Elevated triglycerides and residual cardiovascular risk

September 2025

Elevated triglycerides are related to higher residual cardiovascular risk independent of lipid targets and the intensity of lipid-lowering therapy, according to findings from the Utrecht Cardiovascular Cohort–Second Manifestations of Arterial Disease (UCC-SMART) study.

Schuitema PCE, Visseren FLJ, Nordestgaard BG, et al. Elevated triglycerides are related to higher residual cardiovascular disease and mortality risk independent of lipid targets and intensity of lipid-lowering therapy in patients with established cardiovascular disease. Atherosclerosis 2025; https://doi.org/10.1016/S0140-6736(25)00507-0.

STUDY SUMMARY

Objective

To investigate whether elevated triglycerides are related to higher residual cardiovascular risk in secondary prevention patients, and whether this association is independent of guideline-recommended lipid targets or the intensity of lipid-lowering therapy.  

 

  
Study design

The UCC-SMART study is a prospective cohort study of patients with high cardiovascular risk. The current report was based on patients with established cardiovascular disease, defined as coronary artery disease, cerebrovascular disease, peripheral artery disease, or an aneurysm of the abdominal aorta.

 

  
Study population

The study cohort comprised 9,436 patients (mean age 61 years, 73% men) with established cardiovascular disease and triglyceride levels below 8 mmol/L. Overall, 62% of patients had coronary artery disease, 29% had cerebrovascular disease, 17% had peripheral artery disease, and 8% had an aneurysm of the abdominal aorta.

 

  

Main study variables

 

Primary efficacy outcome: Recurrent cardiovascular events, a composite of myocardial infarction, stroke, and cardiovascular death.

Secondary efficacy outcome: Components of the primary outcome and all-cause mortality.

All outcomes were adjudicated according to standardized definitions.

 

  
Methods Triglyceride data were log-transformed. Cox proportional hazards models were used to analyse the association of baseline triglycerides (continuous data or quartiles) with recurrent cardiovascular events. In addition, baseline triglyceride levels were stratified into six categories (<1 mmol/L, 1-1.99 mmol/L, 2-2.99 mmol/L, 3-3.99 mmol/L, 4-4.99 mmol/L, and 5-8.00 mmol/L) to investigate the association of very high triglyceride levels versus low levels on risk of recurrent cardiovascular events and all-cause mortality. Cox proportional hazards modelling was also used to investigate the effect of low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (HDL-C) treatment target achievement, HDL-C levels, and lipid lowering treatment intensity on the association between baseline triglycerides and risk for recurrent cardiovascular events.  
Results

Over a median follow-up of 9.0 years (interquartile range 4.5–14.1 years) 2,075 recurrent cardiovascular events, 736 myocardial infarctions, 586 strokes, 1,231 cardiovascular deaths, and 2,729 all-cause deaths were recorded.

 

For each 1-unit higher log-triglyceride level, the risk of recurrent cardiovascular events was 1.17-fold higher (95%CI 1.07–1.28). The corresponding risk for individual endpoints was 1.34-fold higher (95%CI 1.16–1.56) for myocardial infarction, 1.23-fold higher (95%CI 1.09–1.38) for cardiovascular mortality, and 1.12-fold higher (95%CI 1.03–1.21) for all-cause mortality. A 2-fold higher triglyceride level was associated with 11% higher risk of recurrent cardiovascular events (Hazard ratio 1.11, 95%CI 1.05–1.19) and 15% higher risk of cardiovascular mortality (Hazard ratio 1.15, 95%CI 1.06–1.25).

 

There was no evidence that guideline-recommended lipid target achievement (LDL-C or non-HDL-C) or the intensity of lipid lowering therapy modified the relationship between baseline triglycerides and risk for recurrent cardiovascular events or cardiovascular mortality.

 
Author conclusions Elevated triglycerides are related to higher residual risk for cardiovascular disease and mortality in patients with established cardiovascular disease. These relationships were unrelated to guideline-recommended lipid target achievement, HDL-C levels, and lipid lowering therapy intensity.

Comment

Elevated triglycerides are a proxy for triglyceride-rich lipoproteins and remnant cholesterol, which are linked to risk for cardiovascular events, supported by observational and genetic studies (1-3). However, some studies showed that this association may be attenuated in patients with established cardiovascular disease (4), leading some to query 1) whether elevated triglycerides represent a causal risk factor for recurrent cardiovascular events, and if proven, 2) whether this association was modified by achievement of guideline recommended lipid targets, or the intensity of lipid lowering therapy. 

 

The results from this large cohort study support elevated triglycerides as a risk factor for recurrent cardiovascular events. Moreover, the association between elevated triglycerides and residual cardiovascular risk was independent of LDL-C and non-HDL-C target achievement, HDL-C levels, and the intensity of lipid lowering therapy. These findings are strengthened by the large patient cohort and extended follow-up period, which provided a substantial number of outcome events adding to the robustness of the study. The authors do, however, recognize that the use of baseline triglycerides as the key triglyceride measure may underestimate long-term triglyceride-related risk, as triglycerides generally increase over time.

 

From a clinical perspective, these findings underline the importance of managing triglyceride-related residual cardiovascular risk. Thus, both triglycerides and LDL-C are critical components of secondary prevention strategies to mitigate the substantial residual risk that persists in these high-risk patients.

 

References

  1. Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology. Circ Res 2016;118:547-63.
  2. Langsted A, Madsen CM, Nordestgaard BG. Contribution of remnant cholesterol to cardiovascular risk. J Intern Med 2020;288:116-27.
  3. 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.
  4. Ambrosy AP, Yang J, Sung SH, et al. Triglyceride levels and residual risk of atherosclerotic cardiovascular disease events and death in adults receiving statin therapy for primary or

secondary prevention: Insights from the KP REACH Study. J Am Heart Assoc 2021:10:https://doi.org/10.1161/JAHA.120.020377.

Key words: triglycerides; residual cardiovascular risk; secondary prevention; recurrent cardiovascular events