EBM Tools for Practice: Icosapent Ethyl-Treated Hypertriglyceridemia to Reduce ASCVD Residual Risk

Hypertriglyceridemia has become a point of great interest lately in the search for better management of residual risk in patients with established ASCVD. The Reduction of Cardiovascular Events with Icosapent Ethyl Intervention Trial (REDUCE-IT) as authored by Bhatt, DL et al, shows strong evidence that icosapent ethyl, in addition to statin, significantly reduced ASCVD risk in patients with hypertriglyceridemia.

Lipoproteins are composed of phospholipids, apolipoproteins, and free cholesterol on the surface along with cholesterol esters and triglycerides in their core. Triglycerides are hydrolyzed for oxidizable substrate and cholesterol is used for cell membrane and hormone synthesis among other functions. All non-high density lipoproteins (non-HDL) are atherogenic and a greater predictor of risk in secondary prevention than low density lipoprotein-cholesterol levels (LDL-C) alone. Non-HDL includes remnant particles, VLDL, IDL, LP(a), and LDL. VLDL is lipolyzed to VLDL-1, VLDL-2, and VLDL-3 then to IDL and finally LDL.(1,2)

Impaired clearance and increased secretion of remnant lipoproteins are seen with obesity, insulin-resistance, metabolic syndrome, and diabetes mellitus.(3,4) In this scenario, there are increased free fatty-acids, increased remnant lipoproteins, and hypertriglyceridemia, the last of which correlates significantly with risk of cardiovascular events.

In the intima, remnant lipoproteins tend to remain there because of their large size. (5,6,7,8,9) Lipoprotein lipase breaks down the triglycerides and this causes injury and inflammation.(10,11,12) Numerous cytokines are produced furthering injury. Hypertriglyceridemia indicates increased remnants which are rich in cholesterol leading to intimal inflammation, foam-cell formation, plaque formation, and finally cardiovascular disease.

There are many genetic mutations that can affect triglyceride levels. Among them, are the APO A-V mutations which are associated with increased triglycerides and increased risk of myocardial infarction.(13) In contrast, R19X mutations in APOC3 cause a 46% decrease in triglycerides and a 65% decrease in risk of coronary artery calcium.(14) Additionally, ANGPTL4 mutations are associated with decreased triglycerides along with a decreased risk of coronary artery disease.(15,16,17)

The effects of statins on triglyceride levels are frequently insufficient. Icosapent ethyl (IPE) 4g per day, decreases VLDL particles by decreasing hepatic release and/or increasing plasma clearance (18), increases beta oxidation, inhibits acyl-CoA: 1, 2-diacylglycerol acyltransferase, decreases lipogenesis in liver, and increases LPL activity in plasma.(18,19) In addition, it decreases LDL particle number and TG’s, lowers non- HDL-C, apolipoprotein B (apoB), and apolipoprotein C3 (apoC3) without raising LDL-C levels in statin-treated patients with persistent hypertriglyceridemia. It significantly reduced remnant lipoprotein cholesterol  and reduced activity of the transcription of the gene for sterol regulatory element binding protein 1c (20, 21). Eicosapentaenoic acid (EPA) has been shown to have pleiotropic effects that beneficially influence multiple steps in atherosclerosis and its progression including endothelial dysfunction, oxidative stress, foam cell formation, inflammation, cytokine effects, plaque formation and progression, platelet aggregation, thrombosis formation, and plaque rupture.(22)

In the Japan Eicosapentaenoic Acid Lipid Intervention Study (JELIS), an open-label blinded study in Japan that investigated the addition of 1.8 grams per day of EPA to statin therapy (pravastatin 10mg or simvastatin 5mg) versus statin alone, a statistically significant (p = 0.01) 19% reduction in major coronary events was observed.(23,24)

The REDUCE-IT is a randomized, doubleblind, placebo-controlled trial which examined the effect of high-dose EPA in addition to statin treatment in 8,179 patients with high cardiovascular risk and elevated triglycerides. Eligible patients were required to have baseline fasting triglyceride levels between 135 mg/ dl and 499 mg/dl despite appropriate statin treatment (median LDL-C was 75 mg/dl). This requirement was to address the issue that previous trials testing Omega 3-fatty acids did not specifically enroll patients with elevated triglycerides. Importantly, REDUCE-IT assessed a significantly higher dose of EPA than previous Omega 3-fatty acid studies and EPA rather than combination EPA/DHA. REDUCE-IT demonstrated a 25% reduction in the composite primary endpoint of cardiovascular death, nonfatal myocardial infarction, non-fatal stroke, coronary revascularization, or unstable angina [HR, 0.75: p<0.001]. The secondary endpoints were similarly reduced, including the hard endpoint of cardiovascular death [HR, 0.80: p=0.03. (23-25)

REDUCE-IT has most certainly shown a cardiovascular benefit when adding EPA to statin treatment for high-risk patients with elevated triglyceride levels. It served as the primary basis for the NLA’s review of evidence for the use of IPE for ASCVD risk reduction (Fig. 1). “Based on this review, the NLA position is that for patients aged >45 years with clinical ASCVD or aged >50 years with diabetes mellitus requiring medication plus >1 additional risk factor, with fasting triglycerides 135 mg/dl to 499 mg/dl on high-intensity or maximally tolerated statin therapy (+ Ezetimibe), treatment with IPE is recommended for ASCVD risk reduction”.(20)

On November 14, 2019, an FDA advisory panel recommended approval of Icosapent Ethyl as add-on treatment to statins in high-risk patients with elevated triglycerides to decrease the risk of cardiovascular events.(27)

The Statin Residual Risk Reduction With Epanova in High Cardiovascular Risk Patients With Hypertriglyceridemia Study (STRENGTH) of omega-3-carboxylic acids was designed to test a similar hypothesis as REDUCE-IT. The study was stopped due to “futility” in the early part of 2020, though further explanation of the findings are not available as of this time.

In conclusion, there is clear evidence that a causal relationship exists between triglyceride-rich lipoproteins/remnant cholesterol and ASCVD. Icosapent ethyl is indicated for clinical ASCVD or Diabetes Mellitus II with risk factors and elevated triglycerides without ASCVD. Perhaps in the near future, patients with hypertriglyceridemia will be prescribed icosapent ethyl earlier in the natural history of their disease to prevent adverse events.

Disclosure statement: Dr. Caballero has no financial disclosures to report. Dr. Lillo has received honoraria from Amarin, Sanofi/Regeneron, and Elite Clinical Studies.

References

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