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Mechanistic Insights from REDUCE-IT STRENGTHen the Case Against Triglyceride Lowering as a Strategy for Cardiovascular Disease Risk Reduction

Open AccessPublished:April 14, 2021DOI:https://doi.org/10.1016/j.amjmed.2021.03.014

      Abstract

      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.

      Keywords

      Clinical Significance
      • Elevated triglycerides (TGs) are associated with increased cardiovascular risk; however, current TG-lowering therapies are ineffective in reducing such risk.
      • Icosapent ethyl, highly purified eicosapentaenoic acid, was recently shown to reduce cardiovascular events by 25% and was not associated with TG lowering.
      • Icosapent ethyl appears to have broad pleiotropic effects associated with on-treatment eicosapentaenoic acid levels.
      • 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.
      • Ganda OP
      • Bhatt DL
      • Mason RP
      • Miller M
      • Boden WE.
      Unmet need for adjunctive dyslipidemia therapy in hypertriglyceridemia management.
      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.
      • Libby P
      Triglycerides on the rise: should we swap seats on the seesaw?.
      ,
      • Varbo A
      • Benn M
      • Tybjærg-Hansen A
      • Jørgensen AB
      • Frikke-Schmidt R
      • Nordestgaard BG
      Remnant cholesterol as a causal risk factor for ischemic heart 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.
      • Aung T
      • Halsey J
      • Kromhout D
      • et al.
      Associations of omega-3 fatty acid supplement use with cardiovascular disease risks: meta-analysis of 10 trials involving 77 917 individuals.
      • Bowman L
      • Mafham M
      • Wallendszus K
      • et al.
      ASCEND Study Collaborative Group
      Effects of n-3 fatty acid supplements in diabetes mellitus.
      • Manson JE
      • Cook NR
      • Lee IM
      • et al.
      Marine n-3 fatty acids and prevention of cardiovascular disease and cancer.
      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
      JELIS (18,645)REDUCE-IT (8179)STRENGTH (13,078)
      Population
      Statin use was 100%.
      HypercholesterolemicHigh cardiovascular risk, Elevated TGHigh cardiovascular risk, Elevated TG, low HDL
      FormulationIPE (1.8 g/d EPA)IPE (4 g/d EPA)EPA/DHA carboxylic acids (4 g/d)
      Baseline median TG (mg/dL)153216240
      Baseline EPA (µg/mL)9726.121.0
      Achieved EPA (µg/mL)16914489.6
      Increase in achieved EPA levels (%)70394269
      TG lowering (%)91719
      Primary endpointMajor coronary eventsComposite of cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable anginaComposite of cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina
      HR, 95% CI of primary endpoint0.81, 0.69-0.95 (P = .011)0.75, 0.68-0.83 (P = .00000001)0.99, 0.90-1.09 (P = .84)
      CI = confidence interval; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; HDL = high-density lipoprotein; HR = hazard ratio; IPE = icosapent ethyl; MI = myocardial infarction; TG = triglyceride.
      low asterisk Statin use was 100%.

      Review of TG-Lowering Trials

      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.
      • Nicholls SJ
      • Lincoff AM
      • Garcia M
      • 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.
      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),
      • Rubins HB
      • Robins SJ
      • Collins D
      • et al.
      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.
      • Group HTC
      • Landray MJ
      • Haynes R
      • et al.
      Effects of extended-release niacin with laropiprant in high-risk patients.
      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.
      • Group AS
      • Ginsberg HN
      • Elam MB
      • et al.
      Effects of combination lipid therapy in type 2 diabetes mellitus.
      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.
      • Boden WE
      • Probstfield JL
      • Anderson T
      • et al.
      AIM-HIGH Investigators
      Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy.
      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.
      • Ference BA
      • Kastelein JJP
      • Ray KK
      • et al.
      Association of triglyceride-lowering LPL variants and LDL-C-lowering LDLR variants with risk of coronary heart disease.
      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).
      • Pradhan AD
      • Paynter NP
      • Everett BM
      • et al.
      Rationale and design of the Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) study.
      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.
      • Qamar A
      • Libby P
      • Bhatt DL
      Targeting RNA to lower triglycerides: long strides from short molecules.
      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.
      • Bhatt DL
      • Steg PG
      • Miller M
      • et al.
      Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia.
      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.
      • Bhatt DL
      • Steg PG
      • Miller M
      • et al.
      Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia.
      ,
      • Bhatt DL
      • Steg PG
      • Miller M
      • et al.
      Effects of icosapent ethyl on total ischemic events: from REDUCE-IT.
      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.
      • Yokoyama M
      • Origasa H
      • Matsuzaki M
      • et al.
      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.
      • Saito Y
      • Yokoyama M
      • Origasa H
      • et al.
      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.
      • Sharma G
      • Martin SS
      • Blumenthal RS
      Effects of omega-3 fatty acids on major adverse cardiovascular events: what matters most: the drug, the dose, or the placebo?.
      Indeed, EPA and DHA differ in their effects on membrane structure, rates of lipid oxidation, inflammatory biomarkers, and tissue distributions (Figure 1).
      • Mason RP
      • Libby P
      • Bhatt DL
      Emerging mechanisms of cardiovascular protection for the omega-3 fatty acid eicosapentaenoic acid.
      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.
      • Mason RP
      • Dawoud H
      • Jacob RF
      • Sherratt SCR
      • Malinski T
      Eicosapentaenoic acid improves endothelial function and nitric oxide bioavailability in a manner that is enhanced in combination with a statin.
      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.
      • Bays HE
      • Ballantyne CM
      • Braeckman RA
      • Stirtan WG
      • Soni PN
      Icosapent ethyl, a pure ethyl ester of eicosapentaenoic acid: effects on circulating markers of inflammation from the MARINE and ANCHOR studies.
      ,
      • Ballantyne CM
      • Bays HE
      • Braeckman RA
      • et al.
      Icosapent ethyl (eicosapentaenoic acid ethyl ester): effects on plasma apolipoprotein C-III levels in patients from the MARINE and ANCHOR studies.
      Thus, EPA and its bioactive lipid metabolites exert complex and multifactorial atheroprotective effects beyond TG lowering (Figure 2).
      Figure 1
      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.
      • Mason RP
      • Libby P
      • Bhatt DL
      Emerging mechanisms of cardiovascular protection for the omega-3 fatty acid eicosapentaenoic acid.
      Figure 2
      Figure 2Atheroprotective effects of eicosapentaenoic acid (EPA) during progression of arterial disease, including endothelial dysfunction, oxidative stress, inflammation, and changes in plaque stability. AA = arachidonic acid; hsCRP = high-sensitivity C-reactive protein; ICAM = intercellular adhesion molecule; IL = interleukin; Lp-PLA2 = lipoprotein-associated phospholipase A2; MMPs = matrix metalloproteinases; Ox-LDL = oxidized low-density lipoprotein; RLP-C = remnant-like lipoprotein particle cholesterol.
      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.
      • Budoff MJ
      • Bhatt DL
      • Kinninger A
      • et al.
      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.
      • Williams MC
      • Moss AJ
      • Dweck M
      • et al.
      Coronary artery plaque characteristics associated with adverse outcomes in the SCOT-HEART study.
      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.
      • Watanabe T
      • Ando K
      • Daidoji H
      • et al.
      A randomized controlled trial of eicosapentaenoic acid in patients with coronary heart disease on statins.
      Thus, laboratory and clinical investigations provide insights into the distinct benefits of IPE in the REDUCE-IT and JELIS trials.
      • Mason RP
      New insights into mechanisms of action for omega-3 fatty acids in atherothrombotic cardiovascular disease.
      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.
      • Olshansky B
      • Chung MK
      • Budoff MJ
      • et al.
      Mineral oil: safety and use as placebo in REDUCE-IT and other clinical studies.
      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).
      • Pisaniello AD
      • Nicholls SJ
      • Ballantyne CM
      • Bhatt DL
      • Wong ND
      Eicosapentaenoic acid: atheroprotective properties and the reduction of atherosclerotic cardiovascular disease events.
      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.
      • Lakshmanan S
      • Shekar C
      • Kinninger A
      • et al.
      Comparison of mineral oil and non-mineral oil placebo on coronary plaque progression by coronary computed tomography angiography.
      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.

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