Inhibitors of PCSK9 by monoclonal antibodies (PSCK9mAb) are efficacious lipid lowering therapies with established outcome benefits. Side effects include nasopharyngitis, influenza-like illness, and injection site reactions.
To describe a less-commonly reported adverse reaction to evolocumab in a patient with severe familial hyperlipidemia (FH), outline applicable testing, and treatment strategies.
We report a patient with severe FH who developed fever, elevated liver function tests (LFTs), pericardial and pleural effusions with evolocumab.
A 70-year-old gentleman with hyperlipidemia presented to preventive cardiology clinic for consultation. His baseline LDL-cholesterol (LDL-C) was 400 mg/dL and examination revealed bilateral arcus senilis and xanthomas. Patient's paternal family members were all on lipid-lowering therapy although there were no early atherosclerotic events. Dutch criteria scoring was 21 (definite FH). His lifestyle was optimal, including a Mediterranean diet with daily walking. Risk assessment revealed a calcium score of 3000 AU, carotid atherosclerosis, and lipoprotein (a) of 233.1 nmol/L. Treatment with ezetimibe 10 mg oral daily and rosuvastatin 40 mg oral daily was initiated, achieving a post-treatment LDL-C of 130 mg/dL. To further improve the patient's outcomes by targeting a LDL-C of <70 mg/dL, evolocumab 140 mg subcutaneous biweekly was prescribed. After the first dose, he had fever. Two weeks after the second dose, he was hospitalized with: fever, elevated inflammatory markers and LFTs, pericardial and pleural effusions. Discontinuation resolved symptoms. Post-hospital discharge, laboratory abnormalities normalized. Colchicine and steroids were administered for pericarditis.
This case underscores complexities of managing lipid disorders when confronted with adverse reactions. Based on delayed-onset symptoms and laboratory abnormalities after medication, it is critically-important to consider the possibility of an immune-mediated reaction. The needle cover of the single-dose prefilled autoinjector of evolocumab contains a derivative of latex, a potential risk factor for triggering Gell-Coombs Type I and IV allergic reactions in latex-sensitive individuals. Percutaneous latex skin prick testing is pending. Evolocumab is fully humanized, reducing the risk of immunogenicity, yet this does not exclude adverse drug reactions. The mechanism for common adverse events associated with monoclonal antibodies involves a cytokine-mediated type alpha immune response, explaining flu-like symptoms and injection site reactions. Because of our patient's extensive atherosclerotic disease, additional evaluation will assist us in risk-stratifying treatment: alirocumab, inclisiran, evanicumab or lipoprotein apheresis to reach a target LDL-C of <70 mg/dL.
Multifactorial chylomicronemia syndrome (MCS), also known as type V hyperlipoproteinemia, is a rare polygenic disorder characterized by severe hypertriglyceridemia. It is triggered by uncontrolled diabetes mellitus (DM), obesity, metabolic syndrome, and certain medications. It is not known whether hypertriglyceridemia associated with MCS accelerates atherosclerotic cardiovascular disease (ASCVD).
To speculate the relationship between ASCVD in a patient with hypertriglyceridemia caused by MCS, uncontrolled DM, and polymorphic APOA5, APOE2/4, LMF1 and LP(a) intron mutations.
We present a 60-year-old male with PMH of severe hypertriglyceridemia (highest 6000mg/dL) with acute pancreatitis at age 40, CAD s/p CABG at age 50, PAD s/p bypass at age 57, HTN, mixed hyperlipidemia, uncontrolled DM, and family history of premature ASCVD. He was subsequently followed at the advanced lipid clinic where his medications included rosuvastatin, ezetimibe, evolocumab, fenofibrate, and icosapent ethyl. He underwent advanced genetic testing with GBinsight.
GBinsight identified various polymorphic genes causing hypertriglyceridemia as follows:
APOA5 - c.*158C>T(rs2266788)
This variant is found in ∼10% of the global population and has been associated with hypertriglyceridemia by multiple genome-wide association studies.
APOA5 - c.457G>A(p.Val153Met)(rs3135507)
This variant is found in ∼5-10% of the global population and has been associated with modest hypertriglyceridemia and lower HDL-C in the UKBiobank cohort.
APOE2
This allele has been associated with a reduction of the major lipolytic enzyme, lipoprotein lipase (LPL) activity, causing modest hypertriglyceridemia.
LMF1 - p.Arg354Trp(rs143076454)
This variant is found in ∼2% of the global population, and has been associated with a reduction of LPL activity causing modest hypertriglyceridemia.
GBinsight identified various pathogenic genes causing elevated Lp(a) as follows:
LPA - Heterozygous for intron c.3947+467T>C(rs10455872)
This variant serves a genetic proxy for short isoforms and is strongly associated with increased Lp(a), total and LDL-cholesterol levels, and increased ASCVD risk.
APOE4
This allele is associated with increased Lp(a) levels.
We speculate that the combination of these polymorphisms works together to increase risk of severe hypertriglyceridemia, also known as MCS. Several smaller studies have suggested MCS is caused by either
Lipoprotein(a) [Lp(a)] is an independent, genetic, and causal risk factor for atherosclerotic cardiovascular disease (ASCVD). Elevated Lp(a) levels increase a person's risk for myocardial infarction, coronary artery disease, ischemic stroke, and aortic stenosis. Guidelines generally recommend testing for Lp(a) in high-risk patients, with some recent guidelines recommending testing once in all adults. It is estimated that >20% of the population carry Lp(a) levels high enough to increase risk, however due to undertesting, many of these patients have not been identified.
To understand the attitudes and barriers to testing for Lp(a) across relevant clinical settings and specialties at the University of Pennsylvania Health Systems (UPHS).
A brief IRB-approved survey in REDCap was distributed via email to select groups of UPHS providers in Cardiology, Neurology, Primary Care, and Vascular Surgery.
The survey was sent to approximately 525 providers in December 2023. Of these, 116 providers completed the survey (54% Internal Medicine/Family Practice, 31% Cardiology, 10% Neurology, 4% Vascular Surgery). Approximately 31.0% (n=36) of all providers routinely tested for Lp(a) in their practice, but this varied by specialty (44% of Cardiologists versus 22% of Internal Medicine/Family Practice providers). For these providers, the most common reasons for testing included a familial history of ASCVD, a history of ASCVD in the patient, and high cholesterol (Table 1). A total of 80 providers (69%) responded that they do not regularly test for Lp(a). The most common reasons for not testing included lack of familiarity with Lp(a), insurance/billing concerns, lack of clinical trial outcomes data, and lack of available pharmaceutical interventions (Table 2).
While there is likely selection bias in the providers who chose to complete the survey, a surprisingly high number of responders (69%) described not regularly testing for Lp(a) in their practice. While results from ongoing clinical trial investigations of novel Lp(a)-lowering treatments may address provider hesitation toward utility of Lp(a)-testing, there is still a large gap to fill in Lp(a) awareness. Increasing provider knowledge of Lp(a) and incorporation into broader clinical guidelines are needed.
This CME activity was supported by an educational grant from Regeneron Pharmaceuticals, Inc.
Despite the clear benefit of early treatment of homozygous familial hypercholesterolemia (HoFH) in reducing the risk of progressive atherosclerotic cardiovascular disease (ASCVD), many patients remain undiagnosed until advanced ASCVD is present. Diagnostic delays may relate to low screening rates found among at-risk children <9 years old.
To study the impact of an online CME program to enhance health care providers' (HCPs') competence in diagnosing and managing HoFH and to overcome barriers to screening for at-risk children.
A 60-minute CME activity was launched live online on 8/2/23 and is available on-demand for 1 year. Knowledge, attitude, and practice-pattern questions were administered before and immediately after the activity (pre vs post). Chi-square tests compared paired responses (P<0.05; pre/post).
As of 1/2/24, 260 HCPs engaged in the program (30% cardiologists, 6% endocrinologists, 29% PCPs; 17% specialize in lipid management or are lipidologists). Nearly 60% of HCPs reported managing patients with very high lipid levels (>400 mg/dL) and the average number of patients with very high lipid levels managed by these participants is 17 per year (approximately 5 of whom are <9 years of age). HCPs' knowledge of the diagnostic criteria for HoFH (30% vs 58%), mechanism of action of ANGPTL3 inhibitors (22% vs 43%), and treatment intensification strategies (48% vs 62%) increased significantly during the CME activity.
Before the activity, approximately 20% of respondents did not measure lipid levels in children <9 years old, 20% only measured in children with a parent diagnosed with familial hypercholesterolemia (FH) or with a family history of CVD, and 24% only measured in children with HoFH symptoms. After the activity, HCPs estimated that 60% of their patients with very high lipid levels (>400 mg/dL) may have undiagnosed HoFH. The proportion of HCPs who strongly agreed with the American Academy of Pediatrics' recommendation for lipid screening for children with a genetic risk of FH or ASCVD as early as age 2 years increased from 14% to 37%.
CME can break down barriers to lipid screening in children at risk for HoFH by enhancing HCPs' knowledge of HoFH diagnosis and risk factors. While the activity enhanced knowledge about the evolving treatment landscape, future education on guidelines and treatment intensification can address remaining gaps in the adoption of best practices and novel agents for HoFH.
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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