Journal of clinical lipidology最新文献

Background/Synopsis

The Atlantic Medical Group Lipid Workgroup at Atlantic Health System is composed of both adult and pediatric cardiologists, internists, endocrinologists and nephrologists. The goal of the workgroup is to address the need for optimal cardiometabolic diagnosis and treatment. Because familial hypercholesterolemia (FH) is dominantly inherited, cascade screening of family members can be highly effective.

Objective/Purpose

To highlight the benefits of collaboration of adult and pediatric specialties for the diagnosis and treatment of FH.

Methods

38-year-old female with a strong family history of early CAD, very high cholesterol levels and xanthelasmas presented to us to establish care. Her two children were diagnosed genetically with FH at age 3 and 6 with cholesterol levels of 269 mg/dL and > 400 mg/dL, respectively. She was initiated on treatment with a statin. Her twin sister was also evaluated and found to have high cholesterol levels and xanthelasmas. This sister's children were also suspected of having FH and were referred to a pediatric cardiologist for diagnosis and treatment.

Results

The children of the index patient were found to be heterozygous for deletion (exon17-18) LDLR gene, pathologic for FH.

Conclusions

The collaborative efforts of adult and pediatric specialists make the Atlantic Medical Group Lipid workgroup unique. Through this program, cascade and reverse cascade screening is utilized to identify and diagnose individuals at risk for familial hypercholesterolemia. Identification of an index patient with FH with effective screening of relatives combines the benefits of universal and cascade screening and has the potential of detecting all living cases of FH. Basseling et al found that although capable of identifying asymptomatic individuals with hypercholesterolemia, the cost effectiveness of universal screening has not yet been determined and cascade screening has proven to be more cost effective than any other screening strategy currently available thus far.

Heterozygous familial hypercholesterolemia (HeFH) is an autosomal dominant disorder causing elevated low density lipoprotein cholesterol (LDL-C) and premature atherosclerotic cardiovascular disease. Universal cholesterol screening in childhood leads to children serving as the index case for their family, but efficacy of cascade screening and genetic counseling in this population is not well understood. The institutional pediatric lipid clinic database was queried from 2011 to 2022 for subjects <18 years who met clinical HeFH diagnostic criteria (N = 256). Median peak LDL-C was 198 mg/dL (interquartile range 179–238 mg/dL) and 69.5 % of subjects were the index case. The number of new HeFH cases identified per index case was 3.55 ± 1.87. Genetic counseling was offered to 38.7 % of subjects and genetic testing was completed by 10.9 %, 53.6 % of whom had a pathogenic or likely pathogenic genetic variant for HeFH. Our findings highlight the effectiveness of cascade screening from pediatric index cases identified through universal screening. However, genetic counseling and genetic testing may be underutilized in this population.

Background/Synopsis

According to the American Heart Association, the accumulation of plaque in the walls of arteries is identified as the primary cause of atherosclerotic cardiovascular disease (ASCVD). Currently, ASCVD-related conditions remain the leading cause of morbidity and mortality globally. Apolipoprotein B has been identified as a more precise cardiovascular risk marker than LDL-C, while hsCRP has shown potential as a cardiovascular disease indicator. This study aims to investigate the diagnostic performance and routine screening cut-off of hsCRP for early atherosclerosis vascular diseases (ASCVD) risk in adult patients, comparing it with Apo B.

Objective/Purpose

To compare the diagnostic performance of high-sensitivity C-reactive protein (hsCRP) with apolipoprotein B in assessing ASCVD risk.

Methods

A sample of 494 individuals from the NHANES 2015-2016 laboratory dataset, with a mean age greater than 17 years, was used for this study. ASCVD risk was measured by non-HDL-C, categorized into low and high risk based on the Mayo Clinic reference range. Predictors included Apo B, and hs-CRP. Binomial logistic regression and ROC curve analyses were conducted using the generalised linear models and pROC packages in RStudio IDE. Hypotheses were validated at p≤0.05, and diagnostic performance metrics such as ROC AUC, sensitivity, and specificity were measured on a scale of 0-1.

Results

The findings revealed that for every 1g/L increase in apo B concentration, the odds of high ASCVD risk were approximately 3.8 × 1011 times higher. Additionally, the model indicated that the odds of high ASCVD risk were 1.03 times higher for every 1mg/L increase in hsCRP concentration. However, this indicate that hsCRP level was not associated with odds of ASCVD risk. The ROC AUC for apo B and hsCRP were approximately 0.9739 and 0.6165, respectively, with cut-off values (sensitivity, specificity) of approximately 0.9g/L (0.927, 0.897) and 2.4 mg/L (0.596, 0.601), respectively. Thus, levels above these thresholds for both apo B and hsCRP are associated with high ASCVD risk.

Conclusions

The study demonstrates that apo B exhibits high discriminatory and diagnostic accuracy, making it a suitable ASCVD risk biomarker compared to hsCRP. While hsCRP shows moderate diagnostic accuracy, it is not sufficient as a standalone ASCVD risk diagnostic marker. Therefore, apo B could serve as a replacement for LDL-C, while hsCRP could possibly serve as an add-on test in ASCVD risk assessment.

Study Funding

NewAmsterdam Pharma.

Background/Synopsis

Obicetrapib is a selective cholesteryl ester transfer protein (CETP) inhibitor currently in clinical development for the treatment of hypercholesterolemia and reduction of cardiovascular risk that strongly reduces apolipoprotein B (ApoB) and low-density lipoprotein cholesterol (LDL-C) and concomitantly increases plasma high-density lipoprotein cholesterol (HDL-C). Ezetimibe reduces absorption of biliary and dietary cholesterol from the small intestine, thereby reducing LDL-C levels.

Objective/Purpose

The current study was carried out to elucidate the mechanism of action responsible for the observed decrease in non-HDL-C by obicetrapib monotherapy and in combination with ezetimibe in a translational mouse model for hyperlipidemia and atherosclerosis.

Methods

Female ApoE*3-Leiden.CETP transgenic mice were fed a Western diet with 0.05% w/w cholesterol (equivalent to daily human intake) or this diet containing obicetrapib alone (2 mg/kg/day), ezetimibe alone (1 mg/kg/day) or the combination of obicetrapib and ezetimibe.

Results

Obicetrapib, ezetimibe and the combination thereof reduced total plasma cholesterol levels (-42%, -23% and -62%), mainly attributed to a decrease in non-HDL-C levels (-61%, -24% and -80%). Obicetrapib alone and in combination with ezetimibe nearly completely blocked CETP activity (-99% and -100%) resulting in increased HDL-C (+260% and +245%) and ApoA1 levels (98% and 81%). Obicetrapib, ezetimibe and to a larger extent the combination thereof enhanced clearance of VLDL-like particles (half-life: -44%, -23% and -57%) and enhanced hepatic LDL receptor expression (+63% and +74%). Fecal analysis demonstrated increased bile acid excretion in obicetrapib-treated mice (+41%) and increased neutral sterol excretion in ezetimibe-treated mice, which was even more pronounced in combination with obicetrapib (+68% and +100%), resulting in a net fecal sterol loss.

Conclusions

Obicetrapib alone and the combination with ezetimibe reduce non-HDL-C levels by increased VLDL lipolysis, increased VLDL clearance and elevated LDL receptor levels accompanied by an enhanced fecal bile acid and neutral sterol excretion.

Study Funding

Kaneka Pharma America: “Lipoprotein(a) Testing at URMC and Referral to Preventive Cardiology Program".

Background/Synopsis

Lipoprotein(a) (Lp(a)) is a cholesterol-containing, genetically determined molecule in our blood. Studies show that an elevated level of Lp(a) can independently predict an increased risk of atherosclerotic cardiovascular disease (ASCVD) events. There are currently no FDA-approved drugs to reduce Lp(a) and cardiovascular disease event risk.

Objective/Purpose

Using the electronic health record (EHR) from the University of Rochester Medical Center (URMC), we determined how well Lp(a) levels predict future cardiovascular disease events currently and over time.

Methods

Data were collected from the URMC EHR database of patients >= 18 years with and without at least one Lp(a) measurement from January 1st, 2011 to August 1st 2023 . Cox regression analysis was performed to investigate the effect of Lp(a) level on ASCVD events, while adjusting for several demographic factors and previous ASCVD event status. The Lp(a) level was dichotomized into a normal-level group (<=30 mg/dL) and a high-level group (>30 mg/dL).

Results

From January 1st, 2011 to August 1st, 2023, we identified 2,698 patients with at least one Lp(a). Among these individuals, 1,594 did not have an ASCVD event after a baseline Lp(a), while 611 individuals did have an ASCVD event after an Lp(a) baseline measurement. The remaining individuals did not have data on ASCVD status. The mean Lp(a) level was 48 mg/dL among all patients, 45.2 mg/dL among patients without an ASCVD event, and 55.2 mg/dL among patients with an ASCVD event. The normal Lp(a) level range in the URMC lab is <30 mg/dL. Among patients without ASCVD history at baseline, the hazard of an ASCVD event in the high Lp(a) level group is 1.44 times the hazard for the normal Lp(a) level group, with a p-value of 0.008. For patients with a previous ASCVD event, the hazard of an ASCVD event in the high Lp(a) level group is 0.87 times the hazard for the normal Lp(a) level group but not at a statistically significant level (p-value = 0.206).

Conclusions

The level of Lp(a) has a varied effect on the hazard of a future ASCVD event. While high Lp(a) level increased the hazard of future ASCVD event for patients with no ASCVD history, high Lp(a) level does not significantly affect the hazard of future ASCVD event for patients with an ASCVD history. It is vital to measure Lp(a) levels to make active steps toward prevention of ASCVD events in the future.

Abetalipoproteinemia (ABL) is a rare recessive genetic disease caused by bi-allelic pathogenic variants in the microsomal triglyceride transfer protein (MTTP) gene. This disease is characterized by a deficiency in the secretion of apolipoprotein B-containing lipoproteins. Patients with ABL present with neurological, hematological, and gastrointestinal symptoms due to fat malabsorption and a deficiency in liposoluble vitamins. In this report, we present a total of four ABL cases, including three new cases, all originating from the same French-Canadian founder population in Saguenay-Lac-Saint-Jean, Québec, Canada. These individuals are homozygous for the same pathogenic variant in the MTTP gene (c.419dup, p.Asn140Lysfs*2). We found that this variant is more common than anticipated in this population, with an estimated carrier frequency of 1:203. Early diagnosis is essential to initiate treatment known to prevent complications associated with ABL. Population carrier screening or newborn screening for ABL should be considered in this French-Canadian founder population.

Study Funding

NewAmsterdam Pharma.

Background/Synopsis

The oral selective cholesteryl ester transfer protein (CETP) inhibitor, obicetrapib, is in development for dyslipidemia in patients unable to achieve sufficient low-density lipoprotein cholesterol (LDL-C) lowering with other lipid-lowering medications. Previous Phase 1 and 2 trials evaluated obicetrapib as monotherapy, in combination with statins and on top of high-intensity statins (HIS).

Objective/Purpose

In this study we tested the efficacy and safety of obicetrapib in combination with ezetimibe on top of HIS.

Methods

ROSE2 enrolled men and women without current clinically manifest cardiovascular disease who had LDL-C >70 mg/dL and triglycerides <400 mg/dL, while taking HIS. Participants continued their HIS and were randomized to obicetrapib 10 mg + ezetimibe 10 mg (n=40), obicetrapib 10 mg (n=39), or placebo (n=40) for 12 weeks. Endpoints included the LDL-C response to combination therapy vs. placebo (primary), and non-high-density lipoprotein cholesterol (non-HDL-C), nuclear magnetic resonance-assessed lipoprotein particles (-P), apolipoprotein B (ApoB), lipoprotein (a) [Lp(a)], small dense (sd)LDL-C, other lipid biomarkers and safety.

Results

Obicetrapib monotherapy and with ezetimibe, respectively, significantly (all P<0.05) reduced LDL-C (43.5 and 63.4%), non-HDL-C (37.5 and 55.6%), ApoB (24.2 and 34.4%), total LDL-P (54.8 and 72.1%), small LDL-P (92.7 and 95.4%), sdLDL-C (30.9 and 44.4%), and Lp(a) (47.2 and 40.2%), and increased HDL-C (142 and 136%). Obicetrapib was well tolerated, with no dose-related adverse events or clinically significant changes in vital signs, electrocardiograms, hematology or biochemistry. The tremendous lowering of LDL particles with obicetrapib + ezetimibe suggests a synergistic effect perhaps due to an additional mechanism of action (MoA) for CETP inhibition; it upregulates LDL receptors (as previous studies have indicated), but also increases cholesterol removal through transintestinal cholesterol excretion (TICE). Ezetimibe meanwhile prevents reuptake of the excreted cholesterol removed via the inhibition of Niemann-Pick C1-like 1 (Figure).

Conclusions

Obicetrapib monotherapy, in combination with HIS, and with HIS plus ezetimibe is safe, well-tolerated and produces robust reductions in LDL-C, LDL particles, sdLDL-C, and Lp(a). ROSE2 obicetrapib monotherapy results concur with findings across the phase 1/2 development program, while combination therapy results support a synergistic effect of obicetrapib + ezetimibe on circulating LDL particles, consistent with the drugs’ known and hypothesized MoAs.

Background/Synopsis

Genetic testing for inherited lipid disorders can facilitate diagnosis, treatment, and family cascade screening. Of the known monogenic dyslipidemias, familial hypercholesteremia (FH) is the most common. FH is caused by inherited pathogenic variants in LDLR, APOB, PCSK9, and LDLRAP1 and is characterized by significantly elevated LDL cholesterol and increased risk for coronary artery disease (CAD). There are limitations to genetic testing and potential insurance implications, thus a shared decision model including a physician and genetic counselor provides optimal decision-making for the patient.

Objective/Purpose

Describe real-world experience of genetic testing at a lipid clinic with involvement of a genetic counselor.

Methods

Electronic health record (EHR) data from October 2021 to December 2023 was reviewed for all patients referred to the Inherited Lipid Disorders Clinic at the University of Pennsylvania for genetic counseling and testing.

Results

A total of 350 patients were referred for genetic testing. Approximately 72% (n=253) were for FH, 13% for other dyslipidemia, 5% for high triglycerides/chylomicronemia syndrome, 3% for partial lipodystrophy, and 5% for cascade screening following positive genetic testing in a family member. Following communication with the genetic counselor, genetic testing orders were placed for 310 patients who agreed to testing, of which 77% (n=239) completed testing. Results for these patients revealed 51 pathogenic variants, 27 positive (but not diagnostic) variants, 72 variants of uncertain significance (VUS), and 128 negative results. Among the 178 FH patients who completed testing, 17% of these patients had genetic testing confirm the diagnosis of FH with pathogenic variants in LDLR, APOB, PCSK9, or LDLRAP1, while 10% of patients were found to have a VUS in one of these 4 genes. Among the 19 hypertriglyceridemia patients, 9 completed testing and 1 pathogenic variant in LPL was detected. Of the 10 patients with partial lipodystrophy, 7 completed testing and 1 pathogenic variant in LMNA was detected. Meanwhile, of the 17 patients referred for cascade screening, 14 completed testing which showed a pathogenic LDLR variant in 8 patients and 1 patient with an LMNA variant. The genetic counselor informed all patients of results.

Conclusions

A high proportion of patients (68%) referred to the lipid clinic for genetic testing completed testing with at-home kits. The majority of patients referred for testing were those with suspected FH. Incorporation of a genetic counselor in the program provides patients with a comprehensive education on the risks and benefits of genetic testing.