Comparison of admission glycemic variability and glycosylated hemoglobin in predicting major adverse cardiac events among type 2 diabetes patients with heart failure following acute ST-segment elevation myocardial infarction

Introduction

Hyperglycemia is associated with adverse outcomes in patients with acute myocardial infarction (AMI) as well as those with heart failure (HF).^[1,2] Evidence suggests that abnormal blood glucose, evaluated through glycosylated hemoglobin (HbA1c) levels, may serve as a prognostic factor not only in patients with AMI but also in those with HF.^[3,4] However, more acute disturbances in glucose metabolism may also exert a negative impact on patient outcomes. Glycemic variability (GV), also known as blood glucose fluctuation or glycemic excursions, is a parameter that reflects changes in blood glucose levels independently of FPG, postprandial blood glucose, and HbA1c. It represents another crucial indicator of glycemic control. Studies have demonstrated that HbA1c cannot directly reflect GV. The same HbA1c level may exhibit diverse daily glucose profiles. Patients with identical HbA1c levels may exhibit different GV, and there is no significant correlation between the two.^[5,6] Historically, HbA1c has been served as the primary indicator for assessing glycemic control and utilized in primary and secondary prevention of coronary heart disease. However, recent research indicates that, in comparison to HbA1c, GV may exhibit a more closely correlation with the severity of both microvascular and macrovascular atherosclerosis. GV appears to potential function as an independent risk factor for cardiovascular complications in individuals with diabetes.^[7,8,9,10,11] Nevertheless, whether admission GV and admission HbA1c levels hold prognostic significance for patients with type 2 diabetes and HF following acute ST-segment elevation myocardial infarction (ASTEMI) remains unclear. Therefore, the aim of this study is to investigate the independent prognostic value of GV assessed by a continuous glucose monitoring system (CGMS) upon admission and admission HbA1c levels in type 2 diabetes patients with HF following ASTEMI.

Methods

Results

Incidences of MACE

At the end of 1-year follow-up, 31 patients had died (6.4%) for cardiac causes, 34 patients had new-onset myocardial infarction (7.0%), and 24 patients were re-hospitalized for acute heart failure (5.0%). Among patients diagnosed with type 2 diabetes and HF following ASTEMI, a notably elevated incidence of MACE was observed in those presenting with MAGE level ≥ 3.9 mmol/L compared to their counterparts with MAGE levels < 3.9 mmol/L (25.3 vs. 13.6%; P = 0.001). There were no statistically significant differences in the rates of adverse cardiovascular events observed between patients with Hemoglobin A1c (HbA1c) levels ≥ 6.5% and those with HbA1c levels < 6.5% (21.8% vs. 15.7%, P = 0.086). Patients with higher MAGE levels demonstrated a significantly increased incidence of cardiac mortality in comparison to those with lower MAGE levels (9.6% vs. 4.2%, P = 0.017). Patients with heightened MAGE levels exhibited a significantly increased incidence of HF rehospitalization when contrasted with individuals characterized by lower MAGE levels (7.6% vs. 3.1%, P = 0.027) (Figure 1). No statistically significant differences were observed in the rates of cardiac mortality, new-onset myocardial infarction, and HF rehospitalization among patients with varying levels of admission HbA1c (Figure 2). Kaplan-Meier survival curves for patient groups by MAGE are shown in Figure 3; those for HbA1c are in Figure 4.

Figure 1

Incidence of major adverse cardiac event (MACE) after 1-year follow-up in relation to MAGE levels. Patients with a higher MAGE level had significantly higher cardiac mortality, the rate of HF rehospitalization and incidence of all MACE.

Figure 2

Incidence of major adverse cardiac event (MACE) after 1-year follow-up in relation to HbA1c levels. There are no significant differences of adverse cardiovascular events rates between different HbA1c level groups (all P > 0.05).

Figure 3

Kaplan-Meier event-free survival curves for freedom from major adverse cardiac event (MACE) in two patient groups by MAGE levels. The event-free survival rate was significantly lower in the high MAGE level group (log-rank test, P < 0.001).

Figure 4

Kaplan-Meier event-free survival curves for freedom from major adverse cardiac event (MACE) in two patient groups by HbA1c levels. There is not significant lower event-free survival rate in high HbA1c level patients (log-rank test, P = 0.061).

Discussion

Elevated blood glucose levels upon admission are frequently observed in patients presenting with AMI, serving as a robust predictor of survival and an elevated risk of MACE in individuals, irrespective of their T2DM status.^[13,14] Additionally, hyperglycemia is significantly associated with adverse outcomes in patients diagnosed with heart failure. There is very limited research on the impact of dysglycaemia at admission on the prognosis of heart failure patients. Furthermore, there is a notable absence of studies specifically addressing the prognostic implications of admission dysglycaemia in diabetic patients developing heart failure after acute myocardial infarction. HbA1c serves as a convenient marker reflecting the longterm glycometabolic status. Elevated levels of HbA1c are associated with an augmented cardiovascular risk in patients. There are two types of disorders in glucose metabolism: sustained chronic hyperglycemia and glucose fluctuation. It has been observed that patients with similar average glucose or HbA1c levels can have very different glucose fluctuations. Acute fluctuations in glucose levels appear to exert more deleterious effects than sustained hyperglycemia in the progression of cardiovascular complications, as both upward and downward changes in glucose activate oxidative stress.^[15,16,17] We explored the relationship between GV, HbA1c and one-year MACE in individuals with type 2 diabetes and HF following ASTEMI. Our investigation revealed that elevated MAGE emerged as a robust and independent predictor of an increased risk of MACE in type 2 diabetes patients with HF following ASTEMI, whereas HbA1c did not exhibit a similar predictive capacity.

Significant differences in baseline characteristics were observed based on levels of MAGE or HbA1c. Patients with elevated MAGE or HbA1c levels exhibited a higher prevalence of cardiovascular risk factors, including an extended duration of DM, impaired left ventricular function, kidney dysfunction, hyperlipemia, and a history of previous CAD. A discernible correlation was observed between GRACE risk scores and both MAGE and HbA1c. These findings suggest that individuals with diabetes and HF following ASTEMI characterized by more severe glycometabolic disorders may be associated with poorer outcomes.

An increasing body of evidence suggests that, despite similar HbA1c levels, there may still be variations in the occurrence and progression of diabetic complications. In recent years, both basic and clinical studies have shown that the occurrence and development of diabetic complications are not only related to the mean blood glucose level (persistence), but also closely related to the fluctuation of blood glucose (stability). GV may serve as an important parameter for addressing potential clinical problems in diabetes. To explore the damage caused by GV to target organs, numerous basic and clinical research studies have been conducted. Temelkova-Kurktschiev et al. identified that postchallenge glucose excursions are more strongly associated with carotid intima-media thickness than FPG and HbA1c levels and substantially modify the risk for atherosclerosis estimated by HbA1c alone, in a cohort at risk for diabetes and in the early diabetes stage.^[18] In our prior investigation, we identified GV as a significant contributing factor to the severity of coronary artery disease, independently of the average blood glucose level.^[19] The Verona Diabetes Study reported that fasting GV independently predicts mortality in patients with T2DM.^[20] Several studies have concluded that GV serves as a substantial predictor of mortality in critically ill patients, independent of mean glucose levels and the severity of illness.^[21,22] In this study, a one-year follow-up revealed a significantly increased incidence of MACE, cardiac mortality, and re-hospitalization for HF among patients with higher MAGE levels. These findings suggest a potential association between elevated glucose fluctuations and the heightened risk of future adverse cardiovascular events in diabetes patients with HF following ASTEMI. Multivariable analysis further demonstrated that, in the diabetic population with HF following ASTEMI, MAGE emerged as an independent predictor of MACE. This association remained significant even after adjusting for all variables that exhibited significant differences between MAGE or HbA1c categories, whereas HbA1c did not demonstrate similar independent predictive capability. Acute hyperglycemia serves as a prevalent acute adrenergic manifestation in response to stress and is observed in myocardial infarction. Elevated catecholamine levels precipitate diminished insulin secretion and heightened insulin resistance during such instances.^[23] While stress-induced hyperglycemia provides partial elucidation for the correlation between admission GV and outcomes, it is crucial to recognize that glycemic excursion itself can independently contribute to deleterious effects. Although stress-induced hyperglycemia provides partial elucidation for the correlation between admission GV and outcomes, glycemic excursion itself can also be harmful. Quagliaro et al. compared the damage to endothelial cells under two abnormal blood glucose conditions: sustained hyperglycemia and glucose fluctuation. Human umbilical vein endothelial cells (HUVECs) were incubated for 14 days in media containing different glucose concentrations: 5 mmol/L, 20 mmol/L, or a daily alternating 5 or 20 mmol/L glucose. The studies performed show that both intermittent and high glucose concentrations stimulate apoptosis, but intermittent glucose concentrations appear to worsen the proapoptotic effects of high glucose on HUVECs.^[24,25] Some studies suggest that sustained hyperglycemia increases the levels of nitrotyrosine, 8-hydroxydeoxyguanosine (8-OHdG), and apoptosis. However, these effects are more pronounced in the context of glucose fluctuation. Protein kinase C (PKC) levels are elevated in both conditions, but particularly in glucose fluctuation. Inhibitors of PKC, such as bisindolylmaleimide-I and LY379196, have been shown to normalize nitrotyrosine levels, reduce 8-OHdG concentration, and decrease cell apoptosis. Glucose fluctuation also stimulates the overproduction of reactive oxygen species (ROS) through PKC-dependent activation of NAD (P) H oxidase, leading to increased cellular apoptosis at the mitochondrial transport chain level.^[24,25] Glycemic excursion may also be an important mediator in inflammatory responses. Studies indicate that glucose fluctuations can activate nuclear factor-ϰB and PKC pathway, leading to a greater expression of the adhesion molecules (ICAM-1, VCAM-1, and E-selectin), and promoting interleukin-6 (IL-6) production, and excess formation of advanced glycation endproducts than stable high glucose.^[26] Furthermore, profound glycemic disorders may exert an unfavorable impact on sympathetic dysfunction, a factor intricately linked with the mortality and morbidity of cardiovascular diseases.^[27]

While both HbA1c and GV may exhibit associations with an adverse prognosis, our study reveals a greater significance attributed to increased MAGE. In our analysis, the relatively unclear association between HbA1c and MACE may be attributed to a restricted number of patients and a relatively short follow-up duration in present study. Elevated HbA1c levels signify prolonged glucose dysregulation, reflecting long-term glycemic control. In contrast, heightened glucose fluctuation not only serves as an indicator of glucose dysregulation but also serves as a manifestation of stress and overall compromised health. Carmen Wong found that both the level of hyperglycaemia and cortisol levels on admission are predictive for the subsequent abnormal glucose tolerance development in hyperglycaemic AMI patients. However, hyperglycaemia in patients who are more unwell (i. e. higher cortisol) reflects the stressed state rather than underlying glucose intolerance. Conversely, if the patient is less sick (i. e. lower cortisol), hyperglycaemia is more likely to reflect underlying glucose intolerance.^[28] A discernible association between HbA1c levels and long-term outcomes in AMI patients is evident following a 3.3-year follow-up period.^[29] Discrepancies observed in predictive power may be attributed to the duration of follow-up. While HbA1c levels may demonstrate limited predictive capacity for short-term prognosis in diabetic patients with HF following ASTEMI, its association with long-term prognosis appears to be more robust.

Ongoing extensive debate persists regarding the status of glycemic excursion as an independent risk factor for cardiovascular complications, distinct from HbA1c.^[30,31] Siegelaar et al. conducted a reanalysis of data from the HEART2D study, revealing that targeting post-prandial glucose to reduce intraday glycemic excursion may not confer benefits in mitigating adverse cardiovascular events in AMI patients.^[32] Nevertheless, it is crucial to note that the HEART2D study was not specifically designed to assess the impact of glycemic excursion on the risk of MACE, and the MAGE levels were not significantly different between contrasting groups in the study. Additionally, the method employed to calculate GV from self-measured blood glucose profiles may lack precision. Overall, more rigorously designed studies are warranted to elucidate whether glycemic excursion plays a significant role in the prognostication of AMI.

Study limitations

The relatively small sample size may limit the power of subgroup comparisons to detect significant differences for selected variables. Due to the absence of data on microvascular complications, these risk factors were not incorporated into the analysis. Despite maintaining patients’ antihyperglycemic therapy and avoiding glucose infusion during CGMS observation, factors such as variations in diet, physical activity, and emotional stress, which can influence glucose fluctuations, could not be entirely mitigated. Furthermore, routine tests for diabetes detection were not conducted, potentially resulting in overlooked cases of diabetes. However, if the observed association between glycemic excursion and MACE were attributed to undiagnosed diabetes, a more pronounced correlation with HbA1c and outcomes would have been anticipated.

Conclusions

In patients with type 2 diabetes and HF following ASTEMI, admission MAGE emerges as a potentially crucial predictor of MACE, whereas HbA1c did not exhibit similar predictive significance. In the glycemic metabolism of patients with type 2 diabetes and HF following ASTEMI, it appears that acute glucose excursion holds greater predictive significance for 1-year outcomes compared to long-term derangements in glucose metabolism. The findings of this study provide support for the perspective that glycemic excursion should be considered as a focal point for the treatment of glycemic disorders observed in patients with type 2 diabetes and HF following ASTEMI. Additional research is warranted to ascertain the benefits of pharmacologic therapy targeting glycemic excursion in patients with type 2 diabetes and HF following ASTEMI regarding the prognosis of this high-risk patient population.