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©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
Impact of achieving glycated hemoglobin targets on cardiovascular events/mortality: Post-hoc analysis of the nephropathy in diabetes type 2 trial
Alfredo Caturano, Vittorio Simeon, Raffaele Galiero, Vincenzo Russo, Luca De Nicola, Paolo Chiodini, Luca Rinaldi, Erica Vetrano, Teresa Salvatore, Caterina Conte, Carlo Acierno, Celestino Sardu, Raffaele Marfella, Roberto Minutolo, Ferdinando C Sasso
Alfredo Caturano, Caterina Conte, Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma University, Rome 00166, Italy
Vittorio Simeon, Paolo Chiodini, Department of Physical and Mental Health and Preventive Medicine, University of Campania “Luigi Vanvitelli”, Naples 80138, Campania, Italy
Raffaele Galiero, Luca De Nicola, Erica Vetrano, Celestino Sardu, Raffaele Marfella, Roberto Minutolo, Ferdinando C Sasso, Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, Naples 80138, Campania, Italy
Vincenzo Russo, Department of Medical Translational Sciences, University of Campania “Luigi Vanvitelli”, Monaldi Hospital, Napoli 80100, Campania, Italy
Luca Rinaldi, Department of Medicine and Health Sciences “Vincenzo Tiberio”, Università degli Studi del Molise, Campobasso 86100, Molise, Italy
Teresa Salvatore, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Naples 80138, Campania, Italy
Carlo Acierno, Infection Disease Unit, Azienda Ospedaliera Regionale San Carlo, Potenza 85100, Basilicata, Italy
Co-corresponding authors: Caterina Conte and Ferdinando C Sasso.
Author contributions: Caturano A and Sasso FC were responsible for the study conception, design and methodology; Nephropathy in diabetes type 2 study group investigators were responsible for data collection; Caturano A and Simeon V performed the formal analysis; Caturano A and Conte C prepared the original draft; Sasso FC was the project administrator; Caturano A, Galiero R, Simeon V, Russo V, De Nicola L, Rinaldi L, Vetrano E, Sardu C, Salvatore T, Conte C, Minutolo R, Acierno C, Marfella R, Chiodini P, Sasso FC critically revised the article for important intellectual content; all authors reviewed and approved the final version to be published.
Supported by the Ministero dell’ Università e della Ricerca (Italian Ministry of University and Research), No. 2007PSYLRX.
Institutional review board statement: The research protocol received ethical approval from the ethics committee of the University of Campania “Luigi Vanvitelli” (previously known as Seconda Università degli Studi di Napoli), No. 20200009378.
Clinical trial registration statement: The research protocol received ethical approval from the ethics committee of the University of Campania “Luigi Vanvitelli” (clinicaltrials.gov No. NCT00535925).
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
CONSORT 2010 statement: The authors have read the CONSORT 2010 Statement, and the manuscript was prepared and revised according to the CONSORT 2010 Statement.
Data sharing statement: Sasso FC is the guarantor of this work and, as such, has full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The datasets generated during and/or analyzed in the current study and annotated R scripts used for statistical analyses are available from the corresponding author upon reasonable request at
ferdinandocarlo.sasso@unicampania.it.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Caterina Conte, MD, PhD, Professor, Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma University, Via di val Cannuta, 247, Rome 00166, Italy.
caterina.conte@uniroma5.it
Received: July 9, 2025
Revised: August 11, 2025
Accepted: October 13, 2025
Published online: November 15, 2025
Processing time: 128 Days and 18.4 Hours
BACKGROUND
Achieving optimal glycemic control is a cornerstone of cardiovascular risk reduction in type 2 diabetes (T2D). However, the extent to which multifactorial interventions influence this relationship remains uncertain.
AIM
To evaluate the association between glycated hemoglobin (HbA1c) target achievement and long-term cardiovascular outcomes in patients receiving standard of care (SoC) or multifactorial intensive therapy (MT).
METHODS
This post-hoc analysis of the nephropathy in diabetes type 2 cluster-randomized trial included 323 patients with T2D, albuminuria, and retinopathy (SoC: n = 139; MT: n = 184), who underwent a 4-year intervention phase. Outcomes were major adverse cardiovascular events (MACE) and all-cause mortality. Associations with HbA1c target achievement (≤ 7% vs > 7%) were assessed using Kaplan-Meier curves and shared frailty Cox regression models.
RESULTS
During a median follow-up of 12.1 years, 190 MACEs and 139 deaths occurred. Achievement of the HbA1c target was not associated with reduced mortality in either group. However, a significant reduction in MACEs was observed only among SoC patients achieving HbA1c ≤ 7% (P = 0.031), whereas no benefit was seen in the MT group (P = 0.645). In multivariable Cox regression models adjusted for cluster effect, in the MT group age [hazard ratio (HR) = 1.07, P < 0.001] and female sex (HR = 0.38, P < 0.001) were independent predictors of MACE, while in the SoC group only age (HR = 1.04, P = 0.009). For all-cause mortality, age (HR = 1.11, P < 0.001) and blood pressure control (HR = 0.55, P = 0.041) were significant predictors in the MT group, whereas age (HR = 1.06, P = 0.002) was independently associated with increased mortality in the SoC group.
CONCLUSION
In high-risk patients with T2D receiving standard care, achieving an HbA1c ≤ 7% was associated with fewer cardiovascular events only under standard care, but not with reduced mortality. This association was not observed in patients managed with a multifactorial strategy. These findings suggest that the prognostic value of glycemic control depends on the broader treatment context and highlight the central role of comprehensive risk factor management in microvascular-complicated T2D.
Core Tip: In high-risk patients with type 2 diabetes, achieving a glycated hemoglobin ≤ 7% was associated with fewer cardiovascular events only under standard care conditions, suggesting that the cardiovascular benefit of glycemic control may depend on treatment intensity. In contrast, younger age, female sex, and blood pressure control were more consistent predictors of improved outcomes. Low-density lipoprotein cholesterol control showed a borderline association with reduced mortality in the standard of care group only.
