Impact of diabetes mellitus and hemoglobin A1c level on outcomes among Chinese patients with acute coronary syndrome

Abstract Background The impact of different glycemic control conditions on in‐hospital and long‐term outcomes among patients with acute coronary syndrome (ACS) is less well defined. Hypothesis Diabetes mellitus (DM) with different admission hemoglobin A1c (HbA1c) levels (different glycemic control) could affect outcomes among Chinese patients hospitalized as ACS. Methods We categorized 8961 Chinese ACS patients into one of the following three groups: “no DM” (group 1, n = 3773; no DM history and admission HbA1c < 6.5%), “DM with optimal control”(group 2, n = 2241; DM with admission HbA1c < 7.0%), “DM with suboptimal control”(group 3, n = 2947; DM with admission HbA1c ≥ 7.0%). The primary outcome was in‐hospital major adverse cardiovascular events (MACEs). 6098 patients were followed for a median of 3.85 years. Adjusted associations of these three groups with in‐hospital MACEs and long‐term mortality were determined. Results DM with suboptimal control (group 3) was associated with greater in‐hospital MACEs (OR 1.46, 95% CI 1.17‐1.81, P = .001) than “no DM” (group 1). DM patients (group 2 and group 3) also had higher in‐hospital MACEs (OR 1.42, 95% CI 1.16‐1.73, P = .001) than “no DM” patients (group 1). It showed no significantly different in‐hospital MACEs between optimal (group 2) and suboptimal (group 3) control group (OR 1.06, 95% CI 0.84‐1.34, P = .63). Both optimal control (group 2) and suboptimal control (group 3) had a higher long‐term mortality (HR 1.26, 95% CI 1.02‐1.56, P = .03; HR 1.42, 95% CI 1.16‐1.73, P = .001). Conclusions ACS patients with DM were associated with higher in‐hospital MACEs and long‐term mortality. Moreover, lower HbA1c level seems to have limited impact on cardiovascular events and long‐term mortality in this high‐risk population.


| INTRODUCTION
In China, more than 700 000 deaths each year, one quarter of all deaths, are caused by coronary events. 1,2 Rapid epidemiological transition and a concomitant increase in the prevalence of major risk factors have led to an increasing numbers of patients being admitted to hospitals with acute coronary syndrome (ACS). More than two thirds of the burden of death and disability from ACS, which is a major contributor to national mortality and economic burden in our country, will occur in adults aged <65 years. 3,4 In 2010, an estimated 6.4% of the world's adult population (approximately 285 million individuals) had diabetes mellitus (DM), and the prevalence is projected to increase to 7.7% (approximately 439 million individuals) by 2030. 5 DM is considered to be a "coronary heart disease (CHD) equivalent" and associated with a 2-to 4-fold increased risk of cardiovascular disease (CVD).
The measurement of hemoglobin A1c (HbA1c) provides a reliable reflection of the glycemic control in the previous 8 to 12 weeks and is minimally affected by stress during ACS. The International Expert Committee has recommended the use of HbA1c in diagnosing diabetes with a cutoff value of 6.5%. 6 The recommended guideline for patients with CVD is HbA1c values <7%. 6 Although the benefit of controlling HbA1c levels (glycemic control) in patients with type 2 diabetes on microvascular events such as retinopathy, neuropathy, or nephropathy is well established, the association between glycemic control and macrovascular or cardiovascular events is less well defined. 7,8 Moreover, most previous studies generally evaluated the impact of diabetes on outcomes in patients after acute myocardial infarction. [9][10][11][12] Further understanding of the impact of normal and different admission glycemic control conditions on in-hospital and long-term outcomes among patients with ACS is essential. In this study, we aimed to investigate the impact of the diabetes and admission HbA1c levels (glycemic control conditions) on in-hospital major adverse cardiovascular events (MACEs) and long-term mortality in a large cohort of Chinese patients hospitalized for ACS who underwent modern treatments in the contemporary post-2000 era.

| Study population
The study population was drawn from the China ACS Registry Study, which was both a planned retrospective registry trial and a real world study that sought to investigate the impact of clinical quality and treatment strategy on the short-term and long-term outcomes among optimal control (group 2, n = 2241; DM with admission HbA1c < 7.0%).
The rest of the 2947 patients in DM group, who had HbA1c levels more than or equal to 7.0%, were classified as DM with suboptimal control (group 3, n = 2947; DM with admission HbA1c ≥7.0%; Figure 1).
In particular, 1529 patients who had no previous history of DM, but had elevated HbA1c level ≥ 6.5% (newly diagnosed DM), were included in those 5188 patients as DM group. In these 1529 patients, 873 patients who had HbA1c levels <7.0% were assigned into group 2 (DM with optimal control), the rest 656 patients who had HbA1c levels ≥7.0% were included in group 3.
The following data regarding long-term all-cause and cardiac mortality of 6201 patients lived in Beijing were identified through the database of Beijing Centers for Disease Control and Prevention (Beijing CDC). Most of these patients (n = 6098) were followed for a median of 3.85 years (3.85 ± 2.14).

| Ethical standards
The medical charts of eligible patients were reviewed to collect requested information by centrally trained and certified research personnel who were not involved with the clinical care of the patients.
The study protocol complied with the Declaration of Helsinki and was approved by the Ethics Committee of all hospitals involved.

| Clinical outcomes
The primary outcome of this study was the in-hospital MACEs comprising cardiac mortality, heart failure, non-fatal reoccurred myocardial infarction, and non-fatal stroke. Second outcomes were longterm all-cause and cardiac mortality: (a) long-term all-cause death and (b) long-term cardiac death.

| STATISTICAL ANALYSIS
Demographics, baseline clinical characteristics, and event rates according to diabetes and HbA1c levels were summarized using means with SD or medians with 25th and 75th percentiles for continuous variables and percentages for categorical variables. Categorical variables were compared using the χ 2 test, and continuous variables were compared using either one-way ANOVA or Kruskal-Wallis test, as appropriate.
Multivariable logistic regression models were created to compare in-hospital MACEs within optimal control (group 2) and suboptimal control (group 3) subgroups, setting no diabetes patients (group 1) as reference, after adjustment for potential confounders associated with in-hospital MACEs including all baseline and clinical characteristics shown in Table 1,  Multivariable Cox proportional hazards models were used to assess the association of diabetic control status with long-term mortality, using no diabetes patients (group 1) as the reference group. Multivariable adjustment for long-term mortality considered variables associated with longterm mortality in the GRACE risk score, and variables from previous modeling in Clinical Pathways for Acute Coronary Syndromes in China (CPACS) risk score, which were considered as confounders and adjusted in previous models.
Associations of diabetic control status with in-hospital and longterm outcomes are presented as ORs or HRs with their 95% confidence intervals (95% CIs). A P value <.05 was considered significant for all two-sided tests. All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC).

| Baseline characteristics
Baseline characteristics stratified by DM and HbA1c levels are shown in Table 1. In general, patients with DM (group 2 and group 3) were older, more were female, had more hypertension, hyperlipidemia, and had more previous coronary artery disease (compared with group 1). Severity of ACS as assessed by presentation with Killip class >II, heart rate ≥ 100 bpm, and GRACE risk score ≥ 140 was markedly more common among patients with DM and suboptimal control (group 3). Although patients in all groups received similar medical and invasive therapy according to contemporary guidelines, patients with DM (group 2 and group 3) tended to be treated with percutaneous coronary intervention (PCI) less frequently, and received angiotensin-converting inhibitors or angiotensin receptor blocks at admission more often than patients with no diabetes (group 1). Baseline and clinical characteristics stratified by diabetes and HbA1c levels in long-term cardiac mortality (Figure 3).
At the longest follow-up period of 8 years, the adjusted cumulative all-cause mortality was 3.00% in group 3 patients, 2.97% in group 2 patients, and 1.89% in the controls without diabetes (group 1).
There was no significant difference between group 2 and group 3. The adjusted cumulative cardiac mortality at 8 years was 2.03% in group 3 patients, 2.07% in group 2 patients, and 1.25% in group 1 patients (Figure 3).

| Propensity score matching analysis
We also performed an analysis with propensity score matching and showed the results in Table S1 and S2 of Supplement Material. Associations were consistent and showed the same trend with the main results.

| Subgroup and sensitivity analysis
Associations were presented in subgroups defined according to the subtypes of ACS, that is, ST elevation myocardial infarction (STEMI) and non-ST elevation acute coronary syndrome (NSTEACS) (Table S3 and S4). In brief, the subsets of STEMI in group 2 and group 3 were associated with greater in-hospital MACEs, but the subgroups of NSTEACS showed the same trend in long-term outcomes.
Thousand five hundred and twenty-nine patients who had no previous history of DM, but had elevated HbA1c level ≥6.5% (newly diagnosed DM), were included in group 2 (873 patients) and group 3 (656 patients). We ran a sensitivity analysis by including only these patients and found the associations with in-hospital MACEs were consistent in these patients (Table S5).
Furthermore, we also performed another sensitivity analysis by excluding all these patients (newly diagnosed DM) in group 2 and group 3, and found that associations were consistent in the remaining patients (Table S6).

| DISCUSSION
This large observational study of 8961 Chinese patients with ACS showed that DM with both optimal and suboptimal glycemic control (different HbA1c levels) were associated with higher in-hospital events and long-term mortality than the ACS patients without DM. Moreover, glycemic control in DM with ACS (ie, controlling optimal HbA1c level <7.0%), which has been proved to be beneficial to lowering microvascular events, seemed to have limited impact on inhospital macrovascular events and long-term mortality in the high-risk population. As far as we know, this is the first study to determine the combined effect of overt DM and different HbA1c conditions (optimal or suboptimal control) on in-hospital and long-term clinical outcomes in Chinese patients with ACS.

| Baseline characteristics
According to the diagnostic criteria of DM in the latest 2020 ADA recommendation (HbA1c ≥ 6.5%), our study could identify newly diagnosed DM patients. 13

| The impact of combined DM and HbA1c level on in-hospital or short-term outcomes of patients with ACS
HbA1c levels during the index admission can reflect the average blood glucose levels and glycemic control during the previous 2 to 3 months before the hospitalization of ACS. In our study, whether or not there is optimal glucose control (HbA1c <7%), DM patients with ACS (group 2 and group 3) was associated with higher in-hospital MACEs than ACS patients without DM (group 1). There were several studies which were designed to analyze the relationship of HbA1c level and shortterm outcomes of patients with ACS. [16][17][18] Since the diagnostic criteria of DM with HbA1c levels had not been recommended at that time, these studies could not show the short-term prognostic value of combine both DM and HbA1c levels in ACS patients. In addition, the samples of these studies were relatively small and could not reflect contemporary treatment. Giraldez et al. studied a large sample (8795 patients with NSTEACS) and found undiagnosed diabetes was associated with greater short-term (30 days) death or myocardial infarction. 19 We also found the significant association of DM with higher in-hospital MACEs in Chinese patients with ACS, even after multivariable adjustment with potential confounders including baseline characteristics, GRACE risk score, history of cardiac disease, history of stroke/TIA, risk factors of cardiovascular disease and in-hospital treatments. The mechanism of DM patients with higher short-term events may be explained by insulin resistance, oxidative stress, as well as enhanced platelet activation. 20,21 One study also reported impaired coronary flow to be associated with high blood glucose in ACS patients. 22 In our study, an additional investigation about association of glycemic control and in-hospital events between DM with optimal con-

| The impact of combined DM and HbA1c level on long-term outcomes of patients with ACS
We found that DM patients with ACS (both group 2 and group 3) were associated with higher long-term mortality than ACS patients without DM (group 1) during a median follow-up period of 3.85 years.
It is in accordance with a recent large-scale study. Stam-Slob et al.
found patients with T2DM and established CVD had a particularly high risk for MACE (the risk increased by about 1.7-fold). 25 Although the ACS patients with DM showed worse long-term outcome, our study suggest that optimal glycemic control would not improve the long-term mortality. It is in accordance with the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, which planned to investigate that optimal or intensive glucose control could reduce MACEs in patients with T2DM and cardiac risk factors. 26 However, the trial was terminated prematurely about 3.5 years because there were 22% more mortality in patients who were controlled intensively. 26

| Different subtypes of ACS with DM and elevated HbA1c
Subgroup analysis showed that different types of ACS were associated with different timing of adverse events. The subsets of STEMI in group 2 and group 3 were associated with greater in-hospital MACEs (short-term outcomes), but the subgroups of NSTEACS showed the same significant trend in long-term outcomes.
The temporal distribution of adverse events in patients with different subtype of ACS has been demonstrated in several studies. [32][33][34] Typically, the risk of adverse events and mortality in patients affected by STEMI is the highest during the first month and then alleviates over time. This timing distribution is completely different with patients diagnosed as NSTEACS, who usually feature a higher risk of longer-term outcome. 34

| LIMITATIONS
There are several limitations of our study. Firstly, the patients without HbA1c levels during the index admission were excluded. This may cause selection bias. Secondly, the duration of DM patients diagnosis, anti-diabetic agents usage and HbA1c levels in the whole follow-up duration cannot be defined. A few studies have showed the significance of long-standing DM and cumulative hyperglycemic damages among patients on the danger for adverse cardiovascular events. 35,36 Although the DM patients with ACS in our study also showed the same trend during the long follow-up period, the exactly timing effect of DM is worth further studies. Finally, we could not accurately define prediabetes in our population. These patients mostly were included in no DM group (group 1). However, in an analysis from the Providing

Regional Observations to Study Predictors of Events in Coronary Tree
(PROSPECT) study, authors defined prediabetes in population with ACS after successful PCI and assessed the related risk of MACEs.
They concluded that DM but not prediabetes is associated with an increased risk for MACEs. Data demonstrated that DM was an independent predictor of MACEs, although patients with neither DM nor prediabetes had more severe CVD than no DM group. 37

| CONCLUSION
ACS with DM should be worth additional attention since these patients were associated with higher in-hospital MACEs and longterm mortality. Moreover, optimal glucose control and controlling HbA1c level, which has been proved to be beneficial to lower microvascular events, seems to have limited impact on macrovascular events and long-term mortality in this specific high-risk population.
Thus, it is more important to get a therapeutic strategy for additional benefit of reducing cardiovascular events, not just anti-diabetic treatment in DM patients with ACS.