Triglyceride-Glucose-Waist-to-Height Ratio links to aging and mortality in cardiovascular-kidney-metabolic syndrome

Abstract

Aim: Cardiovascular-kidney-metabolic (CKM) syndrome accelerates aging and increases mortality. We evaluated whether Triglyceride-Glucose-Waist-to-Height Ratio (TyG-WHtR), a marker of insulin resistance, predicts mortality in CKM and whether age acceleration mediates this association.

Methods: This investigation enrolled 16,145 individuals diagnosed with CKM syndrome. The relationships between TyG-WHtR and mortality were examined using multivariable Cox proportional hazards models, threshold effect analysis, and restricted cubic splines. Besides, the mediating role of age acceleration was investigated through mediation analysis. Risk within different populations was assessed using interaction tests and subgroup analysis.

Results: In multivariate Cox proportional hazards analyses, TyG-WHtR showed a positive association with mortality outcomes. Per one standard deviation (1-SD) increase, the hazard of cardiovascular death was 18% higher (hazard ratio (HR): 1.180; 95% confidence interval (CI): 1.08-1.29), while all-cause mortality risk rose by 8.6% (HR: 1.086, 95%CI: 1.01-1.17). Both cardiovascular and all-cause mortality showed a strong U-shaped association with TyG-WHtR. Mediation analysis revealed that PhenoAge acceleration and Klemera-Doubal Method age acceleration mediated 19.7% and 15.8% of the association between TyG-WHtR and all-cause mortality, respectively, and 20.7% and 16.8% of the association between TyG-WHtR and cardiovascular mortality, respectively.

Conclusion: TyG-WHtR is associated with mortality in patients with CKM syndrome, partly through accelerated aging. It is positively associated with age acceleration and exhibits a U-shaped relationship with mortality. Targeting the metabolic-aging crosstalk may help reduce mortality in CKM patients.

Keywords

Insulin resistance / age acceleration / cardio-kidney-metabolic syndrome / all-cause and cardiovascular mortality / mediation

References

[1] Ndumele CE,Chow SL.Cardiovascular-kidney-metabolic health: a presidential advisory from the American heart association.Circulation2023;148:1606-35

[2] Ndumele CE,Tuttle KR.A synopsis of the evidence for the science and clinical management of cardiovascular-kidney-metabolic (CKM) syndrome: a scientific statement from the american heart association.Circulation2023;148:1636-64

[3] Yang Q,Zhang L.Dyslipidemia and aging: the non-linear association between atherogenic index of plasma (AIP) and aging acceleration.Cardiovasc Diabetol2025;24:181 PMCID:PMC12023499

[4] Li X,Zhang J.Accelerated aging mediates the associations of unhealthy lifestyles with cardiovascular disease, cancer, and mortality.J Am Geriatr Soc2024;72:181-93 PMCID:PMC11078652

[5] Hu L,Tang Z.How does biological age acceleration mediate the associations of obesity with cardiovascular disease? Evidence from international multi-cohort studies.Cardiovasc Diabetol2025;24:209 PMCID:PMC12079857

[6] Zhang Z,Sun Y,Sun J.Type 2 diabetes mellitus: a metabolic model of accelerated aging - multi-organ mechanisms and intervention approaches.Aging Dis2025;17:1399-422

[7] Zhang P,Zeng W.Association between triglyceride-glucose related indices and all-cause and cardiovascular mortality among the population with cardiovascular-kidney-metabolic syndrome stage 0-3: a cohort study.Cardiovasc Diabetol2025;24:92 PMCID:PMC11871745

[8] Kityo A.Association of cardiometabolic factors and insulin resistance surrogates with mortality in participants from the Korean Genome and Epidemiology Study.Lipids Health Dis2023;22:210 PMCID:PMC10691157

[9] Levine ME,Quach A.An epigenetic biomarker of aging for lifespan and healthspan.Aging2018;10:573-91 PMCID:PMC5940111

[10] Pan LY.Association between triglyceride glucose index and biological aging in U.S. adults: National Health and Nutrition Examination Survey.Cardiovasc Diabetol2025;24:100 PMCID:PMC11871761

[11] Ou Y,Yuan Y.Epigenetic age acceleration and rheumatoid arthritis: an NHANES-based analysis and survival prediction models.Clin Epigenet2025;17:111 PMCID:PMC12224362

[12] Aggarwal R,Vaduganathan M.Prevalence of cardiovascular-kidney-metabolic syndrome stages in US adults, 2011-2020.JAMA2024;331:1858-60 PMCID:PMC11079779

[13] Zhu R,He J.Prevalence of cardiovascular-kidney-metabolic syndrome stages by social determinants of health.JAMA Netw Open2024;7:e2445309 PMCID:PMC11574692

[14] Boutouyrie P,Humphrey JD.Arterial stiffness and cardiovascular risk in hypertension.Circ Res2021;128:864-86

[15] Wei Z,Li J,Liu H.Association of triglyceride-glucose index and its related parameters with functional disability: evidence from the China Health and Retirement Longitudinal Study.Front Aging Neurosci2025;17:1488124 PMCID:PMC12127429

[16] Zhang Q,Jiao X.The triglyceride-glucose index is a predictor for cardiovascular and all-cause mortality in CVD patients with diabetes or pre-diabetes: evidence from NHANES 2001-2018.Cardiovasc Diabetol2023;22:279 PMCID:PMC10583314

[17] Sun Y,Snetselaar LG.Association of fried food consumption with all cause, cardiovascular, and cancer mortality: prospective cohort study.BMJ2019;364:k5420 PMCID:PMC6342269

[18] Ashwell M.Waist-to-height ratio as an indicator of 'early health risk': simpler and more predictive than using a 'matrix' based on BMI and waist circumference.BMJ Open2016;6:e010159 PMCID:PMC4800150

[19] Ashwell M,Gibson S.Waist-to-height ratio is a better screening tool than waist circumference and BMI for adult cardiometabolic risk factors: systematic review and meta-analysis.Obes Rev2012;13:275-86

[20] Li S,Fu Z,Liu H.Association between triglyceride-glucose related indices and all-cause and cause-specific mortality in the general population: a cohort study.Cardiovasc Diabetol2024;23:286 PMCID:PMC11304911

[21] Ren Q,Liu Q,Li G.Association between triglyceride glucose-waist height ratio index and cardiovascular disease in middle-aged and older Chinese individuals: a nationwide cohort study.Cardiovasc Diabetol2024;23:247 PMCID:PMC11241990

[22] Zhang Y,Li T,Wang Y.Association of triglyceride-glucose related indices with mortality among individuals with MASLD combined with prediabetes or diabetes.Cardiovasc Diabetol2025;24:52

[23] Dang K,Hu J.The association between triglyceride-glucose index and its combination with obesity indicators and cardiovascular disease: NHANES 2003-2018.Cardiovasc Diabetol2024;23:8 PMCID:PMC10771672

[24] Las Heras N, Lahera V. Relevance of mitochondrial dysfunction in heart disease associated with insulin resistance conditions.Pflugers Arch2022;474:21-31

[25] Laakso M.Cardiovascular disease in type 2 diabetes from population to man to mechanisms: the Kelly West Award Lecture 2008.Diabetes Care2010;33:442-9 PMCID:PMC2809299

[26] Gallo G.New insights into endothelial dysfunction in cardiometabolic diseases: potential mechanisms and clinical implications.Int J Mol Sci2024;25 PMCID:PMC10932073

[27] Li R,Ma XL.Adiponectin resistance and vascular dysfunction in the hyperlipidemic state.Acta Pharmacol Sin2010;31:1258-66 PMCID:PMC4012912

[28] Qiu J,Xu S.Triglyceride glucose-weight-adjusted waist index as a cardiovascular mortality predictor: incremental value beyond the establishment of TyG-related indices.Cardiovasc Diabetol2025;24:306 PMCID:PMC12312566

[29] Hodge AM,O'Dea K,Giles GG.Diabetes and ageing in the melbourne collaborative cohort study (MCCS).Diabetes Res Clin Pract2013;100:398-403

[30] Huang Z,Chen S,Wang P.Factors influencing accelerated aging in patients with type 2 diabetes mellitus and coronary heart disease.Front Endocrinol2024;15:1416234 PMCID:PMC11322350

[31] Zhang Y,Yao Z.The association between the triglyceride-glucose index and serum anti-aging protein α- Klotho: a population-based study.Diabetol Metab Syndr2024;16:259 PMCID:PMC11531173

[32] Oblak L,Higgins-Chen AT,Boks MP.A systematic review of biological, social and environmental factors associated with epigenetic clock acceleration.Ageing Res Rev2021;69:101348

[33] Zhang Y,Li Y.Inflammation macrophages contribute to cardiac homeostasis.Cardiology Plus2023;8:6-17

[34] Lin J.Stress and telomere shortening: insights from cellular mechanisms.Ageing Res Rev2022;73:101507 PMCID:PMC8920518

[35] Park MH,Lee EK.Age-related inflammation and insulin resistance: a review of their intricate interdependency.Arch Pharmacal Res2014;37:1507-14 PMCID:PMC4246128

[36] Zhao Z.Association between triglyceride-glucose index and phenotypic age acceleration: a cross-sectional study based on NHANES database.Front Physiol2025;16:1548690 PMCID:PMC12078276

[37] Yan Z,Cai Y,Liu Z.Biological aging traits mediate the association between cardiovascular health levels and all-cause and cardiovascular mortality among adults in the U.S. without cardiovascular disease.Biogerontology2025;26:40

[38] Goh J,Soh J,Kennedy BK.Targeting the molecular & cellular pillars of human aging with exercise.FEBS J2023;290:649-68

[39] Magliano DJ,Harding JL,Zimmet PZ.Young-onset type 2 diabetes mellitus - implications for morbidity and mortality.Nat Rev Endocrinol2020;16:321-31

[40] Wang C,Zheng M.Association of age of onset of hypertension with cardiovascular diseases and mortality.J Am Coll Cardiol2020;75:2921-30

[41] Vivante A.Exploring the genetic basis of early-onset chronic kidney disease.Nat Rev Nephrol2016;12:133-46 PMCID:PMC5202482

[42] Tromp J,Lau ES.Age dependent associations of risk factors with heart failure: pooled population based cohort study.BMJ2021;372:n461

[43] Janssen JAMJL.Hyperinsulinemia and its pivotal role in aging, obesity, type 2 diabetes, cardiovascular disease and cancer.Int J Mol Sci2021;22:7797 PMCID:PMC8345990