Journal of clinical lipidology最新文献

Background: Homozygous familial hypercholesterolemia (HoFH) is an ultra-rare disorder of lipid metabolism characterized by markedly increased levels of low-density lipoprotein cholesterol (LDL-C), leading to an increased risk of early onset atherosclerotic cardiovascular disease (ASCVD) and premature death.

Objective: To assess the real-world burden of disease for patients with HoFH using healthcare claims data.

Methods: Due to the lack of International Classification of Diseases, Tenth Revision diagnosis codes for HoFH, the real-world HoFH cohort was formed using two sources: prescription claims for evinacumab or lomitapide in the Komodo Healthcare Map™ database; and patients with a physician-confirmed HoFH diagnosis in MyRARE^Ⓡ, a US-based patient support program for commercially available evinacumab. Patients in MyRARE were identified via tokenization and linked with their Komodo claims data.

Results: The real-world cohort comprised 331 patients with HoFH. Mean age was 53.3 years, and 66.8% had a formal diagnosis of familial hypercholesterolemia. Most patients (67.4%) had ASCVD, including 63.4% with coronary heart disease. The most recent mean LDL-C value was 163 mg/dL, and 52.9% of patients had been treated with at least two concomitant lipid-lowering therapies.

Conclusion: This real-world study showed that patients with HoFH are undertreated, resulting in suboptimal control of LDL-C levels and a high prevalence of ASCVD.

Background: High triglyceride (TG) levels are associated with increased atherosclerotic cardiovascular disease (ASCVD) risk in the general population. Yet, the role of TG in familial hypercholesterolemia (FH) remains understudied. This research aims to evaluate the link between TG levels and ASCVD prevalence in adult patients with FH.

Methods: This cross-sectional analysis, derived from the Hellenic Familial Hypercholesterolemia Registry (HELLAS-FH), involves categorizing patients into tertiles based on their TG concentrations.

Results: In our study of 1772 adults with heterozygous FH (HeFH), aged 51 ± 15 years at registration and diagnosed at 44 ± 16 years, TG concentrations in the 1st (80 mg/dL), 2nd (124 mg/dL), and 3rd (200 mg/dL) tertiles revealed varying ASCVD prevalence (18.0%, 28.5% and 28.5%, respectively). Adjusted for ASCVD risk factors, TGs ≥116 mg/dL were linked to higher ASCVD risk than levels <116 mg/dL (OR: 1.37, 95% CI 1.05-1.80, P = .02).

Conclusions: A notable association with ASCVD is evident in FH patients, even at relatively low TG levels, starting from 116 mg/dL (1.31 mmol/L).

Background: Patients with familial hypercholesterolemia (FH) are at increased risk of atherosclerotic cardiovascular disease (ASCVD). However, this risk is heterogeneous, and the contribution of several clinical risk factors has been well demonstrated in this population. The proportion of the risk conferred by the accumulation of common small effect variants in coronary artery disease (CAD) susceptibility genes remains to be determined.

Objective: The objective was to determine if a weighted polygenic risk score (PRS) for CAD (PRS_CAD) is associated with ASCVD risk in patients with heterozygous FH (HeFH).

Methods: This study included 1886 participants with HeFH from 3 independent cohorts: the FH Canada national registry, the UK Biobank, and the Montreal Clinical Research Institute FH cohort. The lifelong ASCVD risk was compared between groups using Kaplan-Meier estimates and Cox proportional hazards regression models.

Results: The group with a high PRS_CAD (>75th percentile) had a ∼2-fold increased risk of ASCVD compared to those with a lower PRS_CAD (≤75th percentile) (HR 1.92 (1.55-2.37), P < .0001). The effect of the PRS_CAD on ASCVD risk remained significant after correction for clinical risk factors (P = .0002). This association was similar between women and men (P interaction = .68), between genetic and clinical FH (P interaction = .48), between cohorts (P interaction = .39), and between the type of PRS (P interaction = .81).

Conclusion: We demonstrated in the largest study to date that the use of a PRS_CAD allowed us to further refine risk stratification in HeFH. Further studies are needed to evaluate the clinical value of adding the PRS_CAD to current risk prediction tools.

Background: Observational studies have suggested potential correlations between unfavorable lipid profiles and the occurrence of intracranial aneurysms (IAs), proposing that lipid-lowering therapies might curb IA progression and prevent rupture. This study aimed to explore the causal impacts of lipid-reducing strategies on the risk of IAs.

Methods: We employed 3 genetic tools as proxies for our exposures and assessed causal effects using outcome genome-wide association study data from the FinnGen Biobank. Single nucleotide polymorphisms strongly associated with low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol, and triglycerides, located within ±100 kb of the region of target genes, were selected as instrumental variables for drug-target Mendelian randomization (MR). Additionally, gene expression and protein MR analyses were conducted to elucidate the causal effects of lipid levels from transcriptional and translational perspectives, using two-sample MR (TSMR) and summary-data-based MR (SMR).

Results: Drug-target MR analysis revealed that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition-mediated LDL-C reduction was associated with an increased risk of IA development (OR = 1.406, P = 3.28E-09). In contrast, protein MR demonstrated that higher PCSK9 expression had protective effects against IA incidence (OR_TSMR = 0.896, P = 1.79E-03; OR_SMR = 0.881, P = 1.78E-02). Subgroup analyses further suggested that PCSK9 might reduce the risk of IA rupture (OR_TSMR = 0.893, P = 1.08E-02; OR_SMR = 0.866, P = 3.39E-02).

Conclusion: Our MR analyses indicated a potential causal relationship between higher PCSK9 expression and a reduced risk of both IA formation and rupture, highlighting the dual role of PCSK9 inhibitors in cerebrovascular disease. Hence, careful consideration is warranted when prescribing PCSK9 inhibitors, particularly in patients at risk for developing IAs.

Background: Non-high-density lipoprotein cholesterol (non-HDL-C) has been reported to exhibit stronger associations with cardiovascular outcomes compared to low-density lipoprotein cholesterol (LDL-C). However, data on this association, particularly among Asians using statins, are limited. This study aimed to compare the predictability of non-HDL-C and LDL-C on long-term 3-point major adverse cardiac events (3P-MACE) in statin-treated patients.

Methods: Data from patients with atherosclerotic cardiovascular disease (ASCVD) or at high risk were obtained from the multicenter national registry, "CORE-Thailand study." The primary outcome was 3P-MACE, including all-cause mortality, non-fatal myocardial infarction, and non-fatal stroke. Patients were stratified into quartiles based on non-HDL-C and LDL-C levels, and Cox proportional hazards regression models were used to analyze their association with 3P-MACE.

Results: A total of 6978 with non-HDL-C data and 7365 with LDL-C data were included. In the fully adjusted model, overall non-HDL-C data and data from the highest quartile showed a significant association with 3P-MACE (HR: 1.008, 95% CI, 1.003-1.012, P < .001 and HR: 1.676, 95% CI, 1.218-2.307, P = .002, respectively). LDL-C did not exhibit a significant association with 3P-MACE. Interestingly, there was a trend suggesting that higher LDL-C levels were associated with a reduced risk of long-term MACEs when adjusted for non-HDL-C. These findings were consistent across all population subgroups.

Conclusions: In patients with high-risk or established ASCVD receiving statin therapy, elevated non-HDL-C, rather than LDL-C, was associated with 3P-MACE. Non-HDL-C may therefore be considered a primary target for addressing residual cardiovascular risk in these individuals.

Trial registration: TCTR20130520001 registered in Thai Clinical Trials Registry (TCTR) https://www.thaiclinicaltrials.org/, date of registration 20 May 2013.

Cholesteryl ester storage disease (CESD) is a rare autosomal recessive metabolic disorder resulting from a deficiency of lysosomal acid lipase (LAL). It is characterized by the accumulation of cholesterol esters in various tissues, leading to atherosclerotic diseases or severe hepatic dysfunction in younger individuals. Pregnancy has remained an essential challenge for women with CESD because of the poor prognosis. Enzyme replacement therapy (ERT) using sebelipase alfa, a recombinant form of LAL, is effective in improving lipid profiles and reversing liver dysfunction in patients with CESD. This novel therapy may facilitate safer pregnancy outcomes. This report details the experience of a 30-year-old pregnant woman with CESD who received ERT. Given the absence of CESD complications, colestimide was the only medication administered during pregnancy. The patient had a full-term vaginal delivery with no obstetric complications or fetal congenital anomalies. Following delivery, transient triglycerides, low-density lipoprotein-cholesterol, and liver enzyme increases were observed. However, restarting ERT led to a gradual improvement in the liver function and lipid profile.

A case of a 29-year-old female patient with a history of a single episode of hypertriglyceridemia-induced pancreatitis 4 years prior is reported. She had been treated with fibrates until 2 months before conception and required hospitalization at 33 weeks of gestation due to severe hypertriglyceridemia (6690 mg/dL) and gestational diabetes. Upon hospital admission, there was no evidence of pancreatitis. A comprehensive treatment approach was initiated, combining a low-fat diet, fibrates, omega-3 fatty acids (2 g/d), and continuous insulin infusion. This regimen resulted in a significant reduction of triglyceride levels to 960 mg/dL. The pregnancy progressed to full term without any maternal-fetal complications. Genetic analysis revealed 2 compound heterozygous mutations in the APOA5 gene, which encodes apolipoprotein AV. Notably, these specific mutations have not been previously reported as causative factors for familial chylomicronemia syndrome (FCS). The diagnosis of FCS was confirmed by the patient's markedly reduced lipoprotein lipase activity of 3.2%.

Background: The ongoing residual cardiovascular risks despite lowering low-density lipoprotein cholesterol (LDL-C) levels suggest the need to identify additional drivers associated with atherosclerosis. Circulating lipoprotein(a) [Lp(a)]promotes formation of foam cells via its proatherogenic properties. However, whether a lower Lp(a) level in combination with favorable LDL-C control could induce a more stable form of disease remains unknown. Near-infrared spectroscopy (NIRS) generates maximum lipid-core burden index in 4 mm (MaxLCBI_4 mm) which is a histologically validated measure of lipidic plaque material in vivo. Therefore, the current study employed NIRS imaging to characterize lipidic plaque in association with LDL-C < 70 mg/dL and Lp(a) <50 mg/dL.

Methods: We analyzed 439 patients with coronary artery disease (CAD) (554 de-novo target lesions receiving percutaneous coronary intervention) in the REASSURE-NIRS registry (NCT04864171). Clinical characteristics and NIRS-derived MaxLCBI_4mm were compared among 4 groups according to LDL-C of 70 mg/dL and Lp(a) of 50 mg/dL.

Results: Almost one-third of study subjects (33.4%) exhibited both LDL-C < 70 mg/dL and Lp(a) <50 mg/dL. They were more likely male with a lower frequency of acute coronary syndrome and lipid lowering therapies were more frequently used in those with LDL-C < 70 mg/dL and Lp(a) <50 mg/dL. On NIRS imaging analysis, a smaller MaxLCBI_4mm (P < .001) and a lower frequency of MaxLCBI_4mm ≥400 (P = .001) were observed in those with both LDL-C < 70 mg/dL and Lp(a) <50 mg/dL. On multivariable logistic regression analysis, the coexistence of these 2 lipid controls showed an approximately 70% lower risk (adjusted odds ratio: 0.30; 95% confidence interval: 0.13-0.68) of MaxLCBI_4mm ≥400 compared with the reference group (LDL-C ≥ 70 mg/dL and Lp(a) ≥50 mg/dL).

Conclusion: Our findings suggest circulating Lp(a) as a potential therapeutic target to stabilize coronary atherosclerosis in CAD patients who achieved LDL-C < 70 mg/dL.

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.

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.