Target both triglycerides and inflammation in secondary stroke prevention
March 2026
This report from the Tokyo Women’s Medical University Stroke Registry demonstrates additive residual stroke risk associated with concurrent hypertriglyceridemia and inflammation.
Hoshino T, Mizuno T, Arai S, et al. Cumulative association of triglycerides and interleukin-6 with recurrent vascular events after ischemic stroke . J Clin Lipidol 2026; doi.org: 10.1016/j.jacl.2026.01.001.
STUDY SUMMARY.
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Objective |
To investigate the cumulative prognostic association of baseline triglycerides (TG) and interleukin-6 (IL-6) levels with the risk of recurrent vascular events after stroke.
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Study design |
The Tokyo Women’s Medical University Stroke Registry is an ongoing, prospective, single-centre observational study.
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Study population |
Patients aged ≥20 years with acute ischemic stroke or high-risk transient ischemic attack within 1 week of onset. Patients were consecutively enrolled between October 2014 and May 2022.
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Main study variables
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The primary endpoint was 1-year major adverse cardiovascular events (MACE), defined as recurrent stroke, acute coronary syndrome, or vascular death. Vascular death was defined as fatal stroke, fatal acute coronary syndrome, or other cardiovascular death, including pulmonary embolism and sudden cardiac death.
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Methods |
Patients were categorized using defined cut-offs for TG (150 mg/dL) and IL-6 (median of 4.0 pg/mL), in one of the following groups: LL (TG<150 mg/dL/IL-6<4.0 pg/mL), HL (TG≥ 150 mg/dL/IL-6<4.0 pg/mL), LH (TG<150 mg/dL/IL-6≥4.0 pg/mL), and HH (TG≥ 150 mg/dL/IL-6≥4.0 pg/mL). Event rates were estimated using the Kaplan-Meier method. Cox proportional hazards regression models were used to evaluate the associations between the TG/IL-6 categories and the risk of recurrent MACE. |
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Results |
The analysis included 962 patients (mean age 71.0 years; 61.1% male, 62.3% on statin treatment). Characteristics of the four groups based on TG/IL-6 category, with event rates and risk for MACE are summarized in Table 1.
The presence of TG≥150 mg/dL or IL-6≥4.0 pg/mL each independently predicted recurrent MACE risk. Patients with both elevated TG and IL-6 had a cumulative increase in MACE risk (Table 1). This association was also evident in patients with atherothrombotic stroke (p=0.001), on statin treatment for secondary prevention (p=0.001) or with controlled LDL-C levels (either <100 mg/dL, p=0.004; or<70 mg/dL, p=0.013). .
Table 1. Characteristics and MACE risk of patients categorized by TG and IL-6 levels
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Author conclusions |
CI confidence interval; IQR interquartile range; LDL-C low-density lipoprotein cholesterol; SD standard deviation
Stratification by TG and IL-6 levels revealed a cumulative increase in MACE risk after stroke, with the highest risk in patients with a dual burden of hypertriglyceridemia and systemic inflammation. |
Comment
Although contemporary secondary prevention strategies have effectively reduced stroke risk in the short-term, approximately 1 in 5 patients remain at risk of recurrent stroke within 10 years, with 10% of subsequent stroke events likely to be fatal (1). Lowering low-density lipoprotein cholesterol to guideline recommended targets still leaves a substantial residual risk (2), underlining the need to identify other targets. Either elevated TG or chronic systemic inflammation have emerged as contributors to this residual risk (3,4). Notably, elevated levels of IL-6 levels, a distal cytokine in the inflammatory cascade, have been consistently associated with an increased risk of recurrent events in ischemic stroke cohorts (5,6), with evidence from Mendelian randomization studies suggesting a causal role in atherothrombosis (7). Moreover, as lipid abnormalities and inflammation act together to increase the risk of plaque progression and thrombosis (8-10), residual risk for cardiovascular risk might be exacerbated when both are present.
The results of this study support this hypothesis. Not only were TG levels ≥150 mg/dL or IL-6 levels ≥4.0 pg/mL each independently predictive of recurrent MACE, but risk was cumulative when both abnormalities were present. This association persisted in patients with atherothrombotic stroke, or those who achieved guideline-recommended LDL-C levels. Although the authors do acknowledge several limitations of the study, notably the single centre design, restriction to Japanese patients, and measurement of TG and IL-6 levels only at admission rather than extending to follow-up, as a registry the study reflects real-world practice. In this context, the findings suggest the potential utility of measuring both TG and IL-6 levels to inform risk stratification for secondary prevention in routine clinical practice, and merit further study, and seeking added value over high-sensitivity C-reactive protein, a validated inflammatory marker with superior analytic characteristics than IL-6 (11), in larger and more widely representative cohorts. Moreover, these results support careful adjudication of stroke events in large ongoing and planned trials targeting IL-6 in other cardiovascular conditions.
References
- Khan F, Yogendrakumar V, Lun R, et al. Long-term risk of stroke after transient ischemic attack or minor stroke: a systematic review and meta-analysis. JAMA 2025;333:1508–19.
- Amarenco P, Kim JS, Labreuche J, et al. A comparison of two LDL cholesterol targets after ischemic stroke. N Engl J Med 2020;382:9.
- Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet 2014;384:626–35.
- Kelly PJ, Lemmens R, Tsivgoulis G. Inflammation and stroke risk: a new target for prevention. Stroke 2021; 52: 2697-706.
- McCabe JJ, Walsh C, Gorey S, et al. C-reactive protein, interleukin-6, and vascular recurrence after stroke: an individual participant data meta-analysis. Stroke 2023;54:1289–99.
- Arai S, Hoshino T, Mizuno T, et al. Association between serum interleukin-6
levels and long-term outcomes after ischemic stroke: a Prospective Cohort Study. J Atheroscler Thromb 2025: doi 10.5551/jat.65842.
- Georgakis MK, Malik R, Gill D, et al. Interleukin-6 signaling effects on ischemic stroke and other cardiovascular outcomes: a Mendelian Randomization Study. Circ Genom Precis Med 2020;13:e002872.
- Ridker PM, Bhatt DL, Pradhan AD, et al. Inflammation and cholesterol as predictors of cardiovascular events among patients receiving statin therapy: a collaborative analysis of three randomised trials. Lancet 2023;401:1293–301.
- Doi T, Langsted A, Nordestgaard BG. Dual elevated remnant cholesterol and C-reactive protein in myocardial infarction, atherosclerotic cardiovascular disease, and mortality. Atherosclerosis 2023;379:117141.
- Kitagawa K, Hosomi N, Nagai Y, et al. Cumulative effects of LDL cholesterol and CRP levels on recurrent stroke and TIA. J Atheroscler Thromb 2019;26:432–441.
- Kurt B, Reugels M, Schneider KM, et al. C-reactive protein and cardiovascular risk in the general population. Eur Heart J 2025: doi: 10.1093/eurheartj/ehaf937.
Key words: Stroke; triglycerides; interleukin-6; residual vascular risk
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