Impact of achieving glycated hemoglobin targets on cardiovascular events/mortality: Post-hoc analysis of the nephropathy in diabetes type 2 trial

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.