen in 141 familial hypercholesterolemia individuals. Efficacy and safety were similar to those reported in the randomized phase 3 studies. Flu-like symptoms were the most frequent cause of treatment discontinuation; injection site reactions tended to reduce with time. Of notice, there was an incremental increase in the liver fat measured by magnetic resonance imaging during the initial 6–12 months. Fat liver diminished with continued mipomersen exposure beyond 1 year, suggesting organ adaptation, and returned toward baseline 24 weeks after the end of treatment. &
Lomitapide &
Cuchel et al. [29 ] evaluated, in an open-label noncontrolled study, the effects of lomitapide on 29 homozygous familial hypercholesterolemia patients. They were in use of maximally tolerated lipid-lowering medication associated or not with LDL apheresis. In this study, lomitapide was administered from 5 to 60 mg/day with weekly dose escalation based on tolerability and safety. The primary end point was mean percentage change in LDL-C concentrations at week 26. Further on patients remained on lomitapide throughout week 78 for safety assessment. Twenty-three patients completed the study protocol, and the average study dose was 40 mg/day. At week 26, there were mean 50, 49, and 45% reductions on LDL-C, apoB, and triglycerides, respectively, and no significant effects were seen on Lp(a) concentrations. The most common side-effects were diarrhea, nausea, vomiting, dyspepsia, and abdominal pain as seen in 28% of patients. Elevations in aminotransferases and an increment in hepatic fat were also observed. As expected by its mechanism of action, hepatic fat measured by magnetic resonance spectroscopy increased from 1% at baseline to 8.6% (range 0– 30%) at week 26, but no further increments were reported at week 78. Dose reduction or temporary drug discontinuation resulted in normalization of liver enzymes.
Monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 Previously on phase 2 studies, the efficacy and safety of two monoclonal antibodies against PCSK9 Volume 25 Number 3 June 2014
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What is new in familial hypercholesterolemia? Santos and Maranhao
alirocumab [30] and evolocumab (AMG 145) [31] were tested against placebo in heterozygous familial hypercholesterolemia. Different doses and injection intervals were evaluated in those trials. The 420 mg dose of evolocumab injected subcutaneously every 4 weeks reduced LDL-C by 60%, while the same dose administered every 2 weeks diminished LDL-C by 70% [31]. Alirocumab injected at the 150 mg dose every 2 weeks reduced LDL-C by 67% [30]. There were also reductions in plasma apoB and Lp(a) under both treatments. These drugs were very well tolerated by the individuals and showed no signs of the muscle and liver abnormalities seen with statin use. These results suggest that increased expression of the LDLR induced by reduction on PCSK9 [32] concentrations may also increase the clearance from plasma of Lp(a). Recently, the results of the 1-year duration OSLER (Open-Label Study of Long-Term Evaluation Against LDL-C) study confirmed both the efficacy and safety of the evolocumab 420 mg dose administered subcutaneously every 4 weeks to hypercholesterolemic individuals presenting of not familial hypercholesterolemia (n ¼ 736) in comparison with standard lipid-lowering therapy [33 ]. There is still questioning about the efficacy of antibodies that bind to PCSK9 in homozygous familial hypercholesterolemia. This is inherent to their mechanism of action, as the expression of a functional LDLR is necessary to reduce plasma LDL-C [32]. Would these drugs work in familial hypercholesterolemia homozygotes presenting null LDLR mutations? In a small open-label proof-ofconcept study, Stein et al. [34] evaluated the effects 420 mg evolocumab every 4 weeks for 12 weeks at least, followed by 420 mg every 2 weeks for an additional 12 weeks. Eight patients with LDLRnegative or defective mutations were treated, but the response to the treatment was variable: LDL-C ranging from þ5.2% to 43.6% (P ¼ N.S.), with no reduction in the two receptor-negative patients. The mean LDL-C reductions in the six LDLR defective patients were approximately 19 and 26% with 4-week and 2-week dosing, respectively (P < 0.05). Treatment was well tolerated. &&
CONCLUSION Familial hypercholesterolemia is frequent, currently underdiagnosed and undertreated, and associated with early CHD onset. Effective cascade screening programs and early and intensive LDL-C lowering can change this picture and turn the tide of the natural history of this disease. Newer treatments might help patients to attain normal LDL-C concentrations.
Acknowledgements None. Conflicts of interest R.D.S. declares the following potential conflicts of interest: Honoraria for consulting and speaking activities for Amgen, Aegerion, AstraZeneca, Biolab, Boehringer Ingelheim, Bristol-Myers Squibb, Genzyme, Merck Sharp & Dohme, Lilly, Nestle, Novartis, Novo Nordisk, Pfizer, Regeneron, and Sanofi. R.C.M. is an awardee of the National Council for Research Development (CNPq), Brasilia, Brazil.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: Consensus Statement of the European Atherosclerosis Society. Eur Heart J 2013; 34:3478–3490. 2. Benn M, Watts GF, Tybjaerg-Hansen A, Nordestgaard BG. Familial hyper&& cholesterolemia in the Danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication. J Clin Endocrinol Metab 2012; 97:3956–3964. In this study, carried out in a general population, heterozygous familial hypercholesterolemia was almost 2.5 times more frequent than usually thought. Familial hypercholesterolemia was associated with a 13-fold and 10-fold risk of cardiovascular disease than normolipidemics. Elevated risk occurred even in those taking statins, suggesting that patients are undertreated. 3. Versmissen J, Oosterveer DM, Yazdanpanah M, et al. Efficacy of statins in familial hypercholesterolaemia: a long term cohort study. BMJ 2008; 337: a2423. 4. Lagace TA, Curtis DE, Garuti R, et al. Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice. J Clin Invest 2006; 116:2995–3005. 5. Raal F, Panz V, Immelman A, Pilcher G. Elevated PCSK9 levels in untreated patients with heterozygous or homozygous familial hypercholesterolemia and the response to high-dose statin therapy. J Am Heart Assoc 2013; 2:e000028. 6. Sniderman AD, Qi Y, Ma CI, et al. Hepatic cholesterol homeostasis: is the lowdensity lipoprotein pathway a regulatory or a shunt pathway? Arterioscler Thromb Vasc Biol 2013; 33:2481–2490. 7. Sposito AC, Lemos PA, Santos RD, et al. Impaired intravascular triglyceride lipolysis constitutes a marker of clinical outcome in patients with stable angina undergoing secondary prevention treatment: a long-term follow-up study. J Am Coll Cardiol 2004; 43:2225–2232. 8. Carneiro MM, Miname MH, Gagliardi AC, et al. The removal from plasma of chylomicrons and remnants is reduced in heterozygous familial hypercholesterolemia subjects with identified LDL receptor mutations: study with artificial emulsions. Atherosclerosis 2012; 221:268–274. 9. Guerin M. Reverse cholesterol transport in familial hypercholesterolemia. & Curr Opin Lipidol 2012; 23:377–385. This excellent review discusses changes in HDL metabolism and reverse cholesterol transport found in familial hypercholesterolemia patients. Low HDL-C is an independent risk factor for cardiovascular disease in familial hypercholesterolemia. 10. Li C, Zhang W, Zhou F, et al. Cholesteryl ester transfer protein inhibitors in the treatment of dyslipidemia: a systematic review and meta-analysis. PLoS One 2013; 8:e77049. 11. Martinez LR, Santos RD, Miname MH, et al. Transfer of lipids to high-density lipoprotein (HDL) is altered in patients with familial hypercholesterolemia. Metabolism 2013; 62:1061–1064. 12. Watts GF, Gidding S, Wierzbicki AS, et al. Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation. Int J Cardiol 2014; 171:309–325. 13. Fahed A, Nemer GM. Familial hypercholesterolemia: the lipids or the genes? Nutr Metab (Lond) 2011; 8:23. 14. Vandrovcova J, Thomas ER, Atanur SS, et al. The use of next-generation sequencing in clinical diagnosis of familial hypercholesterolemia. Genet Med 2013; 15:948–957.
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Lipid metabolism 15. Taylor A, Wang D, Patel K, et al. Mutation detection rate and spectrum in familial hypercholesterolaemia patients in the UK pilot cascade project. Clin Genet 2010; 77:572–580. 16. Talmud PJ, Shah S, Whittall R, et al. Use of low-density lipoprotein cholesterol && gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case–control study. Lancet 2013; 381:1293– 1301. This important study shows that a great proportion of individuals with elevated cholesterol within familial hypercholesterolemia range are, in reality, polygenic hypercholesterolemic individuals. The authors extensively discuss the use of a polygenic score to guide molecular cascade screening. 17. Teslovich TM, Musunuru K, Smith AV, et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 2010; 466:707–713. 18. Hadfield SG, Horara S, Starr BJ, et al. Family tracing to identify patients with familial hypercholesterolaemia: the second audit of the Department of Health familial hypercholesterolaemia cascade testing project. Ann Clin Biochem 2009; 46:24–32. 19. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: a Report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013. doi: 10.1016/j.jacc.2013.11.002. [Epub ahead of print] 20. Napoli C, Glass CK, Witztum JL, et al. Influence of maternal hypercholesterolaemia during pregnancy on progression of early atherosclerotic lesions in childhood: Fate of Early Lesions in Children (FELIC) study. Lancet 1999; 354:1234–1241. 21. Berge LN, Arnesen E, Forsdahl A. Pregnancy related changes in some cardiovascular risk factors. Acta Obstet Gynecol Scand 1996; 75:439– 442. 22. Kusters DM, Avis HJ, Braamskamp MJ, et al. Inheritance pattern of familial hypercholesterolemia and markers of cardiovascular risk. J Lipid Res 2013; 54:2543–2549. 23. Miname MH, Ribeiro MS 2nd, Parga Filho, et al. Evaluation of subclinical atherosclerosis by computed tomography coronary angiography and its association with risk factors in familial hypercholesterolemia. Atherosclerosis 2010; 213:486–491. 24. Hobbs HH, Russell DW, Brown MS, Goldstein JL. The LDL receptor locus in familial hypercholesterolemia: mutational analysis of a membrane protein. Annu Rev Genet 1990; 24:133–170. 25. Ten Kate GJ, Neefjes LA, Dedic A, et al. The effect of LDLR-negative genotype on CT coronary atherosclerosis in asymptomatic statin treated patients with heterozygous familial hypercholesterolemia. Atherosclerosis 2013; 227: 334–341. 26. Raal FJ, Santos RD, Blom DJ, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet 2010; 375:998–1006.
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27. Stein EA, Dufour R, Gagne C, et al. Apolipoprotein B synthesis inhibition with mipomersen in heterozygous familial hypercholesterolemia: results of a randomized, double-blind, placebo-controlled trial to assess efficacy and safety as add-on therapy in patients with coronary artery disease. Circulation 2012; 126:2283–2292. 28. Santos RD, Duell PB, East C, et al. Long-term efficacy and safety of & mipomersen in patients with familial hypercholesterolaemia: 2-year interim results of an open-label extension. Eur Heart J 2013. doi: 10.1093/eurheartj/ eht549. [Epub ahead of print] This open-label study shows that the effectiveness of mipomersen on reducing pro-atherogenic apoB containing lipoproteins of familial hypercholesterolemia patients is maintained after almost 2 years of treatment. Side-effects such as injection-site reactions and increased liver fat tend to reduce with time. However, flu-like symptoms, that were the greatest cause of study discontinuation persist. On median, they occurred in one of every 52 injections. 29. Cuchel M, Meagher EA, du Toit Theron H, et al. Efficacy and safety of a & microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet 2013; 381:40–46. Despite the lack of a placebo control, this study shows the potential of lomitapide to reduce LDL-C in homozygous patients. Safety was acceptable as long as patients followed a low-fat diet; received supplementation of fat-soluble vitamins and care was taken regarding possible pharmacological interaction with medications metabolized by cytochrome P450 3A4 enzymes. 30. Stein EA, Gipe D, Bergeron J, et al. Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial. Lancet 2012; 380:29–36. 31. Raal F, Scott R, Somaratne R, et al. Low-density lipoprotein cholesterollowering effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: the Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder (RUTHERFORD) randomized trial. Circulation 2012; 126:2408–2417. 32. Stein EA. Low-density lipoprotein cholesterol reduction by inhibition of PCSK9. Curr Opin Lipidol 2013; 24:510–517. 33. Koren MJ, Giugliano RP, Raal FJ, et al. Efficacy and safety of longer-term && administration of evolocumab (AMG 145) in patients with hypercholesterolemia: 52week results from the Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER) randomized trial. Circulation 2014; 129:234–243. This very important study shows that efficacy of evolocumab in reducing proatherogenic lipoproteins is maintained after 1 year in hypercholesterolemic patients. Tolerability was similar to standard lipid-lowering therapy that was used as control. 34. Stein EA, Honarpour N, Wasserman SM, et al. Effect of the proprotein convertase subtilisin/kexin 9 monoclonal antibody, AMG 145, in homozygous familial hypercholesterolemia. Circulation 2013; 128:2113–2120.
Volume 25 Number 3 June 2014
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What is new in familial hypercholesterolemia? Raul D. Santos and Raul C. Maranhao
Purpose of review The purpose of this review is to describe advances in the diagnosis, cause, metabolism, risk factors for atherosclerosis, and treatment of familial hypercholesterolemia. Recent findings Heterozygous familial hypercholesterolemia is almost four-fold more frequent than previously thought and is associated with 10-fold to 13-fold risk of cardiovascular disease comparing with normolipidemics. LDL receptor (LDLR) dysfunction and LDL-cholesterol (LDL-C) accumulation disturb the metabolism of other lipoprotein classes, such as chylomicrons and remnants and HDL. Next-generation sequencing can improve familial hypercholesterolemia molecular diagnosis due to its better performance and lower costs than usual techniques. Despite this, roughly 40% of familial hypercholesterolemia patients do not present mutations on the LDLR, apolipoprotein B, or proprotein convertase subtilisin/kexin type 9 genes. Many individuals with familial hypercholesterolemia phenotype have polygenic instead of monogenic cause of their elevated LDL-C concentrations. Individuals with familial hypercholesterolemia show elevated burden of subclinical atherosclerosis. The intensity of atherosclerosis burden is associated with the severity of LDLR mutation rather than maternal or paternal heritability. Newer-approved and on-development medications that reduce LDL-C hold promise for preventing cardiovascular disease in familial hypercholesterolemia. Summary Familial hypercholesterolemia is frequent and currently underdiagnosed and undertreated, but effective cascade screening programs and early and intensive LDL-C lowering can change this picture and the natural history of the disease. Keywords atherosclerosis, familial hypercholesterolemia, genes, LDL, proprotein convertase subtilisin/kexin type 9
INTRODUCTION Familial hypercholesterolemia is defined as an autosomal dominant disease that is caused by defects in four genes that regulate plasma LDL-cholesterol (LDL-C) concentrations: the LDL receptor (LDLR), apolipoprotein (apo) B, proprotein convertase subtilisin/kexin type 9 (PCSK9), and the adaptor protein [LDLRAP, or autosomal recesive hypercholesterolemia-(ARH) protein] [1]. Defects on the first three causing both homozygous and heterozygous phenotypes, whereas defects on the latter cause only the homozygous phenotype. In most instances, familial hypercholesterolemia is diagnosed by criteria that consider elevated LDL-C plasma levels, family history of early coronary heart disease (CHD) and dyslipidemia, the existence of xanthomas, and, when molecular diagnosis is available, the presence of mutations on the four candidate genes [1]. Familial hypercholesterolemia is characterized by elevated LDL-C levels from birth and is associated with and early onset CHD.
EPIDEMIOLOGY: UNDERDIAGNOSED, NOT UNCOMMON HIGH-RISK CONDITION, AND MOSTLY UNDERTREATED It is usually assumed that heterozygous familial hypercholesterolemia affects 1 of 500 individuals in populations not presenting founder effects [1]. However, the prevalence of heterozygous familial hypercholesterolemia in the general population is apparently higher than previously thought [2 ]. Benn et al. evaluating approximately 70 000 individuals from the Copenhagen General Population &&
Heart Institute (InCor), University of Sao Paulo Medical School Hospital, Sao Paulo, Brazil Correspondence to Raul D. Santos, Heart Institute (InCor), University of Sao Paulo Medical School Hospital, Av Dr Eneas C. Aguiar, 44 Segundo Andar Bloco 2, Sala 4, 05403-900 Sao Paulo, Brazil. Tel: +55 11 26615320; fax: +55 11 26615017; e-mail: [email protected], raul. [email protected] Curr Opin Lipidol 2014, 25:183–188 DOI:10.1097/MOL.0000000000000073
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KEY POINTS Familial hypercholesterolemia is more frequent than previously expected in the general population and is associated with more than 10-fold risk of CHD even in individuals taking statins. In approximately 40% of individuals with familial hypercholesterolemia phenotypes, no mutations on LDLR, apolipoprotein B, or PCSK9 genes are found. A great part of these cases could be explained by a polygenic single nucleotide polymorphism (SNP) score. Statins are a cost-effective and well tolerated treatment for familial hypercholesterolemia. Recently, the antisense oligonucleotide mipomersen and the microsomal triglyceride inhibitor lomitapide were approved for the treatment of homozygous familial hypercholesterolemia. Monoclonal antibodies against PCSK9 are apparently well tolerated and very effective in reducing LDL-C in heterozygous familial hypercholesterolemia.
Study found a prevalence of 1 of 137 of individuals presenting definite/probable familial hypercholesterolemia as defined by a modified Dutch Lipid Clinic Network score. In that study, familial hypercholesterolemia was associated with a 13-fold and 10-fold relative risk of CHD in those individuals receiving or not receiving lipid-lowering therapy, respectively, in comparison with nonfamilial hypercholesterolemia individuals. One can conclude that statin therapy, which reduces cardiovascular events in familial hypercholesterolemia [3], is being underused. Recently, the European Atherosclerosis Society Consensus Panel estimated that less than 10% of familial hypercholesterolemia patients are diagnosed and treated worldwide, showing a tremendous and ominous gap in both diagnosis and treatment [1].
LIPID METABOLISM DISTURBANCES IN FAMILIAL HYPERCHOLESTEROLEMIA The LDLR-mediated endocytic pathway is a key mechanism in the regulation of plasma lipids and body cholesterol homeostasis. The increasing number of more than 1200 mutations and polymorphisms documented to date involving this endocytic pathway occur not only in the lipoproteinbinding domains of the receptor but in domains not directly related to binding, but that can affect the affinity of the receptor for the lipoprotein [1]. They can also affect other steps of the endocytosis, such as the recirculation of LDLR from the cytoplasm back to the cell membrane. The more recent 184
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discoveries of PCSK9 and LDLR adaptor protein (LDLRAP or ARH) functions and mutations add up to the great complexity and the vulnerability of this system to genetic defects, which can compromise the homeostatic function of this endocytic pathway [1]. PCSK9 promotes the LDLR degradation and thereby reduces the efficiency of the LDL endocytic function. Secreted PCSK9 decreases the number of LDLR in mice hepatocytes, and in knockout mice lacking PCSK9, there is an inverse association between PCSK9 expression and LDLR levels [4]. If the numbers of LDLR are reduced, as occurs in heterozygous familial hypercholesterolemia and to a much greater extent in homozygous familial hypercholesterolemia, one would expect PCSK9 levels to be increased [5]. LDLR take up not only LDL but also other products of VLDL and chylomicron degradation [6]. Thus, dysfunction of the LDLR can also impair the removal of chylomicron remnants that may contribute to premature atherosclerosis [7]. Recently, Carneiro et al. [8] showed that the plasma clearance of chylomicron remnants is pronouncedly reduced in heterozygous familial hypercholesterolemia individuals with identified LDLR mutations, using artificial chylomicron-like emulsions to probe this metabolism. The accumulation of LDL in the plasma, with delayed LDL residence time, may also affect the non-LDL fractions. There is evidence that HDL-C concentrations and the reverse cholesterol transport are reduced in familial hypercholesterolemia [9 ]. Exchange of lipids among lipoprotein classes is mediated by the transfer proteins: cholesteryl ester transfer protein and phospholipid transfer protein. Cholesteryl ester transfer protein inhibitors are destined to increase HDL-C concentration, but simultaneously a considerable decrease in LDL-C is also obtained with this treatment, showing that lipid transfer affects not only HDL but also LDL plasma levels [10]. The functional aspects of HDL are, however, partly independent of the HDL-C levels. Recently, an in-vitro assay to assess the simultaneous transfer of the four main lipids to HDL, using an artificial emulsion as lipid donor, was developed [11]. Transfer of unesterified cholesterol to HDL was lower in familial hypercholesterolemia patients than in normolipidemic individuals, whereas the transfer to HDL of triglycerides, and phospholipids, was higher and that of esterified cholesterol was equal [11]. The diminished plasma transfer of unesterified cholesterol to mature HDL particles may also contribute to the defects in reverse cholesterol transport seen in familial hypercholesterolemia [9 ]. This may hamper the antiatherogenic properties of the lipoprotein. &
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What is new in familial hypercholesterolemia? Santos and Maranhao
MOLECULAR DIAGNOSIS: NEXTGENERATION SEQUENCING, MONOGENIC VERSUS POLYGENIC FAMILIAL HYPERCHOLESTEROLEMIA? Guidelines recommend that molecular testing should be offered to individuals with clinical diagnosis of familial hypercholesterolemia and also to their relatives in order to better identify affected individuals and to implement early statin therapy [1,12]. Usually, this is made by direct sequencing, use of arrays when there are a limited number of mutations on the population, or by denaturing high-performance liquid chromatography (DHPLC) and melting analysis [13]. Multiplex ligationdependent probe amplification is used for the detection of large insertions or deletions [14]. Nevertheless, these techniques are generally timeconsuming, not widely available and not practical for screening in large populations. Recently, next-generation sequencing that allows the simultaneous testing of different genes from many patient samples at the same time has been validated in confirmed and suspected familial hypercholesterolemia individuals [14]. These methods have the potential for simplifying and broadening the molecular diagnosis because they present high sensitivities and specificities, allowing the detection not only of single-point LDLR mutations but also of the not so frequent deletions and duplications. In addition, they are less costly than the previously used techniques. However, even with the introduction of these up-to-date methods, mutations were found in only 67 and 26% of UK individuals with definite and possible familial hypercholesterolemia diagnoses, respectively, according to the Simon Broome criteria [14]. Indeed, with the exception of world regions where founder effects are common, mutations on the candidate genes are found in approximately 40% of individuals with a clinical familial hypercholesterolemia phenotype [15]. These data suggest that genes other than the classic ones could cause familial hypercholesterolemia phenotypes. Indeed, Talmud et al. [16 ] found that in many patients with the clinical familial hypercholesterolemia phenotype in whom mutations on LDLR, apoB, and PCSK9 were not found, an elevated polygenic score could account for the hypercholesterolemia. This score consisted of SNPs in 12 LDL-C-raising alleles according to the genome-wide meta-analysis reported by the Global Lipid Genetics Consortium [17]. In those cases, familial hypercholesterolemia had polygenic instead of monogenic cause. The presence of those SNPs explained the variability in cholesterol levels occurring even in familial hypercholesterolemia individuals with proven molecular defects. The authors suggested that &&
individuals without mutations on the three classic genes, but with familial hypercholesterolemia phenotype and high polygenic score, should be classified as polygenic hypercholesterolemia rather than as familial hypercholesterolemia. Interestingly, hypercholesterolemic individuals with high polygenic scores have lesser chance of passing this trait to their offspring since the inheritance of these SNPs is independent of each other [18]. Consequently, the frequency of high LDL-C in relatives of polygenic hypercholesterolemias is lower than that in relatives of individuals with monogenic inheritance. This finding could assist the decision to perform or not molecular cascade screening on families. According to Talmud et al., [16] whenever a monogenic defect is found, molecular cascade screening should be performed, as it is cost-effective. However, when those mutations are not found, family testing should be restricted to those from index cases with a low SNP score, as they have a lower chance of a polygenic cause. In those individuals, a further and more extensive search for monogenic causes should be performed using next-generation sequencing techniques. At any rate, LDL-C at familial hypercholesterolemia-like levels must be treated with statins whatever the genetic background [19].
SUBCLINICAL CARDIOVASCULAR DISEASE IN FAMILIAL HYPERCHOLESTEROLEMIA INDIVIDUALS: DO NOT BLAME THE MOTHERS BUT THE MUTATIONS There is evidence that maternal hypercholesterolemia enhances the future prevalence of atherosclerosis in the offspring [20]. This relationship would be more prominent for the offspring of familial hypercholesterolemia women, as they cannot use statins during pregnancy through which the cholesterol levels raise by 30–50% [21]. Kusters et al. [22] studied 2657 molecularly defined familial hypercholesterolemia individuals and their unaffected siblings evaluated for the presence of subclinical vascular disease by carotid intima-media thickness and separated as offspring of familial hypercholesterolemia mothers or fathers. They found no differences in intima-media thickness or serum lipid levels between maternal versus paternal offspring. This occurred for both familial hypercholesterolemia and their nonaffected siblings. Those data strongly suggest that familial hypercholesterolemia parenthood is not influent concerning the incidence of cardiovascular disease. Subclinical CHD disease can be detected by computed tomography angiography (CTA). The
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cholesterol year score has been associated with coronary atherosclerotic plaque burden in heterozygous familial hypercholesterolemia [23]. LDLR mutations can be classified either as LDLR-negative mutations that lead to the absence of a functional LDLR protein or mutations that generate LDLR proteins with residual function (LDLR-defective mutations) [24]. There is evidence that null mutation alleles lead to more severe hypercholesterolemia and associated clinical consequences [1]. Ten Kate et al. [25] evaluated the cross-sectional association between the severity of LDLR mutation and coronary plaque burden in asymptomatic statin-treated heterozygous familial hypercholesterolemia individuals submitted to coronary CTA. The authors concluded that atherosclerotic plaque burden was greater in patients with LDLRnegative mutational familial hypercholesterolemia. Importantly, differences in plaque burden between LDLR-negative and LDLR-positive mutational familial hypercholesterolemia increased with age. This occurred despite statin treatment. The association between the presence of a LDLR negative mutation and plaque persisted after adjustment for LDL-C levels. The authors also evaluated the severity of plaque burden between those familial hypercholesterolemia individuals presenting defective LDLR or apoB mutations with those in whom a mutation was not found (n ¼ 46). Vessel stenosis severity was greater in those with an identified mutation. Despite the limitations because of its cross-sectional design, this study suggests that more severe mutations implicate in a higher risk of CHD in familial hypercholesterolemia individuals.
NEWER TREATMENTS In 2013, both mipomersen, an apoB antisense oligonucleotide, and lomitapide, a microsomal triglyceride protein inhibitor, were approved for the treatment of homozygous familial hypercholesterolemia in the USA [12]. Lomitapide was also approved in Europe for that purpose.
Mipomersen Raal et al. [26] had previously demonstrated in a double-blind study that after 26 weeks mipomersen 200 mg, as administered once a week subcutaneously on top of maximally tolerated lipid-lowering therapy, reduced apoB, LDL-C, and lipoprotein(a) (Lp(a)) in 21, 24, and 23% versus placebo in homozygous familial hypercholesterolemia. Stein et al. [27] showed that mipomersen reduced LDL-C, apoB, and Lp(a) by 28, 26, and 21% (all P < 0.001 versus placebo) in heterozygous familial 186
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hypercholesterolemia patients, respectively. In both studies, main side-effects of treatment were injection site reactions and flu-like symptoms. Because of reduction of hepatic apoB synthesis, mipomersen leads to liver fat accumulation. Recently, Santos et al. [28 ] reported an up to 104-week open-label evaluation of mipomersen in 141 familial hypercholesterolemia individuals. Efficacy and safety were similar to those reported in the randomized phase 3 studies. Flu-like symptoms were the most frequent cause of treatment discontinuation; injection site reactions tended to reduce with time. Of notice, there was an incremental increase in the liver fat measured by magnetic resonance imaging during the initial 6–12 months. Fat liver diminished with continued mipomersen exposure beyond 1 year, suggesting organ adaptation, and returned toward baseline 24 weeks after the end of treatment. &
Lomitapide &
Cuchel et al. [29 ] evaluated, in an open-label noncontrolled study, the effects of lomitapide on 29 homozygous familial hypercholesterolemia patients. They were in use of maximally tolerated lipid-lowering medication associated or not with LDL apheresis. In this study, lomitapide was administered from 5 to 60 mg/day with weekly dose escalation based on tolerability and safety. The primary end point was mean percentage change in LDL-C concentrations at week 26. Further on patients remained on lomitapide throughout week 78 for safety assessment. Twenty-three patients completed the study protocol, and the average study dose was 40 mg/day. At week 26, there were mean 50, 49, and 45% reductions on LDL-C, apoB, and triglycerides, respectively, and no significant effects were seen on Lp(a) concentrations. The most common side-effects were diarrhea, nausea, vomiting, dyspepsia, and abdominal pain as seen in 28% of patients. Elevations in aminotransferases and an increment in hepatic fat were also observed. As expected by its mechanism of action, hepatic fat measured by magnetic resonance spectroscopy increased from 1% at baseline to 8.6% (range 0– 30%) at week 26, but no further increments were reported at week 78. Dose reduction or temporary drug discontinuation resulted in normalization of liver enzymes.
Monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 Previously on phase 2 studies, the efficacy and safety of two monoclonal antibodies against PCSK9 Volume 25 Number 3 June 2014
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What is new in familial hypercholesterolemia? Santos and Maranhao
alirocumab [30] and evolocumab (AMG 145) [31] were tested against placebo in heterozygous familial hypercholesterolemia. Different doses and injection intervals were evaluated in those trials. The 420 mg dose of evolocumab injected subcutaneously every 4 weeks reduced LDL-C by 60%, while the same dose administered every 2 weeks diminished LDL-C by 70% [31]. Alirocumab injected at the 150 mg dose every 2 weeks reduced LDL-C by 67% [30]. There were also reductions in plasma apoB and Lp(a) under both treatments. These drugs were very well tolerated by the individuals and showed no signs of the muscle and liver abnormalities seen with statin use. These results suggest that increased expression of the LDLR induced by reduction on PCSK9 [32] concentrations may also increase the clearance from plasma of Lp(a). Recently, the results of the 1-year duration OSLER (Open-Label Study of Long-Term Evaluation Against LDL-C) study confirmed both the efficacy and safety of the evolocumab 420 mg dose administered subcutaneously every 4 weeks to hypercholesterolemic individuals presenting of not familial hypercholesterolemia (n ¼ 736) in comparison with standard lipid-lowering therapy [33 ]. There is still questioning about the efficacy of antibodies that bind to PCSK9 in homozygous familial hypercholesterolemia. This is inherent to their mechanism of action, as the expression of a functional LDLR is necessary to reduce plasma LDL-C [32]. Would these drugs work in familial hypercholesterolemia homozygotes presenting null LDLR mutations? In a small open-label proof-ofconcept study, Stein et al. [34] evaluated the effects 420 mg evolocumab every 4 weeks for 12 weeks at least, followed by 420 mg every 2 weeks for an additional 12 weeks. Eight patients with LDLRnegative or defective mutations were treated, but the response to the treatment was variable: LDL-C ranging from þ5.2% to 43.6% (P ¼ N.S.), with no reduction in the two receptor-negative patients. The mean LDL-C reductions in the six LDLR defective patients were approximately 19 and 26% with 4-week and 2-week dosing, respectively (P < 0.05). Treatment was well tolerated. &&
CONCLUSION Familial hypercholesterolemia is frequent, currently underdiagnosed and undertreated, and associated with early CHD onset. Effective cascade screening programs and early and intensive LDL-C lowering can change this picture and turn the tide of the natural history of this disease. Newer treatments might help patients to attain normal LDL-C concentrations.
Acknowledgements None. Conflicts of interest R.D.S. declares the following potential conflicts of interest: Honoraria for consulting and speaking activities for Amgen, Aegerion, AstraZeneca, Biolab, Boehringer Ingelheim, Bristol-Myers Squibb, Genzyme, Merck Sharp & Dohme, Lilly, Nestle, Novartis, Novo Nordisk, Pfizer, Regeneron, and Sanofi. R.C.M. is an awardee of the National Council for Research Development (CNPq), Brasilia, Brazil.
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27. Stein EA, Dufour R, Gagne C, et al. Apolipoprotein B synthesis inhibition with mipomersen in heterozygous familial hypercholesterolemia: results of a randomized, double-blind, placebo-controlled trial to assess efficacy and safety as add-on therapy in patients with coronary artery disease. Circulation 2012; 126:2283–2292. 28. Santos RD, Duell PB, East C, et al. Long-term efficacy and safety of & mipomersen in patients with familial hypercholesterolaemia: 2-year interim results of an open-label extension. Eur Heart J 2013. doi: 10.1093/eurheartj/ eht549. [Epub ahead of print] This open-label study shows that the effectiveness of mipomersen on reducing pro-atherogenic apoB containing lipoproteins of familial hypercholesterolemia patients is maintained after almost 2 years of treatment. Side-effects such as injection-site reactions and increased liver fat tend to reduce with time. However, flu-like symptoms, that were the greatest cause of study discontinuation persist. On median, they occurred in one of every 52 injections. 29. Cuchel M, Meagher EA, du Toit Theron H, et al. Efficacy and safety of a & microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet 2013; 381:40–46. Despite the lack of a placebo control, this study shows the potential of lomitapide to reduce LDL-C in homozygous patients. Safety was acceptable as long as patients followed a low-fat diet; received supplementation of fat-soluble vitamins and care was taken regarding possible pharmacological interaction with medications metabolized by cytochrome P450 3A4 enzymes. 30. Stein EA, Gipe D, Bergeron J, et al. Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial. Lancet 2012; 380:29–36. 31. Raal F, Scott R, Somaratne R, et al. Low-density lipoprotein cholesterollowering effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: the Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder (RUTHERFORD) randomized trial. Circulation 2012; 126:2408–2417. 32. Stein EA. Low-density lipoprotein cholesterol reduction by inhibition of PCSK9. Curr Opin Lipidol 2013; 24:510–517. 33. Koren MJ, Giugliano RP, Raal FJ, et al. Efficacy and safety of longer-term && administration of evolocumab (AMG 145) in patients with hypercholesterolemia: 52week results from the Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER) randomized trial. Circulation 2014; 129:234–243. This very important study shows that efficacy of evolocumab in reducing proatherogenic lipoproteins is maintained after 1 year in hypercholesterolemic patients. Tolerability was similar to standard lipid-lowering therapy that was used as control. 34. Stein EA, Honarpour N, Wasserman SM, et al. Effect of the proprotein convertase subtilisin/kexin 9 monoclonal antibody, AMG 145, in homozygous familial hypercholesterolemia. Circulation 2013; 128:2113–2120.
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