REDUCE-IT: findings and implications for practice

Br J Cardiol 2023;30(suppl 2):S15–S18doi:10.5837/bjc.2023.s08 Leave a comment
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Sponsorship Statement: Amarin UK Limited has funded this supplement through an independent grant and has had no control or input into the education content of this activity. Editorial and content decisions were made solely by the BJC.

The Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) was a randomised, double-blind, placebo-controlled trial designed to test the hypothesis that patients with hypertriglyceridaemia and a prior history of cardiovascular (CV) disease or diabetes and multiple CV disease risk factors would benefit from icosapent ethyl (IPE), a highly purified (>96%) form of eicosapentaenoic acid (EPA). Participants (n=8,179) were assigned to IPE 2 g twice daily or matching placebo and monitored for a median period of 4.9 years. Overall, there was a 25% relative risk reduction and 4.8% (p<0.0001) absolute risk reduction in the primary composite end point (CV death, non-fatal myocardial infarction [MI], non-fatal stroke, coronary revascularisation or hospitalisation for unstable angina) in the IPE versus placebo group. Similarly, the key secondary composite end points of CV death, non-fatal MI and non-fatal stroke were reduced by 26% (p<0.0001) with an absolute between-group difference of 3.6%. A number of prespecified and/or post-hoc analyses have consistently demonstrated favourable results with IPE use. Considering the reductions in multiple CV events, REDUCE-IT was a landmark CV clinical trial that demonstrated the benefit of IPE in high-risk patients with hypertriglyceridaemia.

Introduction

Multiple epidemiologic studies have identified elevated levels of blood triglycerides (TGs) or the phenotypic state of hypertriglyceridaemia (HTG) as being associated with an elevated risk of cardiovascular (CV) disease.1 Among therapies demonstrating significant reduction in TGs – beyond fibrates, niacin and statins – are marine-derived omega-3 polyunsaturated fatty acids (n-3 PUFAs); they consist principally of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Notably, the first Gruppo Italiano per lo Studio della Streptochiansi nell’Infarto (GISSI) supported a potential role of n-3 PUFAs in reducing death, non-fatal myocardial infarction (MI) and stroke – prior to studies conducted in the 1990s and the widespread use of statins.2 The Japan EPA Lipid Intervention Study (JELIS) was the first clinical trial to test purified EPA in patients with hyperlipidaemia, which demonstrated a 19% reduction in major CV events in Japanese patients with pre-existing coronary disease assigned to purified EPA and low-dose statin treatment (simvastatin or pravastatin) versus low-dose statin monotherapy.3 In a subgroup of patients with HTG (TG ≥1.7 mmol/L [≥150 mg/dL]) and low levels of high-density lipoprotein (HDL-C), a post-hoc analysis of JELIS found that EPA reduced the risk of CV disease by 53%.4 These impressive results provided the proof-of-concept foundation in support of a large clinical trial testing purified EPA in high-risk patients with HTG, thereby providing the rationale for the Reduction of Cardiovascular Events with Icosapent Ethyl – Intervention Trial (REDUCE-IT).5

REDUCE-IT

Icosapent ethyl (IPE)

REDUCE-IT was a randomised, double-blind, placebo-controlled trial in patients with HTG (fasting TG levels of 1.7–5.6 mmol/L [150–499 mg/dL]) with well-controlled low-density lipoprotein cholesterol (LDL-C) levels of 1.03–2.58 mmol/L (40–100 mg/dL) on stable statin ± ezetimibe therapy and other key inclusion criteria that consisted of 1) age ≥45 years with a prior history of CV disease (secondary prevention cohort) or 2) age ≥50 years with diabetes and at least one additional CV disease risk factor (primary prevention cohort). The CV disease risk factors were more advanced age (men ≥55 years and women ≥65 years), active cigarette smoking (or having quit within three months of study enrolment), hypertension (≥140 mmHg systolic or ≥90 mmHg diastolic), HDL-C ≤1.03 mmol/L (≤40 mg/dL) for men or ≤1.29 mmol/L (50 mg/dL) for women, high-sensitivity C-reactive protein (hsCRP) >3 mg/L, creatinine clearance between 30–60 mL/min/1.73 m2, retinopathy, albuminuria or an ankle brachial index (ABI) <0.9 without symptoms of intermittent claudication. A total of 8,179 patients were randomised to receive either icosapent ethyl (IPE) 2 g twice daily or matching placebo and monitored for a median period of 4.9 years.6 The primary end point was the first occurrence of a major adverse CV event (MACE) defined by five-point MACE (CV death, non-fatal MI, non-fatal stroke, coronary revascularisation or unstable angina necessitating hospitalisation) and the secondary end point was the first occurrence of a MACE defined by three-point MACE (CV death, non-fatal MI and non-fatal stroke). The effects on biomarkers between baseline and year 1 is shown in table 1. There were significant reductions in median TG levels (19.7%) in IPE-treated patients, as well as significant reductions in non-HDL-C, LDL-C, apolipoprotein B (ApoB) and hsCRP. Unsurprisingly, blood EPA levels also increased significantly (359%) between baseline and year 1 following IPE treatment.

Table 1. REDUCE-IT: effects on biomarkers between baseline and year 1

Icosapent ethyl
(n=4,089)
Median		 Placebo
(n=4,090)
Median		 Median between group difference at year 1
Biomarker Baseline Year 1 Baseline Year 1 Absolute change from baseline % Change from baseline % Change p-value
Triglycerides mmol/L (mg/dL) 2.45
(216.5)		 1.98
(175.0)		 2.44
(216.0)		 2.50
(221.0)		 −0.50
(−44.5)		 −19.7 <0.0001
Non-HDL-C mmol/L
(mg/dL)		 3.06
(118.0)		 2.93
(113.0)		 3.07
(118.5)		 3.37
(130.0)		 −0.40
(−15.5)		 −13.1 <0.0001
LDL-C mmol/L
(mg/dL)		 1.92
(74.0)		 1.99
(77.0)		 1.97
(76.0)		 2.18
(84.0)		 −0.13
(−5.0)		 −6.6 <0.0001
HDL-C mmol/L
(mg/dL)		 1.04
(40.0)		 1.01
(39.0)		 1.04
(40.0)		 1.09
(42.0)		 −0.06
(−2.5)		 −6.3 <0.0001
ApoB g/L
(mg/dL)		 0.82
(82.0)		 0.80
(80.0)		 0.83
(83.0)		 0.89
(89.0)		 −0.08
(−8.0)		 −9.7 <0.0001
hsCRP mg/L 2.2 1.8 2.1 2.8 −0.9 −39.9 <0.0001
Log hsCRP mg/L 0.8 0.6 0.8 1.0 −0.4 −22.5 <0.0001
EPA μg/mL 26.1 144.0 26.1 23.3 +114.9 +358.8 <0.0001
Key: ApoB = apolipoprotein B; EPA = eicosapentaenoic acid; HDL-C = high-density lipoprotein cholesterol; hsCRP = high-sensitivity C-reactive protein; LDL-C = low-density lipoprotein cholesterol; REDUCE-IT = Reduction of Cardiovascular Events with Icosapent Ethyl – Intervention Trial

Overall, the results of REDUCE-IT showed that assignment to IPE produced a 25% relative risk reduction and 4.8% (p<0.0001) absolute risk reduction in the primary composite end point compared to placebo. Similarly, the key secondary composite end points were reduced by 26% (p<0.0001) with an absolute between-group difference of 3.6%. Individual secondary end points of fatal/non-fatal MI, fatal/non-fatal stroke and CV death were reduced by 31% (p<0.001), 28% (p=0.01) and 20% (p=0.03), respectively. The treatment was generally well tolerated. While there was a small increase in recurrent AF among IPE-treated patients, the clinical significance is unclear because incident stroke, the primary downstream complication of atrial fibrillation (AF), was reduced. Similarly, there was an increased risk of bleeding with IPE versus placebo (2.7% vs. 2.1%; p=0.06), although no differences were observed in gastrointestinal or central nervous system bleeding. Moreover, patients with a history of AF prior to study enrolment and during the study experienced consistent reductions in primary, key secondary and stroke end points if assigned to receive IPE.7 Taken together, REDUCE-IT provided the first demonstration that with a foundation of statin therapy, IPE effectively reduced CV events beyond statins in patients with HTG and CV disease or an elevated CV disease risk. To date, no other TG-lowering therapies (i.e., niacin, fibrates) have produced similar results.

Following the primary publication of REDUCE-IT, a number of additional analyses (pre-specified and/or post hoc) were performed and all demonstrated a consistent benefit of IPE use compared to placebo. They included a 30% reduction in total primary end point events,8 a 34% reduction in the need for initial coronary revascularisations and a 38% decrease in percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG),9 29% reduction in primary and key secondary end points in patients with renal dysfunction as characterised by an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2.10 Additionally, there were reductions of 24%, 34%, 26% and 13% in the primary outcome events with a prior history of CABG, PCI, MI or heart failure, respectively,11–14 and a reduction of CV events in current and former cigarette smokers to similar levels observed in non-smokers.15 Table 2 illustrates event rates and hazard ratios (HRs) of primary and key secondary end points across the REDUCE-IT substudies published to date.

Table 2. Reduction in primary and key secondary end points in REDUCE-IT and associated substudies

Primary end point Key secondary end points
Placebo IPE HR p-value Placebo IPE HR p-value
N Event rate Event rate
REDUCE-IT 8,179 22% 17.2% 0.75 <0.001 14.8% 11.2% 0.74 <0.001
History of:
PCI 3,408 29.4% 20.8% 0.66 <0.001 17.4% 12.0% 0.66 <0.001
CABG 1,837 28.2% 22.0% 0.76 0.004 20.7% 14.7% 0.69 0.001
MI 3,693 26.1% 20.2% 0.74 <0.001 18.0% 13.3% 0.71 <0.001
HF 1,446 25.2% 22.8% 0.87 NS 19.5% 16.9% 0.85 NS
CKD 1,816 28.9% 21.8% 0.71 <0.001 22.5% 16.8% 0.71 0.001
Smoking* 4,913 30.2% 23.2% 0.77 <0.001 15.3% 12.0% 0.77 <0.001
*Smoking included current and former smokers
Key: CABG = coronary artery bypass grafting; CKD = chronic kidney disease (defined as glomerular filtration rate <60 ml/min/1.73 m2); HF = heart failure; HR = hazard ratio; IPE = icosapent ethyl; PCI = percutaneous coronary intervention; MI = myocardial infarction; NS = not significant; REDUCE-IT = Reduction of Cardiovascular Events with Icosapent Ethyl – Intervention Trial

Use of mineral oil as placebo

The selection of mineral oil as the placebo was based on the following considerations – firstly, mineral oil is similar in colour/translucency as IPE in contrast to other placebo fats, such as corn oil. Secondly, earlier studies evaluating IPE versus mineral oil demonstrated minimal effects on lipids, including LDL-C.16,17 Thirdly, the amount of mineral oil used in REDUCE-IT (4 mL) is considerably lower than the customary laxative dose of 15–30 mL. Despite concerns that mineral oil may have reduced the absorption of statins that, in turn, would seemingly have raised LDL-C and predicted increased CV disease risk, there was, in effect, no difference in CV disease risk among the placebo-treated patients who experienced or did not experience a rise in LDL-C levels.6 Finally, while small increases in inflammatory biomarkers were observed in placebo-treated patients, levels remained within normal limits, suggesting that the statistical increases were not clinically meaningful.18

Mechanism of action for the benefits observed in REDUCE-IT

Since TG lowering in IPE-treated patients was relatively modest in REDUCE-IT (19.7%) and neither the percent of TG reduction nor the on-treatment TG levels affected the IPE-mediated benefits observed,19 it is unlikely that TG lowering, per se, represented the primary mechanism of action for the CV event rate reductions observed in REDUCE-IT. Rather, TG lowering, in combination with changes in the levels of EPA and/or arachidonic acid – as reported in Greenlandic Eskimos where the combination of high levels of EPA, low levels of arachidonic acid and low TG levels have been associated with reduced CV disease risk – may explain these findings.20 Additional analyses of REDUCE-IT may shed further insight into this possibility.

Conclusion

REDUCE-IT was a landmark CV clinical trial that provided the first evidence that patients with HTG and CV disease risk benefit from IPE or highly purified EPA, despite modest TG-lowering effects. This benefit was observed across TG tertiles, thereby suggesting that other factors contributed to the CV disease risk reductions observed.

Key messages

  • Hypertriglyceridaemia is associated with an elevated risk of developing cardiovascular (CV) disease
  • The Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT) was the first clinical trial to demonstrate reduction in CV events in hypertriglyceridaemic patients randomised to icosapent ethyl (IPE), a highly purified form of eicosapentaenoic acid (EPA)
  • The CV benefits observed in REDUCE-IT occurred beyond the triglyceride-lowering effects of IPE

Conflicts of interest

MM is a scientific advisor and consultant for Amarin Corp. He served on the Steering Committee for REDUCE-IT.

Michael Miller
Cardiologist and Professor of Medicine (Hospital of the University of Pennsylvania), and Chief of Medicine (Corporal Michael J Crescenz Veterans Affairs Medical Center)
Philadelphia, Pennsylvania, US
([email protected])

Articles in this supplement

Introduction
Triglyceride-rich lipoproteins and their role in cardiovascular disease
The evidence for fish oils and eicosapentaenoic acid in managing hypertriglyceridaemia
Icosapent ethyl use in clinical practice: current and future directions

References

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2. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico. Lancet 1999;354:447–55. Erratum in: Lancet 2001;357:642. Erratum in: Lancet 2007;369:106.

3. Yokoyama M, Origasa H, Matsuzaki M, et al.; Japan EPA lipid intervention study (JELIS) Investigators. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet 2007;369:1090–8. https://doi.org/10.1016/S0140-6736(07)60527-3

4. Saito Y, Yokoyama M, Origasa H, et al.; JELIS Investigators, Japan. Effects of EPA on coronary artery disease in hypercholesterolemic patients with multiple risk factors: sub-analysis of primary prevention cases from the Japan EPA Lipid Intervention Study (JELIS). Atherosclerosis 2008;200:135–40. https://doi.org/10.1016/j.atherosclerosis.2008.06.003

5. Bhatt DL, Steg PG, Brinton EA, et al.; REDUCE-IT Investigators. Rationale and design of REDUCE-IT: Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial. Clin Cardiol 2017;40:138–48. https://doi.org/10.1002/clc.22692

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10. Majithia A, Bhatt DL, Friedman AN, et al. Benefits of icosapent ethyl across the range of kidney function in patients with established cardiovascular disease or diabetes: REDUCE-IT RENAL. Circulation 2021;144:1750–9. https://doi.org/10.1161/CIRCULATIONAHA.121.055560

11. Verma S, Bhatt DL, Steg PG, et al.; REDUCE-IT Investigators. Icosapent ethyl reduces ischemic events in patients with a history of previous coronary artery bypass grafting: REDUCE-IT CABG. Circulation 2021;144:1845–55. https://doi.org/10.1161/CIRCULATIONAHA.121.056290

12. Peterson BE, Bhatt DL, Steg PG, et al.; REDUCE-IT Investigators. Treatment with icosapent ethyl to reduce ischemic events in patients with prior percutaneous coronary intervention: Insights from REDUCE-IT PCI. J Am Heart Assoc 2022;11:e022937. https://doi.org/10.1161/JAHA.121.022937

13. Gaba P, Bhatt DL, Steg PG, et al.; REDUCE-IT Investigators. Prevention of cardiovascular events and mortality with icosapent ethyl in patients with prior myocardial infarction. J Am Coll Cardiol 2022;79:1660–71. https://doi.org/10.1016/j.jacc.2022.02.035

14. Selvaraj S, Bhatt DL, Steg PG, et al.; REDUCE-IT Investigators. Impact of icosapent ethyl on cardiovascular risk reduction in patients with heart failure in REDUCE-IT. J Am Heart Assoc 2022;11:e024999. https://doi.org/10.1161/JAHA.121.024999

15. Miller M, Bhatt DL, Steg PG, et al. Potential effects of icosapent ethyl on cardiovascular outcomes in cigarette smokers: REDUCE-IT smoking. Eur Heart J Cardiovasc Pharmacother 2023;9:129–37. https://doi.org/10.1093/ehjcvp/pvac045

16. 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. https://doi.org/10.1016/j.amjcard.2011.04.015

17. Ballantyne CM, Bays HE, Kastelein JJ, Stein E, Isaacsohn JL, Braeckman RA, Soni PN. Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study). Am J Cardiol 2012;110:984–92. https://doi.org/10.1016/j.amjcard.2012.05.031

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