14th November 2022, Dr Chee L Khoo
We all have patients with high triglycerides (TG) that warrant intensification of our lipid lowering treatment. Statins are efficacious in reducing total cholesterol (TC), increasing high density lipoprotein cholesterol (HDL-C) and reducing low density lipoprotein cholesterol (LDL-C). Statins also reduce triglycerides levels but often these patients have residual hypertriglyceridaemia that warrants the addition of a fibrate to get our TG to target. What else can we do if the TG remain high despite the addition of fenofibrate? We often resort to adding marine sourced omega-3 oil (or fish oil) supplements. Reducing TG numbers is one thing but do fish oil supplements translate to reducing cardiovascular events? That’s the tricky question.
Two randomised controlled trials have demonstrated benefits in reducing triglycerides in patients with or without prior cardiovascular disease. In JELIS trial, a lipid intervention trial initiated by Yokoyama et al., daily treatment with 1.8 g eicosapentaenoic acid (EPA) in combination with statins proved to be more effective than statins alone in reducing cardiovascular events in patients with high cholesterol (1).
In the GISSI-Prevenzione trial, 11,324 patients who survived a recent (< or = 3 months) myocardial infarction were randomly assigned supplements of n-3 polyunsaturated fatty acid (PUFA) (1 g daily, n=2836), vitamin E (300 mg daily, n=2830), both (n=2830), or none (control, n=2828) for 3.5 years (2). The primary combined efficacy endpoint was death, non-fatal myocardial infarction, and stroke. Intention-to-treat analyses were done according to a factorial design (two-way) and by treatment group (four-way). Treatment with n-3 PUFA, but not vitamin E, significantly lowered the risk of the primary endpoint. Benefit was attributable to a decrease in the risk of death.
However, subsequent trials since these two trials have not been able to repeat those cardiovascular benefits. In a very comprehensive meta-analysis in 2018, Asmaa S Abdelhamid et al found that increasing EPA and docosahexaenoic acid (DHA) has little or no effect on mortality or cardiovascular health (3). The commented that previous suggestions of benefits from EPA and DHA supplements appear to spring from trials with higher risk of bias. Yet, when ShiChun Shen et al conducted a meta-analysis in February this year, they concluded that omega-3 FA supplementation had a positive effect in reducing the incidence of MACE, cardiovascular death and MI (4).
The STRENGTH trial, a large-scale double-blind RCT involving 13,078 subjects with high cardiovascular risks (5) exhibited no significant difference in cardiovascular events between the omega-3 FA and corn oil. The VITAL trial, another large-scale clinical trial for healthy people had similar negative findings (6).
So, when the REDUCE-IT trial reported in 2019, the very positive results came as a surprise. REDUCE-IT was a double-blind, multicentre RCT that aimed to determine the effect of icosapent ethyl on cardiovascular events after providing established statin therapy to patients with CHD or diabetes and other risk factors (7). The results of REDUCE-IT manifested that compared to the control group, icosapent ethyl can significantly reduce the risk of ischemic events by 25%, including cardiovascular death. Additionally, icosapent ethyl can significantly decrease triglyceride levels, and when combined with statin therapy, it appears to be promising than using statins alone.
However, there is now some disquiet over the inertness of the placebo used in the REDUCE-IT trial. Due to its inert properties, highly refined, pharmaceutical-grade mineral oils are commonly used as trial placebos, especially when studying agents formulated in oil-based tablets/capsules or agents that are oils, including omega-3 FAs. Concerns about mineral oil as a placebo arose in both the scientific and regulatory communities because the trial reported increases of 11.4% in LDL-C and 32.3% in high-sensitivity C-reactive protein in the mineral oil group after 2 years’ treatment. Some have suggested that the observed reduction in CV risk was not only due to positive effects of icosapent ethyl but also due to negative effects from the pharmaceutical-grade mineral oil control, a supposition based on small elevations in some lipid levels and inflammatory markers in the placebo arm.
In a literature search by Olshansky B, et al, studies employing mineral oil placebos were identified. Eighty studies were identified and relevant data extracted (8). Adverse events associated with mineral oil were generally gastrointestinal and consistent with use as a lubricant laxative. Changes in triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, high-sensitivity C-reactive protein, and other biomarkers were inconsistent and generally not statistically significant, or clinically meaningful with mineral oil, as were changes in blood pressure. There was no consistent evidence that mineral oil in the amounts used in the REDUCE-IT. They argued that the 5 mg/dL difference between the placebo and treatment groups would be estimated to increase the risk of CVD events by 2–3% in the placebo group,83–87 which cannot account for the overall robust and consistent REDUCE-IT findings, including a 25% relative risk reduction in the primary endpoint, and a 32% reduction in total ischaemic event.
The debate continues…
References:
- Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet. (2007) 369:1090–8. doi: 10.1016/S0140-6736(07)60527-3
- 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 Aug 7;354(9177):447-55. Erratum in: Lancet 2001 Feb 24;357(9256):642. Erratum in: Lancet. 2007 Jan 13;369(9556):106. PMID: 10465168.
- Abdelhamid AS, Brown TJ, Brainard JS, Biswas P, Thorpe GC, Moore HJ, Deane KHO, AlAbdulghafoor FK, Summerbell CD, Worthington HV, Song F, Hooper L. Omega‐3 fatty acids for the primary and secondary prevention of cardiovascular disease. Cochrane Database of Systematic Reviews 2018, Issue 11. Art. No.: CD003177. DOI: 10.1002/14651858.CD003177.pub4. Accessed 14 November 2022.
- Shen S, Gong C, Jin K, Zhou L, Xiao Y, Ma L. Omega-3 Fatty Acid Supplementation and Coronary Heart Disease Risks: A Meta-Analysis of Randomized Controlled Clinical Trials. Front Nutr. 2022 Feb 3;9:809311. doi: 10.3389/fnut.2022.809311. PMID: 35187035; PMCID: PMC8850984.
- Nicholls SJ, Lincoff AM, Garcia M, Bash D, Ballantyne CM, Barter PJ, et al. Effect of high-dose omega-3 fatty acids vs. corn oil on major adverse cardiovascular events in patients at high cardiovascular risk: the STRENGTH randomized clinical trial. JAMA. (2020) 324:2268–80. doi: 10.1001/jama.2020.22258
- Manson JE, Cook NR, Lee I-M, Christen W, Bassuk SS, Mora S, et al. Marine n– 3 fatty acids and prevention of cardiovascular disease and cancer. N Engl J Med. (2019) 380:23–32. doi: 10.1056/NEJMoa1811403
- 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. doi: 10.1056/NEJMoa1812792
- Brian Olshansky, Mina K Chung, Matthew J Budoff, Sephy Philip, Lixia Jiao, Ralph T Doyle, Jr., Christina Copland, Alex Giaquinto, Rebecca A Juliano, Deepak L Bhatt, Mineral oil: safety and use as placebo in REDUCE-IT and other clinical studies, European Heart Journal Supplements, Volume 22, Issue Supplement_J, October 2020, Pages J34–J48, https://doi.org/10.1093/eurheartj/suaa117