Real-world evidence informs trial design for triglyceride-lowering therapies
March 2026
This report from the SWEDEHEART registry provides insights into the magnitude of triglyceride reduction needed to demonstrate cardiovascular benefit in secondary prevention.
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.
STUDY SUMMARY
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Objective |
This analysis aimed to assess the relationship between triglyceride (TG) reduction and achieved levels after myocardial infarction (MI) with subsequent cardiovascular outcomes. A subsequent aim was to define the patient cohort most likely to benefit from TG lowering in future clinical trials.
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Study design |
Real-world prospective registry of patients with first MI between January 2005 and January 2022.
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Study population |
Adults aged 18–79 years with no prior history of atherosclerotic cardiovascular disease who presented with first MI. All patients were subsequently enrolled in cardiac rehabilitation programmes including standardized 1-year follow-up.
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Main study variables |
Major adverse cardiovascular events (MACE), defined as the composite of all-cause mortality, non-fatal MI, or non-fatal ischemic stroke. All-cause mortality and non-fatal MI were also individual outcomes. All outcomes were assessed after 1-year follow-up post-MI (landmark analysis). Events occurring during the first year post-MI were censored.
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Methods |
TG levels were measured at hospital admission and 1-year follow-up. The primary exposures were changes in TG levels from admission to 1-year follow-up and achieved TG levels at 1-year follow-up.
Kaplan-Meier survival estimates were derived from the 1-year follow-up to 12 years of observation for all outcomes and were stratified by the absolute change in TG. Patients were censored at the time of death, study conclusion (April 2022) or 12 years after the 1-year follow-up visit, whichever occurred first. The relationship between TG reduction and clinical outcomes was assessed using Cox proportional hazards regression modelling. To inform trial design, baseline TG levels and achieved TG reductions among patients with the greatest TG lowering were characterized to identify potential TG criteria for enrolment in future trials.
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Key results |
A total of 51,719 adults (median age 64 years, 26% women, 86% statin-naïve) were included. At baseline, median (interquartile range [IQR]) TG levels were 1.4 (1.0-2.0) mmol/L and remnant cholesterol was 0.6 (0.5-0.8) mmol/L. At 1-year post-MI, the median absolute reduction in TG was 0.2 mmol/L. When the change in TG at 1 year was categorized by quartiles (≥0.1 mmol/L increase, <0.1 mmol/L increase to <0.2 mmol/L reduction, ≥0.2 to <0.6 mmol/L reduction, and ≥0.6 mmol/L reduction), those with greatest TG reduction (median reduction 1.0 mmol/L) had the highest TG levels at baseline (median 2.2, IQR 1.8–2.9 mmol/L).
Over a median follow-up of 5.6 years, 9008 (17%) patients experienced a MACE, 5148 (10%) died, and 3696 (7%) had a non-fatal MI. When compared with the quartile with the smallest TG reduction, patients in the quartile with the largest TG reduction had a 15% lower risk for MACE, 10% lower risk for all-cause mortality, and 17% lower risk for non-fatal MI (Table 1). A reduction in TG of 1.0 mmol/L vs. no change was associated with 13% lower risk for MACE (hazard ratio 0.87, 95% CI 0.80–0.94), 9% lower risk for all-cause death (0.91, 95% CI 0.82–1.02), and 16% lower risk for nonfatal MI (0.84, 95% CI 0.75–0.95).
Table 1. Outcomes categorized by TG change (mmol/L) from index MI to 1 year
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Author conclusions |
Patients who achieved TG reductions of at least 1.0 mmol/L had the lowest risk for cardiovascular outcomes. However, only 27% of patients, mostly in the top TG quartile for TG reduction (with baseline TG of 2.2 mmol/L, equating to 46% reduction), achieved this. Among MI patients, TG reductions of ∼1.0 mmol/L were associated with the lowest cardiovascular risk. Only 27% of patients achieved this reduction with baseline TG ∼2.2 mmol/L. These findings may explain neutral results in prior triglyceride-lowering trials and suggest future trials should enrol patients with baseline triglycerides ≥2.2 mmol/L and target reductions ≥1.0 mmol/L. . |
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Comment
Strong evidence from observational and genetic studies provides the basis for clinical trials evaluating the effects of TG-lowering therapies on residual cardiovascular risk (1). To date, however, results from these trials have been inconclusive, largely because the therapies tested had modest TG-lowering efficacy (2-4). Only one study – REDUCE-IT – demonstrated significant reduction in cardiovascular events against a background of contemporary evidence-based preventive treatments (5). However, it is likely that this benefit may have been driven primarily by high achieved plasma eicosapentaenoic acid (EPA) levels, rather than just TG reduction (6-8).
The current study aimed to evaluate the association between TG reduction and cardiovascular outcomes, using real-world data from the SWEDEHEART registry including over 50,000 patients hospitalized with MI. As well as confirming the relationship between elevated TG levels and MACE risk, the study also showed that greater reduction in TG levels resulted in improved cardiovascular outcomes, with the greatest reduction in MACE risk observed with lowering TG by at least 1.0. mmol/L. Yet only a minority of patients (27%) attained this magnitude of TG reduction in routine clinical practice. Most of these patients were in the quartile with highest TG reduction and had median baseline TG levels of 2.2 mmol/L (equating to 46% reduction from baseline).
The findings of this analysis are strengthened by the size of the registry cohort recruited in real-world clinical practice and treated with contemporary evidence-based preventive therapies, not specifically targeting triglyceride-rich lipoproteins. However, the authors do acknowledge that the observational design precludes definitive causal conclusions. Despite this, the results have important implications for the design of future trials testing novel TG-lowering treatments. First, such trials require inclusion of patients with higher baseline TG levels. Second, the investigational therapies should be more efficacious in lowering TG levels, to ensure that patients achieve at least 1.0 mmol/L reduction from baseline levels. The advent of novel RNA-based therapies targeting apolipoprotein C-III or angiopoietin-like protein 3 which have been shown to substantially reduce TG levels clearly satisfy this remit (9-12).
References
- 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.
- The FIELD study investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005;366:1849–61.
- 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.
- Pradhan AD, Glynn RJ, Fruchart J-C, et al. Triglyceride lowering with pemafibrate to reduce cardiovascular risk. N Engl J Med 2022;387:1923–34.
- Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11-22.
- Mason RP, Libby P, Bhatt DL. Emerging mechanisms of cardiovascular protection for the omega-3 fatty acid eicosapentaenoic acid. Arterioscler Thromb Vasc Biol 2020; 40:1135–47.
- 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
- Sherratt SCR, Mason RP, Libby P, Steg PG, Bhatt DL. Do patients benefit from omega-3 fatty acids? Cardiovasc Res 2024; 119:2884–901.
- 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.
- 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.
- 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.
- 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.
Key words: Triglycerides; residual cardiovascular risk; cardiovascular outcomes; clinical trials
