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Complex dyslipidemia induced by lorlatinib therapy: A case study 罗拉替尼治疗诱发的复杂血脂异常:病例研究。
IF 3.6 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-01 DOI: 10.1016/j.jacl.2024.10.003
Julianna West MD , Abhimanyu Garg MD

CONTEXT

Lorlatinib is an anaplastic lymphoma kinase (ALK) inhibitor, which is currently used for the treatment of ALK-positive metastatic non-small cell lung cancer (NSCLC). Previous reports have noticed an association between lorlatinib and hyperlipidemia, however the specific mechanisms for this side effect remain unknown. Some investigators have reported nephrotic syndrome to be the underlying cause of lorlatinib-induced hyperlipidemia.

CASE REPORT

A 59-year-old female with NSCLC presented with marked elevation of lipid levels, including total cholesterol, triglycerides, low-density lipoprotein-cholesterol (LDL-C), and high-density lipoprotein-cholesterol (HDL-C), after initiation of lorlatinib therapy. Despite high dose atorvastatin and ezetimibe, lipid levels remained elevated. A 24-hour urine collection revealed only 226 mg of protein excretion.

CONCLUSIONS

Lorlatinib induced a complex dyslipidemia in our patient with elevations of both LDL-C and HDL-C. The underlying mechanism of lorlatinib-induced hyperlipidemia remains unknown and is unlikely to be secondary to nephrotic syndrome in many patients.
背景:洛拉替尼是一种无性淋巴瘤激酶(ALK)抑制剂,目前用于治疗ALK阳性转移性非小细胞肺癌(NSCLC)。以前的报告注意到了洛拉替尼与高脂血症之间的关联,但这种副作用的具体机制仍不清楚。一些研究者报告称,肾病综合征是洛拉替尼诱发高脂血症的根本原因:病例报告:一名59岁的女性NSCLC患者在开始接受洛拉替尼治疗后出现血脂水平明显升高,包括总胆固醇、甘油三酯、低密度脂蛋白胆固醇(LDL-C)和高密度脂蛋白胆固醇(HDL-C)。尽管服用了大剂量阿托伐他汀和依泽替米贝,血脂水平仍然升高。24小时尿液收集结果显示,蛋白质排泄量仅为226毫克:结论:洛拉替尼在我们的患者中诱发了复杂的血脂异常,低密度脂蛋白胆固醇(LDL-C)和高密度脂蛋白胆固醇(HDL-C)均升高。洛拉替尼诱发高脂血症的根本机制尚不清楚,许多患者不太可能继发于肾病综合征。
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引用次数: 0
Variance in the composition and number of VLDL and LDL particles with increasing triglyceride or increasing ApoB concentrations VLDL 和 LDL 颗粒的组成和数量随甘油三酯或载脂蛋白 B 浓度增加而变化。
IF 3.6 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-01 DOI: 10.1016/j.jacl.2024.09.009
Justine Cole MBChB, MMed , Patrick Couture MD, PhD , André J. Tremblay PhD , Allan D. Sniderman MD

OBJECTIVE

The importance of any enhanced atherogenicity of triglyceride (TG)-rich lipoproteins (TRLs) will depend on the relative abundance of these particles compared with low-density lipoprotein (LDL) or total apolipoprotein (apo)B. Accordingly, we determined the contribution that TRLs make to total apoB as TG or apoB concentrations increase. We also describe compositional changes in TRLs as TG or apoB increases to assess whether very low-density lipoprotein (VLDL-[C]) is a valid proxy for VLDL-apoB.

METHODS

We used sequential ultracentrifugation to separate lipoprotein fractions in plasma samples from 1940 dyslipidemic patients not on lipid-lowering medication, and measured apoB, cholesterol and TG in the plasma and in each subfraction. We analyzed these data in quartiles of TG or apoB.

RESULTS

There was wide variance in all parameters in all quartiles of both TG and apoB. Although VLDL-apoB accounted for almost all the increase in total apoB across TG quartiles, LDL-apoB still accounted for 80% of the total in TG quartile 4. In contrast, LDL-apoB accounted for 90% of the increase in apoB across apoB quartiles. As TG increases, the increase in VLDL-C is explained more by increased VLDL-C/apoB when TG is moderately elevated, and more by increased VLDL-apoB when TG is very high.

CONCLUSIONS

In conclusion, VLDL-apoB only becomes a substantial component of total apoB with extreme hypertriglyceridemia and VLDL-C is not an appropriate proxy for VLDL-apoB.
目的:富含甘油三酯(TG)的脂蛋白(TRLs)致动脉粥样硬化性增强的重要性取决于这些颗粒与低密度脂蛋白或总载脂蛋白(apo)B相比的相对丰度。因此,我们确定了随着 TG 或载脂蛋白 B 浓度的增加,TRL 对总载脂蛋白 B 的贡献。我们还描述了TRL随着TG或apoB增加而发生的成分变化,以评估VLDL-C是否是VLDL-apoB的有效替代物:我们使用顺序超速离心法分离了 1940 名未服用降脂药的血脂异常患者的血浆样本中的脂蛋白组分,并测量了血浆和每个亚组分中的载脂蛋白B、胆固醇和总胆固醇。我们以 TG 或载脂蛋白 B 的四分位数对这些数据进行了分析:结果:在 TG 和载脂蛋白 B 的所有四分位数中,所有参数的差异都很大。虽然 VLDL-apoB 几乎占了 TG 四分位数中载脂蛋白总量增加的全部,但在 TG 四分位数 4 中,LDL-apoB 仍占总量的 80%。相比之下,低密度脂蛋白-脂联素占载脂蛋白四分位数中载脂蛋白增加量的 90%。随着 TG 的增加,当 TG 中度升高时,VLDL-C 的增加更多地由 VLDL-C/apoB 的增加来解释,而当 TG 非常高时,VLDL-apoB 的增加则更多地由 VLDL-C/apoB 的增加来解释:总之,VLDL-apoB只有在极度高甘油三酯血症时才会成为总apoB的重要组成部分,而VLDL-C并不是VLDL-apoB的合适替代物。
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引用次数: 0
Evaluation of plasma phytosterols in sitosterolemia, their kindreds and hyperlipidemia subjects 对 sitosterolemia、其同类和高脂血症患者的血浆植物甾醇进行评估。
IF 3.6 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-01 DOI: 10.1016/j.jacl.2024.09.002
Xuanru Ren BS , Jun Zhang MD , Luya Wang BS , Yuxuan Zhang BS , Jialu Li BS , Hao Yu BS , Zhaohai Zheng BS , Yiqing Zhang BS , Hesong Zeng MD , Yan Chen MD , Junfang Wu PhD

BACKGROUND

Patients suffering from sitosterolemia with ABCG5/8 mutation typically present with early-onset or rapidly progressive atherosclerosis. Their kindreds with partial genetic deficiencies of ABCG5/8 are often considered healthy. However, discerning sitosterolemia from its familial kindreds and hyperlipidemia subjects has remained challenging.

METHODS

Here we retrospectively recruited 7 families including 8 individuals diagnosed with sitosterolemia subjects, and 14 kindreds carrying single gene mutations. Additionally, 17 individuals with hyperlipidemia and 130 healthy controls served as positive and negative controls, respectively. A total of 6 phytosterols combined with cholesterol absorption indices (including sitosterol, campesterol, stigmasterol, and cholestanol) and cholesterol synthesis markers (desmosterol and 7-dehydrocholesterol), was compared across the aforementioned 4 groups.

RESULTS

As expected, the sitosterolemia subjects with double mutations demonstrated significantly elevated levels of sitosterol and other cholesterol absorption indices. Meanwhile, sitosterolemia kindreds with single gene mutation showed a similar pattern of activated cholesterol-absorption ability to the hyperlipidemia group, but not as high as the double mutation group. Notably, the cholesterol-synthesis enzyme 7-dehydrocholesterol reductase displayed an increase in the hyperlipidemia group but a decrease in the sitosterolemia kindred group, suggesting a potential discriminative role of 7-dehydrocholesterol in distinguishing between these 2 groups. The combination of phytosterols was more valuable than clinical lipid index for sitosterolemia diagnosis.

CONCLUSION

Our study revealed mild disruptions of cholesterol absorption capacities in sitosterolemia kindreds with single mutations. Furthermore, the combination of 6 phytosterols proved effective in distinguishing between sitosterolemia, its single mutation carriers, and hyperlipidemia patients.
背景:ABCG5/8突变的坐骨神经油血症患者通常表现为早发或快速进展性动脉粥样硬化。ABCG5/8部分遗传缺陷的家族成员通常被认为是健康的。方法:在此,我们回顾性地招募了 7 个家族,包括 8 个被诊断为坐骨神经胆固醇血症的个体,以及 14 个携带单基因突变的家族。此外,17 名高脂血症患者和 130 名健康对照者分别作为阳性和阴性对照。在上述四个组别中,总共有 6 种植物甾醇与胆固醇吸收指数(包括谷甾醇、坎贝酯醇、豆甾醇和胆甾醇)和胆固醇合成标志物(去甲胆固醇和 7-脱氢胆固醇)进行了比较:结果:不出所料,双重突变的 sitosterolemia 受试者的 sitosterol 水平和其他胆固醇吸收指标明显升高。与此同时,单基因突变的西托脂醇血症患者的胆固醇活化吸收能力与高脂血症组相似,但没有双基因突变组高。值得注意的是,胆固醇合成酶 7-脱氢胆固醇还原酶在高脂血症组中增加,但在 sitosterolemia 样本组中减少,这表明 7-脱氢胆固醇在区分这两个组别方面具有潜在的鉴别作用。在诊断坐骨神经胆固醇血症时,植物固醇组合比临床血脂指数更有价值:结论:我们的研究发现,单一基因突变的坐骨神经胆固醇血症患者的胆固醇吸收能力受到轻微干扰。此外,6 种植物甾醇的组合被证明能有效区分 sitosterolemia、其单一突变携带者和高脂血症患者。
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引用次数: 0
Identification and functional analysis of novel homozygous LMF1 variants in severe hypertriglyceridemia 严重高甘油三酯血症中新型同源 LMF1 变体的鉴定和功能分析
IF 3.6 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-01 DOI: 10.1016/j.jacl.2024.10.004
Candy Bedoya PhD , Rishi Thomas DO , Anna Bjarvin BSc , Wilbur Ji DO , Hanien Samara BSc , Jody Tai DO , Laurie Green BSc , Philip H. Frost MD , Mary J. Malloy MD , Clive R. Pullinger PhD , John P. Kane MD, PhD , Miklós Péterfy PhD

BACKGROUND

The genetic basis of hypertriglyceridemia (HTG) is complex and includes variants in lipase maturation factor 1 (LMF1), an endoplasmic reticulum (ER)-chaperone involved in the post-translational activation of lipoprotein lipase (LPL).

OBJECTIVE

The objective of this study was to identify and functionally characterize biallelic LMF1 variants in patients with HTG.

METHODS

Genomic DNA sequencing was used to identify biallelic LMF1 variants in HTG patients without deleterious variants in LPL, apolipoprotein C-II (APOC2), glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1) or apolipoprotein A-V (APOA5). LMF1 variants were functionally evaluated by in silico analyses and assessing their impact on LPL activity, LMF1 protein expression, and specific activity in transiently transfected HEK293 cells.

RESULTS

We identified four homozygous LMF1 variants in patients with severe HTG: two novel rare variants (p.Asn147Lys and p.Pro246Arg) and two low-frequency variants (p.Arg354Trp and p.Arg364Gln) previously reported at heterozygosity. We demonstrate that all four variants reduce the secretion of enzymatically active LPL by impairing the specific activity of LMF1, whereas p.Asn147Lys also diminishes LMF1 protein expression.

CONCLUSION

This study extends the role of LMF1 as a genetic determinant in severe HTG and demonstrates that rare and low-frequency LMF1 variants can underlie this condition through distinct molecular mechanisms. The clinical phenotype of patients affected by partial loss of LMF1 function is consistent with multifactorial chylomicronemia syndrome (MCS) and suggests that secondary factors and additional genetic determinants contribute to HTG in these subjects.
背景:高甘油三酯血症(HTG)的遗传基础非常复杂,包括脂酶成熟因子1(LMF1)的变异,LMF1是一种参与脂蛋白脂肪酶(LPL)翻译后活化的内质网(ER)伴侣蛋白:本研究的目的是鉴定高血脂症患者中的双侧LMF1变体并确定其功能特征:方法:利用基因组DNA测序技术鉴定高密度脂蛋白血症患者中的双拷贝LMF1变异体,这些变异体中没有LPL、载脂蛋白C-II(APOC2)、糖基磷脂酰肌醇锚定高密度脂蛋白结合蛋白1(GPIHBP1)或载脂蛋白A-V(APOA5)中的有害变异体。LMF1变体的功能评估是通过硅学分析和评估它们对瞬时转染HEK293细胞中LPL活性、LMF1蛋白表达和特异性活性的影响进行的:我们在重度高密度脂蛋白血症患者中发现了四个同源的 LMF1 变体:两个新的罕见变体(p.Asn147Lys 和 p.Pro246Arg)和两个低频变体(p.Arg354Trp 和 p.Arg364Gln),这两个变体以前曾报道过杂合性。我们证明,所有这四个变异体都会通过损害 LMF1 的特异性活性来减少具有酶活性的 LPL 的分泌,而 p.Asn147Lys 也会减少 LMF1 蛋白的表达:本研究扩展了 LMF1 在重度高血压中的遗传决定因素作用,并证明罕见的低频 LMF1 变异可通过不同的分子机制导致该病症。受 LMF1 部分功能缺失影响的患者的临床表型与多因素乳糜微粒血症综合征(MCS)一致,表明次要因素和其他遗传决定因素导致了这些受试者的 HTG。
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引用次数: 0
Burden of atherogenic lipids and association with cardiac allograft vasculopathy in heart transplant recipients 心脏移植受者的致动脉粥样硬化血脂负担及其与心脏异体移植血管病变的关系。
IF 3.6 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-01 DOI: 10.1016/j.jacl.2024.10.005
Antoinette S. Birs MD , Andrew S. Kao MD , Elizabeth Silver MD , Eric D. Adler MD , Pam R. Taub MD , Michael J. Wilkinson MD

BACKGROUND

Cardiac allograft vasculopathy (CAV) is a leading cause of morbidity and mortality after heart transplantation (HTx). There are limited contemporary studies examining post-transplant lipid management and cardiometabolic health.

OBJECTIVE

We study the burden of cardiometabolic derangements post transplantation and its impact on CAV in a modern cohort of HTx recipients.

METHODS

All HTx recipients between January 2019 and December 2020, with 2 lipid assessments and angiographic surveillance were included. Logistic regression was used to assess association of lipid levels with cardiovascular outcomes and CAV.

RESULTS

Among 87 HTx recipients, atherogenic lipids were significantly elevated after Htx. Median low-density lipoprotein cholesterol increased from a baseline level of 69.5 mg/dL to 86.5 mg/dL, p = .002, non-high-density lipoprotein cholesterol (non-HDL-C) 91.5 mg/dL to 118 mg/dL, p < .001, triglycerides 94.5 mg/dL to 133 mg/dL, p < .001, and remnant cholesterol 19 mg/dL to 27 mg/dL, p < .001. Increases in non-HDL-C, triglycerides, and remnant cholesterol were significantly associated with increased risk of CAV (Stanford Grade 4 and intimal thickness). Increases in triglycerides and remnant cholesterol were associated with increased risk of composite major adverse cardiovascular events (MACE).

CONCLUSION

We demonstrate a significant increase in atherogenic lipids 2 years following transplantation with low use (20%) of high-intensity statin. Increase in atherogenic lipids was associated with increased risk of CAV and increase in triglycerides and remnant cholesterol with increased MACE. Future studies examining cardiometabolic consequences of HTx and optimal treatment strategies to reduce risk of CAV and MACE are needed.
背景:心脏移植血管病(CAV)是心脏移植后发病和死亡的主要原因。有关移植后血脂管理和心脏代谢健康的当代研究十分有限:我们研究了现代心脏移植受者队列中移植后心脏代谢紊乱的负担及其对 CAV 的影响:方法:纳入 2019 年 1 月至 2020 年 12 月期间所有接受过两次血脂评估和血管造影监测的心脏移植(HTx)受者。采用逻辑回归评估血脂水平与心血管预后和CAV的关系:结果:在 87 名接受过高密度脂蛋白胆固醇治疗的患者中,动脉粥样硬化血脂在接受高密度脂蛋白胆固醇治疗后明显升高。中位低密度脂蛋白胆固醇从基线水平 69.5 mg/dL 升至 86.5 mg/dL,p = 0.002;非高密度脂蛋白胆固醇从基线水平 91.5 mg/dL 升至 118 mg/dL,p < 0.001;甘油三酯从基线水平 94.5 mg/dL 升至 133 mg/dL,p < 0.001;残余胆固醇从基线水平 19 mg/dL 升至 27 mg/dL,p < 0.001。非高密度脂蛋白胆固醇、甘油三酯和残余胆固醇的增加与 CAV 风险的增加(斯坦福 4 级和内膜厚度)显著相关。甘油三酯和残余胆固醇的增加与复合主要不良心血管事件风险的增加有关:我们的研究表明,移植两年后,高强度他汀类药物的使用率较低(20%),但动脉粥样硬化性血脂却明显升高。致动脉粥样硬化血脂的升高与CAV风险增加有关,甘油三酯和残余胆固醇的升高与MACE增加有关。今后需要对心脏移植的心脏代谢后果以及降低CAV和MACE风险的最佳治疗策略进行研究。
{"title":"Burden of atherogenic lipids and association with cardiac allograft vasculopathy in heart transplant recipients","authors":"Antoinette S. Birs MD ,&nbsp;Andrew S. Kao MD ,&nbsp;Elizabeth Silver MD ,&nbsp;Eric D. Adler MD ,&nbsp;Pam R. Taub MD ,&nbsp;Michael J. Wilkinson MD","doi":"10.1016/j.jacl.2024.10.005","DOIUrl":"10.1016/j.jacl.2024.10.005","url":null,"abstract":"<div><h3>BACKGROUND</h3><div>Cardiac allograft vasculopathy (CAV) is a leading cause of morbidity and mortality after heart transplantation (HTx). There are limited contemporary studies examining post-transplant lipid management and cardiometabolic health.</div></div><div><h3>OBJECTIVE</h3><div>We study the burden of cardiometabolic derangements post transplantation and its impact on CAV in a modern cohort of HTx recipients.</div></div><div><h3>METHODS</h3><div>All HTx recipients between January 2019 and December 2020, with 2 lipid assessments and angiographic surveillance were included. Logistic regression was used to assess association of lipid levels with cardiovascular outcomes and CAV.</div></div><div><h3>RESULTS</h3><div>Among 87 HTx recipients, atherogenic lipids were significantly elevated after Htx. Median low-density lipoprotein cholesterol increased from a baseline level of 69.5 mg/dL to 86.5 mg/dL, <em>p</em> = .002, non-high-density lipoprotein cholesterol (non-HDL-C) 91.5 mg/dL to 118 mg/dL, <em>p</em> &lt; .001, triglycerides 94.5 mg/dL to 133 mg/dL, <em>p</em> &lt; .001, and remnant cholesterol 19 mg/dL to 27 mg/dL, <em>p</em> &lt; .001. Increases in non-HDL-C, triglycerides, and remnant cholesterol were significantly associated with increased risk of CAV (Stanford Grade 4 and intimal thickness). Increases in triglycerides and remnant cholesterol were associated with increased risk of composite major adverse cardiovascular events (MACE).</div></div><div><h3>CONCLUSION</h3><div>We demonstrate a significant increase in atherogenic lipids 2 years following transplantation with low use (20%) of high-intensity statin. Increase in atherogenic lipids was associated with increased risk of CAV and increase in triglycerides and remnant cholesterol with increased MACE. Future studies examining cardiometabolic consequences of HTx and optimal treatment strategies to reduce risk of CAV and MACE are needed.</div></div>","PeriodicalId":15392,"journal":{"name":"Journal of clinical lipidology","volume":"19 1","pages":"Pages 134-145"},"PeriodicalIF":3.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Rapid lipid-lowering response in two cases of autosomal recessive hypercholesterolemia 两例常染色体隐性高胆固醇血症患者的快速降脂反应。
IF 3.6 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-01 DOI: 10.1016/j.jacl.2024.09.003
Havva Yazıcı, Fehime Erdem, Ebru Canda, Sema Kalkan Uçar, Mahmut Çoker

BACKGROUND

Autosomal recessive hypercholesterolemia (ARH) is an ultrarare dyslipidemia caused by variants in the LDLRAP1 gene. Clinically, this condition is indistinguishable from other homozygous familial hypercholesterolemia (HoFH).

CASE

We present the cases of 2 siblings diagnosed with ARH caused by LDLRAP1 gene c.617-14C > A splicing homozygous variant. Over a 5-year treatment period, the older sibling experienced an 81% reduction in low-density lipoprotein cholesterol (LDL-C) levels with the maximal dose of pitavastatin plus ezetimibe, while the younger sibling achieved a 75% reduction. After three sessions, the older brother no longer required LDL apheresis, and the sibling never had LDL apheresis.

CONCLUSION

Our findings demonstrate a rapid and significant response to lipid-lowering therapy (LLT) in patients with ARH caused by c.617-14C > A splicing VUS variant, a condition that mimics HoFH at diagnosis. Long-term follow-up studies in large pediatric cohorts of ARH patients treated with pitavastatin plus ezetimibe from childhood are necessary to better define the risk of cardiovascular disease (CVD) development.
背景:常染色体隐性高胆固醇血症(ARH常染色体隐性高胆固醇血症(ARH)是一种由 LDLRAP1 基因变异引起的超稀有血脂异常。在临床上,这种疾病与其他同型家族性高胆固醇血症(HoFH)没有区别:病例:我们报告了两兄妹因 LDLRAP1 基因 c.617-14C>A 拼接同源变异而被诊断为 ARH 的病例。在五年的治疗期间,哥哥服用最大剂量的匹伐他汀加依折麦布后,低密度脂蛋白胆固醇(LDL-C)水平降低了 81%,而弟弟则降低了 75%。三个疗程后,哥哥不再需要进行低密度脂蛋白清除术,而弟弟从未进行过低密度脂蛋白清除术:我们的研究结果表明,c.617-14C>A剪接VUS变异导致的ARH患者对降脂治疗(LLT)的反应迅速而显著,这种情况在诊断时与HoFH相似。为了更好地确定心血管疾病(CVD)的发病风险,有必要对从小就接受匹伐他汀加依折麦布治疗的大型儿科ARH患者队列进行长期随访研究。
{"title":"Rapid lipid-lowering response in two cases of autosomal recessive hypercholesterolemia","authors":"Havva Yazıcı,&nbsp;Fehime Erdem,&nbsp;Ebru Canda,&nbsp;Sema Kalkan Uçar,&nbsp;Mahmut Çoker","doi":"10.1016/j.jacl.2024.09.003","DOIUrl":"10.1016/j.jacl.2024.09.003","url":null,"abstract":"<div><h3>BACKGROUND</h3><div>Autosomal recessive hypercholesterolemia (ARH) is an ultrarare dyslipidemia caused by variants in the <em>LDLRAP1</em> gene. Clinically, this condition is indistinguishable from other homozygous familial hypercholesterolemia (HoFH).</div></div><div><h3>CASE</h3><div>We present the cases of 2 siblings diagnosed with ARH caused by <em>LDLRAP1</em> gene c.617-14C &gt; A splicing homozygous variant. Over a 5-year treatment period, the older sibling experienced an 81% reduction in low-density lipoprotein cholesterol (LDL-C) levels with the maximal dose of pitavastatin plus ezetimibe, while the younger sibling achieved a 75% reduction. After three sessions, the older brother no longer required LDL apheresis, and the sibling never had LDL apheresis.</div></div><div><h3>CONCLUSION</h3><div>Our findings demonstrate a rapid and significant response to lipid-lowering therapy (LLT) in patients with ARH caused by c.617-14C &gt; A splicing VUS variant, a condition that mimics HoFH at diagnosis. Long-term follow-up studies in large pediatric cohorts of ARH patients treated with pitavastatin plus ezetimibe from childhood are necessary to better define the risk of cardiovascular disease (CVD) development.</div></div>","PeriodicalId":15392,"journal":{"name":"Journal of clinical lipidology","volume":"19 1","pages":"Pages 167-172"},"PeriodicalIF":3.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Extreme LDL-C concentration is associated with increased cardiovascular disease in women with homozygous familial hypercholesterolemia 高LDL-C浓度与纯合子家族性高胆固醇血症女性心血管疾病增加相关
IF 3.6 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-01 DOI: 10.1016/j.jacl.2024.10.008
Martine Paquette MSc , Isabelle Ruel PhD , Simon-Pierre Guay MD, PhD , Zobaida Al-Baldawi MSc , Diane Brisson PhD , Daniel Gaudet MD, PhD , Patrick Couture MD, PhD , Jean Bergeron MD, MSc , Robert A Hegele MD , Gordon A Francis MD , Mark H Sherman MD , Ruth McPherson MD, PhD , Thomas Ransom MD, MSc , Liam R Brunham MD, PhD , GB John Mancini MD , Brian W McCrindle MD MPH , Lulia Latan MD, PhD , Jacques Genest MD , Alexis Baass MD, MSc

BACKGROUND

Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disease of low-density lipoprotein cholesterol (LDL-C) metabolism. Despite the devastating effect of this disease on atherosclerotic cardiovascular health, the disease phenotype and severity are more heterogeneous than previously thought. The predictors of atherosclerotic cardiovascular disease (ASCVD) in HoFH patients have never been systematically studied.

OBJECTIVE

To investigate the univariate and multivariate predictors of ASCVD in HoFH patients.

METHODS

Patients from the Canadian HoFH Registry were included in the present retrospective longitudinal study. Data for these patients were collected using a standardized questionnaire between 2019 and 2022 in 19 academic sites across Canada. Predictors of ASCVD were evaluated using Cox proportional hazards models.

RESULTS

Among 48 HoFH patients, 26 (54%) of them had at least 1 ASCVD event. The average age at baseline was 19 ± 15 years and women represented 56% of the cohort. The independent predictors of ASCVD events were male sex (HR 2.57 [1.13–5.84]), diabetes (HR 16.22 [3.38–77.97]), and LDL-C above the median of 14.45 mmol/L (559 mg/dL) (HR 3.10 [1.24–7.76]). When performing subgroup analysis according to sex, the presence of LDL-C above the median was associated with a significantly higher probability of ASCVD (88% vs 43%, P = .005) in women, but not in men (100% at age 40 in both groups, P = .98).

CONCLUSION

This study reported for the first time the univariate and multivariate predictors of ASCVD in HoFH patients. We demonstrate that predictors of ASCVD in HoFH differ in males and females with respect to LDL-C levels.
背景:纯合子家族性高胆固醇血症(HoFH)是一种罕见的低密度脂蛋白胆固醇(LDL-C)代谢遗传病。尽管这种疾病对动脉粥样硬化性心血管健康具有毁灭性的影响,但这种疾病的表型和严重程度比以前认为的更为异质性。HoFH患者动脉粥样硬化性心血管疾病(ASCVD)的预测因素从未被系统研究过。目的:探讨HoFH患者ASCVD的单因素和多因素预测因素。方法:来自加拿大HoFH登记处的患者被纳入本回顾性纵向研究。这些患者的数据是在2019年至2022年期间在加拿大19个学术站点使用标准化问卷收集的。使用Cox比例风险模型评估ASCVD的预测因子。结果:48例HoFH患者中,26例(54%)至少发生一次ASCVD事件。基线时的平均年龄为19±15岁,女性占队列的56%。ASCVD事件的独立预测因子为男性(HR 2.57(1.13-5.84))、糖尿病(HR 16.22(3.38-77.97))和LDL-C高于中位数14.45 mmol/L [559 mg/dL] (HR 3.10(1.24-7.76))。当根据性别进行亚组分析时,LDL-C高于中位数的存在与女性ASCVD的概率显著升高相关(88%对43%,p = 0.005),但与男性无关(两组在40岁时均为100%,p = 0.98)。结论:本研究首次报道了HoFH患者ASCVD的单因素和多因素预测因素。我们证明,在LDL-C水平方面,HoFH中ASCVD的预测因子在男性和女性中存在差异。
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引用次数: 0
Lipid-lowering efficacy of obicetrapib: A comprehensive systematic review and meta-analysis.
IF 3.6 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-12-30 DOI: 10.1016/j.jacl.2024.12.016
Walter Masson, Leandro Barbagelata, Martin Lobo, Juan Patricio Nogueira, Yehuda Handelsman

Background: Obicetrapib is a next-generation, oral, selective cholesteryl ester transfer protein inhibitor known to significantly affect atherogenic lipoproteins, including low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), non-high-density lipoprotein cholesterol (Non-HDL-C), and lipoprotein(a) [Lp(a)].

Objective: To evaluate the lipid-lowering efficacy of obicetrapib based on available evidence.

Methods: This systematic review was drafted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A comprehensive literature search was conducted to identify randomized clinical trials assessing the lipid-lowering effects of obicetrapib compared to placebo. Fixed- and random-effects models were used.

Results: Five randomized clinical trials (n = 288 patients) were included in this analysis. Patients treated with obicetrapib exhibited significantly greater reductions in LDL-C (mean difference [MD]: 41.4% [95% CI: 45.7 to -37.1]; I²: 6%), ApoB (MD: 26.5% [95% CI: 31.3 to -21.6]; I²: 45%) and Non-HDL-C (MD: 34.5% [95% CI: 37.0 to -31.6]; I²: 80%) compared to those receiving a placebo. Additionally, HDL-C levels were significantly higher in the obicetrapib group (MD: 157.4% [95% CI: 142.2 to 172.6]; I²: 69%). While triglyceride levels did not differ significantly between the 2 groups, Lp(a) levels were notably reduced with obicetrapib treatment (MD: 39.5% [95% CI: 54.6 to -24.3]; I²: 67%).

Conclusion: Obicetrapib is associated with significant reductions in key atherogenic lipoproteins, including LDL-C, ApoB, Non-HDL-C and Lp(a). Further investigation is needed to assess its impact on cardiovascular risk.

{"title":"Lipid-lowering efficacy of obicetrapib: A comprehensive systematic review and meta-analysis.","authors":"Walter Masson, Leandro Barbagelata, Martin Lobo, Juan Patricio Nogueira, Yehuda Handelsman","doi":"10.1016/j.jacl.2024.12.016","DOIUrl":"https://doi.org/10.1016/j.jacl.2024.12.016","url":null,"abstract":"<p><strong>Background: </strong>Obicetrapib is a next-generation, oral, selective cholesteryl ester transfer protein inhibitor known to significantly affect atherogenic lipoproteins, including low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), non-high-density lipoprotein cholesterol (Non-HDL-C), and lipoprotein(a) [Lp(a)].</p><p><strong>Objective: </strong>To evaluate the lipid-lowering efficacy of obicetrapib based on available evidence.</p><p><strong>Methods: </strong>This systematic review was drafted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A comprehensive literature search was conducted to identify randomized clinical trials assessing the lipid-lowering effects of obicetrapib compared to placebo. Fixed- and random-effects models were used.</p><p><strong>Results: </strong>Five randomized clinical trials (n = 288 patients) were included in this analysis. Patients treated with obicetrapib exhibited significantly greater reductions in LDL-C (mean difference [MD]: 41.4% [95% CI: 45.7 to -37.1]; I²: 6%), ApoB (MD: 26.5% [95% CI: 31.3 to -21.6]; I²: 45%) and Non-HDL-C (MD: 34.5% [95% CI: 37.0 to -31.6]; I²: 80%) compared to those receiving a placebo. Additionally, HDL-C levels were significantly higher in the obicetrapib group (MD: 157.4% [95% CI: 142.2 to 172.6]; I²: 69%). While triglyceride levels did not differ significantly between the 2 groups, Lp(a) levels were notably reduced with obicetrapib treatment (MD: 39.5% [95% CI: 54.6 to -24.3]; I²: 67%).</p><p><strong>Conclusion: </strong>Obicetrapib is associated with significant reductions in key atherogenic lipoproteins, including LDL-C, ApoB, Non-HDL-C and Lp(a). Further investigation is needed to assess its impact on cardiovascular risk.</p>","PeriodicalId":15392,"journal":{"name":"Journal of clinical lipidology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Characteristics and outcomes of patients with and without statin-associated muscle symptoms treated with bempedoic acid in the CLEAR Outcomes trial.
IF 3.6 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-12-25 DOI: 10.1016/j.jacl.2024.12.014
Ulrich Laufs, A Michael Lincoff, Stephen J Nicholls, Na Li, LeAnne Bloedon, William J Sasiela, Heather A Powell, Peter M Herout, Paul D Thompson, Steven E Nissen

Background: Cholesterol Lowering via bEmpedoic Acid Regimen (CLEAR) outcomes, a randomized, double-blind, placebo-controlled cardiovascular outcomes trial, and the largest prospective database of patients with statin intolerance (SI), demonstrated that bempedoic acid reduces low-density lipoprotein cholesterol and cardiovascular risk in patients at high cardiovascular risk.

Objective: Assess baseline differences in SI symptoms and whether these influenced the clinical course during CLEAR outcomes.

Methods: Symptoms and impact of SI on daily living were recorded prior to randomization. This posthoc analysis grouped patients as reporting statin-associated muscle symptoms only (SAMS), nonmuscle adverse effects only (nonSAMS), or BOTH.

Results: Of the 13,970 patients at baseline, 49% reported SAMS, 18% NonSAMS, and 33% BOTH. Moderate/severe impact on daily living was recorded for 62% SAMS, 48% NonSAMS, and 69% BOTH. Baseline lipid modifying treatment (LMT) was used in 43% SAMS, 36% nonSAMS, and 42% BOTH. Drop-in use of moderate/high-intensity statin at any time during the study was higher in the placebo group in all SI groups and higher in SAMS and BOTH vs. nonSAMS, but was not generally maintained at study end. SAMS and BOTH groups had more muscle symptoms and higher rates of treatment discontinuation vs. NonSAMS but there was no difference between treatments.

Conclusion: Patients who reported SAMS, regardless of randomization to bempedoic acid or placebo, had higher rates of discontinuation, higher rates of skeletal muscle symptoms, and a greater percentage of patients to attempt statin rechallenge. These findings indicate patients with history of SAMS may have background factors impacting their tolerance to LMT and may require more focused clinical management.

Clinicaltrials:

Gov identifier: NCT02993406.

{"title":"Characteristics and outcomes of patients with and without statin-associated muscle symptoms treated with bempedoic acid in the CLEAR Outcomes trial.","authors":"Ulrich Laufs, A Michael Lincoff, Stephen J Nicholls, Na Li, LeAnne Bloedon, William J Sasiela, Heather A Powell, Peter M Herout, Paul D Thompson, Steven E Nissen","doi":"10.1016/j.jacl.2024.12.014","DOIUrl":"https://doi.org/10.1016/j.jacl.2024.12.014","url":null,"abstract":"<p><strong>Background: </strong>Cholesterol Lowering via bEmpedoic Acid Regimen (CLEAR) outcomes, a randomized, double-blind, placebo-controlled cardiovascular outcomes trial, and the largest prospective database of patients with statin intolerance (SI), demonstrated that bempedoic acid reduces low-density lipoprotein cholesterol and cardiovascular risk in patients at high cardiovascular risk.</p><p><strong>Objective: </strong>Assess baseline differences in SI symptoms and whether these influenced the clinical course during CLEAR outcomes.</p><p><strong>Methods: </strong>Symptoms and impact of SI on daily living were recorded prior to randomization. This posthoc analysis grouped patients as reporting statin-associated muscle symptoms only (SAMS), nonmuscle adverse effects only (nonSAMS), or BOTH.</p><p><strong>Results: </strong>Of the 13,970 patients at baseline, 49% reported SAMS, 18% NonSAMS, and 33% BOTH. Moderate/severe impact on daily living was recorded for 62% SAMS, 48% NonSAMS, and 69% BOTH. Baseline lipid modifying treatment (LMT) was used in 43% SAMS, 36% nonSAMS, and 42% BOTH. Drop-in use of moderate/high-intensity statin at any time during the study was higher in the placebo group in all SI groups and higher in SAMS and BOTH vs. nonSAMS, but was not generally maintained at study end. SAMS and BOTH groups had more muscle symptoms and higher rates of treatment discontinuation vs. NonSAMS but there was no difference between treatments.</p><p><strong>Conclusion: </strong>Patients who reported SAMS, regardless of randomization to bempedoic acid or placebo, had higher rates of discontinuation, higher rates of skeletal muscle symptoms, and a greater percentage of patients to attempt statin rechallenge. These findings indicate patients with history of SAMS may have background factors impacting their tolerance to LMT and may require more focused clinical management.</p><p><strong>Clinicaltrials: </strong></p><p><strong>Gov identifier: </strong>NCT02993406.</p>","PeriodicalId":15392,"journal":{"name":"Journal of clinical lipidology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143408086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Effect of empagliflozin on plasma lipids and lipoproteins in type 2 diabetes and heart failure - Empire HF and SIMPLE.
IF 3.6 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-12-21 DOI: 10.1016/j.jacl.2024.12.015
Frida Emanuelsson, Jesper Jensen, Massar Omar, Mikkel Jürgens, Caroline Kistorp, Niels H Brandt-Jacobsen, Jacob Eifer Møller, Morten Schou, Louise Ellegaard Bechmann, Emil List Larsen, Børge G Nordestgaard, Marianne Benn

Objective: Beyond glucose-lowering, sodium-glucose co-transporter 2 (SGLT2) inhibitors have cardioprotective effects with unclear mechanisms. We examined changes in an extensive panel of plasma lipids, lipoproteins, and apolipoproteins and whether these changes were independent of weight loss, hemoglobin A1c, and hematocrit in patients treated with empagliflozin versus placebo to better understand the observed cardioprotective effects.

Methods: Post-hoc analyses of two double-blind, placebo-controlled trials, the Empire HF trial including 190 patients with heart failure and reduced ejection fraction and the SIMPLE trial including 90 patients with type 2 diabetes randomized to, respectively, 10 mg and 25 mg empagliflozin daily or placebo for 12 weeks.

Results: In studies combined, empagliflozin reduced age and sex adjusted body weight by 1.40 kg (SEM: 0.10; p < 0.001) and hemoglobin A1c by 2.71 mmol/mol (SEM: 0.24; p < 0.001); and increased hematocrit by 1.9% (SEM: 0.12; p < 0.001) compared to placebo. No mean changes were seen in concentrations of total cholesterol, low-density lipoprotein (LDL) cholesterol, small dense LDL cholesterol, very low-density lipoprotein cholesterol, triglyceride rich lipoprotein cholesterol, non-high-density lipoprotein (non-HDL) cholesterol, apolipoprotein B, lipoprotein(a), HDL cholesterol, and triglycerides adjusted for body weight, hemoglobin A1c, and hematocrit with empagliflozin compared to placebo.

Conclusion: Empagliflozin treatment reduced body weight and hemoglobin A1c; and increased hematocrit. No changes were seen in concentrations of lipids and lipoproteins with empagliflozin compared to placebo. This suggests that the cardioprotective effects of SGLT2 inhibitors are independent of lipid and lipoprotein concentrations.

{"title":"Effect of empagliflozin on plasma lipids and lipoproteins in type 2 diabetes and heart failure - Empire HF and SIMPLE.","authors":"Frida Emanuelsson, Jesper Jensen, Massar Omar, Mikkel Jürgens, Caroline Kistorp, Niels H Brandt-Jacobsen, Jacob Eifer Møller, Morten Schou, Louise Ellegaard Bechmann, Emil List Larsen, Børge G Nordestgaard, Marianne Benn","doi":"10.1016/j.jacl.2024.12.015","DOIUrl":"https://doi.org/10.1016/j.jacl.2024.12.015","url":null,"abstract":"<p><strong>Objective: </strong>Beyond glucose-lowering, sodium-glucose co-transporter 2 (SGLT2) inhibitors have cardioprotective effects with unclear mechanisms. We examined changes in an extensive panel of plasma lipids, lipoproteins, and apolipoproteins and whether these changes were independent of weight loss, hemoglobin A1c, and hematocrit in patients treated with empagliflozin versus placebo to better understand the observed cardioprotective effects.</p><p><strong>Methods: </strong>Post-hoc analyses of two double-blind, placebo-controlled trials, the Empire HF trial including 190 patients with heart failure and reduced ejection fraction and the SIMPLE trial including 90 patients with type 2 diabetes randomized to, respectively, 10 mg and 25 mg empagliflozin daily or placebo for 12 weeks.</p><p><strong>Results: </strong>In studies combined, empagliflozin reduced age and sex adjusted body weight by 1.40 kg (SEM: 0.10; p < 0.001) and hemoglobin A1c by 2.71 mmol/mol (SEM: 0.24; p < 0.001); and increased hematocrit by 1.9% (SEM: 0.12; p < 0.001) compared to placebo. No mean changes were seen in concentrations of total cholesterol, low-density lipoprotein (LDL) cholesterol, small dense LDL cholesterol, very low-density lipoprotein cholesterol, triglyceride rich lipoprotein cholesterol, non-high-density lipoprotein (non-HDL) cholesterol, apolipoprotein B, lipoprotein(a), HDL cholesterol, and triglycerides adjusted for body weight, hemoglobin A1c, and hematocrit with empagliflozin compared to placebo.</p><p><strong>Conclusion: </strong>Empagliflozin treatment reduced body weight and hemoglobin A1c; and increased hematocrit. No changes were seen in concentrations of lipids and lipoproteins with empagliflozin compared to placebo. This suggests that the cardioprotective effects of SGLT2 inhibitors are independent of lipid and lipoprotein concentrations.</p>","PeriodicalId":15392,"journal":{"name":"Journal of clinical lipidology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143023627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
期刊
Journal of clinical lipidology
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