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In a randomized trial, patients with type 2 diabetes, hypertriglyceridemia, and low HDL cholesterol who received pemafibrate did not have fewer cardiovascular events, although some lipid levels decreased.

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.

In this multicenter, placebo-controlled trial involving statin-treated patients with hypertriglyceridemia, the risk of ischemic events, including cardiovascular death, was significantly lower with 2 g of icosapent ethyl twice daily than with placebo.

In a phase 2b trial involving patients with hypertriglyceridemia, the use of olezarsen (which targets APOC3 mRNA) for 6 months reduced triglyceride levels by approximately 50% as compared with placebo.

Weekly doses of an antisense inhibitor of apolipoprotein C-III (APOC3) in persons with severe or uncontrolled hypertriglyceridemia resulted in a reduction in APOC3 and triglyceride levels at the end of 13 weeks. Elevated triglyceride levels are associated with several pathologic conditions, including insulin resistance, the metabolic syndrome, diabetes, cardiovascular disease, and hereditary disorders, such as the familial chylomicronemia syndrome, familial combined hyperlipidemia, and familial hypertriglyceridemia. 1 , 2 Patients with triglyceride levels above 2000 mg per deciliter (22.6 mmol per liter), measured at the peak of abdominal pain, are at high risk for pancreatitis. 3 , 4 Current guidelines from the Endocrine Society and the European Atherosclerosis Society recommend that fasting triglyceride levels should be maintained at values below 1000 mg per deciliter (11.3 mmol per liter) or 10 mmol per liter, respectively, to prevent intermittent . . .

Severe hypertriglyceridemia (sHTG) is an established risk factor for acute pancreatitis. Current therapeutic approaches for sHTG are often insufficient to reduce triglycerides and prevent acute pancreatitis. This phase 2 trial ( NCT03452228 ) evaluated evinacumab (angiopoietin-like 3 inhibitor) in three cohorts of patients with sHTG: cohort 1, familial chylomicronemia syndrome with bi-allelic loss-of-function lipoprotein lipase (LPL) pathway mutations ( n  = 17); cohort 2, multifactorial chylomicronemia syndrome with heterozygous loss-of-function LPL pathway mutations ( n  = 15); and cohort 3, multifactorial chylomicronemia syndrome without LPL pathway mutations ( n  = 19). Fifty-one patients (males, n  = 27; females, n  = 24) with a history of hospitalization for acute pancreatitis were randomized 2:1 to intravenous evinacumab 15 mg kg −1 or placebo every 4 weeks over a 12-week double-blind treatment period, followed by a 12-week single-blind treatment period. The primary end point was the mean percent reduction in triglycerides from baseline after 12 weeks of evinacumab exposure in cohort 3. Evinacumab reduced triglycerides in cohort 3 by a mean (s.e.m.) of −27.1% (37.4) (95% confidence interval −71.2 to 84.6), but the prespecified primary end point was not met. No notable differences in adverse events between evinacumab and placebo treatment groups were seen during the double-blind treatment period. Although the primary end point of a reduction in triglycerides did not meet the prespecified significance level, the observed safety and changes in lipid and lipoprotein levels support the further evaluation of evinacumab in larger trials of patients with sHTG. Trial registration number: ClinicalTrials.gov NCT03452228 . The potential of evinacumab, a monoclonal antibody targeting angiopoietin-like 3, for reducing triglyceride levels was tested in patients with severe hypertriglyceridemia due to differing genetic etiologies.

Pegozafermin, a long-acting glycopegylated analog of human fibroblast growth factor 21, is in development for the treatment of severe hypertriglyceridemia (SHTG) and nonalcoholic steatohepatitis. Here we report the results of a phase 2, double-blind, randomized, five-arm trial testing pegozafermin at four different doses ( n  = 67; 52 male) versus placebo ( n  = 18; 12 male) for 8 weeks in patients with SHTG (triglycerides (TGs), ≥500 mg dl −1 and ≤2,000 mg dl −1 ). Treated patients showed a significant reduction in median TGs for the pooled pegozafermin group versus placebo (57.3% versus 11.9%, difference versus placebo −43.7%, 95% confidence interval (CI): −57.1%, −30.3%; P  < 0.001), meeting the primary endpoint of the trial. Reductions in median TGs ranged from 36.4% to 63.4% across all treatment arms and were consistent regardless of background lipid-lowering therapy. Results for secondary endpoints included significant decreases in mean apolipoprotein B and non-high-density lipoprotein cholesterol concentrations (−10.5% and −18.3% for pooled doses compared to 1.1% and −0.6% for placebo (95% CI: −21.5%, −2.0%; P  = 0.019 and 95% CI: −30.7%, −5.1%; P  = 0.007, respectively), as well as a significant decrease in liver fat fraction for pooled treatment ( n  = 17) versus placebo ( n  = 6; −42.2% pooled pegozafermin, −8.3% placebo; 95% CI: −60.9%, −8.7%; P  = 0.012), as assessed in a magnetic resonance imaging sub-study. No serious adverse events were observed to be related to the study drug. If these results are confirmed in a phase 3 trial, pegozafermin could be a promising treatment for SHTG (ClinicalTrials.gov registration: NCT0441186). In a phase 2, randomized clinical trial in patients with severe hypertriglyceridemia, pegozafermin, a long-acting analog of human fibroblast growth factor 21, was safe and met the primary endpoint of the trial for reducing serum triglyceride levels.

Key Points The role of elevated blood triglycerides as an independent risk factor for cardiovascular disease (CVD) has been debated for more than half a century, but without resolution One of the reasons for this uncertainty is that hypertriglyceridaemia is often associated with decreased HDL-cholesterol levels and an increased number of atherogenic small dense LDL particles Large observational, epidemiological, genetic, and Mendelian randomization studies support the hypothesis that elevated blood triglyceride levels, either fasting or nonfasting, are independently associated with an increased risk of CVD Therapeutic targeting of hypertriglyceridaemia might provide further benefit in reducing CVD and events, in addition to that achieved with LDL-cholesterol lowering Hypertriglyceridaemia is currently treated with lifestyle interventions and with fibrates, which can be combined with high doses of omega-3 fatty acids, but CVD outcome studies have produced inconsistent results Some novel drugs, such as pemafibrate and volanesorsen, are being tested, but clinical data are preliminary The role of hypertriglyceridaemia as a risk factor for coronary artery disease (CAD) is debated. In this Review, Reiner summarizes the causes of hypertriglyceridaemia, and discusses whether elevated blood triglyceride levels are an important and independent risk factor for CAD. Finally, current and emerging management options for hypertriglyceridaemia are detailed. An elevated serum level of LDL cholesterol is a well-known risk factor for cardiovascular disease (CVD), but the role of elevated triglyceride levels is debated. Controversies regarding hypertriglyceridaemia as an independent risk factor for CVD have occurred partly because elevated triglyceride levels are often a component of atherogenic dyslipidaemia — they are associated with decreased levels of HDL cholesterol and increased levels of small dense LDL particles, which are highly atherogenic. Findings from several large studies indicate that elevated levels of triglycerides (either fasting or nonfasting) or, more specifically, triglyceride-rich lipoproteins and their remnants, are independently associated with increased risk of CVD. Possible mechanisms for this association include excessive free fatty acid release, production of proinflammatory cytokines, coagulation factors, and impairment of fibrinolysis. Therapeutic targeting of hypertriglyceridaemia could, therefore, reduce CVD and cardiovascular events, beyond the reduction achieved by LDL-cholesterol lowering. Elevated triglyceride levels are reduced with lifestyle interventions and fibrates, which can be combined with omega-3 fatty acids. Some new drugs are on the horizon, such as volanesorsen (which targets apolipoprotein C-III), pemafibrate, and others. However, CVD outcome studies with triglyceride-lowering agents have produced inconsistent results, meaning that no convincing evidence is available that lowering triglycerides by any approach can reduce mortality.

Purpose of Review The omega-3 fatty acids (n3-FAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have recently undergone testing for their ability to reduce residual cardiovascular (CV) risk among statin-treated subjects. The outcome trials have yielded highly inconsistent results, perhaps attributable to variations in dosage, formulation, and composition. In particular, CV trials using icosapent ethyl (IPE), a highly purified ethyl ester of EPA, reproducibly reduced CV events and progression of atherosclerosis compared with mixed EPA/DHA treatments. This review summarizes the mechanistic evidence for differences among n3-FAs on the development and manifestations of atherothrombotic disease. Recent Findings Large randomized clinical trials with n3-FAs have produced discordant outcomes despite similar patient profiles, doses, and triglyceride (TG)-lowering effects. A large, randomized trial with IPE, a prescription EPA only formulation, showed robust reduction in CV events in statin treated patients in a manner proportional to achieved blood EPA concentrations. Multiple trials using mixed EPA/DHA formulations have not shown such benefits, despite similar TG lowering. These inconsistencies have inspired investigations into mechanistic differences among n3-FAs, as EPA and DHA have distinct membrane interactions, metabolic products, effects on cholesterol efflux, antioxidant properties, and tissue distribution. EPA maintains normal membrane cholesterol distribution, enhances endothelial function, and in combination with statins improves features implicated in plaque stability and reduces lipid content of plaques. Summary Insights into reductions in residual CV risk have emerged from clinical trials using different formulations of n3-FAs. Among high-risk patients on contemporary care, mixed n3-FA formulations showed no reduction in CV events. The distinct benefits of IPE in multiple trials may arise from pleiotropic actions that correlate with on-treatment EPA levels beyond TG-lowering. These effects include altered platelet function, inflammation, cholesterol distribution, and endothelial dysfunction. Elucidating such mechanisms of vascular protection for EPA may lead to new interventions for atherosclerosis, a disease that continues to expand worldwide.

This editorial describes the science behind an antisense drug targeting APOC3 mRNA to treat hypertriglyceridemia.