Lower Triglycerides, Lower Risk? Large Real-World Study Finds Only Modest Cardiovascular Benefit, December 2025 Published AHJP Study

Background: Targeting Dyslipidemia Beyond LDL-C

Management of dyslipidemia remains central to cardiovascular event prevention, with LDL-C lowering—primarily via statins, solidly established as first-line therapy in global guidelines. However, elevated triglycerides (TG) have also been consistently linked to higher cardiovascular risk in observational studies. Although high-risk patients with fasting TG levels of 135–499 mg/dL may receive therapies such as high-dose icosapent ethyl (IPE) in addition to statins, randomized controlled trials of TG-lowering agents have shown mixed results. To clarify this uncertainty, this retrospective analysis used a real-world database to evaluate whether actual reductions in TG levels correlate with lower cardiovascular event risk in both primary and secondary prevention populations.

Study Overview

This retrospective study utilized the Japan Medical Data Center (JMDC) Claims Database, a nationwide health insurance database in Japan. The analysis included patients who had baseline TG levels ≥150 mg/dL and underwent a follow-up health checkup at one year. Participants were divided into a large primary prevention cohort (n=350,959) and a smaller secondary prevention cohort (n=4,819) based on their history of cardiovascular diseases. The patients were classified into four groups based on their TG levels measured at the one-year mark: low (≤100 mg/dL), normal (100–149 mg/dL), high (150–499 mg/dL), and very high (≥500 mg/dL).

The primary outcome assessed was Major Adverse Cardiovascular Events (MACE), which included acute myocardial infarction (AMI), hospitalization for unstable angina pectoris (UAP), ischemic stroke, and cardiac death. Outcomes were tracked over a mean follow-up of 3.17±2.56 years.

Key Results: Benefit Limited to Primary Prevention

• In the primary prevention group, multivariable analysis revealed that a reduction in TG levels to the low (≤100 mg/dL) and normal (100–149 mg/dL) ranges was independently associated with a reduced risk of MACE and AMI.

• Specifically, the low TG group showed a 27% lower risk of MACE (HR: 0.73) and a 36% lower risk of AMI (HR: 0.64) compared to the high TG reference group. A reduced risk of stroke was also found in the low TG group (HR: 0.67).

• In contrast, in the secondary prevention group, the low and normal TG groups were not significantly associated with a reduced risk of any outcomes.

• Furthermore, in subgroup analyses, a reduction in TG levels was significantly associated with a reduction in MACE only in patients who were also classified in the high LDL-C group (above target), but not in the normal LDL-C group.

• Finally, pharmacological interventions targeting TG levels were not associated with a reduced risk of MACE in this retrospective analysis.

Clinical Inference: The Need for Targeted Reduction

This large real-world analysis suggested that lowering triglycerides, particularly to below 150 mg/dL, is associated with reduced cardiovascular risk, with the strongest effect seen in primary prevention patients. The benefit was most pronounced in individuals whose LDL-C levels remained above guideline targets, indicating that triglyceride reduction may serve as an important complementary strategy when LDL-C is not yet optimally controlled. Although the observed association was modest, the findings underscore the need for prospective studies to clarify the degree of triglyceride lowering required and to determine which therapies offer the greatest cardiovascular protection.

Reference: Yamashita I, Ishii M, Tokai T, Ikebe S, Yamanouchi Y, Nakamura T, Tsujita K. Association between a reduction in triglyceride levels and risk of cardiovascular events. Am Heart J Plus. 2025 Oct 16;60:100647. doi: 10.1016/j.ahjo.2025.100647. PMID: 41169445; PMCID: PMC12569805.

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