Life-threatening Acute Pancreatitis Research Articles

6503 A Randomized, Placebo-Controlled Phase 3 Study of Olezarsen In Patients With Familial Chylomicronemia Syndrome: The Balance Trial

Abstract Disclosure: E.S. Stroes: Advisory Board Member; Self; Amgen Inc, Sanofi, Novartis Pharmaceuticals, AstraZeneca, Novo Nordisk, Ionis Pharmaceuticals Inc., Merck, Daiichi Sankyo. Grant Recipient; Self; Ionis Pharmaceuticals Inc., Novo Nordisk, Novartis Pharmaceuticals, Sanofi. V. Alexander: Employee; Self; Ionis Pharmaceuticals Inc. E. Prokopczuk: Employee; Self; Ionis Pharmaceuticals Inc. R.A. Hegele: Consulting Fee; Self; Aegerion Pharmaceuticals, Ionis Pharmaceuticals Inc., Amgen Inc, Novartis Pharmaceuticals, Pfizer, Inc., Regeneron Pharmaceuticals, Sanofi, Ultragenyx, Acasti, and HLS Therapeutics. M. Arca: Grant Recipient; Self; Amgen Inc, Ionis Pharmaceuticals Inc., Novartis Pharmaceuticals, Pfizer, Inc., Regeneron Pharmaceuticals, Sanofi, Ultragenyx, Daiichi Sankyo, Alfasigma, Amryt, Sobi, and Viatris. C.M. Ballantyne: Consulting Fee; Self; 89Bio, Abbott Diagnostics, Alnylam Pharmaceuticals, Althera, Amarin, Amgen, Arrowhead, AstraZeneca, Denka Seiken, Esperion, Genentech, Gilead, Illumina, Ionis, Matinas BioPharma Inc, Merck, New Amster. Grant Recipient; Self; Abbott Diagnostic, Akcea, Amgen, Arrowhead, Esperion, Ionis, Merck, Novartis, Novo Nordisk, Regeneron, Roche Diagnostic, NIH, AHA, ADA. H. Soran: Grant Recipient; Self; Akcea Therapeutics, Alexion, Amryt, Kowa, MSD, NAPP, Novartis, Pfizer, Sanofi, Synageva, and Takeda. T.A. Prohaska: Employee; Self; Ionis Pharmaceuticals Inc. S. Xia: Employee; Self; Ionis Pharmaceuticals Inc. H.N. Ginsberg: Research Investigator; Self; Ionis Pharmaceuticals Inc. J.L. Witztum: Consulting Fee; Self; Ionis Pharmaceuticals Inc. S. Tsimikas: Consulting Fee; Self; Novartis. Employee; Self; Ionis Pharmaceuticals Inc.. Stock Owner; Self; Kleanathi, Oxitope. Background: Familial chylomicronemia syndrome (FCS) is a rare genetic disorder of lipoprotein lipase deficiency that results in severe hypertriglyceridemia and an increased risk of potentially life-threatening acute pancreatitis (AP). Decreasing high plasma levels of apolipoprotein C-III (apoC-III) reduces hypertriglyceridemia. Olezarsen is an investigational ligand-conjugated antisense oligonucleotide targeted to hepatic APOC3 mRNA to reduce triglycerides (TG). Methods: Balance is a Phase 3, multicenter, randomized, double-blind, placebo-controlled trial in 66 patients with genetically confirmed FCS and fasting TG ≥880 mg/dL at screening. Patients were advised to consume <20g fat/day and randomized 2:1 to olezarsen (50 mg or 80 mg) or placebo sc every 4 weeks for 53 weeks. The two primary endpoints were the placebo-adjusted % change in fasting TG from baseline to 6-months for (1) olezarsen 80 mg and (2) olezarsen 50 mg. Secondary endpoints included change in 12-month TG and apoC-III levels, and incidence of independently adjudicated AP events. Results: At baseline, TG levels were ∼2600 mg/dL and 47/66 (71%) of FCS patients had a history of AP. Placebo-corrected TG levels at 6 months were significantly reduced in olezarsen 80 mg (-43.5%, P=0.0009), and were numerically lower in the olezarsen 50 mg group (-22.4%, P=0.0775). Placebo-corrected TG levels at 12 months were reduced -59.4% in the olezarsen 80 mg group and -43.8% in the olezarsen 50 mg group. ApoC-III levels were reduced in both dose groups at 6 months (olezarsen 50 mg: -65.5%; olezarsen 80 mg: -73.7%) and 12 months (olezarsen 50 mg: -77.1%; olezarsen 80 mg: -81.3%). During 53 weeks of randomized treatment, 11 episodes of AP were observed in 23 patients on placebo versus 2 episodes in 43 olezarsen-treated patients (1 in 50 mg and 1 in 80 mg group). A favorable safety and tolerability profile was noted with more treatment emergent adverse events (TEAEs) and serious TEAEs in the placebo group. No serious TEAEs were related to study drug. Conclusion: In patients with FCS, olezarsen 80 mg significantly reduced TG levels and both olezarsen 50 and 80 mg groups demonstrated a marked reduction in AP events with a favorable safety and tolerability profile. Presentation: 6/1/2024

Breaking the chains of lipoprotein lipase deficiency: A pediatric perspective on the efficacy and safety of Volanesorsen

RationaleLipoprotein lipase (LPL) deficiency, a rare inherited metabolic disorder, is characterized by high triglyceride (TG) levels and life-threatening acute pancreatitis. Current treatment for pediatric patients involves a lifelong severely fat-restricted diet, posing adherence challenges. Volanesorsen, an EMA-approved RNA therapy for adults, effectively reduces TG levels by decreasing the production of apolipoprotein C-III. This 96-week observational open-label study explores Volanesorsen's safety and efficacy in a 13-year-old female with LPL deficiency. MethodsThe patient, with a history of severe TG elevations, 53 hospital admissions, and life-threatening recurrent pancreatitis despite dietary restrictions, received weekly subcutaneous Volanesorsen injections. We designed a protocol for this investigator-initiated study, primarily focusing on changes in fasting TG levels and hospital admissions. ResultsWhile the injections caused occasional pain and swelling, no other adverse events were observed. TG levels decreased during treatment, with more measurements below the pancreatitis risk threshold compared to pre-treatment. No hospital admissions occurred in the initial 14 months of treatment, contrasting with 21 admissions in the 96 weeks before. In the past 10 months, two pancreatitis episodes may have been linked to dietary noncompliance. Dietary restrictions were relaxed, increasing fat intake by 65% compared to baseline. While not fully reflected in the PedsQL, both parents and the patient narratively reported an improved quality of life. ConclusionThis study demonstrates, for the first time, that Volanesorsen is tolerated in a pediatric patient with severe LPL deficiency and effectively lowers TG levels, preventing life-threatening complications. This warrants consideration for expanded access in this population.

Safety and efficacy of therapies for chylomicronemia

Introduction Primary chylomicronemia is characterized by pathological accumulation of chylomicrons in plasma causing severe hypertriglyceridemia, typically >10 mmol/L (>875 mg/dL). Patients with the ultra-rare familial chylomicronemia syndrome (FCS) subtype completely lack lipolytic capacity and respond minimally to traditional triglyceride-lowering therapies. The mainstay of treatment is a low-fat diet, which is difficult to follow and compromises quality of life. New therapies are being developed primarily to prevent episodes of life-threatening acute pancreatitis. Areas covered Antagonists of apolipoprotein (apo) C-III, such as the antisense oligonucleotide (ASO) volanesorsen, significantly reduce triglyceride levels in chylomicronemia. However, approval of and access to volanesorsen are restricted since a substantial proportion of treated FCS patients developed thrombocytopenia. Newer apo C-III antagonists, namely the ASO olezarsen (formerly AKCEA-APOCIII-LRx) and short interfering RNA (siRNA) ARO-APOC3 appear to show efficacy with less risk of thrombocytopenia. Potential utility of antagonists of angiopoietin-like protein 3 (ANGPTL3) such as evinacumab and the siRNA ARO-ANG3 in subtypes of chylomicronemia remains to be defined. Expert opinion Emerging pharmacologic therapies for chylomicronemia show promise, particularly apo C-III antagonists. However, these treatments are still investigational. Further study of their efficacy and safety in patients with both rare FCS and more common multifactorial chylomicronemia is needed.

Need for Screening Triglyceride Levels in Women on Oral Contraceptives

Introduction: Oral contraceptive pills (OCPs) are the most used form of reversible contraceptives by women. Major risks are cardiovascular but OCPs also cause secondary hypertriglyceridemia (HTG) through effects of estrogen, which decreases hepatic triglyceride lipase and lipoprotein lipase activity. This causes increased triglycerides, cholesterol and free fatty acids,1 which then in turn can lead to life-threatening acute pancreatitis. Case Description: A 23-year-old morbidly obese (BMI 38.2 mg/kg2) female presented with severe epigastric pain, nausea and vomiting. She had a history of mild intermittent asthma, recently diagnosed pre-diabetes and recently started on OCPs. Initial labs were consistent with diabetic ketoacidosis with glucose 528 mg/dL (65-115 mg/dL), anion gap 21 mEq/L (5-15 mEq), and beta-hydroxybutyrate 2.00 mmol/L (0.02-0.27 mmol/L); and acute pancreatitis with triglyceride 4,425 mg/dL (30-200 mg/dL) and lipase >600 U/L (8-78 UL), confirmed on imaging.She rapidly deteriorated, developing acute hypoxemic respiratory distress requiring intubation and distributive shock requiring three vasopressors. She progressed into multi-organ failure with acute respiratory distress syndrome, ischemic liver and acute renal failure despite insulin drip, colloidal fluid resuscitation, continuous veno-venous hemofiltration and high positive end-exploratory pressures. She developed rhabdomyolysis, followed by abdominal compartment syndrome requiring decompressive laparotomy that resulted in large volume blood loss and retroperitoneal necrosis needing multiple laparotomies. Ultimately, she became non-responsive off sedation, attributed to malignant cerebral edema that progressed to brain herniation.While HTG was likely the cause of her pancreatitis, she had normal triglyceride levels on prior routine lab work while not on OCPs. Discussion: Severe acute pancreatitis is a life-threatening complication of HTG which may be precipitated by use of OCPs. We believe that there is a need for more research in this field and even propose periodic monitoring of HTG in women taking OCPs given the severity of the consequences. While there are currently no guidelines for monitoring lipid levels in women on OCP, appropriate clinical awareness of physicians prescribing OCPs to patients may prevent fatal outcomes.

The burden of familial chylomicronemia syndrome from the patients’ perspective

ABSTRACTBackground: Familial chylomicronemia syndrome (FCS) is a rare, inherited lipid disorder characterized by high levels of plasma triglycerides and chylomicrons, which may cause life-threatening acute pancreatitis. Currently no FDA-approved treatment exists. Management is low-fat diet (<20g fat/day), which is difficult to maintain. With the restricted diet, triglycerides may remain elevated. We conducted discussions with patients and caregivers to better understand the burden of FCS from their perspectives.Methods: A panel of FCS patients and caregivers was assembled to discuss and assess the clinical and psychosocial burden of FCS.Results: Ten adults with FCS (median age 48 yr) and their spouses/caregivers were asked specific questions about their experiences living with FCS. Patients with FCS stated their symptoms were abdominal pain, nausea, diarrhea, constipation, bloating, and fatigue. Patients reported a median of 34 episodes of acute pancreatitis over their lifetimes; half of these led to hospitalizations, each with an average stay of 6.5 days. The psychosocial burden of FCS was primarily associated with the restricted diet, anxiety and stress of FCS.Conclusions: Living with FCS imposes a significant clinical and psychosocial burden on patients and caregivers, who reported reduced quality of life, limited employment opportunities, socialization and increased burden on family.

Dyslipidemia-associated skin lesions as a short key for etiology unraveling and management of life-threatening acute pancreatitis in young male

Dyslipidemia-associated skin lesions as a short key for etiology unraveling and management of life-threatening acute pancreatitis in young male

Successful Plasma Exchange for Acute Pancreatitis Complicated With Hypertriglyceridemia: A Case Report.

A 33-year-old male with acute pancreatitis induced by hypertriglyceridemia had problems during treatment with plasma exchange. The hypercoagulable state was prevented by introducing innovative methods for cleaning and warming of the circuit and dialyzer. This enabled successful therapy, and the patient fully recovered from life-threatening acute pancreatitis.

Lipoprotein Lipase Deficiency: Clinical, Biochemical and Molecular Characteristics in Three Patients with Novel Mutations in the LPL Gene

Lipoprotein lipase (LPL) deficiency, caused by mutations in the LPL gene, is a rare autosomal recessive disorder manifesting in early childhood with recurrent abdominal pain, hepatosplenomegaly, acute pancreatitis, lipaemia retinalis and eruptive xanthomas. Typical laboratory findings are lactescent serum, extreme hypertriglyceridaemia and hypercholesterolaemia. The diagnostics is based on postheparin serum LPL assay and DNA analyses of the LPL gene. We report clinical, biochemical and molecular data of three children with LPL deficiency. One child manifested since the first week of life with recurrent abdominal pain (Patient 1), the second with abdominal distension and hepatosplenomegaly since the second month of life (Patient 3) and patient 2, asymptomatic younger brother of patient 1, was diagnosed in the first week of life. Lipaemia retinalis and splenomegaly were present in two symptomatic children, hepatomegaly in patient 3 and acute pancreatitis in patient 1. All children had lactescent serum, profound hypertriglyceridaemia (124 ± 25 mmol/l; controls &lt; 2.2), hypercholesterolaemia (22.8 ± 7.3 mmol/l, controls &lt; 4.2) and their LPL immunoreactive mass in serum did not increase after heparin injection. Molecular analyses revealed that both siblings are homozygous for novel mutation c.476C &gt; G in the LPL gene changing the conserved amino acid of the catalytic centre. The third patient is a compound heterozygote for mutations c.604G&gt;A and c.698A&gt;G in the LPL gene, both affecting highly conserved amino acids. We conclude that LPL deficiency must be considered in neonates and young infants with abdominal pain and hypertriglyceridaemia because early treatment might prevent development of life-threatening acute pancreatitis.

Lipodystrophie

Lipodystrophy syndromes are a heterogenous group of congenital and acquired disorders with generalized or partial absence of subcutaneous adipose tissue. They are associated with severe metabolic abnormalities such as insulin resistance, diabetes mellitus, and hypertriglyceridemia that may result in life-threatening acute pancreatitis, steatohepatitis, and cardiovascular disease. Conventional lipid-lowering and antihyperglycemic medications may be insufficient to control severe metabolic abnormalities. The adipose tissue-derived hormone leptin has been investigated as a novel therapeutic option for severe lipodystrophy and significantly improves metabolic abnormalities in these patients. In Germany, leptin treatment for lipodystrophic patients with severe metabolic abnormalities is offered free of charge by the University Medicine Leipzig within a compassionate use program.

Life-threatening acute pancreatitis due to thalidomide therapy for chronic graft-versus-host disease

Life-threatening acute pancreatitis due to thalidomide therapy for chronic graft-versus-host disease

Hemorheological abnormalities in lipoprotein lipase deficient mice with severe hypertriglyceridemia

Severe hypertriglyceridemia (HTG) is a metabolic disturbance often seen in clinical practice. It is known to induce life-threatening acute pancreatitis, but its role in atherogenesis remains elusive. Hemorheological abnormality was thought to play an important role in pathogenesis of both pancreatitis and atherosclerosis. However, hemorheology in severe HTG was not well investigated. Recently, we established a severe HTG mouse model deficient in lipoprotein lipase (LPL) in which severe HTG was observed to cause a significant increase in plasma viscosity. Disturbances of erythrocytes were also documented, including decreased deformability, electrophoresis rate, and membrane fluidity, and increased osmotic fragility. Scanning electron microscopy demonstrated that most erythrocytes of LPL deficient mice deformed with protrusions, irregular appearances or indistinct concaves. Analysis of erythrocyte membrane lipids showed decreased cholesterol (Ch) and phospholipid (PL) contents but unaltered Ch/PL ratio. The changes of membrane lipids may be partially responsible for the hemorheological and morphologic abnormalities of erythrocytes. This study indicated that severe HTG could lead to significant impairment of hemorheology and this model may be useful in delineating the role of severe HTG in the pathogenesis of hyperlipidemic pancreatitis and atherosclerosis.

Life-threatening acute pancreatitis associated with interferon beta-1a treatment in multiple sclerosis

The treatment goal in patients with relapsing–remitting multiple sclerosis (RR-MS) is to reduce the frequency and severity of relapses and to prevent or postpone the development of disability. Large trials have demonstrated that interferon beta-1a (IFNβ-1a), IFNβ-1b, and glatiramer acetate partially meet this purpose.1 The approved drugs are well tolerated with largely transient adverse effects. Pancreatitis is not mentioned as an adverse effect in the current Summaries of Product Characteristics for IFNβ-1a. However, acute pancreatitis has been associated with IFNα-2b treatment.2 We report a case in which a life-threatening acute pancreatitis developed 8 weeks after the initiation of treatment with IFNβ-1a for RR-MS. A healthy 53-year-old man on no concurrent medication was diagnosed with MS. He started with IFNβ-1a (Rebif) 22 μg subcutaneously three times weekly 8 weeks after diagnosis. Initially, he experienced minor injection site reactions and flu-like symptoms. However, 8 weeks later, he developed symptoms of an acute …

Serum creatinine and chest radiographs in the early assessment of acute pancreatitis

Background: We previously identified serum creatinine values >2 mg/dL (176.8 μmol/L) and pathological chest radiographs due to the presence of pleural effusions or pulmonary densifications as two early prognostic factors of life-threatening acute pancreatitis (AP). The aim of the present study was to validate their prognostic efficacy in combination. Methods: We analyzed as prognostic factors only the data obtained within 24 hours of admission in 539 cases of AP, including 163 patients (30.2%) with acute necrotizing pancreatitis (NP). Eleven patients (2%) presented with infected pancreatic necrosis, and 20 patients (3.7%) died. Results: One hundred and nine cases (20.2%) presented pathological chest radiographs: 32 (5.9%) pulmonary densifications and 77 (14.3%) pleural effusions (18 right, 25 left, 34 bilateral). Fifty-one patients (9.5%) had serum creatinine values >2 mg/dL. Pathological chest radiographs and serum creatinine values >2 mg/dL were significantly associated both with mortality risk ( P <0.00001), with a diagnosis of NP ( P <0.00001), and with risk of developing infected necrosis ( P <0.0001). Considering positivity of either or both tests, the mortality risk sensitivity was 90% (95% confidence interval [CI] 70.7 to 98.3) with a specificity of 76% (CI 72.5 to 79.8), for the NP diagnosis the sensitivity was 60% (CI 52.5 to 67.4) and the specificity 88% (CI 85.0–91.5), whereas for the risk of infected necrosis the sensitivity was 73% (CI 42.2 to 92.6) and specificity 75% (CI 70.1 to 78.4). These data are comparable to those obtained with the Ranson or Glasgow scores at 24 hour in this patient group, with a cut-off ≥3. Conclusions: Serum creatinine and chest radiographs are two indices capable of identifying, within 24 hour of admission, a subgroup of acute pancreatitis patients with a more severe or adverse clinical course.

Effect of tamoxifen on serum lipid metabolism.

The effect of tamoxifen, an antiestrogenic agent, on lipid metabolism was studied in postmenopausal patients with breast cancer who received the drug for postoperative adjuvant treatment following mastectomy. To measure total cholesterol and triglyceride concentrations, fasting blood samples were collected before and 2 months after the initiation of tamoxifen therapy from 16 patients who satisfied the study criteria. All patients were normolipidemic before tamoxifen was administered. Control samples were obtained from hypertriglyceridemia patients who were free from breast cancer. Marked hypertriglyceridemia was observed in 3 of 16 patients after tamoxifen treatment. The activity of lipoprotein lipase and hepatic triglyceride lipase, the key enzymes of triglyceride metabolism, decreased significantly in all of 16 patients as a result of tamoxifen treatment (P = 0.008 and P = 0.007, respectively). However, the mean mass of lipoprotein lipase significantly increased (P = 0.011) after tamoxifen treatment. We therefore conclude that tamoxifen might increase inactive lipoprotein lipase. Because marked hyperlipidemia is a potent risk factor for life-threatening acute pancreatitis and arteriosclerosis, plasma lipid levels should be tested periodically during tamoxifen treatment, even if the patients are normolipidemic during the pretreatment stage.

Effect of Tamoxifen on Serum Lipid Metabolism

The effect of tamoxifen, an antiestrogenic agent, on lipid metabolism was studied in postmenopausal patients with breast cancer who received the drug for postoperative adjuvant treatment following mastectomy. To measure total cholesterol and triglyceride concentrations, fasting blood samples were collected before and 2 months after the initiation of tamoxifen therapy from 16 patients who satisfied the study criteria. All patients were normolipidemic before tamoxifen was administered. Control samples were obtained from hypertriglyceridemia patients who were free from breast cancer. Marked hypertriglyceridemia was observed in 3 of 16 patients after tamoxifen treatment. The activity of lipoprotein lipase and hepatic triglyceride lipase, the key enzymes of triglyceride metabolism, decreased significantly in all of 16 patients as a result of tamoxifen treatment (P = 0.008 and P = 0.007, respectively). However, the mean mass of lipoprotein lipase significantly increased (P = 0.011) after tamoxifen treatment. We therefore conclude that tamoxifen might increase inactive lipoprotein lipase. Because marked hyperlipidemia is a potent risk factor for life-threatening acute pancreatitis and arteriosclerosis, plasma lipid levels should be tested periodically during tamoxifen treatment, even if the patients are normolipidemic during the pretreatment stage.

Tamoxifen-induced hypertriglyceridaemia

We report seven cases of breast adenocarcinoma and hypertriglyceridaemia associated with the use of tamoxifen. Two cases presented with life-threatening acute pancreatitis. Two cases show a rise in serum triglycerides (TG) after starling tamoxifen. Five patients had some degree of insulin resistance or diabetes which may have aggravated the hypertriglyceridaemia. One additional patient had an apolipoprotein phenotype associated with hypertriglyceridaemia. Fibrates effectively reduced serum TG levels. In general, tamoxifen improves the lipid profile and this may account for the reduction in coronary events in patients taking this drug. However, a rise in serum TG levels has been documented in several studies. Our reports suggest that it is important to screen patients on tamoxifen since hypertriglyceridaemia could cause potentially fatal acute pancreatitis or increase the risk of developing ischaemic heart disease.

F299. Rheological changes in hypertensive patients treated with ramipril

Severe hypertriglyceridemia (HTG) is a metabolic disturbance often seen in clinical practice. It is known to induce life-threatening acute pancreatitis, but its role in atherogenesis remains elusive. Hemorheological abnormality was thought to play an important role in pathogenesis of both pancreatitis and atherosclerosis. However, hemorheology in severe HTG was not well investigated. Recently, we established a severe HTG mouse model deficient in lipoprotein lipase (LPL) in which severe HTG was observed to cause a significant increase in plasma viscosity. Disturbances of erythrocytes were also documented, including decreased deformability, electrophoresis rate, and membrane fluidity, and increased osmotic fragility. Scanning electron microscopy demonstrated that most erythrocytes of LPL deficient mice deformed with protrusions, irregular appearances or indistinct concaves. Analysis of erythrocyte membrane lipids showed decreased cholesterol (Ch) and phospholipid (PL) contents but unaltered Ch/PL ratio. The changes of membrane lipids may be partially responsible for the hemorheological and morphologic abnormalities of erythrocytes. This study indicated that severe HTG could lead to significant impairment of hemorheology and this model may be useful in delineating the role of severe HTG in the pathogenesis of hyperlipidemic pancreatitis and atherosclerosis.

Pancreatography after recovery from massive pancreatic necrosis.

Massive retroperitoneal necrosis may follow life-threatening acute pancreatitis. At delayed operation, the surgeon may not be able to delineate dead pancreas from dead adipose tissue. The question arises: has "gloved hand" debridement resulted in pancreatectomy? The histologists report only "necrotic debris, of uncertain origin." To obtain objective data, pancreatography was performed in 13 patients, 10 weeks to 23 months after onset of massive pancreatic necrosis. Each patient had required delayed laparotomy for debridement and external drainage at some earlier stage of their illness. Pancreatography was correlated with the clinical assessment of diabetes and steatorrhea. Except in specific cases involving internal fistulae, pancreatography has not been previously reported in such patients. The results demonstrate that the main pancreatic duct usually maintained its normal length and configuration. Necrosis or stricture of the main duct, if it occurred, was more likely to be followed by diabetes. Steatorrhea was clinically detected in a single patient only. The necrotic tissue, up to several kilograms in wet weight, is largely dead adipose tissue. The pancreas, especially its head, is resistant to necrosis, much more resistant than is the retroperitoneal fat.