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).

April 2025
Triglyceride levels in clinical trials – should we aim higher?
Prof. Peter Libby, Prof. Michel Hermans, Prof. Pierre Amarenco

There is a wealth of evidence from observational studies over the decades linking elevated  plasma triglycerides (TG), a surrogate for TG-rich lipoproteins and their remnants, with increased cardiovascular risk (1). More recently, genetic studies added support for a likely causative role for TG-rich lipoproteins in ASCVD (1,2). However, a critical gap in evidence persists, i.e., whether lowering TG levels translates to reduction in cardiovascular events. To date, only REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial) (3) demonstrated significant cardiovascular benefit from lowering TG levels with high-dose icosapent ethyl treatment against a background of contemporary evidence-based therapy including statin treatment. In contrast, two other major trials – PROMINENT (Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes) and STRENGTH (Long-Term Outcomes Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia)  – were neutral despite lowering TG levels by 26% and 19% (control-corrected), respectively (4,5).  While much has been made of differences in the baseline characteristics of the patient populations of these trials, including the intensity of background statin therapy, the proportion with diabetes mellitus, and the extent of residual inflammatory risk (6), it should be borne in mind that each trial targeted patients with moderate hypertriglyceridemia at screening. Screening TG levels were broadly comparable: 1.5 – 5.6 mmol/L in REDUCE-IT, and 2.0-6.2 mmol/L in PROMINENT and STRENGTH (3-5). 

These conflicting data are perplexing.  A recent study by Nordestgaard et al (7) provides insights into this conundrum by investigating whether cardiovascular risk differs across the range of TG levels. Researchers evaluated cardiovascular risk across a wide range of TG levels in the Copenhagen General Population Study (n=119 573). This was then compared with cardiovascular risk in two cohorts with baseline TG levels between 2.3 and 5.6 mmol/L (the Copenhagen General Population Study and the Women’s Health Study cohorts, n=27,757), as well as the PROMINENT, REDUCE-IT, and STRENGTH trial populations. 

There was clear evidence that increasing TG levels from 0.3 to 11.2 mmol/L was associated with an increasing risk of major cardiovascular events. Notably, when compared with the reference (TG <1.0 mmol/L), individuals with TG levels ≥7.0 mmol/L had more than 2-fold higher risk of cardiovascular events (hazard ratio 2.03; 95% confidence interval [CI] 1.66–2.53).

Among individuals in the Copenhagen General Population study and Women’s Health Study cohorts with moderate hypertriglyceridemia, cardiovascular risk did not increase in the range of 2.5 to <3.0 mmol/L (Hazard ratio 0.95, 95% confidence interval 0.87-1.04) and was only increased by 4% at TG levels of 3.0 to <3.6 mmol/L (Hazard ratio 1.04, 95% CI 0.95-1.13) and 13% at TG levels ≥ 3.6 mmol/L (Hazard ratio 1.13, 95% CI 1.04-1.23), when compared with the reference quartile (<2.5 mmol/L) (5). At TG levels beyond 5.6 mmol/L, the strength of the association with cardiovascular risk increased. Results from the PROMINENT, REDUCE-IT and STRENGTH trial populations were consistent with these observations, with cardiovascular risk only increased by 9% (Hazard ratio 1.09, 95% CI 1.00-1.19) at TG levels exceeding 3.9, 3.1, and 3.5 mmol/L, respectively (7). The authors suggested that the lack of consistency across these trials may relate to only modest increases in cardiovascular risk associated moderate hypertriglyceridemia. To address this, they proposed that future trials of TG-lowering therapies consider a wider range of TG levels for enrolment, with the provisos of exclusion of patients with a history of pancreatitis or excessive alcohol intake (7). In an accompanying editorial, Watts and Chan (8) suggested no upper limit for TG levels in cardiovascular outcome studies testing TG-lowering therapies, but did recognize the need to avoid pancreatitis in patients with multifactorial chylomicronemia syndrome, who are also commonly at increased risk of ASCVD (9). 

These discussions are highly relevant with several novel TG-lowering therapies in clinical development. RNA silencing therapies targeted at APOC3 or ANGPTL3 are a key focus of interest, with evidence of substantial benefit in the settings of moderate and severe hypertriglyceridemia (10-13).  The design of cardiovascular outcomes studies for these novel agents is still under much discussion. Despite this, Watts and Chan (8) noted that initial plans for one trial with plozasiran (previously referred to ARO-APOC3) include secondary prevention patients with TG levels between 2 and 10 mmol/L (and non-high-density lipoprotein cholesterol [non-HDL-C] >2.6 mmol/L) and primary prevention patients with TG levels between 2.8 and 9.0 mmol/L (non-HDL-C >3.4 mmol/L), although the trial design is not yet finalized. Future trials are, however, unlikely to exceed an upper limit for TG levels of 10.0 mmol/L due to the risk of acute pancreatitis for patients in the placebo group. 

Identifying at what TG level cardiovascular risk – and residual cardiovascular risk – increases is an important goal for ASCVD prevention. The report by Nordestgaard and co-workers will undoubtedly impact the design of future cardiovascular outcomes studies for novel TG-lowering therapies. The quest to address the gap in evidence that persists in confirming the role of TG-rich lipoproteins and their cholesterol load in cardiovascular risk continues anew.

References

  1. Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease. Insights from epidemiology, genetics, and biology, Circ Res 2016;118:547-63.
    2. 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.
    3. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019; 380:11-22.
    4. 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.
    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. Fruchart JC, Fruchart-Najib J, Yamashita S, et al. Lessons from PROMINENT and prospects
    for pemafibrate. Cardiovasc Diabetol 2024; 23:279.
    7. Nordestgaard AT, Pradhan AD, Everett BM, et al. Expanding the triglyceride range in clinical trials: therapeutic opportunities. Eur Heart J 2025; doi: 10.1093/eurheartj/ehaf074.
    8. Watts GF, Chan DC. Reaching for the stars: a wider perspective for designing future cardiovascular outcome trials of triglyceride-lowering therapies. Eur Heart J 2025; doi.org/10.1093/eurheartj/ehae931.
    9. Chait A. Hypertriglyceridemia. Endocrinol Metab Clin North Am 2022; 51:539–55.
    10. Bergmark BA, Marston NA, Prohaska TA, et al. Olezarsen for hypertriglyceridemia in patients at high cardiovascular risk. N Engl J Med 2024; 390:1770–80.
    11. 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.
    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.
    13. Gaudet D, Pall D, Watts GF, et al. Plozasiran (ARO-APOC3) for severe hypertriglyceridemia: the SHASTA-2 randomized clinical trial. JAMA Cardiol 2024; 9:620–30.