Icosapent ethyl for reduction in cardiovascular disease risk in adults with hypertriglyceridaemia

Approved indication: reduction in the risk of cardiovascular events in statin-treated adults at high cardiovascular risk with elevated triglycerides (1.7 mmol/L or greater) and one of the following:

• established cardiovascular disease
• diabetes and at least one other cardiovascular risk factor

Vazkepa (Seqirus)
998 mg soft capsules

Beliefs about the benefits of fish oil have spawned many complementary products containing omega-3 fatty acids. One of the purported benefits of fish oil is the prevention of cardiovascular disease, possibly through anti-inflammatory actions, altering the lipid profile, antiplatelet actions and stabilising atherosclerotic plaques. However, evidence of a benefit has been lacking.¹

Elevated triglyceride concentrations contribute to atherosclerotic cardiovascular disease risk, and severely elevated triglycerides increase the risk of acute pancreatitis. In current practice, fish oil has a role in the management of elevated triglyceride concentrations above 4 mmol/L in combination with a statin. Fenofibrate is added for patients who do not respond to treatment, or who have severely elevated triglyceride concentrations (more than 10 mmol/L) to lower the triglyceride concentration and reduce the risk of pancreatitis.² Nondrug measures (including weight loss, exercise, and restriction of alcohol, refined carbohydrates and saturated fats) are essential in all patients to significantly reduce triglyceride concentrations.²

Icosapent ethyl is an ester of eicosapentaenoic acid (EPA), one of the omega-3 fatty acids found in fish oil. It suppresses the synthesis of cholesterol and triglycerides and increases lipoprotein lipase, the enzyme that breaks down triglycerides. The randomised placebo-controlled MARINE trial studied the effect of icosapent ethyl on triglyceride concentrations in 229 adults with very high triglyceride concentrations (between 5.65 and 22.58 mmol/L). After 12 weeks, a dose of 2 g twice daily had reduced the median triglyceride concentration from 7.67 mmol/L to 5.67 mmol/L compared with an increase from 7.94 mmol/L to 8.42 mmol/L in the placebo group – a difference of 33% between groups.³

The effect of icosapent ethyl on cardiovascular events was assessed in the double-blind REDUCE-IT trial.⁴ The primary efficacy endpoint for cardiovascular events was a composite of cardiovascular death, nonfatal stroke, nonfatal myocardial infarction, unstable angina, or coronary revascularisation. The trial randomised 4089 adults to take 2 g twice daily and 4090 to take a mineral-oil placebo. Most (71%) of these patients already had cardiovascular disease, while 29% had diabetes and one additional risk factor. Their triglyceride concentrations were between 1.69 and 5.63 mmol/L and they were taking stable doses of statins. After a year, the triglyceride concentration decreased by a median of 18.3% in the icosapent ethyl group but increased by 2.2% in the placebo group.

After a median follow-up of 4.9 years, 705 patients (17.2%) in the icosapent ethyl group and 901 (22%) in the placebo group had experienced a cardiovascular event (hazard ratio 0.75; 95% confidence interval 0.68 to 0.83). Among the patients with cardiovascular disease, 559 (19.3%) had an event while taking icosapent ethyl compared with 738 (25.5%) in the placebo group. Death from cardiovascular causes occurred in 4.3% of the icosapent ethyl group and 5.2% of the placebo group. Analysis also showed an advantage for icosapent ethyl in outcomes such as myocardial infarction, stroke, revascularisation and hospitalisation for unstable angina.⁴

Adverse events during the trial resulted in treatment being stopped by 7.9% of the icosapent ethyl group and 8.2% of the placebo group. The most frequent adverse effects in both groups were gastrointestinal symptoms, particularly diarrhoea, although its incidence was lower in patients taking icosapent ethyl (9.0%) than with placebo (11.1%). Adverse events that occurred more often with icosapent ethyl included atrial fibrillation, bleeding and peripheral oedema. Bleeding, particularly from the gut, affected 11.8% of the patients taking icosapent ethyl (placebo 9.9%). However, serious bleeding events with icosapent ethyl were only more frequent, compared to placebo, in patients who were also taking antithrombotic drugs. It is unknown if patients with hypersensitivity to fish or shellfish have an increased risk of allergic reactions to icosapent ethyl; use with caution is recommended in these patients.

Icosapent ethyl capsules should be taken with or after a meal. During absorption from the gut, icosapent ethyl is de-esterified into its active metabolite, EPA, which is eventually metabolised in the liver like other fatty acids. No dose adjustments are required in hepatic or renal impairment. Clinically significant interactions with drugs metabolised by the cytochrome P450 system seem unlikely.

In the REDUCE-IT trial, the primary efficacy endpoint for cardiovascular events was reduced by 25% in patients taking icosapent ethyl. The mechanism underlying this outcome is unclear. It appeared to be independent of the triglyceride concentration.⁴ There has also been speculation that the apparent advantage of icosapent ethyl could have been due to the mineral-oil placebo having deleterious effects on the patients in the placebo group.⁵ The favourable result of REDUCE-IT contrasts with the outcomes of other trials. It showed that only 21 patients need to take icosapent ethyl 4 g daily for one patient to avoid one of the composite endpoints.⁴ In contrast, a Cochrane review of 86 trials (including REDUCE-IT) of omega-3 fatty acids found that, for the secondary prevention of coronary heart disease events, 143 patients would need to be treated for 5 years to prevent one event.⁶ The discordant findings may reflect different trial designs, patient populations, baseline therapy, or type or dose of omega-3 fatty acids.⁷ The Australian approval of icosapent ethyl reflects the REDUCE-IT trial.

This new drug comment was finalised on 30 October 2024.

🅃 manufacturer provided the AusPAR and the product information. The Transparency Score is explained in New drugs: transparency, Vol 37 No 1, Aust Prescr 2014;37:27.

At the time the comment was prepared, information about this drug was available on the websites of the Food and Drug Administration in the USA, the European Medicines Agency and the Therapeutic Goods Administration.

 

References

1. Aung T, Halsey J, Kromhout D, Gerstein HC, Marchioli R, Tavazzi L, et al. Associations of Omega-3 Fatty Acid Supplement Use With Cardiovascular Disease Risks: Meta-analysis of 10 Trials Involving 77 917 Individuals. JAMA Cardiol 2018;3:225-34.
2. Cardiovascular. In: Therapeutic Guidelines. Melbourne: Therapeutic Guidelines Limited; 2023.
3. Bays HE, Ballantyne CM, Kastelein JJ, Isaacsohn JL, Braeckman RA, Soni PN. Eicosapentaenoic acid ethyl ester (AMR101) therapy in patients with very high triglyceride levels (from the Multi-center, plAcebo-controlled, Randomized, double-blINd, 12-week study with an open-label Extension [MARINE] trial). Am J Cardiol 2011;108:682-90.
4. Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, et al. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med 2019;380:11-22.
5. Sharma G, Martin SS, Blumenthal RS. Effects of Omega-3 Fatty Acids on Major Adverse Cardiovascular Events: What Matters Most: the Drug, the Dose, or the Placebo? JAMA 2020;324:2262-4.
6. Abdelhamid AS, Brown TJ, Brainard JS, Biswas P, Thorpe GC, Moore HJ, et al. Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev 2020;3:CD003177.
7. Nelson AJ, Nicholls SJ. Managing hypercholesterolaemia. Australian Prescriber 2024;47:7-14.

 The new drug commentaries in Australian Prescriber are prepared by the editors and reviewed by the Editorial Advisory Committee. Some of the views expressed on newly approved products should be regarded as preliminary, as there may be limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Advisory Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.