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Elevated triglyceride (TG) levels have been linked to residual atherosclerotic cardiovascular risk in patients with controlled low-density lipoprotein cholesterol. However, outcome trials testing TG-lowering agents have failed to demonstrate cardiovascular risk reduction in statin-treated subjects. One such example is the recent STRENGTH trial, which tested mixed omega fatty acids (n3-FAs, 4 g/d) in high-risk patients with elevated TGs. Similar to trials using fibrates and niacin, the STRENGTH trial failed despite effective TG lowering. Results from these studies have contributed to skepticism about the use of TG-lowering therapy for cardiovascular risk. However, new mechanistic insights are provided by the REDUCE-IT trial that used icosapent ethyl (IPE), a purified formulation of the n3-FA eicosapentaenoic acid. In high-risk patients, IPE reduced a composite of cardiovascular events (25%, P < .001) in a manner not predicted by TG lowering. Benefits with IPE appear linked to broad pleiotropic actions associated with on-treatment eicosapentaenoic acid levels. These studies indicate that although TGs are a potential biomarker of cardiovascular risk, there is no evidence that TG lowering itself is an effective strategy for reducing such risk.
Elevated triglycerides (TGs) are associated with increased cardiovascular risk; however, current TG-lowering therapies are ineffective in reducing such risk.
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Icosapent ethyl, highly purified eicosapentaenoic acid, was recently shown to reduce cardiovascular events by 25% and was not associated with TG lowering.
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Icosapent ethyl appears to have broad pleiotropic effects associated with on-treatment eicosapentaenoic acid levels.
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Evidence against TG lowering in reducing cardiovascular risk should guide other therapeutic strategies to lower residual risk.
Introduction
Patients with well-controlled low-density lipoprotein cholesterol (LDL-C) levels still have residual cardiovascular risk that may be attributed to atherogenic particles, including triglyceride (TG)-rich lipoproteins.
Elevations in fasting TG levels associate independently with cardiovascular events, which is supported by Mendelian randomization studies that imply causality with TGs in atherothrombotic disease.
This hypothesis has been tested in recent trials with omega-3 fatty acids (n3-FAs) on top of contemporary medical care (Table). The n3-FAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are effective in lowering TG levels, but this has not translated into consistent clinical benefits in cardiovascular outcome trials. Indeed, trials with low-dose, mixed n3-FAs have consistently failed to show cardiovascular benefit.
Along with failures using other agents (fibrates, niacin), this has added to the controversy about what role exists, if any, for TG lowering in statin-treated, high-risk patients. An evaluation of recent n3-FA trials using different formulations have shed new insight into this important debate as will be discussed.
TableRecent Cardiovascular Outcome Trials with Omega-3 Fatty Acids
The Long-Term Outcomes Study to Assess STatin Residual Risk with EpaNova in HiGh Cardiovascular Risk PatienTs with Hypertriglyceridemia (STRENGTH) tested the effects of a carboxylic acid formulation of EPA and DHA on outcomes in 13,708 patients with elevated plasma TGs (median 240 mg/dL) and high cardiovascular risk.
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.
The STRENGTH trial was prematurely stopped due to the low probability of demonstrating a clinical benefit despite a significant reduction in TG levels by 19%. The disappointing results of STRENGTH are consistent with previous trials using fibric acid derivatives (fibrates), such as the Action to Control Cardiovascular Risk in Diabetes (ACCORD)-Lipid (ACCORD-Lipid) trial in simvastatin-treated patients and the Veterans Affairs Cooperative Studies Program High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT),
Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group.
and niacin in statin-treated patients, such as the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) and Heart Protection Study 2: Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trials.
Examples from one fibrate and niacin trial will now be provided.
The ACCORD-Lipid trial examined whether the combination of fenofibrate and statin would reduce major cardiovascular events in high-risk risk patients with type 2 diabetes.
In ACCORD-Lipid, 5,518 patients were treated with fenofibrate plus simvastatin vs. simvastatin alone. Baseline TG levels were 164 mg/dL in the combination therapy group and decreased to 122 mg/dL (26%). At termination, an interval of 4.7 years, combination therapy failed to reduce cardiovascular events. In the subgroup of patients with high TG levels (>204 mg/dL) and low high-density lipoprotein cholesterol (HDL-C) levels (<34 mg/dL), the primary outcome rate was 12.4% in the fenofibrate group, vs. 17.3% in the placebo group, whereas rates were 10.1% in both study groups for all other patients. Importantly, in the entire trial or subgroup there was no reported relationship between the amount of TG lowering and cardiovascular disease outcome.
The AIM-HIGH trial included 3,414 patients with a history of cardiovascular disease and low HDL-C who were randomized to simvastatin plus extended-release niacin (1500-2000 mg/d) or simvastatin alone and ezetimibe as needed for additional LDL-C lowering.
The average patient was aged 64 years with mild to moderate hypertriglyceridemia and low levels of HDL-C (with baseline median TG and HDL-C levels of 168 mg/dL and 35 mg/dL, respectively) who had been on statin therapy for more than 1 year. Over the course of the trial, niacin lowered TGs to 120 mg/dL (a 31% reduction) and increased HDL-C to 42 mg/dL. Overall, the results showed no difference in primary endpoints, including time to first event for coronary death, myocardial infarction, stroke, hospitalized coronary syndrome, and symptom-driven revascularization with niacin, at 3 years. Again, there was no reported cardiovascular benefit despite substantial TG lowering associated with therapy in this trial.
An explanation for the failure of these trials may be due to the limited atherogenicity, if any, of the TG content of TG-rich lipoproteins (very low-density lipoprotein, chylomicrons, remnants) compared with the fate of the cholesterol contained within these particles, best determined by direct measurements of very low-density lipoprotein cholesterol or apolipoprotein B-100 (ApoB). This concept is supported by Mendelian randomization analyses of variants that associated TG-rich lipoprotein and LDL levels with cardiovascular risk. Absolute changes in ApoB levels, as opposed to those of any particular lipoprotein, was the best indicator of risk reduction.
Thus, when added to statins, TG-lowering agents may not provide enough incremental benefit to further reduce cardiovascular risk associated with ApoB-containing particles. This will be tested further using the potent and selective (peroxisome proliferator-activated receptor-alpha) PPAR-α modulator pemafibrate in the Pemafibrate to Reduce cardiovascular OutcoMes by reducing triglycerides IN patiENts with diabeTes (PROMINENT) trial (NCT03071692).
Other novel approaches for lowering TG, such as targeting key proteins involved in regulating circulating TG levels, are also being evaluated for their potential benefit in reducing cardiovascular risk.
In contrast to STRENGTH and other TG-lowering trials, the Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT) demonstrated that an ethyl ester of EPA, icosapent ethyl (IPE), at 4 g/d significantly reduced a composite of cardiovascular events in at-risk patients with elevated TGs (serum median of 216 mg/dL) on top of statin.
First ischemic events fell by 25% (P < .001) and total (first and subsequent) ischemic events by 31% (P < .001), with consistent benefits across multiple pre-specified subgroups, including primary and secondary prevention.
In REDUCE-IT, the large reductions in endpoints actually exceeded what would be expected from the 17% decrease in TG levels; the benefits of IPE were independent of baseline TG levels, observed among ~10% of participants with normal TG levels, and unrelated to the amount of TG lowering. Prior to REDUCE-IT, the Japan EPA Lipid Intervention Study (JELIS) was conducted without a pre-specified minimum TG level for study inclusion.
Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.
This open label, randomized trial of 18,645 patients showed that IPE (1.8 g/d) on top of a statin produced a 19% (P = .011) reduction in a composite of cardiovascular events compared with statin alone. The study population included patients for both primary and secondary prevention. The median plasma TG level at baseline was 153 mg/dL such that half of the patients had “normal” TGs and an overall reduction of 9% compared with baseline. There was a 53% reduction (P = .043) in events with IPE among those subjects with higher TG levels (>150 mg/dL) and low HDL-C levels (<40 mg/dL) based on a post hoc analysis, but importantly, no relationship between the extent of TG lowering and cardiovascular events.
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).
Atheroprotective Effects of Omega-3 Fatty Acids Beyond TG Lowering
The different outcomes in STRENGTH, JELIS, and REDUCE-IT despite similar reductions in TGs is very perplexing (Table). Explanations include differences in formulation, on-treatment achieved levels of EPA, negating or “diluting” effects of DHA, type of placebo used in the study, and patient profile.
Indeed, EPA and DHA differ in their effects on membrane structure, rates of lipid oxidation, inflammatory biomarkers, and tissue distributions (Figure 1).
In endothelial cells, EPA, unlike DHA, reversed endothelial dysfunction with small dense LDL exposure and increased nitric oxide release, a potent inhibitor of platelet aggregation and leukocyte adhesion.
In subjects with elevated or very high TGs, IPE (2-4 g/d) reduced lipoprotein associated phospholipase A2, interleukin-6, high-sensitivity C-reactive protein, apolipoprotein C-III, and oxidized LDL-C concentrations compared with placebo controls.
Thus, EPA and its bioactive lipid metabolites exert complex and multifactorial atheroprotective effects beyond TG lowering (Figure 2).
Figure 1Schematic illustration of the proposed location and contrasting effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on membrane structure, lipid oxidation, and tissue distribution. Eicosapentaenoic acid and DHA have distinct effects on membrane structure and dynamics due to differences in their hydrocarbon length and number of double bonds. The greater hydrocarbon length and number of double bonds for DHA leads to more rapid isomerization and conformational changes that result in increased membrane fluidity and promotion of cholesterol domains. Eicosapentaenoic acid has a more stable and extended structure that contributes to membrane stability as well as inhibition of lipid oxidation and cholesterol domain formation under disease-like conditions.
To elucidate its mechanism, the effect of IPE treatment on plaque development was followed over 18 months using coronary computed tomography angiography. The Effect of Vascepa On Improving Coronary Atherosclerosis in People with High Triglycerides Taking Statin Therapy (EVAPORATE) trial included 80 patients with documented coronary atherosclerosis treated with 4 g/d of IPE in addition to maximally tolerated statin therapy.
Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: final results of the EVAPORATE trial.
Patients randomized to IPE had a relative reduction of 17% (P < .01) in low attenuation plaque volume compared with placebo. Low attenuation plaque volume is the strongest predictor of fatal or nonfatal myocardial infarction.
A previous imaging study in patients with coronary heart disease also demonstrated a significant reduction in plaque volume for a statin and IPE combination compared with statin alone.
There may also be a required threshold of achieved EPA level (~100 µg/mL) to produce a clinical benefit. In particular, the on-treatment levels of EPA in the STRENGTH trial (89.6 µg/mL) were lower than the baseline EPA levels in the JELIS trial (97 µg/mL) and 38% lower than on-treatment levels in the REDUCE-IT trial (144 µg/mL). Eicosapentaenoic acid and DHA levels were also essentially the same in the STRENGTH trial unlike the IPE trials. As a result, there was no relationship between EPA levels and reduced clinical events in the STRENGTH trial. The use of mineral oil placebo has also been proposed as a confounding variable in the REDUCE-IT trial due to increased LDL-C among those randomized to placebo. However, post hoc analyses demonstrated that the favorable effects of IPE were not influenced by increases (or decreases) in LDL-C levels in the placebo arm.
Additionally, the benefits of IPE were directly related to EPA plasma levels and reproduced in a large outcome trial that did not use a placebo (JELIS).
Coronary computed tomography angiography analysis further demonstrated that mineral oil did not affect progression of total plaque and total non-calcified plaque volume, when compared with non-mineral oil placebo in randomized trials.
A review of the REDUCE-IT trial by the US Food and Drug Administration concluded that only a small fraction, if any, of the difference in outcomes between IPE and mineral oil could be explained by the use of this placebo based on comparative trials.
Food and Drug Administration. Endocrinologic and Metabolic Drugs Advisory Committee briefing document. Available at: https://www.fda.gov/media/132479/download. Accessed March 1, 2021.
Finally, patients in the REDUCE-IT trial had modestly higher risk with secondary-prevention participants, representing 71% of the trial vs. 56% of subjects in the STRENGTH trial. This translated into a higher event rate in the REDUCE-IT trial associated with a longer, 4.9-year follow-up compared with the STRENGTH trial (3.5-year follow-up with early termination); however, it is unlikely that this can account for such large differences in event outcomes.
Conclusion
The well-conducted STRENGTH trial has provided valuable insights into the relationship between TG lowering and residual cardiovascular risk. In 3 major n3-FA trials, there was no relationship between TG lowering and cardiovascular events, consistent with previous fibrate and niacin trials. Thus, while plasma TGs are a potential biomarker for and associated with cardiovascular risk, there is no evidence that current TG-lowering therapies are effective in such patients when using evidence-based LDL-C lowering therapies. The benefits with IPE in the REDUCE-IT and JELIS trials indicate that reduction in cardiovascular events was likely due to broad pleiotropic actions that correlated with on-treatment EPA levels. Elucidating such mechanisms for EPA beyond TG lowering will lead to further insights into our understanding of atherosclerosis and strategies for treatment.
Acknowledgments
We thank Robert F. Jacob, PhD, Elucida Research LLC, for preparing artwork for the figures and for providing editorial assistance. We would also like to thank Samuel C.R. Sherratt, Elucida Research LLC, for helpful scientific discussions.
References
Ganda OP
Bhatt DL
Mason RP
Miller M
Boden WE.
Unmet need for adjunctive dyslipidemia therapy in hypertriglyceridemia management.
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.
Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group.
Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.
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).
Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: final results of the EVAPORATE trial.
Food and Drug Administration. Endocrinologic and Metabolic Drugs Advisory Committee briefing document. Available at: https://www.fda.gov/media/132479/download. Accessed March 1, 2021.
Conflict of Interest: RPM reports research grants and consulting fees from Amgen, Amarin, Pfizer, and the Cleveland Clinic. RHE provides consulting and advisory services to Kaleido, Kowa Corp, Provention Bio, and The Healthy Again Company.
Authorship: All authors had access to the data and a role in writing this manuscript.
Statin use was 100%.
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