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The results of this phase 3 trial of the effect of olezarsen, a drug that targets APOC3 mRNA, on plasma triglyceride levels and acute pancreatitis in familial chylomicronemia syndrome support further clinical research.

This phase 3 trial showed that treatment with volanesorsen, an antisense oligonucleotide drug complementary to mRNA encoding apolipoprotein C-III, resulted in a mean reduction in triglyceride levels of 77% over the course of 3 months.

Persistent chylomicronemia is a genetic recessive disorder that is classically caused by familial chylomicronemia syndrome (FCS), but it also has multifactorial causes. The disorder is associated with the risk of recurrent acute pancreatitis. Plozasiran is a small interfering RNA that reduces hepatic production of apolipoprotein C-III and circulating triglycerides. In a phase 3 trial, we randomly assigned 75 patients with persistent chylomicronemia (with or without a genetic diagnosis) to receive subcutaneous plozasiran (25 mg or 50 mg) or placebo every 3 months for 12 months. The primary end point was the median percent change from baseline in the fasting triglyceride level at 10 months. Key secondary end points were the percent change in the fasting triglyceride level from baseline to the mean of values at 10 months and 12 months, changes in the fasting apolipoprotein C-III level from baseline to 10 months and 12 months, and the incidence of acute pancreatitis. At baseline, the median triglyceride level was 2044 mg per deciliter. At 10 months, the median change from baseline in the fasting triglyceride level (the primary end point) was -80% in the 25-mg plozasiran group, -78% in the 50-mg plozasiran group, and -17% in the placebo group (P<0.001). The key secondary end points showed better results in the plozasiran groups than in the placebo group, including the incidence of acute pancreatitis (odds ratio, 0.17; 95% confidence interval, 0.03 to 0.94; P = 0.03). The risk of adverse events was similar across groups; the most common adverse events were abdominal pain, nasopharyngitis, headache, and nausea. Severe and serious adverse events were less common with plozasiran than with placebo. Hyperglycemia with plozasiran occurred in some patients with prediabetes or diabetes at baseline. Patients with persistent chylomicronemia who received plozasiran had significantly lower triglyceride levels and a lower incidence of pancreatitis than those who received placebo. (Funded by Arrowhead Pharmaceuticals; PALISADE ClinicalTrials.gov number, NCT05089084.).

In this study, investigators found that APOC3, a key regulator of triglyceride metabolism, had a profound and clinically relevant effect on triglyceride levels through a mechanism that is independent of lipoprotein lipase. The familial chylomicronemia syndrome is a rare autosomal recessive disease characterized by the buildup in the blood of fat particles called chylomicrons (chylomicronemia), severe hypertriglyceridemia, and the risk of recurrent and potentially fatal pancreatitis and other complications. 1 It is caused by mutations in the gene encoding LPL or, less frequently, by mutations in genes encoding other proteins necessary for LPL function. 2 Patients with this syndrome have plasma triglyceride levels ranging from 10 to 100 times the normal value (1500 to 15,000 mg per deciliter [17 to 170 mmol per liter]), eruptive xanthomas, arthralgias, neurologic symptoms, lipemia retinalis, and hepatosplenomegaly. 3 Nearly . . .

Six patients with severe hypertriglyceridemia (chylomicronemia) were found to have autoantibodies against a capillary endothelial-cell protein (GPIHBP1) that transports lipoprotein lipase to the capillary lumen. A protein in the lymphocyte antigen 6 (Ly6) superfamily, called GPIHBP1 (glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1), is expressed on the surface of capillary endothelial cells. GPIHBP1 binds lipoprotein lipase in the interstitial spaces (where the lipase is secreted by myocytes and adipocytes) and shuttles it to its site of action in the capillary lumen. 1 , 2 In patients with GPIHBP1 deficiency, lipoprotein lipase is mislocalized in the interstitial spaces and never reaches the capillary lumen. The absence of intraluminal lipoprotein lipase prevents the lipolytic processing of triglyceride-rich lipoproteins and results in severe hypertriglyceridemia (chylomicronemia, defined as a triglyceride level of . . .

Abstract Background Multifactorial chylomicronemia syndrome (MCS) is a severe form of hypertriglyceridemia (hyperTG) associated with an increased risk of acute pancreatitis. However, the risk of acute pancreatitis is very heterogenous in MCS. Previous studies suggested that inflammation might promote disease progression in hyperTG-induced acute pancreatitis. Objective To determine if low-grade inflammation is associated with acute pancreatitis in MCS. Methods This study included 102 subjects with MCS for whom high-sensitivity C-reactive protein (hsCRP) concentration was measured at their first visit at the Montreal Clinical Research Institute. Results Patients with MCS who had a previous history of acute pancreatitis had a significant higher hsCRP concentration (4.62 mg/L vs 2.61 mg/L; P = .003), and high hsCRP concentration (≥ 3 mg/L) was independently associated with acute pancreatitis prevalence (P < .05). Up to 64% of the variability in acute pancreatitis prevalence was explained by the maximal triglycerides (TG) concentration, hsCRP concentration, the presence of rare variants in TG-related genes, and fructose intake, based on a stepwise multivariate regression model (P < .0001). Conclusion This retrospective study showed for the first time that hsCRP concentration is strongly associated with acute pancreatitis prevalence in MCS. It also suggests that low-grade inflammation may be a driver of acute pancreatitis in severe hypertriglyceridemia. Prospective studies could help determine the causality of this association and assess whether medication known to reduce low-grade inflammation could help prevent acute pancreatitis in individuals with severe hypertriglyceridemia.

Abstract Context Patients with type 1 hyperlipoproteinemia (T1HLP), a rare genetic disorder, have extreme chylomicronemia and recurrent episodes of acute pancreatitis. Currently, the only therapeutic option is to consume an extremely low-fat diet because the triglyceride-lowering medications are not efficacious. Objective To determine the efficacy of orlistat, a gastric and pancreatic lipase inhibitor, in reducing serum triglyceride levels in patients with T1HLP. Design and Setting We conducted a randomized, open-label, clinical trial with a four-period, two-sequence (“orlistat” and “off orlistat” for 3 months), crossover study design. Patients Two unrelated young Asian Indian males (11 and 9 years old) with T1HLP due to homozygous large GPIHBP1 deletions were enrolled at the UT Southwestern Medical Center. The patients were randomized to receive 3 months of orlistat or no therapy (off), then crossed over to the other arm, and this sequence was then repeated. Fasting serum triglyceride levels, fat-soluble vitamins, and gastrointestinal side effects were assessed. Results Compared with the two off periods, orlistat therapy reduced serum triglycerides by 53.3% and 53.0% in patient 1 and 45.8% and 62.2% in patient 2. There was no deficiency of fat-soluble vitamin levels, and their growth continued. There were no serious adverse effects of orlistat; patient 1 had a mild increase in passage of gas and bloating, and patient 2 had constipation with mild stool leakage. Conclusion Orlistat is safe and highly efficacious in lowering serum triglycerides in children with T1HLP and should be the first-line therapy in conjunction with an extremely low-fat diet. Patni et al. conducted a randomized clinical trial of orlistat in two children with type 1 hyperlipoproteinemia and showed that it was well tolerated and lowered serum triglycerides by more than 50%.

Cardiovascular diseases (CVD) have overtaken infectious diseases and are currently the world’s top killer. A quite strong linkage between this type of ailments and elevated plasma levels of triglycerides (TG) has been always noticed. Notably, this risk factor is mired in deep confusion, since its role in atherosclerosis is uncertain. One of the explanations that aim to decipher this persistent enigma was provided by apolipoprotein C-III (apoC-III), a small protein historically recognized as an important regulator of TG metabolism. Preeminently, hundreds of studies have been carried out in order to explore the APOC3 genetic background, as well as to establish a correlation between its variants and dyslipidemia-related disorders, pointing to an earnest predictive power for future outcomes. Among several polymorphisms reported within the APOC3, the SstI site in its 3′-untranslated region (3′-UTR) was the most consistently and robustly associated with an increased CVD risk. As more genetic data supporting its importance in cardiovascular events aggregate, it was declared, correspondingly, that apoC-III exerts various atherogenic effects, either by intervening in the function and catabolism of many lipoproteins, or by inducing endothelial inflammation and smooth muscle cells (SMC) proliferation. This review was designed to shed the light on the structural and functional aspects of the APOC3 gene, the existing association between its SstI polymorphism and CVD, and the specific molecular mechanisms that underlie apoC-III pathological implications. In addition, the translation of all these gathered knowledges into preventive and therapeutic benefits will be detailed too.

Background Familial chylomicronemia syndrome (FCS) is a rare lipid disease caused by complete lipoprotein lipase (LPL) deficiency resulting in fasting chylomicronemia and severe hypertriglyceridemia. Inhibition of diacylglycerol acyltransferase 1 (DGAT1), which mediates chylomicron triglyceride (TG) synthesis, is an attractive strategy to reduce TG levels in FCS. In this study we assessed the safety, tolerability and TG-lowering efficacy of the DGAT1 inhibitor pradigastat in patients with FCS. Methods Six FCS patients were enrolled in an open-label clinical study. Following a 1-week very low fat diet run-in period patients underwent baseline lipid assessments, including a low fat meal tolerance test. Patients then underwent three consecutive 21 day treatment periods (pradigastat at 20, 40 & 10 mg, respectively). Treatment periods were separated by washout periods of ≥4 weeks. Fasting TG levels were assessed weekly through the treatment periods. Postprandial TGs, ApoB48 and lipoprotein lipid content were also monitored. Results Following once daily oral dosing, steady-state exposure was reached by Day 14. There was an approximately dose proportional increase in pradigastat exposure at studied doses. Pradigastat was associated with a 41% (20 mg) and 70% (40 mg) reduction in fasting triglyceride over 21 days of treatment. The reduction in fasting TG was almost entirely accounted for by a reduction in chylomicron TG. Pradigastat treatment also led to substantial reductions in postprandial TG as well as apo48 (both fasting and postprandial). Pradigastat was safe and well tolerated, with only mild, transient gastrointestinal adverse events. Conclusion The novel DGAT1 inhibitor pradigastat substantially reduces plasma TG levels in FCS patients, and may be a promising new treatment for this orphan disease. Trial registration ClinicalTrials.gov identifier NCT01146522 .

A 5-year-old boy presented to our department with a 2-day history of acute febrile illness. During evaluation, his blood samples were found to be so lipaemic (figure) that it caused interference in analyte measurements.