Letter to the Editor: Cardiovascular outcomes in high-risk type 2 diabetes mellitus: Standard of care vs multifactorial intensive therapy

Abstract

The study by Caturano et al published in the recent issue of the World Journal of Diabetes focused on high-risk type 2 diabetes patients, particularly those with albuminuria and retinopathy. The key finding was that maintaining glycated hemoglobin A1c (HbA1c) levels at or below 7% was significantly associated with a reduced incidence of major adverse cardiovascular events (MACE) only in the standard care group, while this association was not evident in the intensive multifactorial treatment group. Additionally, there was a U-shaped relationship between continuous HbA1c levels and both MACE and all-cause mortality. However, the study had limitations, including the exclusion of sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists and a focus on specific high-risk subgroups. These findings align with current guidelines and support a personalized management strategy for type 2 diabetes, emphasizing that comprehensive multifactorial intervention is more beneficial for improving long-term patient outcomes than solely targeting HbA1c levels.

Key Words: Type 2 diabetes mellitus; Glycated hemoglobin A1c; Standard of care; Multifactorial intensive therapy; Major adverse cardiovascular events; Mortality

Core Tip: The study by Caturano et al focused on high-risk type 2 diabetes patients and found that a hemoglobin A1c (HbA1c) level ≤ 7% was associated with a reduced incidence of major adverse cardiovascular events only in the standard care group, with no such association observed in the intensive multifactorial treatment group. Additionally, there was a U-shaped relationship between continuous HbA1c levels and adverse outcomes. The study has limitations, but the results support individualized management and emphasize that comprehensive intervention is superior to solely controlling HbA1c.

TO THE EDITOR

This is a letter to the editor on the manuscript by Caturano et al[1]. We have examined with considerable interest the manuscript entitled “Impact of achieving glycated hemoglobin targets on cardiovascular events/mortality: Post-hoc analysis of the nephropathy in diabetes type 2 trial”, recently published in the World Journal of Diabetes. As clinicians and researchers dedicated to the management of cardiovascular risk in diabetes, we commend the authors for their investigation into a persistent clinical question: Whether attaining glycated hemoglobin A1c (HbA1c) targets (≤ 7% vs > 7%) yields additional cardiovascular or survival advantages in high-risk individuals with type 2 diabetes mellitus (T2DM), particularly those presenting with albuminuria and retinopathy, and how these outcomes differ according to treatment intensity, namely standard of care (SoC) compared to multifactorial intensive therapy (MT). Given the current global prevalence of T2DM of 11.1% among adults (approximately one in nine) and the fact that cardiovascular disease (CVD) accounts for 68% of diabetes-related mortality worldwide[2], this research provides critical insights that enhance the precision of clinical decision-making. Such findings are congruent with the principles outlined in the 2025 International Diabetes Federation (IDF) Global Clinical Practice Guidelines for T2DM, which advocate for individualized management of risk factors[3].

Core content and extension

The principal findings of this study are both innovative and clinically significant, particularly within the framework of contemporary T2DM management strategies. Notably, the association between achieving an HbA1c level of ≤ 7% and a reduced incidence of major adverse cardiovascular events (MACE) was observed exclusively in the SoC cohort (P = 0.031), whereas no such association was evident in the MT group (P = 0.645). The optimized management of hypertension, dyslipidemia, and lifestyle factors in the MT group likely mitigated the additional benefit of strict HbA1c control. This observation addresses a critical gap in the existing literature. While seminal trials such as Action to Control Cardiovascular Risk in Diabetes (ACCORD), Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE), and United Kingdom Prospective Diabetes Study have produced inconsistent findings regarding the cardiovascular benefits of glycemic control, few have differentiated outcomes based on treatment intensity[4]. The present post hoc analysis of the nephropathy in diabetes type 2 (NID-2) trial elucidates that, among patients undergoing structured, protocol-driven MT, which includes standardized lifestyle modifications, renin-angiotensin system inhibition, and statin/aspirin therapy, comprehensive management of cardiovascular risk factors, rather than isolated achievement of HbA1c targets, underpins cardiovascular protection. This interpretation is corroborated by the MT group’s superior baseline control of risk factors (e.g., 69.9% blood pressure control vs 45.1% in SoC; 50.5% low-density lipoprotein-cholesterol control vs 18.7% in SoC) and a correspondingly lower incidence of MACE (50.5% vs 69.8% in SoC). Collectively, these findings reinforce the concept that multidimensional risk factor reduction constitutes the fundamental approach for managing microvascular complications in T2DM[3].

Significantly, this finding corroborates recent empirical data from a 2024 evaluation of the NHS Type 2 Diabetes Path to Remission (T2DR) program, which encompassed 7540 individuals with T2DM. This study demonstrated that although lifestyle modifications enhanced glycemic control, the most substantial cardiovascular benefits were observed in patients who concurrently achieved control of blood pressure and lipid levels[5]. The NID-2 analysis further refines this understanding by revealing that when multiple risk factors are managed intensively, as exemplified by the MT group, the additional advantage conferred by maintaining HbA1c at or below 7% becomes less pronounced. The emphasis of the NHS T2DR program on intensive lifestyle interventions aligns with the MT group’s comprehensive approach, suggesting that dietary and weight management strategies may further reduce MACE. This insight carries significant implications for healthcare providers with limited resources, where SoC remains predominant. In such settings, prioritizing HbA1c management may still lead to meaningful reductions in MACE, whereas in contexts where MT is feasible, clinical focus should shift toward comprehensive risk factor optimization. This distinction is explicitly acknowledged in the 2025 IDF Guidelines within the “Basic Care vs Optimal Care” framework[3].

Furthermore, the observed U-shaped relationship between continuous HbA1c levels and both MACE and all-cause mortality offers a critical safety consideration consistent with current clinical guidelines. The lowest risk was identified within HbA1c ranges of 6.28%-7.65% for MACE[1] and 6.12%-7.50% for all-cause mortality[1], with increased risk evident at both lower and higher glycemic levels. This pattern cautions against excessively stringent glycemic targets in high-risk populations, a concern initially highlighted by the ACCORD trial and now substantiated in patients with preexisting albuminuria and retinopathy, and supports the 2025 IDF Guidelines’ recommendation for individualized HbA1c targets that account for patient age, comorbid conditions, and hypoglycemia risk[3]. The guidelines specifically emphasize that severe hypoglycemia (≤ 3.0 mmol/L)[3] is associated with heightened risks of cognitive decline and cardiovascular mortality, thereby reinforcing the rationale for avoiding suboptimal HbA1c thresholds identified in the analysis by Caturano et al[1]. Additionally, the U-shaped association complements emerging evidence suggesting that glycemic variability, as quantified by time in range (TIR), may serve as a more robust predictor of diabetic complications than static HbA1c measurements[6]. For instance, a 2023 investigation demonstrated an inverse relationship between TIR and diabetic cardiovascular autonomic neuropathy independent of HbA1c levels[7], indicating that future research should incorporate both metrics to comprehensively evaluate glycemic control quality.

The authors are to be commended for their methodological rigor, which enhances the validity of their findings. Notably, the application of shared frailty Cox regression models to address the cluster-randomized design of the NID-2 trial is particularly commendable, as cluster effects are frequently neglected in post hoc analyses, potentially leading to biased risk estimates[4]. The sensitivity analysis incorporating patients who experienced early MACE or death further substantiates the robustness of age as the most significant predictor of outcomes [hazard ratios (HR) ranging from 1.04 to 1.11 across groups], thereby reducing concerns related to selection bias. Moreover, the identification of non-glycemic factors, such as female sex serving as a protective factor against MACE in the medical therapy group (HR = 0.38, P < 0.001), and blood pressure control, being associated with decreased mortality in the same group (HR = 0.55, P = 0.041), is consistent with the 2025 American Diabetes Association (ADA)[8] and IDF guidelines[3], which emphasize the prioritization of cardiovascular risk factors beyond glycemic control. For instance, the 2025 ADA guidelines advocate for cardiovascular risk assessment prior to the initiation of glucose-lowering therapies, recommending agents such as sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 (GLP-1) receptor agonists for patients with atherosclerotic CVD or chronic kidney disease. The findings from the NID-2 trial reinforce this approach by demonstrating associations between blood pressure and lipid management and improved clinical outcomes[8].

Limitations and shortcomings

A notable limitation identified by the authors pertains to the absence of SGLT2i and GLP-1 receptor agonists within the study cohort, given that the NID-2 intervention concluded in 2011. This omission merits further investigation, as these pharmacological agents have significantly transformed the management of T2DM over the past decade. Contemporary clinical trials have substantiated their cardiorenal protective effects independent of glycemic control. For instance, the semaglutide and cardiovascular outcomes in subjects with overweight or obesity (SELECT) trial (2024) demonstrated that semaglutide, a GLP-1 receptor agonists, reduced the risk of MACE by 20%[9] in overweight or obese patients with CVD but without diabetes. Concurrently, the heart failure outcomes with Semaglutide (FLOW) trial (2023) is assessing the renal protective properties of semaglutide in T2DM patients with chronic kidney disease[10]. Additionally, a 2023 real-world investigation CardioCHUS-T2D reported that combined therapy with SGLT2i and GLP-1 receptor agonists significantly decreased the incidence of heart failure events (HR = 0.651, P = 0.017) and all-cause mortality (HR = 0.602, P = 0.001) among elderly, overweight individuals with T2DM[11]. Collectively, these findings imply that in the current therapeutic landscape, metabolic benefits extending beyond glycemic regulation may predominantly influence clinical outcomes. This raises an important question regarding the continued prognostic relevance of achieving HbA1c targets in patients treated with these agents, particularly those presenting with microvascular complications.

Another critical consideration involves the study’s emphasis on a high-risk subgroup characterized by T2DM accompanied by albuminuria and retinopathy, a population with considerable unmet clinical needs. The 2025 IDF Guidelines underscore that T2DM patients exhibiting microvascular complications face a two- to fourfold increased risk of CVD compared to those without such complications[3]. Nevertheless, evidence delineating optimal glycemic targets within this subgroup remains limited. This study only included extremely high-risk T2DM patients with concomitant albuminuria and severe retinopathy, which showed significant differences compared to ordinary T2DM patients, severely limiting the external validity of the conclusions. The former is a late-stage patient with dual microvascular complications, without serious complications and standardized treatment (significantly lower prevalence in conventional T2DM). Ordinary patients are mostly in the early to mid-stages, with no/single complications, complex comorbidities, non-standard treatment, and often use new hypoglycemic drugs that have not been studied. Therefore, this conclusion is only applicable to high-risk populations of the same type and cannot be directly extended to most ordinary patients. Clinical judgment needs to be based on individual patient situations. The observation by Caturano et al[1] that MT negates the benefits associated with HbA1c reduction suggests that “early intensive multifactorial intervention”, as advocated by consensus guidelines aligned with international best practices[12], may exert a more substantial impact than stringent glycemic control alone in this vulnerable cohort. This perspective is corroborated by findings from the T2DR program, which demonstrated in real-world settings that weight loss and comprehensive lifestyle modifications, rather than isolated glycemic management, are pivotal drivers of sustained remission and reduction in diabetes-related complications[13].

The statistical power of this study is limited to 80%, which may hinder the detection of all significant differences. In the post hoc analyses, numerous exploratory tests were performed, including overall and subgroup analyses of MACE and mortality, as well as analyses treating HbA1c as a continuous variable. However, no adjustment procedures were applied to control for the inflation of type I error associated with multiple comparisons. The absence of correction methods increases the likelihood of false-positive findings. Furthermore, marginal P values that did not achieve statistical significance were not interpreted in the context of potential false positives arising from multiple testing, which could lead to misinterpretation by readers. The manuscript simply divides HbA1c into two groups: ≤ 7% vs > 7%, which may reduce the ability to discover true associations. HbA1c is a continuously changing indicator, and binary is equivalent to compressing a large amount of continuous information into two points, which will lose a lot of details. For example, for every 0.5% increase in HbA1c, there may be a slight increase in risk, but this small but significant change cannot be detected even after binary analysis, making it easy to miss clinically significant associations.

Conclusion

The study conducted by Caturano et al[1] provides a valuable contribution to clinical practice by elucidating that the cardiovascular advantages associated with HbA1c control are contingent upon the clinical context. Specifically, for patients with T2DM who present with high-risk features such as albuminuria and retinopathy, a comprehensive MT approach offers greater benefits compared to focusing solely on HbA1c targets. Conversely, patients receiving SoC may still experience cardiovascular benefits from maintaining HbA1c levels at or below 7%. These findings offer direct support for the individualized management strategies emphasized in the 2025 IDF Guidelines[3], thereby assisting clinicians in optimizing the balance between therapeutic efficacy, safety considerations, and resource allocation. As the discipline increasingly adopts an integrated “cardio-renal-metabolic” framework[12], this research underscores the imperative that glycemic control should not be considered in isolation; rather, a comprehensive risk reduction strategy remains paramount for enhancing long-term outcomes in T2DM.