VAZKEPA Soft capsule Ref.[50397] Active ingredients: Eicosapentaenoic acid

Pharmacotherapeutic group: Lipid modifying agents, Other lipid modifying agents
ATC code: C10AX06

Mechanism of action

Icosapent ethyl is a stable ethyl ester of the omega-3 fatty acid, eicosapentaenoic acid (EPA). The mechanisms of action contributing to reduction of cardiovascular events with icosapent ethyl are not completely understood. The mechanisms are likely multi-factorial including improved lipoprotein profile with reduction of triglyceride-rich lipoproteins, anti-inflammatory, and antioxidant effects, reduction of macrophage accumulation, improved endothelial function, increased fibrous cap thickness/stability, and antiplatelet effects. Each of these mechanisms can beneficially alter the development, progression, and stabilisation of atherosclerotic plaque, as well as the implications of plaque rupture, and preclinical and clinical studies support such benefits with EPA. Systemic and localised anti-inflammatory effects of EPA may result from displacement of pro-inflammatory arachidonic acid (AA), directing catabolism away from eicosanoids (2-series prostaglandins and thromboxanes, and 4-series leukotrienes) to non- or anti-inflammatory mediators. However, the direct clinical meaning of individual findings is not clear.

Pharmacodynamic effects

Icosapent ethyl improves the lipoprotein profile by suppressing cholesterol-, fatty acid- and triglyceride (TG)-synthesising enzymes, increasing fatty acid β-oxidation, and reducing microsomal triglyceride transfer (MTP) protein, resulting in decreased hepatic TG and very low-density lipoprotein (VLDL) synthesis and release. Icosapent ethyl also increases expression of lipoprotein lipase leading to increased TG removal from circulating VLDL and chylomicron particles. In patients with elevated TG levels, icosapent ethyl lowers TG, VLDL, remnant lipoprotein cholesterol, and levels of inflammatory markers such as C-reactive protein. However, TG reduction appears to provide only a minor contribution to the reduction in risk of cardiovascular events with icosapent ethyl.

Clinical efficacy and safety

REDUCE-IT was a multinational, double-blind, randomised, placebo-controlled, event-driven trial in 8,179 (4,089 icosapent ethyl, 4,090 placebo) statin-treated adult patients enrolled with low-density lipoprotein cholesterol (LDL-C) >1.03 mmol/L (40 mg/dL) and ≤2.59 mmol/L (100 mg/dL) and moderately elevated triglyceride (TG) levels (≥1.53 mmol/L and <5.64 mmol/L [≥135 mg/dL and <500 mg/dL] as measured during patient screening, i.e. qualifying visits pre-enrolment) and either established cardiovascular disease (70.7%) or diabetes and other risk factors for cardiovascular disease (29.3%). Patients with established cardiovascular disease were defined as being at least 45 years of age and having a documented history of coronary artery disease, cerebrovascular or carotid disease, or peripheral artery disease. Patients in the other risk group were defined as being at least 50 years of age with diabetes requiring medical treatment and at least one additional risk factor i.e., hypertension or on an antihypertensive medicinal product; age at least 55 years (men) or at least 65 years (women); low high-density lipoprotein cholesterol levels; smoking; raised high-sensitivity C-reactive protein levels; renal impairment; micro or macroalbuminuria; retinopathy; or reduced ankle brachial index. Patients were randomly assigned 1:1 to receive either icosapent ethyl or placebo (as 4 capsules daily). The median follow-up duration was 4.9 years. Overall, 99.8% of patients were followed for vital status until the end of the trial or death.

The baseline characteristics were balanced between the groups, median age at baseline was 64 years (range: 44 years to 92 years), with 46% being at least 65 years old; 28.8% were women. The trial population was 90.2% White, 5.5% Asian, 4.2% identified as Hispanic ethnicity, and 1.9% were Black. Regarding prior diagnoses of cardiovascular disease, 46.7% had prior myocardial infarction, 9.2% had symptomatic peripheral arterial disease, and 6.1% prior unknown stroke or transient ischemic attack (TIA). Selected additional baseline risk factors included hypertension (86.6%), diabetes mellitus (0.7% type 1; 57.8% type 2), eGFR <60 mL/min per 1.73 m² (22.2%), congestive heart failure (17.7%), and current daily cigarette smoking (15.2%). Most patients were taking moderate-intensity (63%) or high-intensity (31%) statin therapy at baseline. Most patients at baseline were taking at least one other cardiovascular medicinal product including antiplatelet and/or antithrombotic agents (85.5%), beta blockers (70.7%), antihypertensives (95.2%), angiotensin converting enzyme (ACE) inhibitors (51.9%), or angiotensin receptor blockers (ARB; 26.9%); 77.5% were taking an ACE inhibitor or ARB. The protocol excluded patients taking PCSK9 inhibitors. On stable background lipid-lowering therapy, the median [Q1, Q3] LDL-C at baseline was 1.9 [1.6, 2.3] mmol/L (75.0 [62.0, 89.0] mg/dL); the mean (SD) was 2.0 (0.5) mmol/L (76.2 [20.3] mg/dL). On stable background lipid-lowering therapy, the median [Q1, Q3] fasting TG was 2.4 [2.0, 3.1] mmol/L (216.0 [176.0, 272.5] mg/dL); the mean (SD) was 2.6 (0.9) mmol/L (233.2 [80.1] mg/dL).

Icosapent ethyl significantly reduced the risk for the primary composite endpoint (time to first occurrence of cardiovascular death, myocardial infarction, stroke, coronary revascularisation, or hospitalisation for unstable angina; p<0.0001) and the key secondary composite endpoint (time to first occurrence of cardiovascular death, myocardial infarction, or stroke; p<0.0001). The results of the primary and secondary efficacy endpoints are shown in Table 2. The Kaplan-Meier estimates of the cumulative incidence of the key secondary composite endpoint over time are shown in Figure 1.

Table 2. Effect of icosapent ethyl on time to first occurrence of cardiovascular events in patients with elevated triglyceride levels and cardiovascular disease or diabetes and other risk factors in REDUCE-IT:

Figure 1. Kaplan-Meier estimated incidence of key secondary composite endpoint in REDUCE-IT:

Key secondary composite endpoint consisted of cardiovascular death, myocardial infarction, or stroke (3-point MACE) Abbreviations: CI confidence interval

The median TG and LDL-C baseline values were similar between the icosapent ethyl group and placebo group. The median change in TG from baseline to Year 1 was -0.4 mmol/L (-39 mg/dL, -18%) in the icosapent ethyl group and 0.1 mmol/L (5 mg/dL, 2%) in the placebo group. The median change in LDL-C from baseline to Year 1 was 0.1 mmol/L (2 mg/dL, 3%) in the icosapent ethyl group and 0.2 mmol/L (7 mg/dL, 10%) in the placebo group. Prespecified analyses of the effect of icosapent ethyl on cardiovascular outcomes in the REDUCE-IT trial showed little to no correlation between either TG or LDL-C response and cardiovascular effect based on baseline or on-study achieved TG or LDL-C levels. See section 5.1 mechanism of action for more information.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with icosapent ethyl in all subsets of the paediatric population for the treatment of hypertriglyceridemia and to reduce the risk of cardiovascular events (see section 4.2 for information on paediatric use).