Background: The triglyceride-glucose (TyG) index is a reliable surrogate marker of insulin resistance and is associated with major adverse cardiovascular events (MACEs) in patients with type 2 diabetes mellitus (T2DM). However, the long-term effect of the TyG index on the incidence of MACEs remains unclear. We aimed to investigate the association between the cumulative TyG index and the risk of MACEs in patients with T2DM. Methods: This post-hoc analysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial assessed patients’ (T2DM > 3 months) cumulative TyG index and MACE data from the study database. Five fasting blood glucose and triglyceride measurements, at baseline and the first four visits, were taken from 5695 participants who had not experienced MACEs. Cumulative exposure to the TyG index was calculated as the weighted sum of the mean TyG index value for each time interval (value × time). Multivariable-adjusted Cox proportional hazard models and restricted cubic spline analysis were used to determine the association between the cumulative TyG index and MACEs. The incremental predictive value of the cumulative TyG index was further assessed. Results: Over a median follow-up of 5.09 years, 673 (11.82%) MACEs occurred, including 256 (4.50%) cardiovascular disease (CVD) deaths, 288 (5.06%) non-fatal myocardial infarctions (MIs), and 197 (3.46%) strokes. The risk of developing MACEs increased with the cumulative TyG index quartile. After adjusting for multiple potential confounders, the hazard ratios for the very high cumulative TyG index group versus the low group were 1.59 (95% confidence interval [CI], 1.17–2.16), 1.97 (95% CI 1.19–3.26), and 1.66 (95% CI 1.02–2.70) for overall MACEs, CVD death, and non-fatal MI, respectively. Restricted cubic spline analysis also showed a cumulative increase in the risk of MACEs with an increase in the magnitude of the cumulative TyG index. The addition of the cumulative TyG index to a conventional risk model for MACEs improved the C-statistics, net reclassification improvement value, and integrated discrimination improvement value. Conclusions: In patients with T2DM, the cumulative TyG index independently predicts the incidence of MACEs, and monitoring the long-term TyG index may assist with optimized-for-risk stratification and outcome prediction for MACEs. Trial registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000620.

Recent studies have demonstrated that dapagliflozin, a sodium-glucose cotransporter type 2 (SGLT2) inhibitor, prevents endothelial dysfunction; however, direct effects of dapagliflozin on the endothelium under oxidative stress and the underlying mechanism of action are not completely understood. This study aimed to define the role and related mechanisms of dapagliflozin in hydrogen peroxide (H₂O₂)-induced endothelial dysfunction. The endothelium-dependent vasorelaxation effect of dapagliflozin was assessed in an organ bath study. Endothelial dysfunction was assessed using protein expression level and phosphorylation of endothelial nitric oxide synthase (eNOS), nitric oxide (NO), reactive oxygen species (ROS), senescence-associated beta-galactosidase (SA-β-gal) activity, and senescence marker proteins (p21, p53). Co-immunoprecipitation and protein acetylation were performed to detect protein interactions. Dapagliflozin exerted a direct vasorelaxant effect in the aortic rings of C57BL/6 J mice. Furthermore, there was a significant improvement in endothelium-dependent vasorelaxation in dapagliflozin-treated diabetic mice compared to vehicle controls. Moreover, intracellular ROS levels and ONOO- levels, increased by H₂O₂, were reduced by dapagliflozin. Importantly, dapagliflozin inhibited H₂O₂-induced senescence in the human umbilical vein endothelial cells (HUVECs), as indicated by reduced SA-β-gal, p21, and p53. Mechanistically, dapagliflozin reversed the H₂O₂-mediated inhibition of eNOS serine phosphorylation and sirtuin 1 (SIRT1) expression in endothelial cells. In particular, SIRT1-mediated eNOS deacetylation is reportedly involved in dapagliflozin-enhanced eNOS activity. These findings indicate that dapagliflozin ameliorates endothelial dysfunction by restoring eNOS activity, restoring NO bioavailability, and reducing ROS generation via SIRT1 activation in oxidative stress-stimulated endothelial cells.

Background and Aims: This study aimed to evaluate the association of the triglyceride-glucose (TyG) index with the cardiovascular incidence in patients with type 2 diabetes mellitus (T2DM).Methods and Results: Secondary analysis in patients with long-lasting T2DM from the Action to Control Cardiovascular Risk in Diabetes study was performed. The primary outcome was the first occurrence of major adverse cardiovascular events (MACEs). The association between the baseline and trajectories of the TyG index and MACEs was evaluated by Cox proportional hazards regression analysis. During a median follow-up period of 8.8 years, 1,815 (17.8%) patients developed MACEs. After traditional cardiovascular risk factor adjustments, each 1-standard deviation increase in the TyG index was associated with a 19.00% higher MACE risk, similar to that in the TyG index quartile characterization. Four distinct trajectories of TyG indexes were identified: low (16.17%), moderate (40.01%), high (34.60%), and very high (9.30%). In multivariate analysis, high and very high TyG index trajectories showed a greater risk of future MACE incidence than the low TyG index trajectory. A similar association was observed between the TyG index and the occurrence of coronary heart disease.Conclusions: The baseline and trajectories of the TyG index were significantly associated with the occurrence of MACEs in patients with T2DM.Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT00000620.

To determine whether cumulative blood pressure (BP) could predict stroke in individuals with type 2 diabetes (T2D). BP levels at baseline and the initial three visits were obtained from individuals participating in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial who had not experienced a stroke. Cumulative elevations in BP were assessed by adding the weighted mean BP values at various time intervals. The association of cumulative BP with stroke was evaluated by a multivariate-adjusted Cox proportional hazard model analysis. Overall, 8282 participants were included (62.10% males and 37.90% females; mean age, 62.73 years). With a median follow-up period of 6.36 years, 324 (3.91%) and 305 (3.68%) patients had any and nonfatal stroke events, respectively. Only baseline systolic BP (SBP) independently predicted any stroke after adjustment for potential confounders, whereas cumulative SBP and pulse pressure independently predicted elevated stroke events. A strong dose-response relationship between cumulative BP and stroke was identified, and conventional risk factors combined with cumulative SBP improved prediction efficiency. Cumulative SBP independently predicts stroke in individuals with T2D and provides an incremental predictive value for stroke compared with baseline BP assessments. URL: http://www. gov. Unique identifier: NCT00000620).

Macrophages are pivotal players in innate immunity, orchestrating host defense, tissue repair, and tissue homeostasis. Accumulating studies suggest that macrophages themselves can undergo cellular senescence in response to aging, metabolic stress, and chronic inflammation, leading to a state of “immunosenescence.” Senescent macrophages exhibit a distinct phenotype characterized by pro-inflammatory secretory activity (SASP), impaired phagocytosis, metabolic dysfunction, and altered polarization. These features exert context-dependent dual effects on tissue integrity: while facilitating tissue remodeling and the resolution of acute injury, they also fuel inflammaging, tissue degeneration, and the progression of age-related pathologies such as atherosclerosis, metabolic disorders, neurodegenerative diseases, and cancer. This review synthesizes current advances on the molecular mechanisms driving macrophage senescence, including persistent DNA damage, mitochondrial dysfunction, epigenetic remodeling, and cGAS-STING signaling activation. We further discuss the beneficial versus detrimental roles of senescent macrophages across organ systems and disease contexts. Finally, we explore the translational potential of macrophage-targeted interventions—including senolytics, SASP modulation, and metabolic rejuvenation—and highlight current challenges and future perspectives in harnessing macrophage senescence to combat aging and age-related diseases.