12th December 2024, A/Prof Chee L Khoo
Back in August this year, when we last highlighted the benefits of the new pure eicosapentaenoic acid (EPA), icosapent ethyl (Vazkepa®), in reducing cardiovascular outcomes in patients with high triglycerides and high cardiovascular risk, we foreshadowed that it will be available on the PBS for patients with established cardiovascular disease. It is now on PBS Authority and there isn’t much of a launch of the drug which is a pity as many of our patients who may benefit from icosapent ethyl who should be on it aren’t because most of us (including me) are still confused as to who will benefit and who is eligible. We better have a look at the state of play. We will look at why icosapent ethyl and who should be on icosapent ethyl.
Hypertriglyceridaemia has undergone quite a bit of a transformation or should I say, rehabilitation over the years. It had always played second fiddle to low density lipoprotein cholesterol (LDL-C) because most of the cardiovascular outcome trials were concentrating on the atherosclerotic carnage caused by LDL-C. Most of the initial trials excluded patients with hypertriglyceridaemia to isolate the effects of cholesterol lowering agents on cardiovascular outcomes. Further, the earlier trials (pre-statin era) of triglyceride-lowering agents seems to be beneficial but subsequent trials have not shown benefit of benefit triglyceride lowering in reducing cardiovascular outcomes.
You can see that we are a bit confused where hypertriglyceridaemia sits in atherosclerosis. It seems to be contributing to the process in some patients but the outcomes in reducing triglycerides in these patients doesn’t seem to work. At least when statins are also used. Are we shooting at the wrong target? Are we targeting the wrong patient?
It would seem that hypertriglyceridaemia is an independent risk factor for ASCVD. We discussed the role of TG, TRL and remnants four months ago here. All those intermediaries can be absorb directly into the arterial wall and excite inflammatory cells which contribute to the atherosclerosis. Thus, patients with hypertriglyceridaemia have high cardiovascular risk and reducing TG is only a small part of the management to reduce CV events.
Treating patients with HTG must involve treating their CV risk. These patients usually have high LDL-C and statins +/- ezetimibe +/- PCSK8 therapy are essential before we consider TG-lowering therapy. All the above agents often reduce TG because of their effect on the lipoproteins. It is after the above therapy and the TG is still elevated that TG-lowering agents are indicated.
We are used to considering omega-3 fatty acids when we think of TG-lowering agents but the effect on reducing CV events have been disappointing. Two studies stand out as exceptions – the JELIS and the REDUCE-IT studies. These two studies used “pure” EPA as the intervention. We now know that most of the benefit from omega-3 fatty acid supplementation comes from the EPA. Commercial over the counter preparation contain both the EPA and DHA and all the benefits from the EPA are pretty much negated by the DHA.
Furthermore, the beneficial effects of EPA appear to be independent of the TG lowering. It is thought that EPA have other pleiotropic effects – reduce steps in the atherogenesis pathway, lower TG and non-high density lipoprotein cholesterol (non-HDL-C) levels, increase anti-inflammatory and anti-thrombotic mediators through its metabolism and improve endothelial function.
In the REDUCE-IT trial, 70% of the subjects had established CVD and 30% had diabetes and other risk factors. All subjects had to be on a statin for at least 4 weeks. Over a 5-year period, it demonstrated a 25% reduction in the primary endpoint of composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina. Specifically, there was a significant reduction in cardiovascular death. The magnitude of triglyceride lowering was modest – a reduction of a mean TG level of 2.44 mmol/L to 2.0 mmol/L. The reduction in CV outcomes were the same irrespective of baseline triglyceride levels.
Thus, based pretty much on the results from the REDUCE-IT study, the PBS authority’s criteria for Vazkepa (icosapent ethyl) is:
- Evidence of established CVD
- Already on statins (unless intolerant)
- Triglyceride levels > 1.7 mmol/L but < 5.6 mmol/L despite statins
We all have many patients that fit the above bill and can benefit from the addition of icosapent ethyl to their lipid-lowering management. Remember, icosapent ethyl reduces CV events by 25% over a 5-year period.
Incidentally, you may be used to reaching out for fenofibrate when you come across a patient with high triglyceride. It is reasonable to initiate fenofibrate in patients with retinopathy and microalbuminuria/CKD as fenofibrate has microvascular benefits. However, fenofibrate has not been shown to reduce CV endpoints. If you see an elevated TG in patients already on statins and are at high CV risk, do consider icosapent ethyl and not fenofibrate.
References:
Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Doyle RT Jr, Juliano RA, Jiao L, Granowitz C, Tardif JC, Ballantyne CM; REDUCE-IT Investigators. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med. 2019 Jan 3;380(1):11-22. doi: 10.1056/NEJMoa1812792.