Statin therapy and risk of diabetes in patients with heterozygous familial hypercholesterolemia or familial combined hyperlipidemia

Objective

Controversial findings exist regarding potential influence of statin therapy on diabetic incidence. Aim of this study was to investigate the role of long duration statin treatment on diabetes mellitus (DM) incidence of Heterozygous Familial Hypercholesterolemia (hFH) and Familial Combined Hyperlipidemia (FCH) patients.

Methods

Study population consisted of 212 hFH and 147 FCH patients that visited Lipid Outpatient Department (mean follow up of 11 and 10 years respectively). Several clinical data such as history of DM, cardiovascular disease, thyroid function, metabolic syndrome, glucose levels, lipid profile and lifestyle data were obtained. In order to compare the effects of different doses of different types of statins, a “statin treatment intensity product” was used.

Results

14% of FCH and only 1% of hFH patients developed DM during follow up. Although univariate analysis showed a statistical trend (p = 0.06) in the association between new onset DM and statin treatment intensity (STI) in the FCH subgroup of patients with normal baseline glucose levels, this was no longer significant after adjusting for several confounders. Furthermore, the type of statins used did not seem to play a role in the development of DM either in hFH or FCH patients.

Conclusion

Long duration of high STI does not seem to be associated with diabetic risk in hFH patients. High STI used in the FCH population is not associated with increased risk of new onset DM compared to low STI. Further studies are required in order to clarify the potential diabetogenic effects of statins in these high risk populations.     

家族性高胆固醇血症一家系分析

目的高胆固血脂一家系调查。调查一家族性高胆固醇血症（FH）三代共20名成员，其中包括一对孪生兄弟的患病情况。结果提示HF患者共8例。总患病率为40％，男性患病率为54．5％（6／11），女性患病率为22．2％（2／9），符合常染色体显性遗传。结论本例FH的家系特点为：①血清总胆固醇（TC）从儿重期始有增高，且随年龄的增长有增高趋势；②家系中一对单卵双生的孪生同胞均为患病者，其后代亦有TC增高；③先证者41岁起即以典型的卧位型心绞痛起病，冠状动脉造影提示三支冠状动脉多处严重狭窄，似提示FH家系中的冠心病患者发病早且病变严重。     

Long-term effect of low-density lipoprotein apheresis in patients with homozygous familial hypercholesterolemia

Patients that are homozygous for familial hypercholesterolemia (FH) exhibit severe hypercholesterolemia, cutaneous and tendon xanthomas and premature atherosclerosis beginning in childhood. They are resistant to drug therapy and low-density lipoprotein (LDL) apheresis is the practical treatment. Here we review the technique of LDL apheresis treatment, the long-term effects of LDL apheresis, the effect of apheresis on pregnancy, and the drugs that have proven beneficial in patients with homozygous FH. We also record our experiences of treating eight homozygous FH patients using the LDL apheresis treatment. Among the eight patients, one has been free from cardiovascular disease and two patients have each regressed once. In two patients, aortic valve stenosis developed and the other two patients died for acute myocardial infarction. Furthermore, two patients delivered healthy babies in spite of coronary artery disease. Thus, LDL apheresis therapy has the possibility of preventing the progression of atherosclerosis, but the prognosis assessed by long-term observation is still not satisfactory. A recent clinical trial showed some efficacy of the combination therapy of LDL apheresis and atorvastatin for reducing serum cholesterol levels in homozygous FH, suggesting that this combination therapy may be useful for prevention of atherosclerosis in patients homozygous for FH.     

家族性高胆固醇血症一家系基因突变分析和临床治疗

目的]总结1例家族性高胆固醇血症(FH)家系的基因突变分析和临床治疗方案。 [方法]先证者因“反复气喘伴胸痛4个月,加重2天”入院,血浆低密度脂蛋白胆固醇(LDLC)异常升高,且早发冠心病,对先证者进行全外显子测序和载脂蛋白E(ApoE)、对氧磷酶1(PON1)、前蛋白转化酶枯草溶菌素9(PCSK9)等位点进行测序分析,针对可疑致病突变在家系成员中进行检测,对先证者及其父亲进行了冠状动脉介入治疗和降脂治疗。 [结果]先证者、其父亲和其儿子在低密度脂蛋白受体(LDLR)基因中均检出了6个突变位点,分别为c.191+13G＞A(rs200621482)、c.1598G＞T(rs200427089)、c.883T＞G(rs553235458)、c.3536A＞G(rs201300867)、c.2215+6G＞A(rs540060615)、c.162+5A＞T(rs146596406)。这3例患者的6个位点均为杂合突变。3例患者的ApoE基因型结果如下:先证者及其儿子的ApoE基因型均为ε3/ε3型,蛋白表型为E3(ApoE2位点为CC型,ApoE4位点为TT型);其父亲的ApoE基因型为ε2/ε3型,蛋白表型为E2(ApoE2位点为CT型,ApoE4位点为TT型)。3例患者的PON1(A575G,rs662)位点基因型均为AG型,3例患者的PCSK9基因型为GG、CC、CC、GG型。基于该家系遗传学检测结果,给予先证者及其父亲个体化的降脂治疗方案,阿托伐他汀钙与依折麦布联合PCSK9抑制剂,且先证者及其父亲成功行冠状动脉介入治疗术,随访两年LDLC控制较好,未出现药物不良反应。 [结论]本研究中该家系患者的LDLR基因均发现6个位点突变,其中LDLR c.191+13G＞A、c.162+5A＞T在国内尚未见报道,丰富了中国人群的LDLR基因突变谱。本研究有利于阐明FH的发病机制,进一步指导FH患者的临床治疗。     

Long-term effect of low-density lipoprotein apheresis in patients with heterozygous familial hypercholesterolemia

Clinical efficacy and safety of the therapeutic tool which directly removes LDL particles from circulation (LDL apheresis) have already been established in the treatment for refractory hypercholesterolemia in patients with familial hypercholesterolemia (FH). Two clinical studies with event-based assessment have demonstrated remarkably beneficial outcomes of long-term LDL apheresis using dextran sulfate cellulose columns plus adjunctive cholesterol-lowering drug therapy in the prevention of cardiovascular events in heterozygous FH with coronary artery disease. The results of several studies with angiographic and ultrasound-based assessment indicate a possible role for LDL apheresis in restructuring and stabilization of atherosclerotic lesions. These clinical improvements caused by LDL apheresis in heterozygous FH support the efficacy and importance of aggressive cholesterol-lowering therapy for secondary prevention of atherosclerotic cardiovascular disease in hypercholesterolemic patients.     

Cardiovascular disease in familial hypercholesterolaemia: influence of low-density lipoprotein receptor mutation type and classic risk factors

Aim

To determine the effect of the type of mutation in low-density lipoprotein receptor gene and the risk factors associated with the development of premature cardiovascular disease (PCVD) in a large cohort of heterozygous familial hypercholesterolemia (hFH) subjects with genetic diagnosis in Spain.

Methods and results

A cross-sectional study was conducted on 811 non-related FH patients (mean age 47.1 ± 14 years, 383 males and 428 females) with a molecular defect in the low-density lipoprotein receptor (LDLR) gene from the Spanish National FH Register. Prevalence of PCVD was 21.9% (30.2% in males and 14.5% in women, P < 0.001). Mean age of onset of cardiovascular event was 42.1 years in males and 50.8 years in females. Of those patients with PCVD, 59.5% of males and 27% of females suffered a second cardiovascular (CV) event. In multivariate analysis male gender, age, tobacco consumption (ever), and total cholesterol/HDL-cholesterol (TC/HDL-C) ratio were significantly associated with PCVD. Two hundred and twenty different mutations were found with a large heterogeneity. Patients carrying null-mutations had significantly higher frequency of PCVD and recurrence of CV events. No relationship with Lp(a) levels and genotype of Apo E were found.

Conclusions

This study confirms the importance of identifying some classic risk factors such as smoking and TC/HDL-C ratio, and also the type of mutation in LDLR gene in order to implement early detection and intensive treatment for the prevention of cardiovascular disease in FH patients.     

Association of heterozygous familial hypercholesterolemia with smaller HDL particle size

Small, dense HDL particles have been associated with factors known to increase the risk of cardiovascular disease, such as obesity, hypertriglyceridemia, small dense LDL particles, decreased HDL-cholesterol levels and increased apoA-I fractional catabolic rate from plasma. In order to assess the potential contribution of HDL particle size to atherosclerosis in heterozygous familial hypercholesterolemia (FH), we examined the electrophoretic characteristics of HDL particles in a large cohort of well defined FH heterozygotes and controls. A total of 259 FH heterozygotes and 208 controls participated in the study. FH subjects were carriers of one of the nine French Canadian mutations in the LDL receptor gene. All subjects were apoE3 homozygotes. HDL particles were characterized by non-denaturing polyacrylamide gradient gel electrophoresis following a 6-week lipid-lowering drug-free baseline period. The integrated HDL size was significantly smaller in the FH group compared to controls (FH = 87.3 ± 5.2 Å versus controls = 91.6 ± 4.9 Å, P < 0.0001). In each groups, men had smaller HDL particles than women. Multiple regression linear analyses showed that the FH/Control status accounted for 20.3% of the variance in the integrated HDL size. These results suggest that the FH/control status was independently associated with variations in HDL particle size and that these variations could contribute to the development of premature atherosclerosis in these patients.     

Biliary lipid composition in heterozygous familial hypercholesterolemia and influence of treatment with probucol

The lipid composition of fasting duodenal bile was determined in 11 healthy subjects with normolipidemia and 15 patients with heterozygous familial hypercholesterolemia (FH) (12 with type IIa, three with type IIb). The age distribution among the groups of subjects was similar. In the patients with heterozygous FH type IIa, the mean value for molar percentage of cholesterol and lithogenic index (LI) of bile were significantly higher than those of controls (8.4±1.0%, 1.47±0.18 calculated by Hegard, Dam, and Holzbach vs 4.3±0.4%, 0.81±0.07, respectively). The value of LI in the patients with FH type IIb was also found to be significantly higher than that of the controls. In the patients with heterozygous FH type IIa, we observed both a significant decrease in the molar percentages of glycochenodeoxycholic acid, glycoursodeoxycholic acid, and glycolithocholic acid, and a significant increase of taurochenodeoxycholic acid compared to the corresponding values in the controls. Bile analysis of six patients was reexamined during probucol treatment after 16 weeks. Probucol significantly lowered serum cholesterol levels. However, biliary lipid composition and individual bile acid proportions was not altered by the treatment. The results suggest that most of the patients with heterozygous FH have supersaturated bile and are predisposed to cholesterol gallstone formation. In addition, the mechanism by which probucol lowers serum cholesterol appears to be independent of any change in the metabolism of biliary lipid.     

A novel type of familial hypercholesterolemia: double heterozygous mutations in LDL receptor and LDL receptor adaptor protein 1 gene

Background

Autosomal recessive hypercholesterolemia (ARH) is an extremely rare inherited hypercholesterolemia, the cause of which is mutations in low-density lipoprotein (LDL) receptor adaptor protein 1 (LDLRAP1) gene.

Methods

A total of 146 heterozygous familial hypercholesterolemic (FH) patients with a mutation in LDLR gene were screened for genes encoding proprotein convertase subtilisin/kexin type 9 (PCSK9) and LDLRAP1.

Results

Among the 146 subjects, we identified a 79-year-old Japanese female with double mutations in LDLR gene (c.2431A > T) and LDLRAP1 gene (c.606dup). Two other relatives with double mutations in those genes in her family were also identified. Although the proband exhibited massive Achilles tendon xanthoma and coronary and aortic valvular disease, serum LDL-C level of subjects with double mutations was similar with that of subjects with single LDLR mutation (284.0 ± 43.5 versus 265.1 ± 57.4 mg/dl).

Conclusion

Additional mutation in LDLRAP1 may account for severer phenotype in terms of xanthoma and atherosclerotic cardiovascular disease in FH patients.     

Maternal inheritance of familial hypercholesterolemia caused by the V408M low-density lipoprotein receptor mutation increases mortality

Objective

Fetal exposure to maternal hypercholesterolemia increases the extent of fatty-streak formation in fetal aortas as well as the rate of progression, and may therefore increase coronary heart disease (CHD) risk later in life. We hypothesized that the risk of CHD in untreated individuals with familial hypercholesterolemia (FH) is more extreme when the disease is transmitted maternally.

Methods

In a large Dutch pedigree carrying the V408M mutation in the low-density lipoprotein (LDL) receptor gene, 161 individuals over seven generations were identified for which FH status and parent of origin of FH were known. We calculated standardized mortality ratios (SMR) and compared the consequences of maternal and paternal inheritance of FH by Poisson regression analysis.

Results

Maternally inherited FH was associated with significantly higher excess mortality than FH transmitted by fathers (relative risk 2.2; p = 0.048): the SMR of maternal inheritance was 2.49 (95% confidence interval (CI) 1.45–3.99; p = 0.001), whereas it was not significantly increased in paternally inherited FH (SMR 1.30, 95% CI 0.65–2.32; p = 0.234).

Conclusion

Mortality rates are more increased when FH is inherited through the mother, supporting the fetal origin of adulthood disease hypothesis with all cause death, the most indisputable outcome measure. Future research should explore safe options for cholesterol-lowering therapy of pregnant women with FH in order to prevent unfavourable (epigenetic) consequences leading to atherosclerosis in their children.     

肝脏移植治疗纯合型家族性高胆固醇血症的研究进展

家族性高胆固醇血症(FH)是一种常染色体遗传代谢性疾病,患者血清中低密度脂蛋白胆固醇(LDLC)水平显著升高,导致早发动脉粥样硬化性心血管疾病(ASCVD).未经治疗的纯合型家族性高胆固醇血症(HoFH)患者多因动脉粥样硬化性心血管疾病于30岁前死亡.HoFH的降胆固醇治疗包括治疗性生活方式改变、降脂药物治疗、血脂净化...     

The extended abnormalities in lipoprotein metabolism in familial hypercholesterolemia: Developing a new framework for future therapies

Familial hypercholesterolemia (FH) is a dominantly inherited disorder characterized by marked elevation of plasma low-density lipoprotein (LDL) cholesterol concentrations and premature coronary artery disease (CHD). In addition to impaired LDL receptor-mediated clearance of LDL particles, in vitro and in vivo studies suggest that hepatic oversecretion of apolipoprotein (apo) B may contribute to the hypercholesterolemia in FH. This may be due to an effect of the expanded hepatic pool of cholesterol (a consequence of increased receptor-independent uptake of LDL) and/or a direct effect of the LDL receptor on apoB secretion. Hepatic oversecretion of apoB may depend on the type and severity of the genetic mutation causing FH. FH can also increase plasma Lp(a) concentration by an undefined mechanism that may not directly involve the LDL receptor pathway. Decreased catabolism of triglyceride-rich lipoproteins could also be due to deficient LDL receptor function, accounting for postprandial dyslipidemia in FH. The metabolism of high-density lipoprotein (HDL) in FH is poorly understood, but preliminary data suggest abnormal HDL composition and functionality, as well as altered transport of apoA-I. Beyond effects related to specific genetic defects in the LDL pathway, co-existing secondary causes, particularly obesity and insulin resistance, and other genetic variants may also perturb lipoprotein metabolism in individuals with FH. Furthermore, residual risk remains high in statin-treated FH. Knowledge of an extended metabolic framework will, therefore, provide the basis for judiciously selecting new pharmacotherapies to treat FH, including apoB antisense oligonucleotides, microsomal transfer protein (MTP) inhibitors and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.     

Impact of high neutrophil-to-lymphocyte ratio on the cardiovascular benefit of PCSK9 inhibitors in familial hypercholesterolemia subjects with atherosclerotic cardiovascular disease: Real-world data from two lipid units

Background and aimsNeutrophil-to-lymphocyte ratio (NLR) is a novel inflammatory biomarker strongly associated with atherosclerotic cardiovascular disease (ASCVD). Our aim was to evaluate the role of NLR on pulse wave velocity (PWV) after adding-on proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9-i) in familial hypercholesterolemia (FH) subjects with ASCVD.Methods and resultsIn this prospective observational study, we evaluated 45 FH subjects with ASCVD on high-intensity statins plus ezetimibe and with an off-target LDL-C. Study population was divided into two groups according to the mean value of NLR. All patients received PCSK9-i therapy and obtained biochemical analysis as well as PWV evaluation at baseline and after six months of PCSK9-i. After six months of add-on PCSK9-i therapy, a significant reduction of TC, LDL-C, Non-HDL-C, Lp(a) and ApoB plasma levels was observed in the two groups; while low-NLR group exhibited a significant PWV reduction after six-month therapy with PCSK9-i (Δ −16.2%, p < 0.05), no significant changes in PWV were observed in the high-NLR group.ConclusionsOnly FH subjects with low-NLR experienced a significant reduction of PWV after PCSK9-i. Our findings suggest a role of NLR in predicting PCSK9-i effect in FH subjects with ASCVD.     

Adherence to a Mediterranean diet,dyslipidemia and inflammation in familial hypercholesterolemia

Background and aimsFamilial Hypercholesterolemia (FH) is characterized by elevated LDL-cholesterol (LDL-C) and high atherosclerosis risk. The impact of different dietary patterns on atherosclerosis biomarkers has been poorly studied in FH.This study verified the association of adherence to a Mediterranean diet with biomarkers of dyslipidemia and low-grade inflammation in molecularly proven FH adults from Brazil (BR) and Spain (SP).Methods and resultsIn this cross-sectional study adherence to the Mediterranean diet was assessed by a validated score and generalized estimating equations were used to evaluate its association with plasma LDL-C, apolipoprotein-B (ApoB) and high sensitivity C-reactive protein (hs-CRP) concentrations. We included 92 (mean age 45 years, 58.7% females) and 98 FH individuals (mean age 46.8 years, 60.2% females) respectively from BR and SP. FH causing variants did not differ between countries. LDL-C, ApoB and hs-CRP concentrations were higher in BR than in SP: 179 (135–250) and 161 (133–193) mg/dL; 141 (109–181) and 103 (88–134) mg/dL; and 1.6 (0.8–4.0) and 0.8 (0.4–1.5) mg/L respectively (all p < 0.001). Most of BR had low adherence (n = 77, 83.7%), while the majority of SP were divided into moderate (n = 35, 35.7%) and strong adherence to the Mediterranean diet (n = 37, 37.8%), p < 0.001. There was a significant inverse association of adherence to the Mediterranean diet score with higher LDL-C, ApoB, and hs-CRP after adjusting for socio economic parameters, caloric and fatty acid intakes as well as pharmacological lipid lowering therapies.ConclusionsHigher adherence to a Mediterranean diet was associated with better dyslipidemia and low-grade inflammation profiles in FH.