R3i Editorials

R3i editorials, created by members of the R3i board, focus on addressing the persistent challenges of residual cardiovascular risk. These editorials serve to educate healthcare professionals about emerging insights and therapeutic strategies related to lipid-related risk factors, such as triglyceride-rich lipoproteins and lipoprotein(a).

Latest Editorial

March 2026
Lessons for future trials of triglyceride-lowering therapy
Prof. Peter Libby, Prof. Michel Hermans, Prof. Pierre Amarenco, Prof. Lale Tokgözoglu 

For decades, evidence from population studies linked higher triglycerides (indicative of higher levels of triglyceride-rich lipoproteins and remnant cholesterol) with increased cardiovascular risk (1). Genetic studies further supported this relationship (2). Together, these data catalysed testing whether lowering elevated triglycerides reduced cardiovascular events in high-risk patients managed with contemporary preventive therapies. However, trials to date have largely disappointed (3-6). REDUCE-IT did show a significant reduction in cardiovascular events with high-dose icosapent ethyl (a pharmaceutical grade formulation of eicosapentaenoic acid) (7), although this may relate to the effects of high achieved plasma eicosapentaenoic acid levels, rather than just triglyceride reduction (8,9). Thus, the premise for targeting elevated triglycerides to lower residual cardiovascular risk remains unproven. Given the escalating burden of hypertriglyceridemia – currently affecting more than one in four individuals globally (10) – new thinking on trial design is urgently needed.

A recent report from the SWEDEHEART registry of patients hospitalized with myocardial infarction (MI) provides new insights (11). As discussed in this month’s Landmark report, a key aim was to investigate the magnitude of triglyceride lowering required for cardiovascular benefit, to define which patients might benefit most. This observational registry included 51,719 MI patients who had triglyceride measurements at admission and 1 year follow-up. These patients were stratified by quartiles of change in triglyceride levels between these timepoints. The cohort did not undergo systematic intervention to target triglycerides. Over a median follow-up of 5.6 years, 9008 (17%) patients had a major adverse cardiovascular event (MACE), 5148 (10%) died, and 3696 (7%) had a non-fatal MI. Patients in the top quartile of triglyceride reduction (≥0.6 mmol/L) had the lowest rates for MACE and all-cause mortality. Overall, patients who achieved at least 1.0 mmol/L reduction in baseline triglycerides (equating to at least 46% reduction from baseline) had a 13% reduction in risk for MACE, 9% reduction in all-cause mortality, and 16% reduction in non-fatal MI. However, only 27% of patients in the registry, of whom most were in the top quartile, achieved this magnitude of triglyceride reduction (11).

These findings offer explanations into why previous trials of triglyceride lowering therapies did not demonstrate significant cardiovascular benefit. First, baseline triglycerides of the trial populations were too conservative, mostly in the range of 1.7–4.9 mmol/L (3-6). Second, although the treatments resulted in significant percentage reductions in triglycerides, the absolute reductions were insufficient to achieve relevant biological changes. Thus, future trials should ensure inclusion of patients with higher triglyceride

levels, and test more efficacious triglyceride-lowering therapies. These take-home messages align with previous calls for inclusion of patients with higher triglycerides in clinical outcomes studies testing the triglyceride hypothesis (12).

With the advent of RNA-based therapeutics, the future appears positive. A raft of novel therapies targeting other hepatic proteins that regulate lipid metabolism, notably apolipoprotein CIII (APOC3) or angiopoietin like 3 protein (ANGPTL3), are in development. Clinical trials in the setting of mixed dyslipidemia have shown substantial triglyceride reductions, in excess of 50% and even 70% for ANGPTL3-directed therapies (13-17). In addition, there may be other favourable lipid changes; APOC3-directed treatments primarily reduce triglycerides but also raise high-density lipoprotein cholesterol, whereas those targeting ANGPTL3- offer broader lipid modulation, including substantial reductions in low-density lipoprotein cholesterol (13-17). Other members of the ANGPTL family, notably ANGPTL4 (18) are also in the pipeline.

These novel RNA therapeutics have promise to offer a true test of the relevance of triglyceride lowering to residual cardiovascular risk.

References

  1. Ginsberg HN, Packard CJ, Chapman MJ, et al. Triglyceride-rich lipoproteins and their remnants: metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies-a consensus statement from the European Atherosclerosis Society. Eur Heart J 2021;42:4791–806.
    2. Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology. Circ Res 2016;118:547–63.
    3. ACCORD Study Group; Ginsberg HN, Elam MB, Lovato LC, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;362:1563–74.
    4. Scott R, O’Brien R, Fulcher G, et al; Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study Investigators. Effects of fenofibrate treatment on cardiovascular disease risk in 9,795 individuals with type 2 diabetes and various components of the metabolic syndrome: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Diabetes Care 2009;32:493–8.
    5. 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. JAMA 2020;324:2268–80.
    6. Das Pradhan A, Glynn RJ, Fruchart JC, et al. Triglyceride lowering with pemafibrate to reduce cardiovascular risk. N Engl J Med 2022;387:1923-34.
    7. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11–22.
    8. Szarek M, Bhatt D, Miller M, et al. Eicosapentaenoic acid, arachidonic acid, and triglyceride levels mediate most of the benefit of icosapent ethyl in REDUCE-IT. Eur Heart J 2023; doi: 10.1093/eurheartj/ehad655.1309.
    9. Sherratt SCR, Mason RP, Libby P, Steg PG, Bhatt DL. Do patients benefit from omega-3 fatty acids? Cardiovasc Res 2024; 119:2884–901.
    10. Ballena-Caicedo J, Zuzunaga-Montoya FE, Loayza-Castro JA, et al. Global prevalence of dyslipidemias in the general adult population: a systematic review and meta-analysis. J Health Popul Nutr 2025; 44: 308.
    11. Schubert J, Hagström E, Westerbergh J, et al. Triglyceride reduction after MI and major adverse outcomes in SWEDEHEART—insights for future trials. Eur J Prev Cardiol 2026; doi: 10.1093/eurjpc/zwag076.
    12. Nordestgaard AT, Pradhan AD, Everett BM, et al. Expanding the triglyceride range in clinical trials: therapeutic opportunities. Eur Heart J 2025;46:1835-48.
    13. Bergmark BA, Marston NA, Bramson CR, et al. Effect of vupanorsen on non–high-density lipoprotein cholesterol levels in statin-treated patients with elevated cholesterol: TRANSLATE-TIMI 70. Circulation 2022;145:1377–86.
    14. Rosenson RS, Gaudet D, Hegele RA, et al. Zodasiran, an RNAi therapeutic targeting ANGPTL3, for mixed hyperlipidemia. N Engl J Med 2024;391:913–25.
    15. Tardif J-C, Karwatowska-Prokopczuk E, Amour ES, et al. Apolipoprotein C-III reduction in subjects with moderate hypertriglyceridaemia and at high cardiovascular risk. Eur Heart J 2022;43:1401–12.
    16. Ballantyne CM, Vasas S, Azizad M, et al. Plozasiran, an RNA interference agent targeting APOC3, for mixed hyperlipidemia. N Engl J Med 2024;391:899–912.
    17. Gao Y, Bai Y, Mu X. Pang X. Efficacy and safety of small interfering RNA (siRNA) therapies for hypertriglyceridemia and mixed dyslipidemia: an updated systematic review and meta-analysis. Front Pharmacol 2026;17:1736821. doi: 10.3389/fphar.2026.1736821
    18. Cummings BB, Joing MP, Bouchard PR, et al. Safety and efficacy of a novel ANGPTL4 inhibitory antibody for lipid lowering: results from phase 1 and phase 1b/2a clinical studies. Lancet 2025;405:1923-34.
  2. Key words: Triglycerides; clinical trials; residual cardiovascular risk; APOC3; ANGPTL3