Faculdade de Medicina da Universidade do Porto. Alameda Prof. Hernâni Monteiro 4200 – 319 Porto PORTUGAL
The effect of intensive control of glucose levels on mortality and morbidity in diabetic patients with acute coronary event: a meta-analysis of clinical trials
Baraças, C. (); Cardoso, M. (); Cerqueira, M. (); Dantas, S. (); Esteves, G. (); Ferrão, J. (); Ferreira, R. (); Lopes, R. (); Marcos, A. (); Moreira, A. (); Oliveira, N. (
Advisers: Almeida, F. (); Pereira, A. ().
Class number: 7
ABSTRACT
Background: DM is a metabolic disorder of multiple aetiology characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat, and protein metabolism, resulting from defects of insulin secretion, insulin action, or a combination of both. Diabetes mellitus (DM) is associated with the development of cardiovascular disease (CVD). Coronary syndrome, in its turn, corresponds to the most common cause of mortality in patients with diabetes mellitus types I and II. The combination of type 2 diabetes and previous coronary artery disease (CAD) identifies a group of patients with particularly high risk for coronary deaths. Thus a history of diabetes and myocardial infarction markedly increases CVD and all-cause mortality. The increased risk of CAD in subjects with diabetes was only partly explained by the presence of concomitant risk factors, such as smoking, hypertension, obesity and dyslipidaemia. Thus the diabetic state or hyperglycaemia is very important for the increased risk of CVD and related mortality.
In-hospital mortality after myocardial infarction has declined over the years. Unfortunately patients with diabetes have not benefited from improvements to the same extent as those without this disease. Information on the prognosis of patients admitted with acute coronary events and treated with an intensive control regimen of glucose levels is scarce. The objective of this study was to explore the mortality and morbidity rate in relation to different glucose control regimens of patients admitted with acute coronary syndrome.
Objective: do a systematic review of randomized controlled trials that compare intensive blood glucose level control with standard glucose lowering therapy during the first days after an acute coronary event, evaluating mortality rate, re-infarction and quality of life.
Key-words: Diabetes Mellitus; Glucose Intolerance; Insulin Resistance; Coronary Arteriosclerosis; Myocardial Infarction; (Diet Therapy); Review; Meta-Analysis.
INTRODUCTION
DM is a metabolic disorder of multiple aetiology characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat, and protein metabolism, resulting from defects of insulin secretion, insulin action, or a combination of both [1].
CAD is one of the major long-term consequences of DM and simultaneously the greatest cause of death (nearly 75% [2]) among diabetic subjects [3] (figure 1). Several studies have demonstrated that diabetic patients have a two to three times higher risk of CAD than that among people without diabetes [4]. Indeed, the incidence of atherosclerosis in those patients is so markedly expressed, that makes imperative the need of searching for efficacious therapies.
Type 1 diabetes is characterized by deficiency of insulin due to destructive lesions of pancreatic β-cells. This is an autoimmune disease in which pancreatic insulin-secreting β-cells are destroyed by T-lymphocytes, Such an irregularity in T-cells’ procedure is generally owed to a failure in thyme’s checking activity, which, in normal situations, only release into the blood stream those lymphocytes with little or none affinity to self-antigens of the organism (self-Major Histocompatibility Complex). This type of diabetes usually progresses to the stage of absolute insulin deficiency. The only treatment available is insulin administration.
In spite of being the most representative syndrome among patients who suffer from diabetes and CAD (90-100%) [5], the causal mechanisms that yield DM type II (DMT II) are the least known. It is caused by a combination of decreased insulin secretion and decreased insulin sensitivity, leading to both hyperglycemia and hyperinsulinemia. Usually, insulin-resistant patients have a high genetic propensity for that phenotype [6] owing to a mutation in the gene that codifies the cell insulin receptor, which leads to a non functional transmembrane insulin receptor. Thereafter, glucose uptake for the cells is no longer possible and blood glucose concentration increases (hyperglycemia). Insulin resistance seems to derive from synergistic effects of the expression of some different mutated alleles [7]. As showed above, the etiology of DMT II implies differentiated types of therapy. As type 2 diabetes comprises over 90% of adults with diabetes, typically after middle age, obese and physically inactive [6], the main objective of the treatment is the reduction of mortality and morbidity rates, as well as the preservation of quality of life [8].
A longstanding case of diabetes progressively aggravates, and is related to some other hard complications that start appearing in the organism. The most dangerous one involves the cardiovascular system, originating essentially two levels of atherosclerosis, characteristic of diabetes’ pathophysiology: the microangiopathy and macroangiopathy [9].
The first stage of atherogenesis is the damage of the blood vessels endothelium. Hyperglycemia increases glucose toxicity, provoking the intracellular decrease of NADPH (the first biological antioxidant) concentration, which leads to oxidative stress, i.e. to a greater exposure to reactive oxygen species (ROS), like superoxide (O2-), hydrogen peroxide (H2O2) and hydroxyl radical (OHl) [5, 6, 10]. ROS promote lipid peroxidation and protein oxidation. Nitrogen monoxide (NO), an important endothelium-secreted vasodilator which stimulates smooth muscle cells (SMC) to relax (increasing blood flow), is then chemically obliterated by superoxide, inducing vasoconstriction as long as endothelin-1 production is simultaneously increased [5]. Additionally, LDL’s (low-density lipoprotein cholesterol) harmfulness is amplified when it is oxidized by free radicals, functioning as an immune-signal for monocytes, which are attracted and hypertrophy into macrophages – inflammatory response [6, 11]. Such leucocytes start ingesting the oxidized LDL, becoming large foam cells and eventually dying within tunica intima (see figure 2). This local deposition of lipid-rich macrophages forms the early fatty streak [5, 11]. The localized necrosis, either of dysfunctional endothelium and macrophages, induces the release of cytokines, which act as signalling proteins, stimulating SMCs’ proliferation [6]. Atherosclerotic plaque thus begins its growth, reducing the vessel lumen’s diameter and opposing itself to blood flow.
When microvascular disease first starts developing, it influences the capillary systems of specific organs, resulting on the failure of their blood supply and their dysfunction, causing retinopathy (blindness) and nephropathy (problems at urine filtration) [10].
On a second long-term stage of atherosclerosis, the diabetic patient might be subjected to CVD. In this case, the main blood vessels which reach the heart are affected and the consequences could be much more drastic (macrovascular disease). Diabetics are hence at higher risk of suffering MI than other nondiabetic subject [12] (figure 3).
Diabetes is a major contributor to cardiovascular diseases, including coronary heart, cerebrovascular and peripheral artery disease, as well as an independent predictor for adverse outcomes in patients with coronary artery disease (CAD) [13]. It has been scientifically proved that the tight blood glucose regulation is an important way of controlling the development of atherosclerosis of both DMT I and II and in improving the quality of life in these patients.
The GAMI study (Glucose tolerance in patients with Acute Myocardial Infarction) revealed that abnormal glucose tolerance is an important risk factor for future cardiovascular events after myocardial infarction [14]. This is of major concern, as Norhammer [etal] [15] demonstrated that abnormal glucose regulation is present in most patients with CAD. Factors of possible importance for the poor prognosis among diabetic patients with acute myocardial infarction may act before, during, or after an event. As recently reviewed, these include diffuse coronary atherosclerosis, a possible diabetic cardiomyopathy and increased heart rate, an increased propensity to thrombus formation, and an impaired fibrinolytic function. Some of these factors are related to the metabolic control and are favourably influenced by insulin [16]. In diabetic myocardium, the consumption of fatty acid as metabolic fuel is thought to be increased, whereas glycolysis is impaired both in ischaemic and non-ischaemic areas. As the consumption of fatty acids instead of glucose requires more oxygen, such a shift may be deleterious particularly when oxygen supply is limited [17]. Yet, information on the prognosis of patients admitted with CAD who where submitted to a tight glycemic control regimen during the first days after admission when compared with patients with usual control of diabetes is lacking.
AIM OF THE STUDY
The aim of this study is to do a systematic review of randomized controlled trials that compare tight blood glucose level control with standard glucose lowering therapy during the first days after an acute coronary event. The main outcomes evaluated will be mortality during the admission period and during the 6 months after admission, re-infarction, cerebrovascular diseases and the quality of life.
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