Intensive Glycemic Control in Patients with Acute Myocardial Infarction: Diabetes Time Duration Counts!

Fundamentos: A doença cardíaca coronariana é a principal causa de morte em pacientes diabéticos. A presença do diabetes mellitus tipo II (DMTII) põe os pacientes com e sem história prévia de infarto do miocárdio em risco cardiovascular significativo. Objetivo: Avaliar o impacto prognóstico do tempo de duração e controle metabólico do DMTII em uma população hospitalizada por síndrome coronariana aguda. Métodos: Estudo retrospectivo realizado com 731 pacientes consecutivos admitidos por síndrome coronariana aguda no período de maio de 2007 a agosto de 2013. Os pacientes foram estratificados em: Grupo 1 (n=297), com diabetes mellitus (DM) conhecido (previamente à hospitalização) e hemoglobina A1c (HbA1c) <6,5%; Grupo 2 (n=383), com DM conhecido e HbA1c ≥6,5%; Grupo 3 (n=39), com DM recentemente diagnosticada (durante a hospitalização) e HbA1c <6,5% e Grupo 4 (n=12), com DM recentemente diagnosticada e HbA1c ≥6,5%. O desfecho primário foram todas as causas de morte (cardiovascular ou não cardiovascular) em um ano, e o desfecho secundário em dois anos de seguimento. Resultados: A distribuição por sexo e idade foi semelhante nos grupos. A mortalidade total intra-hospitalar foi maior no Grupo 2 (4,4%). A mortalidade por todas as causas durante um ano foi superior nos Grupos 1 (8,3%) e 4 (8,3%), e em dois anos foi maior no Grupo 1 (9,8%) O Grupo 3 teve melhor prognóstico. Conclusão: Dos dados apresentados, os autores consideram que o tempo de duração do diabetes é importante para decidir o regime terapêutico e ajustar o alvo do controle metabólico dos pacientes com SCA.


Introduction
Cardiovascular disease (CVD) is the leading cause of death in patients with diabetes.Patients with acute myocardial infarction (AMI), previously diagnosed with diabetes mellitus (DM), have worse short-term prognosis than those without diabetes.Despite major advances in the diagnosis and treatment of cardiovascular disease and, specifically, in the treatment of acute coronary syndrome (ACS) with incredible impact on morbidity and mortality of AMI, type 2 diabetes mellitus (T2DM) also puts patients with and without history of myocardial infarction at significant cardiovascular risk 1,2 .The presence of diabetes doubles the risk adjusted for age for cardiovascular disease in men and triples it in women, according to the Framingham study, and remained as an independent risk factor, even after adjustment for age, hypertension, smoking, hyperlipidemia and left ventricular hypertrophy 3,4 .
Hyperglycemia on admission is a predictor of poor outcome in diabetic and non-diabetic patients, and the Diabetes Time Duration Counts!Int J Cardiovasc Sci.2015;28 (6): 487-495  Original Manuscript

ABBREVIATIONS AND ACRONYMS
• ACS -acute coronary syndrome • AMI -acute myocardial infarction • DM -diabetes mellitus • LBBB -left bundle branch block • LVEF -left ventricular ejection fraction • T2DM -type 2 diabetes mellitus role of an intensive glycemic control in ACS adjustment has been discussed 5 .
The latest European guidelines on AMI with ST segment elevation suggest a "strict but not too strict" control of glucose to prevent hypoglycemia (blood glucose levels ≤198 mg/dL) and the American College of Cardiology/ American Heart Association guidelines suggest the maintenance of blood glucose levels <180 mg/dL, regardless of a previous diagnosis of diabetes mellitus 6,7 .
Another interesting question is: what is the real influence of diabetes duration on the occurrence of cardiovascular events?In some studies, the diabetes mellitus time of duration was a powerful independent risk factor for cardiovascular mortality, but this statement needs further study to be confirmed.The objectives of this study were to quantify the impact of prognosis of type 2 diabetes mellitus duration time in a population hospitalized for ACS and evaluate how metabolic control influences the prognosis of this specific population.

Methods
Retrospective observational study involving 731 consecutive patients (690 with known T2DM and 41 diagnosed during the hospital stay) admitted for ACS (33.2% with AMI with ST-segment elevation, 62.9% with AMI without ST-segment elevation, 3.8% with new or supposedly new left bundle branch block (LBBB) in a single coronary care unit from May 2007 to August 2013.
Clinical, analytical and demographic data were retrospectively collected, using the computer software used in the coronary care unit.Since the data are systematically recorded for all patients, no data was missing for the parameters analyzed.Hemoglobin A1c was obtained on the first day and oral glucose tolerance test was measured on the third or fourth day after admission.
All patients underwent standard echocardiographic evaluation and coronary angiography and percutaneous coronary intervention, if indicated according to the instructions available at the time.
Follow-up was conducted by personal interview at the clinic, reviewing hospital records, by telephone and review of official mortality records.

This study has been approved by the Research Ethics Committee of the institution (no number).
The primary endpoint was death from all causes (cardiovascular or non-cardiovascular) in the first year of follow-up; and the secondary endpoint was death from all causes over two years of follow-up.

Statistical analysis
Continuous variables were normally distributed and assessed using the Shapiro-Wilk test, and expressed as means±standard deviations, and those with asymmetric distribution were expressed as medians (semiquartiles).Dichotomous variables were expressed as frequencies (percentages).
To compare data between the groups studied, analysis of variance was used for continuous data and the chisquare test (Fisher, as appropriate) for dichotomous data.
All variables with a significant value (p≤0.10) were tested for mortality using the multivariate Cox-regression testing.Variables with significant relevance between the groups in the univariate analysis (age, type of ACS, heart rate, Killip class on admission, left ventricular function, maximum troponin, minimum hemoglobin and previous use of acetylsalicylic acid, beta blockers and statins) were included in the model to adjust the final analysis for all possible confounding factors.Kaplan-Meyer survival curves were constructed and compared using the logrank test.
The entire analysis was performed using SPSS for Windows, version 16.0 (SPSS Inc.; Chicago, Illinois, USA).In this study, p≤0.05 was considered statistically significant.

Results
The baseline characteristics of the patients are listed in Table 1.Distribution by sex and age was similar between groups.

Figure 1
In-hospital mortality (%) of the patients studied

Discussion
This population-based study emphasizes the magnitude of DM as an important risk factor for cardiovascular mortality.
As expected, in-hospital mortality was higher in Group 2 (4.4%), which included patients with known type 2 diabetes mellitus and worse glycemic control.The dysmetabolism effects on the cardiovascular system have been studied over the years 8.9 .It has been recently demonstrated that hyperglycemia could increase infarct size, inducing cardiac myocyte death (apoptosis) or exaggerate ischemia -repercussion of cell damage and consequent reduction in collateral coronary blood flow 10 .In this analysis, Group 2 had the highest peak value of troponin I (35.8±65.4;36.4±63.3;32.7±39.8;30.1±44.3;without statistical significance, respectively, from Group 1 to 4) during the hospital stay, which also helps explain the higher in-hospital mortality occurred.
Considering the data presented, the following questions were asked: Should we treat all diabetic patients in the same way?Glycemic control should be strict for everyone?The answer seems to be no!Three major randomized trials have shown no benefit in reducing cardiovascular events in diabetic patients at high cardiovascular risk under intensive glycemic control [11][12][13][14] .Evidence suggests that the potential benefits or dangers of intensive glycemic control depend on the presence or absence of significant atherosclerotic disease and DM duration 15,16 .
Patients newly diagnosed with diabetes without significant cardiovascular disease and long life expectancy are good candidates for the establishment of intensive hypoglycemic therapy aiming at HbA1c values close to normal.On the other hand, diabetics with long evolution, with micro and/or macro-vascular complications and limited life expectancy should be subject to less strict metabolic control (target HbA1c between 7-7.5%) 17,18 .
Analyzing the data presented in this study, Group 1 (known T2DM and hemoglobin A1c (HbA1c) <6.5%) had worse prognosis at one year (primary endpoint) and at two years (secondary endpoint).On the other hand, mortality was significantly lower in Group 3 (5.4%).This confirms the potential danger of high glycemic control in patients with established disease, and the benefits of intensive glycemic control at the time of diagnosis of DM 19 .
Another reason for the better results found in Group 3 can be attributed to increased use of angiotensinconverting enzyme blockers (ACE)/angiotensin receptor blockers after hospital discharge (65.0%; 77.3%; 94.9%; 66.7%; p<0.001, respectively, from Group 1 to 4).There is growing evidence that aspirin, statins, ACE inhibitors and reduce cardiac death in such patients.
Two studies of prevention: HOPE (Heart Outcomes Prevention Evaluation) using ACE inhibitor in heart patients, and the LIFE (Losartan Intervention For Endpoint reduction in hypertension) using angiotensin II receptor blockers in hypertensive patients with proven left ventricular hypertrophy on electrocardiogram demonstrated to decrease the incidence of cardiovascular events in this high-risk population 20,21 .
The growing number of DM in developed countries and the cardiovascular consequences related to it, in the diabetic population, deserve intensive risk reduction strategies in both primary and secondary prevention.Recommendations of observational and intervention studies specifically focused on diabetic populations may help physicians apply the guidelines and appropriate treatment in order to achieve the main goals of cardiovascular disease prevention 22 .

Limitations
This is a retrospective study based on the records of a single center.The evaluation of post-discharge death was performed by reviewing medical records and phone interview with relatives, which contributed to the rate of patients lost during follow-up.
The primary and secondary endpoints were death from any cause.A significant number of patients died out of the hospital and the causes of death could not be assessed accurately.Some of the items of clinical history and previous risk factors were based on patient report (not always completely reliable).Despite all these aspects, the results can be extrapolated to other ACS populations, as the demographic and clinical data are in line with those reported in the most published ACS records.

Conclusion
Patients with known T2DM and smaller HbA1c had long-term prognosis similar to those with newly diagnosed T2DM with worse metabolic control.
Considering this data, it can be said that the diabetes duration is important to decide the therapy and the goal of metabolic control.
Patients newly diagnosed with T2DM should have tighter glycemic control than those with known T2DM.

Potential Conflicts of Interest
This study has no relevant conflicts of interest.

Sources of Funding
This study had no external funding sources.

Academic Association
This study is not associated with any graduate programs.

D i a g
n o s i s o f A C S w a s b a s e d o n c l i n i c a l , electrocardiographic and analytical criteria, according to the instructions available at the time of hospital admission.

Figure 2 3
Figure 2Kaplan-Meier analysis: all-cause mortality over one year of follow-up