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............................................................................................................................................................................. ASCVD outcomes in people with elevated serum TGs; the trial enrolled 8000 patients on statin therapy, with LDL-C levels between 1.02.6 mmol/L (41100 mg/dL) and various CV risk factors, including persistent elevated TGs between 1.75.6 mmol/L (150499 mg/dL), and either established ASCVD or DM, and at least one other CV risk factor. Use of high doses (2 g b.i.d.) of EPA as compared with placebo (mineral oil) resulted in a 25% relative risk reduction (P < 0.001) in major adverse CV events (MACE). Another randomized placebo-controlled trial, Outcomes Study to Assess STatin Residual Risk Reduction with EpaNova in HiGh CV Risk PatienTs with Hypertriglyceridemia (STRENGTH),332 which aims to determine whether reduction of TRLs and remnants in statin-treated patients will provide additional ASCVD risk reduction, is ongoing. The VITamin D and OmegA-3 TriaL (VITAL), which reported recently, was a 22 factorial design study in which healthy participants were randomized in a 1:1 fashion to either vitamin D3 (at a dose of 2000 IU per day) vs. matching placebo, and n-3 fatty acids (1 g per day as a fish-oil capsule containing 840 mg of n-3 fatty acids, including 460 mg of EPA and 380 mg of DHA) vs. matching placebo. It showed that supplementation with either n-3 fatty acids at a dose of 1 g/day, or vitamin D3 at a dose of 2000 IU/day, was not effective for primary prevention of CV or cancer events among healthy middle-aged men and women over 5 years of follow-up.333

8.8.4 Safety and interactions The administration of n-3 fatty acids appears to be safe and devoid of clinically significant interactions. The most common side effect is GI disturbance. The antithrombotic effects may increase the propensity for bleeding, especially when given in addition to aspirin/clopidogrel. Recently, data from one study have associated a risk of prostate cancer with high dietary intake of n-3 PUFAs.334

8.9 Nicotinic acid

Nicotinic acid has key action sites in both the liver and adipose tissue. In the liver, nicotinic acid inhibits diacylglycerol acyltransferase-2 resulting in decreased secretion of VLDL particles, which is also reflected in reductions of plasma levels of both IDL and LDL particles.335 Nicotinic acid primarily raises HDL-C and ApoA1 by stimulating ApoA1 production in the liver.335 Two large randomized trials with nicotinic acid—one with extended-release niacin66 and one with niacin plus laropiprant67—have shown no beneficial effect and an increased frequency of serious adverse effects. No medication containing nicotinic acid is currently approved in Europe.

8.10 Cholesteryl ester transfer protein

inhibitors To date, the pharmacological approach that has led to the greatest elevations in HDL-C levels has been direct inhibition of CETP by small-molecule inhibitors, which may induce an increase in HDL-C by >_100% on a dose-dependent basis. Torcetrapib was studied in the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial, which was stopped early due to increased mortality.336 Dalcetrapib raises HDL-C levels by 3040% with no appreciable effect on LDL-C, offering specific insight into pure HDL-C raising. However, dalcetrapib failed to show any benefit in ACS patients in the dal-OUTCOMES trial. Evacetrapib, which raises HDL-C levels by 130% and lowers LDL-C by 37%, was studied in the ACCELERATE trial,63 which was terminated due to futility. Recently, anacetrapib, which raises HDL-C and ApoA-I levels (by 104 and 36%, respectively), and lowers LDL-C and ApoB (by 17 and 18%, respectively), was studied in the REVEAL trial. Anacetrapib reduced major coronary events by 9% over a median of 4.1 years.64

The magnitude of the relative risk reduction appeared to be consistent with the magnitude of LDL-C- or non-HDL-C-level lowering.337 This drug has not been submitted for regulatory approval.

8.11 Future perspectives

8.11.1 New approaches to reduce low-density lipoprotein cholesterol An alternative approach targeting PCSK9 consists of RNA interference. In a phase I and a phase II trial, the small interfering RNA (siRNA) molecule inclisiran—which inhibits the synthesis of PCSK9—reduced LDL-C by up to 50% and the reduction was dosedependent. Reductions in PCSK9 and LDL-C levels were maintained for <_6 months.338,339 No specific serious adverse events were observed. HPS4/TIMI65/ORION4, with a planned mean duration of 5 years, is currently comparing inclisiran vs. placebo among 15 000 patients with a prior MI or stroke. Bempedoic acid is a novel, first-in-class, oral small molecule that inhibits cholesterol synthesis by inhibiting the action of ATP citrate lyase, a cytosolic enzyme upstream of 3-hydroxy-3-methylglutarylcoenzyme A reductase.340 So far, it has been tested in diabetic patients, and patients with or without statin ‘intolerance’. In monotherapy, bempedoic acid reduces LDL-C levels by 30% and by about 50% in combination with ezetimibe. Bempedoic acid is currently being tested in phase III trials and some trials have been completed.341,342

8.11.2 New approaches to reduce triglyceride-rich lipoproteins and their remnants As genetic studies indicate that angiopoietin-like protein 3 (ANGPTL3) deficiency protects against atherosclerotic disease and that this relationship is causal,343 an ANGPTL3 antibody (evinacumab) is being developed. Evinacumab has been shown to decrease TGs, LDL-C, and Lp(a) levels in HoFH patients.344 Another approach that is currently being investigated is the inhibition of ANGPTL3 production by antisense oligonucleotides.345 IONIS-ANGPTL3-LRx, an antisense oligonucleotide targeting ANGPTL3, another critical protein in the clearance of TRLs, reduces plasma TGs by about 85%. Thus, the future may yield tools to improve TRL clearance that will be reflected in the atherogenic load of the remnant particles. The rapid development of gene-silencing technology has allowed proteins (ApoC-III) that are critical in the regulation of TRL clearance processes to be targeted. A second-generation antisense oligonucleotide targeting ApoC-III mRNA has been developed.346 Two phase III trials have evaluated the safety and efficacy of volanesorsen in patients with elevated TG levels.347,348 Volanesorsen reduced plasma TGs by 70% and ApoC-III by 8090%.349 The EMA recently issued a marketing authorization for Waylivra (volanesorsen) as an adjunct to diet in adult patients with genetically confirmed familial chylomicronaemia syndrome (FCS) who are at high-risk for pancreatitis, in whom response to diet and TG-lowering therapy has been inadequate. Downloaded from academic.oup.com/eurheartj/article/41/1/111/5556353 by guest on 07 October 2026