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Comprehensive evaluation of the prevalent insulin resistance indices for pan-cancer incidence and mortality
Shuhang Luo1, Shengjie Lin2, Li Ma3
1Department of Urology, Beijing Hospital, National Center of Gerontology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China.
Background:
Insulin resistance (IR) is increasingly recognized as a significant factor for cancer development and progression. While the triglyceride-glucose (TyG) index and its derivatives (TyG-BMI (body mass index), TyG-WC (waist circumference), and TyG-WHtR (waist-to-height ratio)) have been developed as reliable and straightforward surrogate tools for reflecting IR status, their comparative associations with pan-cancer incidence and mortality remain unclear. This study aimed to systematically evaluate the associations of these four IR-related indices with pan-cancer incidence and cancer-specific mortality in a large prospective cohort.
Methods:
This prospective cohort study analyzed data from 333,297 participants in the UK Biobank. The four IR-related indices mentioned above were calculated from baseline measurements. The primary outcomes were pan-cancer incidence and pan-cancer-specific mortality. Cox regression models, adjusted for demographic, socioeconomic, lifestyle, and clinical factors, were used to estimate hazard ratios (HRs) across participants' quartiles for each index. Besides, we assessed Dose-response relationships via restricted cubic splines (RCSs), and robustness via sensitivity and subgroup analyses.
Results:
Over a median follow-up of 15.2 years, 49,695 cases of different types of cancer and 12,852 cancer-specific deaths were recorded. All four IR-related indices showed significant non-linear associations with both outcomes (p < 0.001). After full adjustment, TyG-WC demonstrated the strongest and most graded association with pan-cancer incidence, with HRs progressively increasing from Q2 to Q4 (all p < 0.05 vs. Q1), and HR of Q4 was 1.11 (95% CI (confidence interval): 1.08, 1.15, p = 0.001). For pan-cancer-specific mortality, TyG-WC (HR = 1.37, 95% CI 1.28, 1.46; p < 0.001), TyG-WHtR (HR = 1.25, 95% CI 1.18, 1.33; p < 0.001), and TyG-BMI (HR = 1.22, 95% CI 1.15,1.29; p < 0.001) were significantly elevated in Q4, with TyG-WC again showing a significant dose-response trend across all quartiles. In contrast, the original TyG index showed the weakest predictive performance. Subgroup analyses indicated effect modifications by sex, smoking status, and comorbidities. Sensitivity analyses confirmed the robustness of the associations, particularly for TyG-WC.
Conclusion:
IR-related indices, especially TyG-WC, are significantly associated with both pan-cancer incidence and cancer-specific mortality. Compared with TyG, TyG-BMI, and TyG-WHtR, TyG-WC demonstrated stronger associations, suggesting its potential utility for stratifying cancer risk and prognosis in clinical and public health settings.
