Insulin resistance surrogates predict major adverse cardiovascular events in patients with heart failure with preserved ejection fraction and chronic kidney disease: a retrospective cohort study

Wang et al. Lipids in Health and Disease (2025) 24:349 https://doi.org/10.1186/s12944-025-02764-7 Lipids in Health and Disease Open Access RESEARCH Insulin resistance surrogates predict major adverse cardiovascular events in patients with heart failure with preserved ejection fraction and chronic kidney disease: a retrospective cohort study Feng Wang1,2†, Wendi Huang2†, Zhuoquan Wang2, Di Zhang3, Hongyang Qiao1, Nianshao Chen2*, Xiaoqiu Ni1*, Jinguo Cheng1* and Weicheng Ni1* Abstract Background Heart failure with preserved ejection fraction (HFpEF) and chronic kidney disease (CKD) frequently coexist and portend a poor prognosis. Insulin resistance (IR) is implicated in cardiorenal pathophysiology, but practical surrogate IR indices for predicting risk in this high-risk and understudied population are lacking. This study evaluated and compared the prognostic value of four IR indices for major adverse cardiovascular events (MACE) in patients with HFpEF and CKD, and assessed their incremental value over the established Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) risk score. Methods This retrospective analysis included 2412 patients admitted with HFpEF and CKD from 2012 to 2023. Baseline metabolic parameters computed four IR indices: triglyceride-glucose (TyG) index, TyG-body mass index (TyGBMI), atherogenic index of plasma (AIP), and Metabolic Score for Insulin Resistance (METS-IR). The composite primary endpoint was MACE, defined as all-cause mortality or first heart failure hospitalization. Associations were evaluated using Kaplan-Meier analysis, multivariable Cox proportional hazards regression, and restricted cubic splines. Predictive capability was assessed using the area under the receiver operating characteristic curve (AUC), continuous net reclassification improvement (cNRI), and integrated discrimination improvement (IDI). † Feng Wang and Wendi Huang contributed equally to this work. *Correspondence: Nianshao Chen Xiaoqiu Ni Jinguo Cheng Weicheng Ni Full list of author information is available at the end of the article © The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creati vecommons.org/licenses/by-nc-nd/4.0/. Wang et al. Lipids in Health and Disease (2025) 24:349 Page 2 of 13 Results Over a median follow-up of 1.58 years, 1122 (46.52%) MACE events occurred. Unadjusted analyses showed that all four IR indices were significantly associated with MACE risk. The TyG index demonstrated the strongest association (Q4 vs. Q1: adjusted hazard ratio [HR] = 2.60, 95% confidence interval [CI] 2.05–3.29, P < 0.001) and the best discrimination (AUC = 0.676). After adjustment, AIP (adjusted HR = 2.07) and METS-IR (adjusted HR = 1.42) remained significant predictors, whereas TyG-BMI did not (P = 0.09). TyG significantly outperformed the other indices in AUC, cNRI, and IDI (all P < 0.001). All IR indices added significant incremental prognostic value to the MAGGIC score (AUC 0.560), with TyG providing the largest improvement (AUC = 0.679, IDI = 0.052, cNRI = 0.189; all P < 0.001). These associations were consistent across prespecified subgroups. Conclusion In patients with coexisting HFpEF and CKD, surrogate IR indices independently predicted MACE risk. The TyG index exhibited the strongest association and best predictive performance, offering significant incremental utility beyond the MAGGIC score. Integrating the TyG index into clinical practice could enhance risk stratification and management, directly improving patient outcomes by identifying those at highest risk for MACE. Keywords Chronic kidney disease, Triglyceride-glucose index, MAGGIC score, Heart failure with preserved ejection fraction Introduction Heart failure with preserved ejection fraction (HFpEF) frequently coexists with chronic kidney disease (CKD), affecting approximately half of patients with CKD stages 3–5 [1]. Studies report an extremely high 5-year major adverse cardiovascular events (MACE) rate among patients with HFpEF and CKD, with all-cause mortality exceeding 50% and heart failure (HF) re-hospitalization rates exceeding 20% [2, 3]. Compared to patients with either condition alone, these individuals experience substantially higher MACE rates, including 1-year mortality exceeding 30% and HF re-hospitalization rates approaching 50% [2, 3]. Renal dysfunction exacerbates myocardial fibrosis and endothelial inflammation; concurrently, cardiac impairment accelerates renal hemodynamic stress. This interaction creates a vicious cycle that drives MACE [4, 5]. However, pivotal HFpEF trials have systematically excluded patients with severe CKD, leading to inadequate representation of this vulnerable subpopulation in evidence-based guidelines [6, 7]. Consequently, early identification of modifiable risk factors in patients with HFpEF and CKD is of heightened clinical significance. Conventional risk stratification methods have proven insufficient for addressing the unique pathophysiology of cardiovascular-kidney-metabolic (CKM) syndrome [4]. This complex clinical entity—defined by the triad of metabolic dysregulation, renal impairment, and cardiovascular (CV) pathology—drives progressive multisystem damage [4]. Emerging evidence identifies insulin resistance (IR) as a pivotal mediator of cardiorenal crosstalk in HFpEF [4, 5]. Beyond impairing myocardial energetics and promoting diastolic dysfunction [8–10], IR induces glomerular hyperfiltration, podocyte injury, and renal fibrosis via hyperinsulinemia-driven oxidative stress and chronic inflammation [11, 12]. The efficacy of sodiumglucose cotransporter 2 inhibitors (SGLT2i) in HFpEF underscores the therapeutic relevance of metabolic pathways. In addition to natriuresis, these agents improve insulin sensitivity and reduce ectopic fat deposition— mechanisms potentially underlying their cardiorenal benefits [5, 13]. These advances position IR not only as a therapeutic target but also as a predictor of residual risk in patients with HFpEF and CKD. Although the hyperinsulinemic-euglycemic clamp remai (...truncated)