A Highly Bioavailable Omega-3 Free Fatty Acid Formulation Improves the Cardiovascular Risk Profile in High-Risk, Statin-Treated Patients With Residual Hypertriglyceridemia (the ESPRIT Trial)

Maki, Kevin C.; Orloff, David G.; Nicholls, Stephen J.; Dunbar, Richard L.; Roth, Eli M.; Curcio, Danielle; Johnson, Judith; Kling, Douglas; Davidson, Michael

doi:10.1016/j.clinthera.2013.07.420

Cited by 98 publications

(93 citation statements)

References 31 publications

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“…In the absence of direct head-to-head studies, potential similarities and differences between these drug classes and icosabutate must be interpreted cautiously. Triglyceride and non-HDL-C responses with 600 mg icosabutate appear to be at least as large as that achieved by 4 g of OM3-FA or fenofibric acid in similar populations [21,22,23]. The magnitude of apo C-III reduction from baseline with icosabutate closely mirrors the findings in patients with severe hypertriglyceridemia, where icosabutate reduced apo C-III by 41% versus at baseline.…”

Section: Discussionsupporting

confidence: 64%

Icosabutate, a Structurally Engineered Fatty Acid, Improves the Cardiovascular Risk Profile in Statin-Treated Patients with Residual Hypertriglyceridemia

Kastelein

Hallén²,

Vige³

et al. 2016

Cardiology

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Objectives: To evaluate the efficacy and safety of icosabutate, an oral, once-daily, first-in-class medication, in reducing non-high-density lipoprotein cholesterol (non-HDL-C) in patients with persistent hypertriglyceridemia despite statin therapy. Methods: The study was designed to randomly assign 140 patients with fasting triglyceride levels ≥200 but <500 mg/dl on a stable dose of statin therapy to receive either masked icosabutate 600 mg once daily or a control for 12 weeks. The primary end point was a percentage change in non-HDL-C from baseline to 12 weeks. Results: With icosabutate, non-HDL-C levels were reduced (-9.2%) when compared with the control (-0.4%) for a between-group difference of -7.4% (p = 0.02). Compared with the control, icosabutate reduced triglycerides (-27.0%, p < 0.001), very- low-density lipoprotein (VLDL) cholesterol (-31.5%, p < 0.001) and apolipoprotein C-III (-22.5%, p < 0.001). LDL-C levels did not change (0.5%, p = 0.87). HDL-C (10.2%, p < 0.001) was increased. After 113 subjects had been randomized, the study was terminated due to a partial clinical hold imposed by US regulators after observing QT prolongation at supratherapeutic doses of icosabutate in a dog study. In this study, adverse events were balanced between treatment arms, and there were no discontinuations due to adverse events. Conclusions: Icosabutate was efficacious in lowering non-HDL-C and other biomarkers of cardiovascular risk and was generally well tolerated.

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Section: Discussionsupporting

confidence: 64%

Icosabutate, a Structurally Engineered Fatty Acid, Improves the Cardiovascular Risk Profile in Statin-Treated Patients with Residual Hypertriglyceridemia

Kastelein

Hallén²,

Vige³

et al. 2016

Cardiology

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“…products [32,49,50]. Increased mild infections, such as upper respiratory infections, have also been reported with omega-3 fatty acid consumption.…”

Section: Discussionmentioning

confidence: 93%

“…A potential limitation of this trial that has been described previously [50] was the use of olive oil as the placebo, which may have had non-neutral effects on some of the outcome variables. For this reason, the responses to placebo and PDL-0101 treatments have been reported separately, instead of calculating placebo-corrected responses.…”

Section: Discussionmentioning

confidence: 98%

Safety and lipid-altering efficacy of a new omega-3 fatty acid and antioxidant-containing medical food in men and women with elevated triacylglycerols

Maki

Geohas

Dicklin

et al. 2015

Prostaglandins, Leukotrienes and Essential Fatty Acids

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“…In this study, non-HDL-C, TC/non-HDL-C, VLDL, remnant-like particle cholesterol, apoC-III, Lp-PLA 2 , and arachidonic acid (AA) levels were significantly lowered as compared with placebo, but LDL-C was also substantially increased. One advantage is that the availability of the FFA form is up to fourfold higher than from the EE form under low-fat dietary conditions [155][156][157]. In the Epanova combined with a Statin in Patients with hypeRglyerIdemia to reduce non-HDL cholesTerol (ESPRIT) trial, FFA omega-3 was administered to high-risk patients taking statins with TGs between 2.26 and 5.63 mmol/L (200-499 mg/dL); a dose of 2 g/day was found to be effective and well-tolerated for lowering non-HDL-C and TGs, as opposed to a higher dose of 4 g/day of other forms [157].…”

Section: Omega-3 Polyunsaturated Long-chain Fatty Acidsmentioning

confidence: 99%

“…One advantage is that the availability of the FFA form is up to fourfold higher than from the EE form under low-fat dietary conditions [155][156][157]. In the Epanova combined with a Statin in Patients with hypeRglyerIdemia to reduce non-HDL cholesTerol (ESPRIT) trial, FFA omega-3 was administered to high-risk patients taking statins with TGs between 2.26 and 5.63 mmol/L (200-499 mg/dL); a dose of 2 g/day was found to be effective and well-tolerated for lowering non-HDL-C and TGs, as opposed to a higher dose of 4 g/day of other forms [157]. Two ongoing large CV outcomes trials, STRENGTH (STatin Residual risk reduction with EpaNova in hiGh cardiovascular risk paTients with Hypertriglyceridaemia) and REDUCE-IT will report whether n-3 PUFA added to statin therapy in high-risk patients improves CV outcomes.…”

Section: Omega-3 Polyunsaturated Long-chain Fatty Acidsmentioning

confidence: 99%

Current Treatment of Dyslipidemia: Evolving Roles of Non-Statin and Newer Drugs

Kones¹,

Rumana²

2015

Drugs

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Since their introduction, statin (HMG-CoA reductase inhibitor) drugs have advanced the practice of cardiology to unparalleled levels. Even so, coronary heart disease (CHD) still remains the leading cause of death in developed countries, and is predicted to soon dominate the causes of global mortality and disability as well. The currently available non-statin drugs have had limited success in reversing the burden of heart disease, but new information suggests they have roles in sizeable subpopulations of those affected. In this review, the status of approved non-statin drugs and the significant potential of newer drugs are discussed. Several different ways to raise plasma high-density lipoprotein (HDL) cholesterol (HDL-C) levels have been proposed, but disappointments are now in large part attributed to a preoccupation with HDL quantity, rather than quality, which is more important in cardiovascular (CV) protection. Niacin, an old drug with many antiatherogenic properties, was re-evaluated in two imperfect randomized controlled trials (RCTs), and failed to demonstrate clear effectiveness or safety. Fibrates, also with an attractive antiatherosclerotic profile and classically used for hypertriglyceridemia, lacks evidence-based proof of efficacy, save for a subgroup of diabetic patients with atherogenic dyslipidemia. Omega-3 fatty acids fall into this category as well, even with an impressive epidemiological evidence base. Omega-3 research has been plagued with methodological difficulties yielding tepid, uncertain, and conflicting results; well-designed studies over longer periods of time are needed. Addition of ezetimibe to statin therapy has now been shown to decrease levels of low-density lipoprotein (LDL) cholesterol (LDL-C), accompanied by a modest decrease in the number of CV events, though without any improvement in CV mortality. Importantly, the latest data provide crucial evidence that LDL lowering is central to the management of CV disease. Of drugs that inhibit cholesteryl ester transfer protein (CETP) tested thus far, two have failed and two remain under investigation and may yet prove to be valuable therapeutic agents. Monoclonal antibodies to proprotein convertase subtilisin/kexin type 9, now in phase III trials, lower LDL-C by over 50 % and are most promising. These drugs offer new ability to lower LDL-C in patients in whom statin drug use is, for one reason or another, limited or insufficient. Mipomersen and lomitapide have been approved for use in patients with familial hypercholesterolemia, a more common disease than appreciated. Anti-inflammatory drugs are finally receiving due attention in trials to elucidate potential clinical usefulness. All told, even though statins remain the standard of care, non-statin drugs are poised to assume a new, vital role in managing dyslipidemia.

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A Highly Bioavailable Omega-3 Free Fatty Acid Formulation Improves the Cardiovascular Risk Profile in High-Risk, Statin-Treated Patients With Residual Hypertriglyceridemia (the ESPRIT Trial)

Cited by 98 publications

References 31 publications

Icosabutate, a Structurally Engineered Fatty Acid, Improves the Cardiovascular Risk Profile in Statin-Treated Patients with Residual Hypertriglyceridemia

Icosabutate, a Structurally Engineered Fatty Acid, Improves the Cardiovascular Risk Profile in Statin-Treated Patients with Residual Hypertriglyceridemia

Safety and lipid-altering efficacy of a new omega-3 fatty acid and antioxidant-containing medical food in men and women with elevated triacylglycerols

Current Treatment of Dyslipidemia: Evolving Roles of Non-Statin and Newer Drugs

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