Estimated glucose disposal rate outperforms thirteen other insulin resistance indices in predicting new-onset cardiometabolic multimorbidity: a longitudinal study from the china health and retirement longitudinal study (CHARLS) and cross-sectional replication from the national health and nutrition examination survey (NHANES).
多种心脏代谢疾病的共同发生在机制上与胰岛素信号传导受损有关，但替代胰岛素抵抗（IR）标志物在区分心脏代谢多发病率（CMM）风险方面的相对效用尚未得到系统证实。本研究旨在系统地评估和比较中国纵向队列中14个IR指标与CMM发病率的关联，并在美国具有全国代表性的样本中进行外部复制。这项研究包括来自中国健康与退休纵向研究（CHARLS）的8522名参与者，基线时（2011年）没有CMM。CMM被定义为同时存在以下三种心脏代谢疾病中的至少两种：2型糖尿病、心脏病和中风。所有14个IR指数均在基线时进行了评估，并作为2011年和2015年重复测量得出的累积时间加权平均值进行了评估。使用多变量逻辑回归检验了IR指数与CMM风险之间的关联，并通过限制三次样条（RCS）建模表征了剂量反应关系。通过受试者操作特征（ROC）曲线分析量化辨别能力，辅以净重新分类改善（NRI）和综合辨别改善（IDI）指标。为了验证主要发现的稳健性，进行了Cox比例风险回归和预定义的亚组分析作为补充敏感性分析。在国家健康和营养检查调查（NHANES；1999-2018）中进行了外部横断面复制。在2020年的随访期间，591名CHARLS参与者（6.9%）开发了事件CMM。经过全面的协变量调整后，14个替代IR指数中的每一个都与CMM风险事件表现出统计学上的显著和独立关联。eGDR和SPISE显示出显著的负相关，表明较高的值反映了更高的胰岛素敏感性和更低的CMM风险（每SD的累积eGDR：OR 0.51，95%CI 0.41-0.65；每SD的累计SPISE：OR 0.64，95%CI 0.54-0.75），而其余12个指标显示出显著正相关。RCS分析显示，除TyHGB和TyG AIP表现出显著的非线性外，大多数指标的剂量反应关系主要是线性的。eGDR在基线（AUC:0.716）和累积（AUC:0.727）评估中均表现出最高的鉴别性能，显著优于TyG（所有P < 0.001),在所有14个指标中，NRI和IDI的改善最大。这些发现在NHANES横断面验证中得到了一致的验证：eGDR和SPISE再次显示出最强的负相关（eGDR每SD：OR 0.598，95%CI 0.499-0.717；SPISE每SD：OR0.704，95%CI 0.614-0.807），eGDR在所有指标中实现了最高的AUC（0.756）和最大的NRI和IDI改善。在中国和美国的研究人群中，所有14个评估的IR指标均与CMM存在统计学上显著和独立的相关性。其中，eGDR在纵向和横断面设置、单一时间点和累积评估以及不同种族的人群中始终表现出最优越的鉴别性能和风险重新分类能力，支持将其作为CMM风险分层的首选、临床可及的标志物。两个具有不同种族背景的具有全国代表性的大型人群的趋同发现进一步强调了eGDR的跨人群普遍性及其在不同临床环境中的潜在转化效用。
The co-occurrence of multiple cardiometabolic conditions has been mechanistically linked to impaired insulin signaling, yet the relative utility of surrogate insulin resistance (IR) markers in stratifying cardiometabolic multimorbidity (CMM) risk has not been systematically established. This study aimed to systematically evaluate and compare the associations of 14 IR indices with CMM incidence in a longitudinal Chinese cohort, with external replication in a U.S. nationally representative sample. This study included 8,522 participants from the China Health and Retirement Longitudinal Study (CHARLS) without CMM at baseline (2011). CMM was defined as the concurrent presence of at least two of the following three cardiometabolic conditions: type 2 diabetes, heart disease, and stroke. All 14 IR indices were evaluated both at baseline and as cumulative time-weighted averages derived from repeated measurements in 2011 and 2015. Associations between IR indices and CMM risk were examined using multivariable logistic regression, with dose-response relationships characterized through restricted cubic spline (RCS) modeling. Discriminatory capacity was quantified via receiver operating characteristic (ROC) curve analysis, complemented by net reclassification improvement (NRI) and integrated discrimination improvement (IDI) metrics. To verify the robustness of primary findings, Cox proportional hazards regression and pre-defined subgroup analyses were performed as supplementary sensitivity analyses. External cross-sectional replication was performed in the National Health and Nutrition Examination Survey (NHANES; 1999-2018). During follow-up through 2020, 591 CHARLS participants (6.9%) developed incident CMM. After comprehensive covariate adjustment, each of the 14 surrogate IR indices demonstrated statistically significant and independent associations with incident CMM risk. eGDR and SPISE demonstrated significant inverse associations, indicating that higher values reflect greater insulin sensitivity and lower CMM risk (cumulative eGDR per SD: OR 0.51, 95% CI 0.41-0.65; cumulative SPISE per SD: OR 0.64, 95% CI 0.54-0.75), whereas the remaining 12 indices showed significant positive associations. RCS analyses revealed predominantly linear dose-response relationships across most indices, except for TyHGB and TyG-AIP, which exhibited significant non-linearity. eGDR achieved the highest discriminatory performance at both baseline (AUC: 0.716) and cumulative (AUC: 0.727) assessments, significantly outperforming TyG (all P < 0.001), and yielded the greatest NRI and IDI improvements among all 14 indices. These findings were consistently replicated in the NHANES cross-sectional validation: eGDR and SPISE again demonstrated the strongest inverse associations (eGDR per SD: OR 0.598, 95% CI 0.499-0.717; SPISE per SD: OR 0.704, 95% CI 0.614-0.807), and eGDR achieved the highest AUC (0.756) and the greatest NRI and IDI improvements among all indices. Across both the Chinese and U.S. study populations, statistically significant and independent associations with CMM were consistently observed for all 14 evaluated IR indices. Among these, eGDR consistently demonstrated the most superior discriminatory performance and risk reclassification capability across longitudinal and cross-sectional settings, single time-point and cumulative assessments, and ethnically distinct populations, supporting its adoption as a preferred, clinically accessible marker for CMM risk stratification. The convergent findings across two large, nationally representative populations of distinct ethnic backgrounds further underscore the cross-population generalizability of eGDR and its potential translational utility in diverse clinical settings.
Enfa Zhao, Hang Xie, Ruimeng Wang, Bingtian Dong, Chaoxue Zhang. Estimated glucose disposal rate outperforms thirteen other insulin resistance indices in predicting new-onset cardiometabolic multimorbidity: a longitudinal study from the china health and retirement longitudinal study (CHARLS) and cross-sectional replication from the national health and nutrition examination survey (NHANES).. Cardiovascular diabetology. 2026; doi:10.1186/s12933-026-03218-9.
Enfa Zhao, Hang Xie, Ruimeng Wang, Bingtian Dong, Chaoxue Zhang (2026). Estimated glucose disposal rate outperforms thirteen other insulin resistance indices in predicting new-onset cardiometabolic multimorbidity: a longitudinal study from the china health and retirement longitudinal study (CHARLS) and cross-sectional replication from the national health and nutrition examination survey (NHANES).. Cardiovascular diabetology. https://doi.org/10.1186/s12933-026-03218-9
Enfa Zhao, Hang Xie, Ruimeng Wang, Bingtian Dong, Chaoxue Zhang. Estimated glucose disposal rate outperforms thirteen other insulin resistance indices in predicting new-onset cardiometabolic multimorbidity: a longitudinal study from the china health and retirement longitudinal study (CHARLS) and cross-sectional replication from the national health and nutrition examination survey (NHANES).[J]. Cardiovascular diabetology, 2026 doi:10.1186/s12933-026-03218-9.
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