Homozygous familial hypercholesterolemia (HoFH) is characterized by mutations in the low-density lipoprotein (LDL) receptor leading to highly elevated levels of LDL-cholesterol (LDL-C). As a result, patients with HoFH develop atherosclerotic cardiovascular disease in childhood and have a low life expectancy of ∼18 years without appropriate treatment. Diagnosis in early childhood is essential to reduce morbidity and mortality. Lomitapide is a selective microsomal triglyceride transfer protein inhibitor approved for adults with HoFH that works independently of the LDL receptor to lower LDL-C. APH-19 (NCT04681170) is the first clinical trial of lomitapide in pediatric patients with HoFH and met its primary endpoint (LDL-C reduction of -53.5% at Week 24; p<0.0001).
We report additional parameters from APH-19 relating to the efficacy and safety of lomitapide in pediatric patients.
APH-19 is a phase 3, open-label, single-arm clinical trial in HoFH patients aged 5–17 years (N=43) consisting of a run-in period followed by 24-week efficacy and 80-week safety phases. Patients were stratified by age into three dose escalation groups, where the maximum doses were 20, 40 and 60 mg. Here, additional data at Week 24 of patient-level LDL-C reductions, lipoproteins (apolipoprotein B [ApoB] and lipoprotein A [Lp(a)]) and additional safety endpoints (growth/maturation and fat-soluble vitamin levels) are reported.
Lomitapide treatment resulted in up to a 95% reduction of LDL-C from baseline at Week 24 with 53.5% of patients (n=23) having >50% reduction in LDL-C from baseline (Figure). Mean reduction in ApoB was -52.4% at Week 24 (p<0.0001); an ApoB subgroup analysis indicated general consistency across a range of parameters. Mean change from baseline in Lp(a) was -23.6% (p=0.0030) for nmol/L methodology and -11.3% (p=0.2884, Fisher Combined p-value p=0.0070) for mg/dL analysis. Subgroup results will be presented.
There were no clinically significant mean changes in weight or height from Baseline to Week 24. The mean change in weight-for-age Z-score was -0.371 for patients aged 5–10 years (11–17, N/A). Changes in height-for-age Z-score were -0.064 and -0.060 for patients aged 5–10 and 11–17 years, respectively. Fat-soluble vitamins at Week 24 were within normal range for individuals aged 5–17 years; vitamin E increased in 10.0% of patients aged 5–10 years, considered mild in severity.
These data further support the efficacy and safety of lomitapide across various parameters in pediatric patients. The lack of impact on patient maturation endpoints is encouraging; however, further long-term data are required.
Cardiac catheterization remains the gold standard for the evaluation of obstructive coronary artery disease in patients presenting with acute coronary syndrome (ACS). Although this procedure is lifesaving, there are several potential life-threatening complications such as coronary artery dissection. The impact of familial hypercholesterolemia (FH) on complication rates in patients presenting with acute coronary syndrome has not been well studied.
The purpose of this study was to assess the impact of familial hypercholesterolemia on the development of coronary artery dissection in patients presenting with ACS undergoing percutaneous coronary intervention (PCI).
We performed a retrospective analysis of the NIS database from 2016 to 2018 to identify patients presenting with ACS and PCI using ICD-10-CM/PCS codes. We compared the primary outcome of coronary artery dissection in patients with and without familial hypercholesterolemia. The primary outcome was in-hospital mortality, and secondary outcomes were hypertension, acute kidney injury, cardiogenic shock, obesity, type 2 diabetes mellitus, length of stay, and total hospitalization cost. We performed multivariate logistic regression analysis to identify associations for coronary artery dissection.
A total of 58,685 patients presented to the hospital with ACS and underwent PCI. The mean age was 64.85 ± 12.70 years, and most patients were male (69.69%) and Caucasian (75.51%). Patients with familial hypercholesterolemia (FH) had a higher coronary artery dissection rate at 2.27% vs. 1.22%, p = 0.52. There was a difference between patients with and without FH for in-hospital mortality, 0% compared to 4.40%, but not statistically significant (p = 0.15). The length of stay was longer for patients without FH, 4.45 days compared to 3.93 days (p = 0.38). Multiple logistic regression analysis revealed that type 2 diabetes was not a statistically significant predictor of coronary artery dissection, Table 1.
The presence of familial hypercholesterolemia was not a statistically significant predictor of coronary artery dissection, but cardiogenic shock was statistically significant. Further pragmatic clinical trials are needed to evaluate familial hypercholesterolemia and association with complications in patients presenting with acute coronary syndrome.
Studies reveal increased incidences of cardiovascular events such as heart attacks and strokes in patients with elevated lipoprotein(a) levels. Niacin-ER has shown to lower lipoprotein(a) levels by approximately 30% though unknown if niacin-ER reduces cardiovascular events in this population. This single center study evaluates 129 patients with a personal or family history of a premature cardiovascular event whose lipoprotein(a) levels were greater than 75nmol/L and prescribed niacin-ER.
Identify patients with personal or family history of premature cardiovascular events through history and screen patients for baseline serum lipoprotein(a); levels greater than or equal to 75nmol/L were included. Patients were monitored for incidences of cardiovascular events, elevation of liver enzymes, and side-effects of niacin-ER.
The study is an effort to determine if niacin-ER can reduce cardiovascular events. While current ASO-RNA and siRNA studies are undergoing trials, niacin-ER may be a less costly alternative.
The study followed 129 adult patients seen by a Board Certified Lipidologist/Cardiologist from 2014-2024 with baseline lipoprotein(a) greater than 75 nmol/L. Patients were started on 1000 mg-2000 mg (mean 1713 mg) of niacin-ER and a high intensity statin. In the study, 118 patients were prescribed niacin-ER, while 11 were a better fit for PCSK-9 therapy. Of the 118 patients, 36 could not tolerate the flushing, despite mitigating strategies. Patients’ hospital and outpatient records were reviewed for cardiovascular events.
The average baseline value of lipoprotein(a) was 221.59 nmol/L, higher than 35-70 nmol/L in AIM-HIGH and HPS2-THRIVE trials. Current trials with siRNA and ASO-RNA therapies set inclusion criteria at >150 nmol/L. The average lipoprotein(a) after starting niacin-ER amounted to 157.71 nmol/L, a 33.68% reduction.
Fifteen patients laboratory tests resulted in non-prohibitive mildly elevated liver function tests (LFTs), with maximum ALT and AST of 85 U/L and 68 U/L, respectively, after starting niacin.
All patients were on high-intensity statin.
Niacin-ER reduced lipoprotein(a) levels by 33.68%, comparable to published data of 30%.
Niacin-ER continues to be shown as safe and well-tolerated with no incidences of strokes, infections, gastrointestinal symptoms, or rhabdomyolysis; there was a non-significant elevation in LFTs.
In the 83 patients taking niacin-ER, there were no subsequent cardiovascular events up to ten years follow up.
Reduction in cardiovascular events could not be observed with the low sample size. The study reinforces the need to further assess the effectiveness of niacin-ER on cardiovascular events while prospective therapies continue through trials.
Familial Chylomicronemia Syndrome (FCS) is a rare autosomal recessive disorder affecting chylomicron metabolism, resulting in severe hypertriglyceridemia (sHTG) associated with recurrent acute pancreatitis (AP). We present a case of young woman with a rare instance of familial lipoprotein lipase (LPL) deficiency during pregnancy.
Despite that FCS is associated with poor quality of life and increased lifelong risk of sHTG and AP, there is lack of awareness about the disease. We aim to describe clinical features and complications associated with FCS, with the overarching objective of enhancing awareness regarding this condition. Additionally, we explore emerging therapies for the treatment of sHTG.
Literature review and retrospective review of electronic health records were performed.
17-year-old Guatemalan female at 25 weeks gestation presented with acute abdominal pain and was found to have a lipase of 4076 mg/dL, amylase of 860 mg/dL and triglyceride (TG) level of 2233 mg/dL requiring apheresis for sHTG induced AP. She re-presented multiple times with sHTG and required treatment for recurrent AP. Genetic testing showed homozygous LPL gene mutation involving novel early truncation and ABCA1 transporter heterozygosity linked to reduced HDL levels. Patient continues to experience a sequela of complications despite treatment with fibrates, statins, omega-3-acid ethyl esters and a low-fat diet.
There are currently no treatments for FCS except for lifelong fat restrictive diet. Orlistat, a gastric and pancreatic lipase inhibitor has shown some promise in terms of reducing TG levels. Prior therapies have targeted various phenotypes of sHTG in familial combined hyperlipidemia syndromes with off-label use in FCS. More recently, targeted pharmacotherapies for FCS including apoC-III hepatocyte-directed antisense oligonucleotide such as Volanesorsen (approved in Europe) and Olezarsen (currently in phase-3 trial) have shown promise. Preliminary results from the CORE trials have shown significant reduction in TG levels in FCS patients and 100% reduction in AP. Additionally, small interfering ribonucleic acid (siRNA) based therapies are being studied in patients with FCS.
Albeit a rare genetic disorder, FCS should be suspected in patients with sHTG in the absence of secondary causes and should be referred to lipid specialists for further management. FCS in pregnancy can pose even more challenges given increased insulin resistance and fetal and maternal burden of disease. Trials for novel targeted therapies have shown encouraging results and may help reduce ASCVD risk and complications associated with FCS.
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