Severe Hypertriglyceridemia Research Articles

Inhibition of Angiopoietin-Like Protein 3 or 3/8 Complex and ApoC-III in Severe Hypertriglyceridemia.

The role of the inhibition of ANGPTL3 in severe or refractory hypercholesterolemia is well documented, less in severe hyperTG. This review focuses on the preclinical and clinical development of ApoC-III inhibitors and ANGPTL3, 4, and 3/8 complex inhibitors for the treatment of severe or refractory forms of hypertriglyceridemia to prevent cardiovascular disease or other morbidities. APOC3 and ANGPTL3 became targets for drug development following the identification of naturally occurring loss of function variants in families with a favorable lipid profile and low cardiovascular risk. The inhibition of ANGPTL3 covers a broad spectrum of lipid disorders from severe hypercholesterolemia to severe hypertriglyceridemia, while the inhibition of ApoC-III can treat hypertriglyceridemia regardless of the severity. Preclinical and clinical data suggest that ApoC-III inhibitors, ANGPTL3 inhibitors, and inhibitors of the ANGPTL3/8 complex that is formed postprandially are highly effective for the treatment of severe or refractory hypertriglyceridemia. Inhibition of ANGPTL3 or the ANGPTL3/8 complex upregulates LPL and facilitates the hydrolysis and clearance of triglyceride-rich lipoproteins (TRL) (LPL-dependent mechanisms), whereas ApoC-III inhibitors contribute to the management and clearance of TRL through both LPL-dependent and LPL-independent mechanisms making it possible to successfully lower TG in subjects completely lacking LPL (familial chylomicronemia syndrome). Most of these agents are biologicals including monoclonal antibodies (mAb), antisense nucleotides (ASO), small interfering RNA (siRNA), or CRISPR-cas gene editing strategies.

How to Handle Elevated Triglycerides: Life after PROMINENT.

Hypertriglyceridaemia (HTG) is a common condition characterised by elevated levels of plasma triglycerides (TG), which are transported in the blood mainly by TG-rich lipoproteins (TRL). Elevated TG levels (150-400 mg/dL) are associated with increased cardiovascular risk. Severe HTG (>880 mg/dL) is associated with a risk of acute pancreatitis only. Randomised clinical trials investigating the clinical benefit of TG-lowering drugs in patients with elevated TG levels have provided conflicting results. Elevated TG levels are only one marker of altered lipid/lipoprotein metabolism and indeed reflect altered concentrations of one or more classes or subfractions of TRL, which in turn may have a different association with CV risk. Fibrates, the drugs most commonly used to treat HTG, provide cardiovascular benefits to only a specific subgroup of patients. The lack of clinical benefit from pemafibrate has emphasised the concept that lowering TG levels is not sufficient to reduce the CV risk unless it is accompanied by a reduction in the number of circulating atherogenic lipoproteins, which can be assessed by determining apolipoprotein B levels. Treatment with omega-3 fatty acids was also ineffective in reducing CV risk, with the exception of icosapent ethyl, which, however, appears to have beneficial effects beyond lipids. New drugs are currently being developed that aim to lower TG levels by targeting apolipoprotein C-III or angiopoietin-like-3, both of which are involved in the metabolism of TGs. TG reduction can be achieved by various drugs, but most of them are ineffective in reducing CV risk. The results of outcome studies on new TG-lowering drugs will clarify whether lowering apoB levels is critical to achieve clinical benefit.

Premature coronary artery disease and severe hypertriglyceridemia in a patient with monogenic diabetes: a case report

Aim. Maturity- onset diabetes of the young (MODY) is a group of monogenic diseases with an autosomal dominant inheritance. This is a rarely diagnosed disease, occurring in 1 of 10 thousand adults and in 1 of 23 thousand children. Brief description. We present a case report of a patient with a monogenic diabetes HNF4A-MODY, severe hypertriglyceridemia, progressive premature coronary artery disease and a HNF4A gene pathogenic variant (ENST00000316099.8:c.1145dup).Discussion. This case demonstrates the effectiveness of triple hypoglycemic therapy, including empagliflozin for the treatment of monogenic diabetes. Despite the fact that the patient with diabetes reached the target glycated hemoglobin level, the combination of the disease with other cardiovascular risk factors (hypertension, hypertriglyceridemia, obesity, smoking, male sex) led to the progression of coronary and peripheral atherosclerosis. Considering the data of genetic testing, returning to sulfonylurea therapy should be considered. It is important for patient to follow a strict lipid-lowering diet and taking combination lipid-lowering therapy (rosuvastatin, fenofibrate and omega-3 polyunsaturated fatty acids) in order to achieve the target level of low-density lipoprotein cholesterol <1,4 mmol/l and triglycerides <1,7 mmol/l.

AAV-mediated hepatic LPL expression ameliorates severe hypertriglyceridemia and acute pancreatitis in Gpihbp1 deficient mice and rats

GPIHBP1 plays an important role in the hydrolysis of triglyceride (TG) lipoproteins by lipoprotein lipases (LPLs). However, Gpihbp1 knockout mice did not develop hypertriglyceridemia (HTG) during the suckling period but developed severe HTG after weaning on a chow diet. It has been postulated that LPL expression in the liver of suckling mice may be involved. To determine whether hepatic LPL expression could correct severe HTG in Gpihbp1 deficiency, liver-targeted LPL expression was achieved via intravenous administration of the adeno-associated virus (AAV)-human LPL gene, and the effects of AAV-LPL on HTG and HTG-related acute pancreatitis (HTG-AP) were observed. Suckling Gpihbp1-/- mice with high hepatic LPL expression did not develop HTG, whereas Gpihbp1-/- rat pups without hepatic LPL expression developed severe HTG. AAV-mediated liver-targeted LPL expression dose-dependently decreased plasma TG levels in Gpihbp1-/- mice and rats, increased post-heparin plasma LPL mass and activity, decreased mortality in Gpihbp1-/- rat pups, and reduced the susceptibility and severity of both Gpihbp1-/- animals to HTG-AP. However, the muscle expression of AAV-LPL had no significant effect on HTG. Targeted expression of LPL in the liver showed no obvious adverse reactions. Thus, liver-targeted LPL expression may be a new therapeutic approach for HTG-AP caused by GPIHBP1 deficiency.

Severe hypertriglyceridemia and its correlation with clinical atherosclerosis and pancreatitis investigated in beta-quantification

Abstract Background Severe hypertriglyceridemia is commonly associated with pancreatitis and questionably atherosclerotic cardiovascular disease (ASCVD). However, while some patients develop those sequelae at relatively low levels, others with extreme levels remain spared from it. Purpose This study serves to validate, whether the distribution of triglycerides (TG), either in very-low-density lipoprotein (VLDL) particles or chylomicrons (CM) can be decisive for the development of clinical disease. Methods Patients with TG levels above 500 mg/dL, who routinely visited our lipid outpatient clinic between 2016 and 2021 with their lipid panel done via beta-quantification were retrospectively investigated for the presence of clinical pancreatitis and ASCVD via electronic chart-review. Results In total, 221 patients met eligibility criteria, with a mean age of 48 years, BMI of 29.7, with 72.4% males. Median TG and low-density lipoprotein cholesterol levels were 827 mg/dL and 62 mg/dL, respectively. A history of pancreatitis was present in 13.7% of patients, while ASCVD was present in 20.7%. TG distribution, described as the ratio of TG in VLDL per TG in CM showed no significant differences with regards to pancreatitis incidence (p=0.393). For ASCVD, the ratio was significantly higher in those with ASCVD vs those without (3.54 vs 2.25) (p=0.008). CM-dominant TG distribution was present in 19.5% of patients and was associated with higher total TG levels (2122 mg/dL vs 825 mg/dL), compared to VLDL-dominant TG distribution. Conclusion A higher relative amount of TGs in VLDL compared to CM, as most prevalent pattern, was associated with ASCVD, while very high levels of TG frequently relate to hyperchylomicronemia.

Cross-sectional analysis of demographic and clinical characteristics of patients using icosapent ethyl

Abstract Background/Introduction Icosapent ethyl (IPE) is an ethyl ester of eicosapentaenoic acid first approved in 2012 in the United States for the treatment of severe hypertriglyceridemia (triglyceride [TG] levels ≥500 mg/dL).1 Following results from the global REDUCE-IT trial in 2019 in which IPE substantially reduced the risk of cardiovascular (CV) events,2 IPE was approved in European countries and the United States to reduce the risk of CV events in adults treated with statins who have elevated TG levels (≥150 mg/dL) and established CV disease (CVD) or diabetes mellitus (DM) with additional risk factors for CVD.1,3 An estimated 3 million American adults are eligible to receive IPE for primary and secondary CVD prevention.4 Purpose Provide the first descriptive study of demographic and clinical characteristics of US patients taking IPE. Methods A database with electronic medical records of >89 million patients from 56 US health care organizations was used to identify those taking IPE, defined as those for whom at least 2 IPE prescriptions were documented (ie, on 2 separate dates). No specific date range or exclusion criteria were applied. Patient demographic information, prior/existing conditions, prior/concomitant medications, and laboratory data were retrieved. Results As of January 19, 2023, a total of 40,408 patients taking IPE were identified; they had a mean (SD) age of 60.3 years (12.9) and a body mass index of 31.9 kg/m2 (6.07). Most patients started taking IPE after January 1, 2019 (72.8%), were men (60.5%), White (75.2%), non-Hispanic or Latino (73.1%), and from the southern (46.0%) or northeastern (34.0%) United States (Table). In line with the indication of IPE, 65.3% had prior atherosclerotic CVD or DM and at least 1 risk factor. Common prior or existing conditions associated with those indicated for IPE treatment were DM (41.0%), coronary artery disease (30.2%), prior myocardial infarction (11.0%), prior stroke (7.4%), and severe hypertriglyceridemia (8.1%); hypertension (68.4%) and obesity (40.9%) were common comorbidities. Mean (SD; median) TG level in the 3 months before IPE initiation was 422 mg/dL (506; 300). Treatment with statins was very high (71.8%), and common other concomitant medications included anticoagulants (53.3%), antidiabetic agents (52.3%), and antiplatelets (46.0%; Table). Fibrates were used by 26.0% of patients taking IPE any time on or before IPE initiation. Conclusion(s) Patients using IPE commonly had a history of CVD, DM, or both, took statins, and had elevated levels of TG, thereby meeting the indication for IPE treatment. The high baseline TG levels in this population suggest that IPE is underutilized.

Abstract 12564: Safety, Pharmacokinetics, and Lipid Lowering Effects of the Oral, Liver-Targeted Liver X Receptor (LXR) Inverse Agonist TLC-2716 in Healthy Volunteers

Background: The liver X receptors are oxysterol-activated nuclear hormone receptors that regulate cholesterol homeostasis and de novo lipogenesis. TLC-2716 is an oral, liver-targeted inverse agonist of LXRα/β in development for severe hypertriglyceridemia (SHTG) and NASH. Methods: In this randomized, double-blind, placebo (PBO)-controlled Phase 1 study (NCT05483998), healthy subjects (n=8/2 TLC-2716 vs PBO/cohort) received single ascending doses (SAD) of TLC-2716 (0.5, 2, 6, 12, or 20 mg) or multiple ascending doses (MAD) QD for 14 days (0.5, 2, 6, or 12 mg) while fed or 6 mg fasted. Safety, PK, serum lipid parameters by NMR LipoProfile ® , and gene expression in PBMCs were evaluated. Results: The proportion of subjects with adverse events (AEs) was 60% with PBO and 13-50% with TLC-2716 in the SAD cohorts (n=50), and 40% and 13-88%, respectively, in the MAD cohorts (n=50). All AEs were mild except an unrelated, Grade 2 thrombophlebitis in a subject on TLC-2716 2 mg. TLC-2716 was rapidly absorbed (T max 2-4h) with a short steady-state half-life (T 1/2 ~1.5-2.5h) and low maximal plasma concentrations (C max <7 ng/mL), consistent with rapid hepatic uptake. With fed dosing, TLC-2716 AUC and C max increased less than dose proportionally and were 25-50% lower on Day 14 vs Day 1. With fasted dosing, exposures were similar on Days 1 and 14 and ~3-fold higher than with fed dosing. Significant, dose-dependent reductions in serum triglycerides, total and LDL-C, total and small LDL particles, and TG/HDL-C ratio—but not HDL-C—were observed with TLC-2716 ( Figure ). Lipid reductions were greatest in subjects with higher baseline values. TLC-2716 did not impact LXR target gene expression (e.g., reverse cholesterol transporters ABCA1 , ABCG1 ) in PBMCs, supporting its liver-targeted profile. Conclusion: The liver-targeted LXR inverse agonist TLC-2716 was well tolerated and caused significant lipid lowering in healthy subjects, supporting its evaluation in patients with SHTG and NASH.

Molecular genetic testing and measurement of levels of GPIHBP1 autoantibodies in patients with severe hypertriglyceridemia: The importance of identifying the underlying cause of hypertriglyceridemia

Severe hypertriglyceridemia can be caused by pathogenic variants in genes encoding proteins involved in the metabolism of triglyceride-rich lipoproteins. A key protein in this respect is lipoprotein lipase (LPL) which hydrolyzes triglycerides in these lipoproteins. Another important protein is glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1) which transports LPL to the luminal side of the endothelial cells. Our objective was to identify a genetic cause of hypertriglyceridemia in 459 consecutive unrelated subjects with levels of serum triglycerides ≥20 mmol/l. These patients had been referred for molecular genetic testing from 1998 to 2021. In addition, we wanted to study whether GPIHBP1 autoantibodies also were a cause of hypertriglyceridemia. Molecular genetic analyses of the genes encoding LPL, GPIHBP1, apolipoprotein C2, lipase maturation factor 1 and apolipoprotein A5 as well as apolipoprotein E genotyping, were performed in all 459 patients. Serum was obtained from 132 of the patients for measurement of GPIHBP1 autoantibodies approximately nine years after molecular genetic testing was performed. A monogenic cause was found in four of the 459 (0.9%) patients, and nine (2.0%) patients had dyslipoproteinemia due to homozygosity for apolipoprotein E2. One of the 132 (0.8%) patients had GPIHBP1 autoantibody syndrome. Only 0.9% of the patients had monogenic hypertriglyceridemia, and only 0.8% had GPIHBP1 autoantibody syndrome. The latter figure is most likely an underestimate because serum samples were obtained approximately nine years after hypertriglyceridemia was first identified. There is a need to implement measurement of GPIHBP1 autoantibodies in clinical medicine to secure that proper therapeutic actions are taken.

Abstract 16437: An Infectious Rise in Fats - Severe Hypertriglyceridemia Secondary to SARS-CoV-2 Infection

Intro There are many complications because of COVID-19 infections. These have ranged from organ dysfunctions to severe disease states. The global nature of SARS-CoV-2 pandemic has allowed clinicians to discover new pathophysiology associated with infections. We present a case of a patient with severe hypertriglyceridemia (HTG) after a SARS COVID-19 infection and propose a correlation between his infection and elevated triglyceride (TG) levels. Case A 64 y/o man living with a history of HFpEF, COPD, and HLD presented to our clinic after being diagnosed with SARS-CoV-2 infection two days prior. He had upper respiratory symptoms of a productive cough, fevers, decreased appetite, and mild dyspnea with exertion not requiring supplemental oxygen. He was prescribed paxlovid and discharged home. On follow up his symptoms had improved. He was due for a repeat lipid level and this was drawn during his visit. His last lipid panel results were normal. His repeat TG was 2,186 mg/dL. It was thought his levels were elevated because of his SARS-CoV-2 infection. His fasting TG levels were repeated and found to have normalized with a low-fat diet alone and had no further interventions. Discussion There have been few reports demonstrating a rise in TG levels after SARS-CoV-2 infections. Hepatic injury secondary to the infection or medications prescribed for treatment may lead to elevated TGs levels. When these are excluded, it is unknown what leads to HTG. Studies have evaluated lipoprotein lipase (LPL) activity levels and how they were decreased after SARS-CoV-2 infections. LPL assists in the metabolism of TG’s and activity is decreased in many disease states. It is thought that the COVID-19 infection causes HTG secondary to acquired LPL deficiency. These patients require close monitoring to decrease complications. Conclusion HTG is known to cause increased incidence of pancreatitis and ASCVD events. While treating these, one must assess the underlying etiology that led to the disease state. In patients found to have elevated TG levels it is important to include questions pertaining to recent infectious processes. Further research is needed to deduce how infectious processes can lead to elevated TG levels. Treatment consists of initiating a low-fat diet and may include fibrates.

An unexpected presentation of very severe hypertriglyceridemia in a boy with Coffin-Lowry syndrome: a case report

BackgroundCoffin-Lowry syndrome (CLS) is a rare X-linked condition with intellectual disability, growth retardation, characteristic facies and skeletal anomalies. To date, hypertriglyceridemia has not been reported in literature to be associated with CLS.Case PresentationHerein, we report a case of very severe hypertriglyceridemia 32 mmol/L (2834 mg/dL) detected incidentally at three months old in an otherwise well boy born late preterm with intrauterine growth restriction, when he presented with lipaemic plasma. He was later diagnosed with CLS. No pathogenic mutations were found for hypertriglyceridemia, and no secondary causes could explain his very severe hypertriglyceridemia.ConclusionsThe very severe hypertriglyceridemia in this case may appear to be a serious presentation of an unrecognised clinical feature of CLS, further expanding its phenotype.

Pegozafermin Is a Potential Master Therapeutic Regulator in Metabolic Disorders: A Review.

Pegozafermin (PGZ), a novel glycopegylated version of human fibroblast growth factor 21 (FGF21), has demonstrated potential for addressing metabolic comorbidities, including severe hypertriglyceridemia, insulin resistance, nonalcoholic fatty liver disease, and obesity. FGF21 is a naturally occurring peptide hormone primarily produced by the liver, with a half-life of 0.5 to 2 hours. It can influence metabolic processes through endocrine cellular effects. FGF21 receptors are found in the liver, adipose, skeletal muscles, and pancreatic tissues. Those receptors rely on the beta klotho (KLB) coreceptors, a transmembrane protein, to activate the FGF21 signaling pathway and FGF21's associated transcription factors. PGZ, through its extended half-life of 55 to 100 hours, has evidenced significant improvements in metabolic functions. Its mechanism of action includes promoting adiponectin levels, enhancing insulin sensitivity, increasing triglyceride uptake, and reducing de novo lipogenesis. This emerging pharmaceutical compound has shown promise in treating liver fibrosis and inflammation linked to nonalcoholic steatohepatitis. The ENTRIGUE trial, a phase 2 clinical trial of PGZ, has demonstrated a 57% reduction in triglyceride level compared to placebo; a 45% reduction in liver hepatic steatosis; improved insulin sensitivity; reductions in nonhigh-density lipoprotein-cholesterol; and reductions in apolipoprotein B-100.

Evaluation of apolipoprotein A5 variants: A cohort of patients with severe hypertriglyceridemia from Turkiye

This study aims to show the clinical and biochemical features in patients with severe hypertriglyceridemia (HTG) associated with rare variants in the apolipoprotein A-V (APOA5) gene. Demographics, blood lipid levels, body mass index (BMI) and APOA5 mutation subtypes were collected from the endocrinology clinic registry and analyzed for a retrospective cohort study of ten patients with severe HTG and APOA5 gene variants. Of the 10 cases, four were female, and six were male. The median age was 45.0 years (min-max: 21-60 years), the median triglyceride was 2429.5 mg/dL (27.5 mmol/L) (min-max: 1351-4087 mg/dL, 15.3-46.2 mmol/L), and the mean BMI was calculated as 30.4 ± 4.4 kg/m2 (min-max: 24.9-41.0 kg/m2). Four cases had diabetes mellitus (DM); two were on intensive insulin therapy, and two were on basal insulin therapy. The mean hemoglobin A1c was 9.2 ± 1.2 % (min-max: 8.3-11.0 %). Among the study group, eight different APOA5 gene mutations were detected. These variants were heterozygous in 2 patients and homozygous (bi-allelic) in 8 patients. One patient was homozygous for APOA5 p.Ser19Trp, a relatively common polymorphism that is a risk variant for HTG. We report a cohort of patients with biallelic and single copy APOA5 variants, who were diagnosed later in life. Most had secondary factors, such as DM or obesity with increased BMI. Most rare APOA5 variants found in our patients were of uncertain significance. Our results add to the growing evidence that rare variants in certain candidate genes may predispose to developing HTG, together with secondary factors such as obesity. The genetic basis of HTG in many other patients is still unknown and remains the subject of further investigation.

Lipoprotein Lipase/Apolipoprotein Cll Gene Polymorphism in Kurdish Patients With Severe Hypertriglyceridemia.

Background Polymorphisms in thelipoprotein lipase(LPL) and apolipoprotein CII (APO CII)genes have been linked to severe hypertriglyceridemia in several populations. This study investigated the frequency ofLPL-Hind lllandAPO Cll-Ava ll polymorphism among Kurdishpatientswith severe hypertriglyceridemia. Methodology We investigated LPL-Hind llland APO Cll-Ava ll gene polymorphism in a sample of Kurdish patients receiving treatment at Azadi Teaching Hospital in Duhok, Kurdistan Region, Iraq. We included a total of 100 subjects in this study, of which 64 had severe hypertriglyceridemia, and 36 had normotriglyceridemia. There were 56 males and 44 females. We used the polymerase chain reaction-restriction fragment length polymorphism technique to determine the polymorphism of the LPL-Hind lll and APO Cll-Ava ll genes. Results In those with severe hypertriglyceridemia, the most frequent alleles were H+H+LPL-Hind lll polymorphism (42, 65.6%) followed by A1A1APO Cll-Ava ll polymorphism (30, 46.9%), whereas these frequencies were 16 (44.4%) and 6 (16.7%) in those with normotriglyceridemia, respectively. The H+H+ genotype group had considerably higher triglyceride levels and lower high-density lipoprotein cholesterol levels compared with the H-H- genotype group. A similar pattern was observed when comparing the A1A1 and A2A2 genotype groups, with both patterns being statistically significant. Conclusions Our results showed a high frequency of H+H+LPL-Hind III polymorphism in those with hypertriglyceridemia, which may be a hereditary indicator of vulnerability to this condition in the Kurdish population.

FRI105 Getting Fam-iliar With Familial Chylomicronemia Syndrome: A Case Report

Abstract Background: Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive lipid disorder of chylomicron metabolism causing severe hypertriglyceridemia that affects ∼1/1,000,000 individuals. Case Presentation: A 36-year-old male with a history of severely elevated triglyceride levels, recurrent pancreatitis, and biopsy-proven focal segmental glomerulosclerosis presented with severely elevated triglycerides. His initial acute pancreatitis episode was at 30 years old and attributed to alcohol intake. Triglyceride levels were not obtained at the time. He abstained from alcohol; however, his follow up triglyceride level was elevated (5,005 mg/dL, n=35-160 mg/dL) which normalized on an insulin infusion. He started fenofibrate and fish oil. After several additional hospital admissions for either pancreatitis or asymptomatic hypertriglyceridemia with a peak triglyceride level of 14,385 mg/dL, he committed to a low fat and vegan diet. Generic fish oil was transitioned to icosapent ethyl, and he was additionally started on niacin and atorvastatin. Even after following a strict diet and medication adherence, he continued having multiple admissions for acute pancreatitis, most recently complicated by dialysis dependent acute kidney injury in the setting of necrotizing pancreatitis. He has no known history of hypertriglyceridemia in his family. Due to persistent and severe hypertriglyceridemia despite conventional treatment, we suspected an underlying genetic cause, such as FCS. FCS should be suspected in those with recurrent pancreatitis, lipemia retinalis, and/or milky colored blood specimens. Eruptive xanthomas may also be present. Our patient did not have evidence of eruptive xanthomas on physical examination, but ophthalmology evaluation did show lipemia retinalis. The most common genetic pathologic variant in FCS is in the lipoprotein lipase-1 gene (LPL) that codes for an enzyme which assists in the lipolysis of plasma triglycerides (TG) in chylomicrons. Other common genes associated with severe hypertriglyceridemia are APOC2, APOAV, LMF-1, and GPIHBP-1. The mainstay of treatment for FCS are medications to reduce triglyceride levels and a significantly low-fat diet below 25 grams daily. Medium chain triglycerides can be utilized as they do not require enzymes to break down. Otherwise, there are currently no FDA-available therapies specifically targeted for use in those with FCS. Conclusions: This case demonstrates the unfortunate outcome of familial chylomicronemia syndrome despite concerted efforts to reduce triglyceride levels and eliminate additional risk factors. Presentation: Friday, June 16, 2023

FRI095 Pseudo Anion Gap Metabolic Acidosis Secondary To Severe Hypertriglyceridemia

Abstract Disclosure: G.C. Connery: None. S. Ward: None. K.E. Izuora: None. A. Champion: None. Background/Objective: Severe hypertriglyceridemia can falsely alter multiple lab parameters due to the high lipid fraction of the blood sample. We present a patient who initially presented with severe metabolic acidosis but proved to have normal pH and bicarbonate after correction for hypertriglyceridemia. Case Report: A 34-year-old female with past medical history of recurrent acute on chronic pancreatitis secondary to hypertriglyceridemia, type 2 diabetes, obesity, and hypertension presented to the emergency department with epigastric pain. The patient was initially diagnosed with acute pancreatitis, diabetic ketoacidosis (DKA), and hyponatremia. Initial labs showed sodium 116 mmol/L, glucose 617 mg/dL, bicarbonate < 5 mmol/L, blood ketones 0.8 mmol/L, lactic acid 2.57 mmol/L, and creatinine 0.95 mg/dL. A venous blood gas (VBG) revealed pH 7.42, pCO2 36 mmHg, pO2 62 mmHg, and bicarbonate 24 mmol/L. Her lipid panel revealed triglyceride levels > 4000 mg/dL. The discrepancy in bicarbonate levels between the blood chemistries and VBG were attributed to a pseudo-anion gap metabolic acidosis secondary to her hypertriglyceridemia. After treatment with insulin infusion, hypertriglyceridemia resolved and her bicarbonate levels on renal function panel normalized. Discussion: The high lipid fraction of blood plasma in patients with severely high triglyceride levels can confound other laboratory parameters. Pseudo hyponatremia secondary to elevated triglycerides is one example of a commonly known lab abnormality. In our patient, her initial bicarbonate levels on renal function panel led to concern for severe metabolic acidosis that was not consistent with her mild blood ketones and lactic acid levels. Further investigation with VBG revealed normal pH and bicarbonate levels. Conclusion: Severe hypertriglyceridemia may significantly alter bicarbonate measurement on blood chemistries. Further investigations with blood gasses should be pursued to confirm these abnormalities when suspected. Presentation: Friday, June 16, 2023

SAT401 The Aftermath Of Pueraria mirifica: A Case Of Hypertriglyceridemia And Necrotizing Pancreatitis In A Non-binary Individual With Surreptitious Use Of Oral Estrogenic Compounds

Abstract Disclosure: S. Tobolsky: None. F.J. Hayes: None. J. Lo: None. Background Prescription of gender-affirming hormone therapy (GAHT) has become an increasingly prevalent aspect of endocrine care meriting greater attention from our specialty. We report a case where surreptitious use of an unregulated compound with estrogenic activity in a patient with gender dysphoria resulted in severe hypertriglyceridemia and necrotizing pancreatitis. The compound, Pueraria mirifica, is readily available for purchase online. CaseThe patient is a 26yo non-binary individual assigned male at birth who presented to the ED with 1.5 days of abdominal pain and vomiting. CT abdomen showed acute necrotizing pancreatitis. On arrival, serum triglycerides 2,559 mg/dl (nl 40-150 mg/dL) and lipase 481U/L (nl 13-60 U/l). The patient reported no alcohol use. Family history of unspecified hyperlipidemia in father. Patient was admitted, made NPO, and started on insulin/dextrose infusions, continued until serum triglycerides dropped to <1,000 mg/dL. Fenofibrate started and extensive nutritional counseling on low-carbohydrate and low-fat diet given. In absence of clear etiology for hypertriglyceridemia, patient was questioned carefully on supplement use and revealed they took 2 tablets of Pueraria mirifica daily with intent of transitioning without medical guidance given prior negative encounters with healthcare. Patient discharged on fenofibrate 200 mg, atorvastatin 20 mg and omega-3 acid ethyl esters 2 g BID, with plan for endocrinology follow-up for initiation of medically supervised GAHT. At follow-up on this regimen, LDL was 79 mg/dL and triglycerides 160 mg/dL. Goals of transition were discussed with the patient as was importance of avoiding oral estrogens, prescribed or over-the-counter. Given patient’s desire for partial transition, low dose transdermal estradiol 0.05 mg patch and spironolactone 50mg BID started. On above regimen, estradiol was 179 pg/mL and total testosterone suppressed at 72 ng/dL. The patient’s triglycerides remained <150 mg/dL with no further complications. ConclusionThis case highlights a potentially fatal complication of hormone use in a transgender individual with likely underlying familial hypertriglyceridemia. It also illustrates how distrust of the medical system led to surreptitious hormone use and emphasizes the need to create a safe, welcoming environment for individuals with gender dysphoria. Finally, it emphasizes the need to interrogate possible surreptitious hormone use in patients with unusual presentations and for endocrinologists to be aware of the need to avoid oral estrogen use in patients with hypertriglyceridemia. Presentation: Saturday, June 17, 2023

FRI090 Patterns Of Triglyceride Testing And Results Over Time Among Patients With Diabetes And Severe Hypertriglyceridemia In US Clinical Practice

Abstract Disclosure: E. Kutrieb: Consulting Fee; Self; Ionis Pharmaceuticals Inc. S.J. Baum: Advisory Board Member; Self; Altimmune, Amgen Inc, Axcella, Boehringer Ingelheim, Eli Lilly & Company, Esperion, Madrigal Pharmaceuticals, Novartis Pharmaceuticals, Regeneron Pharmaceuticals. Consulting Fee; Self; Altimmune, Amgen Inc, Ionis Pharmaceuticals Inc., Madrigal Pharmaceuticals, Merck, Novartis Pharmaceuticals, Regeneron Pharmaceuticals. Speaker; Self; Amgen Inc, Boehringer Ingelheim, Esperion, Eli Lilly & Company, Regeneron Pharmaceuticals. Other; Self; Madrigal Pharmaceuticals. E. Dukes: Consulting Fee; Self; Ionis Pharmaceuticals Inc. A. Sikora Kessler: Employee; Self; Ionis Pharmaceuticals Inc. D. Weycker: Consulting Fee; Self; Ionis Pharmaceuticals Inc. M. Vera Llonch: Employee; Self; Ionis Pharmaceuticals Inc. J. Respress: Employee; Self; Ionis Pharmaceuticals Inc. D. Soffer: Consulting Fee; Self; Akcea Therapeutics, Amgen Inc, Ionis Pharmaceuticals Inc., Kaneka, Novartis Pharmaceuticals. Research Investigator; Self; Akcea Therapeutics, Amgen Inc, Amryt, AstraZeneca, Ionis Pharmaceuticals Inc., Novartis Pharmaceuticals, Regeneron Pharmaceuticals, RegenXBio. Introduction: Evidence on patterns of triglyceride (TG) testing and test results among patients with diabetes in US clinical practice, especially those with severe hypertriglyceridemia (SHTG, defined as TG ≥1000 mg/dL), is sparse. We undertook a real-world study to address this evidence gap. Methodology: A retrospective observational cohort design and data from the Merative Linked MarketScan-Labs Database (01/01/13-12/31/19) were employed. Study population included patients with diabetes and ≥1 TG value, stratified by first TG value (<500, 500-999, ≥1000 mg/dL); for selected analyses, patients were limited to those with multiple TG values. Study measures were assessed beginning with the first TG value and included: number of TG tests (all patients), days between tests (patients with ≥2 TG values), TG values by test (all patients), and TG values across tests (patients with ≥3 TG values receiving statins only or TG-targeting therapy only [fenofibrate, fenofibric acid, icosapent ethyl, gemibrozil, omega-3 fatty acid]). Study measures were summarized using means (standard deviations [SD]) and percentages. Results: Among 465,034 patients with diabetes in the study population, 0.5% (N=2,247) were classified as having SHTG (TG ≥1000 mg/dL) based on their first value. Mean age of SHTG patients was 49 years, 75% were male, and 52% had a recent history (ie, within 12 months) of lipid-lowering therapy (statins: 38%; fenofibrate: 21%). Mean value for first TG was 1,924 mg/dL, and most patients (75%) had ≤3 TG values (1: 39%; 2: 23%; 3: 13%) during a mean follow-up of 22 (SD=21) months. Among patients with ≥2 TG values (N=1,366), mean interval between first and second TG values was 221 (SD=267) days; days between subsequent TG values were comparable to the first interval. Among SHTG patients with ≥3 TG values receiving only statin therapy (N=163), the second TG value was <500 mg/dL for 45%, 500-999 mg/dL for 21%, and ≥1000 mg/dL for 34%; all 3 TG values were ≥1000 mg/dL for 16% of patients. Among SHTG patients with ≥3 TG values receiving only TG-targeting therapy (N=121), the second TG value was <500 mg/dL for 30%, 500-999 mg/dL for 44%, and ≥1000 mg/dL for 26%; all 3 TG values were ≥1000 mg/dL for 12% of patients. Among patients with lower initial TG values (<500: N=453,940; 500-999: N=8,847), TG testing patterns were largely comparable to those among SHTG patients. Conclusions: TG testing among patients with diabetes and SHTG is relatively infrequent in US clinical practice, and test results are highly variable. Understanding these patterns is important for identifying, testing, and treating patients with diabetes and SHTG to reduce health risks. Presentation: Friday, June 16, 2023

SAT676 Severe Recurrent Pancreatitis In A Familial Partial Lipodystrophy Patient On Metreleptin

Abstract Disclosure: P. Sargin: None. M. Vinicky: None. A. Biglione: None. Lipodystrophy syndromes are congenital or acquired disorders characterized by either total or partial lipoatrophy and often unrecognized by clinicians due to their rarity. Patients with lipodystrophy may demonstrate severe complications of metabolic syndrome since lipids are deposited in non-adipose organs where they induce lipotoxicity resulting in insulin resistance, diabetes mellitus, hypertriglyceridemia, and hepatic steatosis. Familial Partial Lipodystrophy (FPLD) syndromes are one of the four major subtypes of lipodystrophy syndromes. These are heterogeneous, mostly autosomal dominant, and characterized by site-specific subcutaneous adipose tissue loss. The management of patients with FPLD can be challenging with life-threatening complications, heavy dependence on lifestyle modifications, limited treatment options and medication availability. One of the important complications seen in these patients is pancreatitis, related to high triglyceride levels. It can be recurrent and the episodes can be more severe compared to the general patient population. Metreleptin, the human leptin analogue, is the only disease-specific treatment for lipodystrophy syndromes and it has been shown to reduce the complications of leptin deficiency, but it is not currently approved for FPLD in the USA. Previous studies showed improvement of the complications of FPLD with its use. Our case is a 29-year-old woman who has Dunnigan type FPLD with a history of numerous bouts of pancreatitis while on fenofibrate, statin and omega-3-acid ethyl esters, later was on metreleptin for almost 3 years, presented to our hospital with typical symptoms of acute pancreatitis incited by severe hypertriglyceridemia (>1,500 mg/dL). Lipase levels were high at 27,501. Patient was treated with vigorous intravenous hydration, insulin and home metreleptin was continued at the hospital. Despite the initial improvement of the symptoms, on the 6th day of hospitalization, she developed worsening abdominal pain, nausea, and vomiting. CT angiogram of the abdomen showed 2.0 cm splenic artery pseudoaneurysm. Coiled embolization of the superior segmental branch of the splenic artery performed by interventional radiologist which was further complicated by splenic infarction. Her condition improved eventually, she was able to be discharged home. Importance of adherence to medications and special diet was discussed with the patient in length. This case report aims to bring attention to this rare disease and urgent need for further treatment options for these patients to prevent serious complications in this young patient population. Metreleptin is a daily injection which could be challenging to adherence and the consequence can be relapse of pancreatitis. Lack of other treatment options, treatment availability, physician awareness are barriers to optimize the treatment for these complex patients. Presentation: Saturday, June 17, 2023

FRI101 Marked Reduction In Severe Resistant Hypertriglyceridemia On PCSK9 Inhibitor

Abstract Disclosure: S. Kaul: None. A. Gupta: None. Introduction: PCKS9 inhibitors, such as evolocumab, have been shown to lower triglyceride levels by approximately 10-20% (1). However, there have not been any reports of PCSK9 inhibitors lowering triglyceride levels by more than 100%. Clinical Case: A 35-year-old white man presented with hypertriglyceridemia for more than eight years. Past medical history was significant for recurrent pancreatitis and diabetes mellitus type 2 with recent HbA1c of 7.6% (normal range <5.7%) on metformin 1 gram BID and insulin glargine 15 units daily. He had multiple hospitalizations for pancreatitis requiring insulin drip. His triglycerides remained elevated on fenofibrate, atorvastatin, and icosapent ethyl despite alcohol avoidance and changes in diet with progressive elevation to 5000 mg/dL (normal range 0-150 mg/dL) requiring four sessions of plasmapheresis and hospitalization requiring intravenous insulin drip. His family history also included hypertriglyceridemia in his mother. He was started on evolocumab 140 mg subcutaneously every 2 weeks and noted to have drastic improvement of triglycerides down to a normal level of 138 mg/dL. On recent labs, his triglyceride level was noted to be 921 mg/dL with HbA1c at 8.0%. He did admit non-compliance to diet but did not require any more hospitalizations for pancreatitis since starting evolocumab. Conclusions: This is the first reported case of an unexplored potential of evolocumab in patients with severe hypertriglyceridemia. Reference: (1) Warden BA, Fazio S, Shapiro MD. The PCSK9 revolution: Current status, controversies, and future directions. Trends Cardiovasc Med. 2020;30(3):179-185. doi:10.1016/j.tcm.2019.05.007 Presentation: Friday, June 16, 2023

SAT089 Natural History Of Generalized Lipodystrophy Following Early Vs. Late Metreleptin Treatment

Abstract Disclosure: M. Brush: None. M. Lightbourne: None. S. Auh: None. R.J. Brown: None. Generalized lipodystrophy (GLD) is characterized by near total loss of subcutaneous fat resulting in low leptin concentrations. Patients with GLD exhibit metabolic abnormalities such as severe insulin resistance, diabetes mellitus, hypertriglyceridemia, proteinuria, and non-alcoholic fatty liver disease (NAFLD), that are progressive over time. Leptin replacement therapy using metreleptin is effective in improving these metabolic abnormalities. It is unknown if starting metreleptin therapy early versus late in the clinical course will change the natural history of this disease. We hypothesize that starting metreleptin early versus late will lead to better long-term control of diabetes, hypertriglyceridemia, and proteinuric nephropathy. This is a single-center retrospective analysis of subjects with congenital and acquired generalized lipodystrophy (n=67). Fasting serum insulin, glucose, lipids, HbA1c (A1c), and 24 hr urine protein excretion, and insulin and c-peptide areas under the cover (AUC) from oral glucose tolerance tests were assessed at baseline, after 6 months of metreleptin, and at 12 month intervals thereafter. For each outcome parameter, subjects were divided into early and late treatment groups. For A1c, early treatment was defined as <7%. For all other parameters, early treatment was defined as being < the upper limit of normal for that parameter. The effect of early vs late treatment for each parameter was analyzed using linear mixed models adjusted for age and genetics, and excluding baseline metabolic parameters. Follow-up diabetes control was better with early metreleptin treatment as assessed by both glucose and A1c. Fasting glucose was 47 mg/dl lower during follow-up with early (<100 mg/dL) vs. late (≥ 100 mg/dL) treatment (p=0.0038) and A1c was 1.37% lower with early (<7%) vs late (≥7%) treatment (p=0.0015). At baseline, the early group defined by A1c had higher insulin secretion based on 48.3% higher c-peptide AUC (p=0.0185) and 161% higher insulin AUC (p=0.0029). At follow-up, the early group maintained a 37.8% higher c-peptide (p<0.0001) and 80.4% higher insulin AUC (p<0.0001). Urine protein excretion was 366 mg/24hr lower during follow-up in the early group (<300 mg/24hr) compared to the late group (≥300 mg/24hr) (P=0.0031). Triglycerides were 96 mg/dL lower during follow-up between the early (<150 mg/dL) vs late (≥150) groups (p=0.0116). In conclusion, patients with generalized lipodystrophy treated with metreleptin prior to the onset of clinically significant metabolic disease showed better age-adjusted metabolic control over time for diabetes, hypertriglyceridemia, and proteinuria. Lower insulin and C-peptide secretion in the late treatment group suggest that worse diabetes control after metreleptin in this group may be attributable to irreversible loss of beta cell function prior to metreleptin. Presentation: Saturday, June 17, 2023