Journal of clinical lipidology最新文献

Background: Conflicting results have been reported as to the relative importance of apolipoprotein A-1 (apoA-1) vs high-density lipoprotein cholesterol (HDL-C) as markers of atherosclerotic cardiovascular disease (ASCVD) risk.

Objective: To compare the apoA-I and HDL-C as predictors of cardiovascular risk.

Methods: Residual discordance analysis with Cox proportional hazard models comparing apoA-1 and HDL-C as markers of ASCVD risk was applied to a sample of 291,995 UK Biobank participants, followed for a median of 11 years. Interaction tests for the 2 markers and estimation of the effects of partitioning HDL-C into apoA-I, log-triglyceride, and the remaining residual were also performed.

Results: ApoA-1 and HDL-C had similar associations with ASCVD risk (hazard ratios [HRs] of 0.85, P value <.001 for both). The residual of HDL-C added significantly to the risk associated with apoA-1, as did the residual of apoA-1 to HDL-C. There was a statistically significant interaction between apoA-I and HDL-C (HR = 1.05, 95% CI: (1.04-1.06); P < .001). Decomposing HDL-C into the 3 components, apoA-I accounted for the largest portion of the effect, with an HR of 0.85 (95% CI: 0.83-0.86), with smaller effects for lnTG: 1.04 (95% CI: 1.02-1.06) and the residual of HDL-C: 0.98 (95% CI: 0.96-0.995).

Conclusion: HDL-C and apoA-1 have associations of equivalent strength with ASCVD risk, with significant interaction modifying the effect of one by the other. Upon decomposition, apoA-I retained more of the effect of HDL-C as compared with log-triglycerides. While only observational, the results are consistent with the relation of HDL to risk not being determined by the concurrent level of triglyceride.

Background: Many patients receiving maximally tolerated statins fail to achieve recommended low-density lipoprotein cholesterol (LDL-C) levels, and multiple add-on nonstatin therapies are now available or in development, including obicetrapib and bempedoic acid. However, no direct comparison between these drugs is available.

Objective: We conducted a network meta-analysis of randomized, double-blind, placebo-controlled trials evaluating obicetrapib or bempedoic acid on top of statin therapy.

Methods: We conducted a network meta-analysis of randomized, double-blind, placebo-controlled trials evaluating obicetrapib or bempedoic acid on top of statin therapy. The primary outcome was the mean percentage change in LDL-C from baseline vs placebo. The secondary outcome was the mean percentage change in non-high-density lipoprotein cholesterol (non-HDL-C), treatment safety, including adverse events, serious adverse events, and cardiovascular composite endpoint. A random-effects model was used to synthesize evidence, test consistency, and generate treatment rankings. Heterogeneity and publication bias were also assessed.

Results: Six trials involving 6025 participants met the inclusion criteria. Obicetrapib resulted in a pooled LDL-C reduction of -33.17% (95% CI, -36.21 to -30.13) vs placebo, whereas bempedoic acid produced a reduction of -18.02% (95% CI, -18.83 to -17.21). The comparison of treatments showed an additional 15.15% in LDL-C reduction, favoring obicetrapib (95% CI, -18.30 to -12.00). There was no evidence of heterogeneity or inconsistency across the network (τ² = 0; I² = 0). Obicetrapib also showed a greater non-HDL-C reduction of -16.1% (95% CI, -19.1 to -13.1). Both drugs showed a comparable safety profile. Findings were consistent across multiple sensitivity analyses. No evidence of publication bias was detected.

Conclusion: Among statin-treated patients requiring further LDL-C lowering, obicetrapib may represent an additional oral option to achieve the LDL-C target. Results should be interpreted in the context of currently available cardiovascular outcomes evidence, pending dedicated outcomes and long-term safety data.

Background: Pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, has shown potent triglyceride-lowering effects. However, evidence regarding its long-term effects on liver fibrosis in metabolic dysfunction-associated steatotic liver disease (MASLD) remains limited.

Objective: Using magnetic resonance elastography (MRE), we evaluated the effects of 2-year pemafibrate treatment on liver fibrosis in patients with MASLD and hypertriglyceridemia.

Methods: This single-center retrospective study included 25 patients with MASLD and hypertriglyceridemia who received pemafibrate for ≥2 years and underwent MRE-based liver stiffness measurements (MRE-LSMs) before and after treatment. The primary endpoint was the change in MRE-LSMs over 2 years. Secondary endpoints included changes in lipid parameters, liver enzyme levels, liver function parameters, serum fibrosis markers, and the proton density fat fraction. Responders were defined as those showing ≥19% reduction in MRE-LSMs.

Results: The median MRE-LSM decreased significantly from 3.05 to 2.52 kPa (P < .001), with 92% of the patients showing improvement and 36% meeting the responder criteria. The proportion of patients showing significant fibrosis decreased from 44.0% to 28.0%. The triglyceride levels decreased from 231 to 125 mg/dL (P < .001). The liver enzyme levels, liver function parameters, and serum fibrosis markers improved significantly. These improvements occurred without changes in body weight, glycemic control, or hepatic fat content. No treatment discontinuations occurred due to adverse events.

Conclusion: Two-year pemafibrate treatment significantly improved liver stiffness and hepatic parameters independent of weight loss or fat reduction, indicating potential antifibrotic mechanisms. These real-world findings support the hepatoprotective role of pemafibrate and warrant validation in prospective trials.

Background: Residual atherosclerotic cardiovascular disease (ASCVD) risk remains common among adults treated with moderate-intensity statins, necessitating nonstatin therapy. Ezetimibe is the preferred first-line oral nonstatin therapy. However, bempedoic acid is emerging as an alternative, particularly in patients with statin intolerance. Cardiovascular outcomes with bempedoic acid among patients receiving moderate-intensity statins in routine care are not well-established.

Objective: To compare cardiovascular outcomes associated with bempedoic acid vs ezetimibe when added to background moderate-intensity statin therapy in the real world.

Methods: This retrospective cohort study used the TriNetX global federated health research network. Adults aged 18 years or older receiving moderate-intensity statin therapy with add-on bempedoic acid or ezetimibe were included. The primary outcome was a composite of stroke, myocardial infarction, ischemic heart disease, new-onset heart failure, or peripheral artery disease. Risk ratios (RRs) with 95% CIs were calculated.

Results: After matching, 6706 patients were included (n = 3353 per cohort). Bempedoic acid was associated with a significantly lower risk of the composite outcome compared with ezetimibe (16.7% vs 22.8%; RR: 0.73; 95% CI: 0.63-0.84). All individual cardiovascular endpoints favored bempedoic acid. Low-density lipoprotein cholesterol (LDL-C) reduction was greater with ezetimibe.

Conclusion: Among adults on moderate-intensity statins, bempedoic acid was associated with significantly lower cardiovascular event rates compared with ezetimibe, despite smaller LDL-C reductions. These findings complement Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen (CLEAR) Outcomes and suggest greater ASCVD risk-reducing potential for bempedoic acid than currently reflected in clinical guidelines.

Background: Familial hypobetalipoproteinemia is a rare autosomal codominant disorder, often caused by a defect in apolipoprotein B (apoB) production required for lipoprotein formation and secretion.

Objective: Characterization of the lipid profiles of 3 family members exhibiting very low circulating cholesterol levels.

Methods: Plasma samples from the control sibling and the affected patients were analyzed. Fast protein liquid chromatography and high-performance liquid chromatography were used to characterize the lipid profiles, size, and distribution of lipoprotein particles. Exome sequencing of family members revealed a single-nucleotide deletion in APOB in the 3 affected individuals. The effect of the single-nucleotide deletion on the secretion of apoB was analyzed in Immortalized Human Hepatocyte (IHH) cells.

Results: Plasma lipid profiles revealed that the affected individuals have low levels of total cholesterol and low-density lipoprotein cholesterol, with no difference in lipoprotein particle size. DNA sequencing of APOB revealed a single heterozygote deletion of an adenosine in exon 3 at the nucleotide position 1268 in all affected members. This deletion introduces a reading frame shift at glutamine 380, resulting in a stop codon at position 397. The C-terminally truncated apoB, called apoB9, is a variant spanning ∼9% of the full-length protein. Upon expression of apoB9 in IHH cells, the protein did not exit the endoplasmic reticulum/cis-Golgi and, hence, was not secreted into the media. Molecular modeling revealed that apoB9 lacks the βA- and βB-sheets that are required for lipid particle formation, which can explain the absence of apoB9 secretion.

Conclusion: Our data suggested that the affected family members have ∼50% to 60% lower apoB levels and are likely protected against the development of atherosclerosis and cardiovascular diseases.

Background: Keeping lipid levels under control is key to preventing secondary cardiovascular events; however, few studies have detailed in depth the characteristics of patients with coronary artery disease according to low-density lipoprotein cholesterol (LDL-C) levels.

Objective: To characterize patients with heart failure (HF) of ischemic or nonischemic etiology according to their LDL-C levels and considering the thresholds of <70 mg/dL and <100 mg/dL for LDL-C goals.

Methods: We present the results from the third phase of the Colombian Registry of Heart Failure (RECOLFACA). Sociodemographic, clinical, and laboratory data were collected at baseline. For the LDL-C goal analysis, we conducted a logistic regression model.

Results: We included 1124 patients, 554 with ischemic and 570 with nonischemic HF. The cohort included 379 women (33.7%) and 745 men (66.3%). There was a difference in the prescription of statins observed for both ischemic and nonischemic HF groups. Patients with ischemic HF had a 62% probability of being at the LDL-C <70 mg/dL goal (odds ratio [OR] = 1.62) and a 43% probability of being at the <100 mg/dL goal (OR = 1.43). Rosuvastatin was more used by patients with ischemic HF in the <70 mg/dL LDL-C goal group in comparison to those on the same goal group but with nonischemic HF (40.4% vs 19.6%, respectively). Similar results were reported for the <100 mg/dL LDL-C goal.

Conclusion: Our findings provide insights into distinct clinical profiles, treatment patterns, and LDL goal attainment in patients with ischemic and nonischemic HF, emphasizing the need for tailored management strategies based on HF etiology.

Background: Sitosterolemia is a rare autosomal recessive lipid disorder caused by mutations in the ABCG5 or ABCG8 genes, resulting in excessive intestinal absorption and impaired biliary excretion of plant sterols, which leads to their accumulation in plasma and tissues. Clinical manifestations include premature coronary artery disease, liver dysfunction, hepatosplenomegaly, and hematologic abnormalities.

Objective: We report the first Polish family diagnosed with sitosterolemia.

Methods: A 19-year-old male patient with severe hypercholesterolemia and resistance to statin therapy and his family members were examined, including biochemical and imaging studies, serum sterol assessment by gas chromatography-mass spectrometry, and genetic testing using next-generation sequencing of genes involved in lipid metabolism.

Results: The proband presented with total cholesterol of 8.0 mmol/L, low-density lipoprotein cholesterol of 5.80 mmol/L, high-density lipoprotein cholesterol of 1.24 mmol/L, and triglycerides of 2.38 mmol/L. Genetic analysis revealed 2 variants in the ABCG8 gene in the patient and his brother: a pathogenic variant c.1083G>A (p.Trp361Ter), present in the patient's father, and a variant of uncertain significance c.1534G>A (p.Gly512Arg), present in the patient's mother. Serum sterol concentrations in the patient were markedly elevated, including campesterol (139.8 µmol/L), stigmasterol (2.2 µmol/L), isofucosterol (56.9 µmol/L), and sitosterol (333.9 µmol/L). Introduction of ezetimibe therapy combined with a low-plant sterol diet resulted in improvement of the lipid profile.

Conclusion: These findings highlight the role of genetic testing and serum sterol measurement in the differential diagnosis of inherited lipid disorders, especially in patients with statin-resistant hypercholesterolemia. Early diagnosis of sitosterolemia is important to introduce an appropriate diet and pharmacotherapy.

Background: Inclisiran is approved to reduce low-density lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH). Cost-related nonadherence remains a significant challenge underlying the use and optimization of lipid-lowering therapies.

Objective: To describe the real-world changes in LDL-C levels and the out-of-pocket (OOP) costs associated with inclisiran in patients initiating treatment in infusion centers.

Methods: This retrospective, observational study reviewed electronic medical records of patients with a history of atherosclerotic cardiovascular disease or HeFH initiating inclisiran treatment between March 1, 2022, and November 30, 2022; patients were followed up until February 2024. Study outcomes included changes in LDL-C levels from baseline, OOP cost by payer type, and adverse events (AEs), if documented.

Results: Among 562 patients included in this analysis, the mean (SD) age at index was 70.6 (9.6) years, and 50.9% of patients were male. Most patients (80.2%) were covered by Medicare. In 274 patients with LDL-C measurements, mean (SD) baseline LDL-C was 147.2 (59.7) mg/dL. The average percent reduction from mean baseline LDL-C to mean follow-up was 51%. The median (IQR) OOP costs for the initial dose were $0 ($0-$0) for Medicare-insured patients and $0 ($0-$95) for patients covered by commercial insurance. Of patients insured by Medicare, 96% paid $0 OOP for both doses. AEs were reported by 24 patients (4%), of whom 12 (50%) discontinued treatment.

Conclusion: These real-world data demonstrate significant LDL-C reductions within 1 year in patients who initiated inclisiran. Nearly all patients with Medicare had no OOP costs.

Background: Niemann-Pick disease (NPD) is a rare autosomal recessive lysosomal storage disorder caused by acid sphingomyelinase (ASM) deficiency, resulting in progressive lipid accumulation in multiple cell types and organs.

Objective: To describe a rare case of suspected NPD type B with secondary sea-blue histiocytosis and to explore its diagnostic implications.

Methods: Comprehensive clinical and laboratory evaluations were conducted to assess the patient's condition.

Results: We report a rare case of Niemann-Pick disease type B accompanied with secondary sea-blue histiocytosis in a 32-year-old woman who had previously undergone splenectomy for congenital splenomegaly. She presented with abdominal distension, poor appetite and abdominal pain. Clinical evaluations revealed decompensated cirrhosis with no neurologic abnormalities. Transjugular liver biopsy demonstrated foamy cells infiltration, while bone marrow examination identified sea-blue histiocytes (approximately 4.5% of nucleated cells) and Niemann-Pick cells (approximately 2.5%). Although acid sphingomyelinase activity testing and SMPD1 sequencing were recommended, the patient declined further evaluation for financial reasons.

Conclusion: This case highlights the significance of considering acid sphingomyelinase deficiency in patients with cryptogenic cirrhosis and underscores the diagnostic value of histopathology when definitive gene or enzyme testing is unavailable. It also raises the possibility that prior splenectomy may influence the clinical presentation of the disease.

Background: Analyses of statin trials by the Cholesterol Treatment Trialists' Collaboration have suggested larger relative risk reduction (RRR) for major adverse cardiovascular events (MACE) per 1 mmol/L (38.7 mg/dL) low-density lipoprotein cholesterol (LDL-C) lowering in primary prevention than in secondary prevention. However, controversy remains about the value of LDL-C lowering in primary prevention.

Objective: This meta-analysis examined the relationship between LDL-C reduction and MACE risk in primary prevention with statin and nonstatin LDL-C-lowering therapies in cardiovascular outcomes trials (CVOTs).

Methods: PubMed and Cochrane Central Register of Controlled Trials were searched from inception through August 26, 2025. The primary endpoint was the pooled RRR vs controls for 4-point composite MACE (coronary heart disease death, nonfatal myocardial infarction, fatal and nonfatal stroke, and coronary revascularization) per 1 mmol/L LDL-C lowering.

Results: Eleven CVOTs of solely primary prevention participants (n = 74,466) and 3 in which >80% of participants were primary prevention (n = 24,071) were identified (11 statin, 1 bempedoic acid, 1 ezetimibe, 1 statin+ezetimibe). In 13 trials, the pooled mean difference between groups in LDL-C reduction was 1.00 mmol/L (95% CI: 0.82-1.18 mmol/L) with a pooled estimate of 30% (relative risk: 0.70; 95% CI: 0.67-0.74) RRR for 4-point MACE per 1 mmol/L LDL-C reduction vs control.

Conclusion: In CVOTs of solely or predominantly primary prevention participants, each 1 mmol/L reduction in LDL-C was associated with a 30% RRR in 4-point MACE. These results strengthen the evidence and rationale for the benefits of LDL-C lowering in primary prevention.