Author + information
- Deepak L. Bhatt, MD, MPH∗ (, )@DLBhattMD,
- Ph. Gabriel Steg, MD,
- Michael Miller, MD,
- Eliot A. Brinton, MD,
- Terry A. Jacobson, MD,
- Lixia Jiao, PhD,
- Jean-Claude Tardif, MD,
- John Gregson, PhD,
- Stuart J. Pocock, PhD,
- Christie M. Ballantyne, MD,
- on behalf of the REDUCE-IT Investigators†
- ↵∗Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115
Triglyceride elevation has re-emerged as a potent marker of residual cardiovascular risk in statin-treated patients (1). Converging lines of evidence from epidemiological analyses, Mendelian randomization studies, and outcome data from REDUCE-IT (Reduction of Cardiovascular Events with EPA-Intervention Trial) support even moderately elevated triglycerides as being associated with increased cardiovascular risk and as a potential target of therapy (1,2).
REDUCE-IT randomized 8,179 statin-treated patients with triglycerides ≥135 and <500 mg/dl (median baseline of 216 mg/dl); low-density lipoprotein (LDL) cholesterol >40 and ≤100 mg/dl (median baseline of 75 mg/dl); and with a history of atherosclerosis (coronary, cerebral, or peripheral) or with diabetes and other risk factors to icosapent ethyl 4 g/day or placebo (3,4). Patients were followed for a median of 4.9 years. The primary endpoint, a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina, was reduced by 25% (hazard ratio: 0.75; 95% confidence interval: 0.68 to 0.83; p < 0.0001). In a pre-specified analysis, total primary endpoint events (first and subsequent events) were significantly reduced by 30% (rate ratio: 0.70; 95% CI: 0.62 to 0.78; p < 0.0001) (5). Here, we examined by pre-specified baseline triglyceride tertiles the primary endpoint of first event (Cox proportional-hazards model) and total events (negative binomial regression model). REDUCE-IT inclusion criteria specified fasting triglycerides ≥135 and <500 mg/dl at screening, although lower or higher triglycerides were possible at baseline, which was an average of screening and randomization visits. Baseline triglycerides ranged from 81 to 1,401 mg/dl. Median triglycerides across ascending tertiles were 163, 217, and 304 mg/dl. There were large, consistent, statistically significant reductions with icosapent ethyl in the primary endpoint for first (Figure 1A) and total events (Figure 1B) across all tertiles. Elevated risk occurs at lower triglyceride levels than previously appreciated. While placebo event rates were highest in the upper tertile, where a numerically larger relative risk reduction was suggested, cross-tertile interaction p values were nonsignificant.
To explore this observation further, we considered absolute risk differences, where statistically significant risk reductions with icosapent ethyl across all tertiles and larger reductions in the highest tertile were again observed; but here, unadjusted cross-tertile interaction p values were p = 0.12 for first events and p = 0.03 for total events. The highest baseline triglyceride tertile likely impacted the interaction p values, with 21.0 (p < 0.0001) fewer first events (45.3 vs. 66.3) and 48.3 (p < 0.0001) fewer total events (64.4 vs. 107.4) per 1,000 patient-years for icosapent ethyl versus placebo, compared with 11.0 (p = 0.0055) (39.6 vs. 50.5) and 10.7 (p = 0.0168) (45.9 vs. 56.7) fewer first events, and 21.2 (p = 0.0028) (56.4 vs. 74.5) and 21.3 (p = 0.0113) (63.2 vs. 86.8) fewer total events in the lowest and middle tertiles, respectively, with icosapent ethyl compared with placebo. In the full cohort, 14.0 first events (43.4 vs. 57.4) and 30.2 total events (61.1 vs. 88.8) were avoided per 1,000 patient-years with icosapent ethyl compared with placebo (p < 0.0001 for both).
This suggestion of potential additional benefit in patients with higher triglycerides may be due to a higher baseline risk (triglyceride elevation as a marker of risk) and/or greater icosapent ethyl benefit in patients with higher triglycerides. Further studies are needed to distinguish the contributions of each aspect to the large risk reductions with icosapent ethyl. These REDUCE-IT analyses may help redefine a lower “normal” triglyceride level, analogous to the redefinition of lower normal LDL cholesterol as data emerged supporting therapeutic benefits of LDL lowering with statins, ezetimibe, and PCSK9 inhibitors.
In conclusion, icosapent ethyl 4 g/day significantly reduced first and total ischemic events in statin-treated patients with well-controlled LDL cholesterol across a wide range of baseline triglycerides, suggesting that the cardiovascular benefits of icosapent ethyl are tied primarily to baseline risk and non–triglyceride-related effects. Nonetheless, while approximately 10% of REDUCE-IT patients had triglycerides currently considered normal (<150 mg/dl), almost all REDUCE-IT patients had triglycerides greater than what might now be considered an optimal level of <100 mg/dl. Future REDUCE-IT biomarker studies and data analyses will explore the potential mechanisms behind the substantial reductions in cardiovascular risk observed with icosapent ethyl.
↵† A complete list of the REDUCE-IT trial investigators can be found at NEJM.org in the supplemental appendix of Bhatt et al. (3). (Reduction of Cardiovascular Events with Icosapent Ethyl—Intervention Trial [REDUCE-IT]; NCT01492361).
Please note: The study was funded by Amarin Pharma, Inc. Dr. Deepak L. Bhatt has served on the advisory board of Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, PhaseBio, and Regado Biosciences; has served on the Board of Directors of Boston VA Research Institute, Society of Cardiovascular Patient Care, and TobeSoft; has served as Chair of the American Heart Association Quality Oversight Committee, NCDR-ACTION Registry Steering Committee, and VA CART Research and Publications Committee; has served on data monitoring committees for Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi-Sankyo), and the Population Health Research Institute; has received honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice-Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim), Belvoir Publications (Editor-in-Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), HMP Global (Editor-in-Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Medtelligence/ReachMD (CME steering committees), Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national coleader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), and WebMD (CME steering committees); has served as Deputy Editor of Clinical Cardiology; has received research funding from Abbott, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Idorsia, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi Aventis, Synaptic, and The Medicines Company; has received royalties from Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); has served as site co-investigator for Biotronik, Boston Scientific, St. Jude Medical (now Abbott), and Svelte; is a Trustee of the American College of Cardiology; and has performed unfunded research for FlowCo, Fractyl, Merck, Novo Nordisk, PLx Pharma, and Takeda. Dr. Steg has received research grant funding from Amarin, Bayer, Merck, Sanofi, and Servier; and has received speaking or consulting fees from Amarin, Amgen, AstraZeneca, Bayer/Janssen, Boehringer Ingelheim, Bristol-Myers Squibb, Idorsia, Lilly, Merck, Novartis, Novo Nordisk, Pfizer, Regeneron, Sanofi, and Servier. Dr. Miller has received consulting fees from Amarin and Akcea; and has served as an advisor for Amarin. Dr. Brinton has received speaker fees from Akcea, Amarin, Amgen, Boehringer Ingelheim, Kowa, Merck, Novo Nordisk, Regeneron, and Sanofi; and has received consulting fees from Akcea, Amarin, Amgen, Kowa, Merck, Precision Biosciences, PTS Diagnostics, Regeneron, and Sanofi. Dr. Jacobson has received consulting fees from AstraZeneca, Amarin, Amgen, Esperion, Novartis, Regeneron, and Sanofi. Dr. Jiao is employed by and is a stock shareholder of Amarin Pharma. Dr. Tardif has received grant support from AstraZeneca, Esperion, and Ionis; has received grant support and consulting fees from DalCor; has received grant support and fees for serving as co-chairman of an executive committee from Pfizer; has received grant support and fees for serving on an executive committee from Sanofi; has received grant support and consulting fees from Servier; holds a minor equity interest in DalCor; and holds a patent (U.S. 9,909,178 B2) on Dalcetrapib for Therapeutic Use. Drs. Gregson and Pocock have received consultancy fees from Amarin Pharma, Inc. Dr. Ballantyne has received consulting fees from Akcea, Amgen, Amarin, Arrowhead, AstraZeneca, Corvidia, Matinas BioPharma, Merck, Boehringer Ingelheim, Novo Nordisk, Janssen, Intercept, Esperion, Regeneron, and Sanofi-Synthelabo; and has received grant/research support from Akcea, Amgen, Esperion, Novartis, Regeneron, and Sanofi-Synthelabo.
- 2019 The Authors
- Ganda O.P.,
- Bhatt D.L.,
- Mason R.P.,
- Miller M.,
- Boden W.E.
- Picard F.,
- Bhatt D.L.,
- Ducrocq G.,
- et al.