Journal of clinical lipidology最新文献

Background: We aimed to precisely quantify the risk of coronary heart disease (CHD) among antihypertensive medication users compared to non-users. We similarly assessed the potential CHD risk among lipid-lowering medication users.

Methods: This retrospective cohort study used claims and health checkup data from 2014 to 2021 provided by DeSC Healthcare, Inc. We used percutaneous coronary intervention (PCI) risk as a proxy for the CHD outcome.

Results: Among the 1,740,153 participants without a history of cardiovascular and kidney diseases, 3803 underwent PCI during a mean follow-up of 3.2 years. The Cox model with health insurers as the stratified factor showed that blood pressure (BP) classification according to the hypertension guidelines was linearly associated with PCI risk. In contrast, this association was weaker in antihypertensive medication users than in nonusers. After restricting to 1,309,460 participants with BP <140/<90 mm Hg, the antihypertensive medication users had a 1.51 (95% CI: 1.37-1.66) times higher PCI risk than nonusers even after adjusting for baseline characteristics including systolic BP. This was consistent in all subgroups stratified by characteristics including body mass index, drinking status, diabetes, systolic BP, and follow-up years. Meanwhile, the use of lipid-lowering medications was not associated with PCI risk (HR: 0.98, 95% CI: 0.88-1.09 in 1,221,390 patients with low-density lipoprotein cholesterol <3.62 mmol/L [<140 mg/dL]).

Conclusions: Especially for hypertension, it is important not only to lower BP with medication but also to avoid the need for medication through early prevention and lifestyle changes.

Background: Widespread familial hypercholesterolemia screening requires a large upfront economic investment, but the health benefits and cost savings of cardiovascular disease prevention directed by screening occur over many years.

Objective: We evaluated the cost-effectiveness of population genetic screening for familial hypercholesterolemia compared to cascade testing to US payers while accounting for patient insurance switching between commercial and Medicare insurance.

Methods: We developed a hybrid decision-tree Markov model to assess genetic screening in 20-year-old adults over a lifetime horizon in which cohort members transitioned between commercial payers representing three commercial plans and Medicare. Health state and coverage transition probabilities, utilities, and event costs were primarily sourced from published literature. We estimated incremental cost-effectiveness ratios per quality-adjusted life year gained and conducted probabilistic and one-way sensitivity analyses to explore parameters.

Results: Population genetic screening cost an additional $1,024,126, $495,909, and $479,170 per quality-adjusted life year gained for the high, medium, and low benefit commercial payers. Medicare experienced both cost savings and greater quality-adjusted life years in its members under population genetic screening.

Conclusions: Insurance switching substantially affects the cost-effectiveness of population genetic screening for familial hypercholesterolemia to US payers. Future research examining screening and treatments for other rare diseases that require high investment early in life for downstream health benefits should consider the impact of insurance switching in the US.

Background: Increases in the prevalence of type 2 diabetes (T2D) pose significant challenges to its prediction and prevention.

Objective: We aimed to evaluate whether cumulative exposure to a high triglyceride to high-density lipoprotein-cholesterol (TG/HDL-C) ratio is associated with increased T2D risk in young adults.

Methods: We collected South Korean National Health Insurance Service data between 2009 and 2012 from 1,840,251 young adults without T2D aged 20 to 39 years who underwent 4 consecutive annual health checkups. Participants were classified into 5 groups based on exposure to a high TG/HDL-C ratio, defined as the highest TG/HDL-C ratio quartile. T2D risk was evaluated using a multivariate Cox proportional hazard model.

Results: During the 6.53-year follow-up period, 40,286 participants (2.2%) developed T2D. The cumulative incidence of T2D increased with higher TG/HDL-C exposure scores. The adjusted hazard ratios of TG/HDL-C ratio exposure scores for T2D were 1.584 (95% confidence interval (CI), 1.488-1.686), 2.101 (95% CI, 1.980-2.228), 2.942 (95% CI, 2.787-3.106), and 4.962 (95% CI, 4.718-5.219) for groups with scores of 1 to 4, respectively, compared with those with a score of 0. Further subgroup analyses stratified by age, sex, and statin use revealed no significant differences in risk of T2D.

Conclusion: Cumulative exposure to high TG/HDL-C ratio was associated with increased risk of T2D in young Korean adults, suggesting its importance in prediction and prevention. Subgroup analysis revealed no significant differences in age, sex, or statin use. Further research is required to explore the underlying mechanisms and develop effective interventions.

Background: Homozygous familial hypercholesterolemia (HoFH) is a severe form of familial hypercholesterolemia (FH), characterized by high low-density lipoprotein cholesterol (LDL-C) levels and increased coronary artery disease risk. This study reports a novel Alu insertion in the LDLR gene in a consanguineous Indian family, causing FH.

Objective: To identify and characterize the mutation causing HoFH in a proband and their family members.

Methods: Clinical exome sequencing was conducted on the proband with subsequent bioinformatic analysis of single nucleotide variants, loss-of-function variants, structural variants, and mobile element insertions (MEI). Polymerase chain reaction (PCR) amplification and Sanger sequencing of exon 17 of the LDLR gene were performed to elucidate the sequence and length of the Alu insertion. Additionally, RNA analysis of the proband identified splice site events.

Results: Bioinformatic analysis revealed a small sequence duplication followed by an Alu element insertion. PCR amplification and Sanger sequencing uncovered a 17 base pair (bp) duplication at the breakpoint, a "T" base insertion, followed by a 309 bp Alu Yb8 insertion. This led to a 70 bp deletion at the beginning of exon 17 due to alternative splicing, resulting in a frameshift and extended protein truncation. The proband and siblings were homozygous for the mutation, while the parents and two other family members were heterozygous.

Conclusion: Our study uncovers a novel AluYb8 element insertion in the LDLR gene, highlighting the need for MEI detection in genetic screening for FH. Reanalyzing FH cohorts for MEIs could significantly improve diagnostic accuracy and enhance our understanding of FH genetics.

Background: Lipoprotein(a) [Lp(a)] is a driver of residual cardiovascular risk. Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) decrease Lp(a) with significant heterogeneity in response. We investigated contributors to the heterogeneous response.

Methods: CHOlesterol Reduction and Residual Risk in Diabetes (CHORD) was a prospective study examining lipid lowering in participants with a low-density lipoprotein cholesterol (LDL-C) >100 mg/dL with and without diabetes (DM) on lipid lowering therapy (LLT) for 30-days with evolocumab 140 mg every 14 days combined with either atorvastatin 80 mg or ezetimibe 10 mg daily. Lp(a) level was measured by immunoturbidometry, and the apolipoprotein (a) [apo(a)] isoform size was measured by denaturing agarose gel electrophoresis and western blotting. We examined the change in Lp(a) levels from baseline to 30 days.

Results: Among 150 participants (mean age 50 years, 58% female, 50% non-White, 17% Hispanic, 50% DM), median (interquartile range) Lp(a) was 27.5 (8-75) mg/dL at baseline and 23 (3-68) mg/dL at 30 days, leading to a 10% (0-36) median reduction (P < 0.001). Among 73 (49%) participants with Lp(a) ≥30 mg/dL at baseline, there was a 15% (3-25) median reduction in Lp(a) (P < 0.001). While baseline Lp(a) level was not correlated with change in Lp(a) (r = 0.04, P = 0.59), apo(a) size directly correlated with Lp(a) reduction (P < 0.001). After adjustment for age, sex, race/ethnicity, DM, and type of LLT, apo(a) size remained positively associated with a reduction in Lp(a) (Beta 0.95, 95% confidence interval, 0.93-0.97, P < 0.001).

Conclusion: Our data demonstrate variation in Lp(a) reduction with potent LLT. Change in Lp(a) was strongly associated with apo(a) isoform size.

This report describes a rare case of lipoprotein glomerulopathy. A 63 year-old man presented with nephrotic syndrome unresponsive to rituximab and tacrolimus. Blood tests showed a mild- to moderate hypertriglyceridemia suggesting familial dysbetalipoproteinemia (FD). Additional diagnostic procedures including lipoprotein ultracentrifugation, fast protein liquid chromatography and agarose gel electrophoresis were performed, which showed increased very-low-density lipoprotein remnants corresponding to the lipid profile observed in FD patients. However, instead of the expected APOE ε2/ε2 genotype, our patient showed APOE ε3/ε4. The APOE gene was sequenced, revealing a c.509C>A:p. (Ala170Asp) variant (also known as APOE Las Vegas), which has been described once in a patient with lipoprotein glomerulopathy. Lipid-lowering therapy was initiated, which resulted in a slight improvement of renal function and lipid profile. This Dutch case further supports the pathogenicity of the APOE Las Vegas variant and emphasizes the importance of timely diagnosis of lipoprotein glomerulopathy to institute appropriate treatment.

Background: Elevated lipoprotein(a) (Lp[a]) is the most common inherited dyslipidemia that is independently and causally associated with increased atherosclerotic cardiovascular disease (ASCVD) risk. However, data from diverse populations with ASCVD are lacking.

Objective: To evaluate Lp(a) levels in a diverse, contemporary United States (US) population with ASCVD, stratified by race, ethnicity, and sex.

Methods: Lp(a)HERITAGE (NCT03887520) was a multicenter study that estimated the prevalence of elevated Lp(a) in adults (18-80 years) with ASCVD. US participants with Lp(a) measured in nmol/L pre- or post-enrollment were included in this subanalysis. This study was descriptive; therefore, no statistical comparisons were made.

Results: Of all US participants, 14% had an Lp(a) measurement pre-enrollment. This subanalysis included 7679 US participants with Lp(a) measurements in nmol/L (80.5% White; 66.4% male; mean age 63.8 years [standard deviation ± 9.7]). Median Lp(a) was >2.5-fold higher in Black participants (132.0 nmol/L; IQR, 57.1-239.6) vs the overall population (52.1 nmol/L; IQR, 15.7-167.8), and higher in females compared with males (69.4 nmol/L; IQR, 20.1-194.7 vs 45.6 nmol/L; IQR, 14.0-152.6, respectively). Lp(a) levels ≥125 nmol/L were more prevalent among Black (52.0%) and female (38.9%) participants vs the overall population (33.3%).

Conclusion: In US Lp(a)HERITAGE participants, only 14% had an Lp(a) measurement pre-enrollment, despite having ASCVD. One-third of participants demonstrated Lp(a) levels ≥125 nmol/L, the threshold for high ASCVD risk, which was higher among Black (1/2) and female (2/5) participants, suggesting a greater need for Lp(a) testing in these groups to inform ASCVD risk mitigation.

Background: Plasma sulfur amino acids (SAAs), particularly cysteine, are associated with obesity. One proposed mechanism is the altered regulation of the stearoyl-CoA desaturase (SCD) enzyme. Changes in the SCD enzyme activity have been linked to obesity, as well as to plasma SAA concentrations.

Objective: This study aimed to investigate whether estimated SCD activity mediates the associations between plasma SAAs and measures of overall adiposity and specific fat depots.

Methods: We examined cross-sectional data from a subset of the Maastricht Study (n = 1129, 50.7% men, 56.7% with (pre)diabetes). Concentrations of methionine, total homocysteine, cystathionine, total cysteine (tCys), total glutathione (tGSH) and taurine were measured in fasting plasma. Outcomes included measures of overall, peripheral and central adiposity, and liver fat. SCD activity was estimated by ratios of serum fatty acids as SCD16 and SCD18 indices. The associations between plasma SAAs and measures of adiposity or liver fat were examined with multiple linear regression analysis. Multiple mediation analysis was used to investigate whether the significant associations were mediated by SCD16 and SCD18 indices.

Results: Plasma tCys was positively associated with all adiposity measures (β ranged from 0.15 to 0.30). SCD16 significantly mediated all associations (proportion mediated ranged from 5.1% to 9.7%). Inconsistent mediation effects were found for SCD18. Despite a significant inverse association of plasma tGSH with all adiposity measures (β ranged from -0.08 to -0.16), no significant mediation effect was found.

Conclusions: Plasma tCys may promote excessive body fat accumulation via upregulation of SCD activity.

Background: Homozygous familial hypercholesterolaemia (HoFH) is a severe lipid disorder leading to accelerated atherosclerotic cardiovascular disease (ASCVD). This study aimed to evaluate the efficacy of ezetimibe, a cholesterol absorption inhibitor, in reducing low-density lipoprotein cholesterol (LDL-C) levels in patients with genetically confirmed HoFH.

Methods: This retrospective review included 48 individuals with genetically confirmed HoFH attending the Lipid Clinic at an Academic Hospital in Johannesburg, South Africa. All patients were on stable high-intensity statin therapy for at least 6 months before starting ezetimibe 10 mg orally daily. Lipid profiles at baseline and after 3 and 6 months of ezetimibe therapy were documented. Responders (LDL-C reduction ≥20%) were compared to nonresponders (LDL-C reduction <20%).

Results: Ezetimibe led to a 19.1% further reduction in LDL-C at 6 months. Among the participants, 23 were considered responders and 25 were nonresponders. Responders showed a 26.4% LDL-C reduction at 3 months and 31.6% at 6 months, compared to nonresponders with 8.5% and 5.9% reductions in LDL-C respectively. Individuals with the null LDL receptor variant c.1285G>A (p.Val429Met) were less likely to respond. However, response to ezetimibe was highly variable across all pathogenic variants.

Conclusion: Ezetimibe, in combination with high-intensity statin therapy, significantly reduces LDL-C levels in patients with genotypically confirmed HoFH. However, the response to ezetimibe is highly variable and unpredictable across genotypes. This study supports the inclusion of ezetimibe in the treatment regimen for all HoFH patients to reduce the risk of ASCVD. Further studies are needed to understand the variable responses to ezetimibe among different genotypes and in HoFH individuals with the same genotype.