Diabetes and cardiovascular diseases

I - Diabetes : Generalities

Diabetes mellitus, a disease characterised by altered carbohydrate metabolism is increasing in the world and its incidence becoming a significant social disease both in terms of patient health and healthcare costs.
The causes are to be found in the inappropriate lifestylefollowed not only in the developed world: economic wellbeing has led to a progressively sedentary society and an increased daily calories intake in respect to the real dietary needs of the individual.

Epidemiology

Prevalence of diabetes, common and widespread, is increasing both in the industrialised and developing countries. It has doubled between 1995 and 2005, from 100 million to 200 million cases and is expected to triple by 2030-2040.
The World Health Organisation has defined the disease as an epidemy. The complications of the disease are disastrous. Diabetes mellitus is the sixth cause of overall death and the leading cause of limb amputation due to peripheral arterial occlusive disease.
In the diabetic patient, the incidence of cardiovascular death is between two - and fourfold higher. Glucose is the main fuel for the muscles and other organs and the only source of energy for the brain. Diabetis melis is :

A heterogeneous group of disorders in glucose metabolism, characterised by chronic hyperglycaemia and caused by reduced pancreatic insulin secretion (type 1 Diabetes)

• A combination of peripheral insulin resistance and/or reduced insulin secretion (type 2).

Insulin

The hormone which regulates carbohydrate transportation to the tissues is insulin. It is produced by beta-cells in the islets of Langerhans, which after meals secrete it in a sufficient quantity for the rapid consumption, storage or use of glucose by tissues, but particularly by the liver, the muscles and fat tissues. The liver stores about 60% of the glucose present in food and then puts it back into circulation when needed, such as in periods of fasting, intense physical activity or stress.

In the diabetic patient the glucose regulation system is compromised and blood glucose tends to rise, leading to an excessive elimination of glucose by the kidneys, in turn, causing glycosuria. Blood glucose levels rise not only after meals, but also during the day, due to intervention of the liver. Exposure to chronic hyperglycaemia may result in a series of distinctive conditions, including microvascular complications, particularly affecting the kidney and the retina, macrovascular diseases, i.e. affecting larger diameter vessels with a consequent early and generalised atherosclerosis, and diabetic neuropathy, which is characterised by motor and sensory alterations of the peripheral and autonomic nervous system.

The classification that was used up until a few years ago dates back to 1979 and was based both on etiology and on the pharmacological therapy to treat the disease. A distinction was made between two main clinical forms: type I diabetes, also called insulin-dependent diabetes mellitus (IDDM) and type II diabetes, also called non-insulin-dependent diabetes mellitus (NIDDM).

Type I diabetes

The first form – Type I diabetes- is characterised by absolute insulin deficiency, due to the idiopathic or autoimmune destruction of the pancreatic beta-cells producing insulin, and usually develops before adulthood, when most pancreatic beta-cells (about 80%) are destroyed. Various data provide evidence that there is a genetic predisposition to the action of some exogenous stimulation. Other studies have demonstrated a 50% concordance in identical twins, although no genetic model has been put forward to explain the hereditary transmission. In addition to genetic factors, immune factors (positive test for the antigens HLA-DR3/DR4) have also been identified as possible causes for the disease. Lastly, environmental factors, such as bacteria, viruses and chemicals, can be considered precipitating events for the autoimmune process, with the production of auto antibodies able to destroy the insulin-producing cells of the pancreas.

Type II diabetes

Type II diabetes, instead, mostly affects the adult or elderly population and is characterised (although not always) by overweight. In the early phase, treatment involves oral hypoglycaemic agents, above all insulin-sensiting drugs such as metformin and diet, and only later, in certain cases, the administration of insulin.

Genetics

Studies carried out on homozygotic twins suggest that genetic factors play a more important role in this form of diabetes. With increasing age, the agreement may reach 100%: nonetheless, there is still no viable explanation for this genetic mechanism. There is also a resistance of body tissues to the action of insulin still produced by the pancreas. The glucose is unable to penetrate within the cell, thus producing hyperglycaemia, which in turn functions as a stimulus for the further production of insulin; this condition down-regulates the number of insulin receptors on all sensitive cells. This pathogenetic mechanism is a good explanation for diabetes in the obese subject, who manages to find a better mechanism of metabolic control than weight loss. The mechanism behind type II diabetes in non-obese patients is, however, still partly unknown, although peripheral resistance at the level of the receptors has been hypothesised.

Acquired factors are fundamental for this type of diabetes. First place among the environmental factors is undoubtedly held by poor diet, although reduced physical activity, stress, drugs, alcohol abuse and lifestyle modernisation with all that it brings are all precipitating factors which can compete, together with genetic predisposition, causing the disease. Increases in calories intake together with physical inactivity lead to weight gain and consequent obesity, dyslipidemia and insulin resistance.

The metabolic syndrome

These last conditions together with chronic inflammatory damage, lead to endothelial dysfunction. All of these elements together define a metabolic syndrome, and the common denominator which lies at the basis of the disease is precisely the presence of a marked insulin resistance. When present together, the individual factors of the metabolic syndrome are able to amplify the global risk of an individual developing atherosclerosis.

New classification

In 1997 the American Diabetes Association (ADA) published new criteria for the classification of diabetes which were based more on practical observations than etiologic considerations. The new classification eliminated the terms insulin and non-insulin dependent and their abbreviations, although the distinction between diabetes 1 and 2 was kept (opting, however, for Arabic numbers), since clinical experience revealed that even type 2 diabetes required insulin treatment.

New diagnostic criteria

In 1999 the World Health Organization also adopted new diagnostic criteria.

1. Autoimmune diabetes mellitus is caused by the destruction of the pancreatic cells by auto antibodies. These have been found in over 90% of patients at the time of diagnosis.
2. Type 2 diabetes mellitus is differentiated in obese and non-obese, with their relevant treatment implications.
3. The term impaired glucose tolerance was maintained; it occurs when a subject has a postprandial plasma glucose > 140 and < 200 mg/dL.
4. A new category of patients with impaired fasting glucose was introduced, i.e. those with a fasting plasma glucose between > 100 and < 126 mg/dL. This is the class of subjects in which preventive measures can be implemented to avoid the onset of diabetes or slow the progression to overt disease.

Diagnosis

According to the new criteria, diabetes mellitus can be diagnosed on the basis of the following parameters:

1. Fasting plasma glucose > 126 mg/dL after 2 glucose tests;
2. Symptoms of diabetes and a casual plasma glucose = 200 mg/dL;
3. Plasma glucose = 200 mg/dL during an oral glucose tolerance test (OGTT).

Compared to the previous criteria, the plasma glucose level for diagnosing diabetes has fallen from 140 mg/dL to 126 mg/dL. This is because many studies have demonstrated that complications of diabetes appear with plasma glucose levels lower than those of the previous classification.
The following diagnostic criteria are taken into account for the diagnosis of impaired glucose tolerance (IGT):

1. Fasting plasma glucose <126 mg/dL
2. 2-h plasma glucose during OGTT = 140 mg/dL and < 200 mg/dL

For the diagnosis of impaired fasting glucose (IFG):
1. Fasting plasma glucose = 100 mg/dL and < 126 mg/dL

Screening

Table 1 : Screening of patients for diabetes. Screening should be performed on patients > 45 years with at least one of the following characteristics:

Clinical findings

Diabetes mellitus type 1 affects subject < 20 years in 50% of cases, with cases occurring even in the first year of life. The main symptoms are polyuria, polydipsia secondary to polyuria, and polyphagia, which is not accompanied by weight gain, but rather, by weight loss. Onset can occur after a stressful event, such as a trauma or an infection, with ketoacidosis-induced coma.

Type 2 diabetes mellitus can be silent and is only casually diagnosed by routine laboratory examinations, such that the complications of the disease may already be advanced, with localised or diffuse atherosclerosis, representing sometimes the first clinical manifestations. In addition, other values are often elevated, such as hypercholesterolemia or hypertriglyceridemia, thus confirming that diabetes is a metabolic disorder resulting from inappropriate lifestyle and an exaggerated and unhealthy diet. Polyuria and polydipsia in this form are also the most frequent symptoms.

Treatment

Treatment of diabetes is not only pharmacological, it also seeks to introduce lifestyle changes regarding diet, physical activity and smoking. If correctly implemented, these measures can improve prognosis not only in terms of correcting blood glucose levels in the strict sense, but also in the long term with the prevention of vascular complications which are often disabling for the patient and expensive for healthcare.

Pharmacologic therapy differs according to the type of disease.

• Type 1 diabetes mellitus: intense insulin therapy is required to achieve a situation as close as possible to that produced by a healthy pancreas.
• Type 2 diabetes mellitus: initial treatment is not pharmacologic, but rather involves diet and physical activity. The next step is the use of oral hypoglycaemic agents. For overweight patients the chosen drug should belong to the biguanide class (metformin), which principally acts by reducing insulin resistance, so that the intracellular penetration of glucose at the peripheral level is increased.

If optimal blood glucose control is not achieved, a drug belonging to the sulfonylurea class can be added, which will stimulate the liberation of residual insulin by the pancreas and reducing the liberation of glucose stored in the liver. Another treatment option is the addition of insulin to metformin or intensive insulin treatment as the final stage. Each of these approaches can be combined with an intestinal alpha-glycosidase inhibitor.

Since November 2006, exenatide in the European Union, has been authorised for marketing for the treatment of type II diabetes in combination with metformin and /or sulphonylureas in patients who have not achieved adequate glycaemic control on maximally tolerated doses of oral therapies. It was also approved by the US Food and Drug Administration (FDA) for similar indications in April 2005. Exenatide is an incretin mimetic and glucagon-like peptide-1 (GLP-1) analogue, whose exact mechanism of action is still not completely clear, but it appears to improve fasting and postprandial glycaemic control by enhancing acute glucose-dependent insulin secretion from pancreatic beta-cells, suppressing glucagon levels from alpha-cells of the pancreas, delaying gastric emptying and inducing early satiety  . Exenatide is only available as a subcutaneous injection and not as an oral preparation.

Recent reviews redefine the role of another class of oral hypoglycaemic agents, the thiazolidinediones (TZDs, or glitazones) class, which currently includes rosiglitazone and pioglitazone, both in monotherapy and in combination with other similar medications; they are able to reduce insulin resistance by linking the nuclear transcription factor peroxisome proliferator-activated receptor gamma (PPAR-?), thereby turning on and off speci?c genes for the regulation of glucose, lipids and protein metabolism  .
For the diabetic subject with normal weight the first drug of choice, after having began with lifestyle interventions, should be a stimulator of insulin secretion (sulfonylurea or other secretagogues). Metformin or intermediate-acting insulin can be added, until in the most advanced phases of the disease intensive insulin therapy is introduced.
The use of insulin and oral hypoglycaemic agents can cause hypoglycaemic crises, which are evident in the patient with symptoms of fatigue, sweating and tachycardia which can be easily resolved with the rapid infusion of glucose.

Complications of diabetes

The complications of diabetes can be divided into acute and chronic. The classic acute complications of type 1 and type 2 diabetes are diabetic ketoacidosis and hyperosmolar nonketotic coma, respectively. Fortunately this type of complication occurs less and less frequently thanks to careful monitoring of blood glucose levels, but the same cannot be said for the long-term complications, which are encountered increasingly more frequently, also due to increasing longevity. Microvascular disease (including diabetic glomerulopathy and retinopathy), macrovascular disease (including coronary artery disease, cerebrovascular disease and peripheral artery disease due to atherosclerosis) and neuropathy are the complications found in both type 1 and type 2 diabetes patients usually within 10-15 years after onset of the disease.

II - Diabetes and the Heart

Numerous studies have demonstrated that cardiovascular diseases are more prevalent among the diabetic population than the general population. In fact, patients with type II diabetes without prior myocardial infarction (MI) have a similar risk of death from CAD as patients without diabetes with prior MI. Moreover the mortality risk at 30 days and 1 year following acute coronary syndrome is higher in diabetics.

Coronary heart disease is the leading complication of diabetes. Not only diabetic are patients more likely to suffer myocardial infarction, but their prognosis is usually worsened.

Euro heart Survey Diabetes

The Euro Heart Survey Diabetes is a study that examined the correlation between acute coronary syndromes and diabetes. It has provided evidence that diabetes is particularly common in patients with chest pain in the intensive coronary care unit (ICCU). Patients with a normal blood glucose level account for only one third of the patients admitted to the ICCU. Another third is made up patients with known diabetes, whereas the remaining patients have newly diagnosed diabetes, i.e. diagnosed at admission, or an impaired glucose tolerance. A study by Norhammer shows that there is an important difference between patients with a plasma glucose level <133 mg/dL and those with a plasma glucose level >133 mg/dL, both in terms of survival alone and survival without further coronary events. 

In patients hospitalised for acute coronary syndromes (ACS) with or without ST-segment elevation, baseline hyperglycaemia predicts adverse outcomes whether they have known diabetes mellitus or not. Glucose levels are usually highest at baseline (upon diagnosis of acute myocardial infarction - AMI) and then the levels gradually decrease as the acute stress response subsides. The CARDINAL study demonstrates that higher baseline glucose levels are predictive of higher 30-day and 180-day mortality in patients with AMI undergoing reperfusion therapy. This study shows that a more substantial drop in glucose in the first 24 hours after AMI is associated with improved 30-day and 180-day survival. This finding has potential implications for the management of elevated glucose levels following AMI.

A recent prospective study confirms these results: persistent increases of fasting glucose during hospitalisation for acute myocardial infarction has greater prognostic effect than baseline fasting glucose. Changes in fasting glucose during hospitalisation are simple and sensitive indicators of dynamic changes in long term mortality risk.

Diabetes and coronary artery atherosclerosis

Numerous in vitro and animal studies have demonstrated how the migration and proliferation of arterial smooth muscle cells increases in the presence of hyperglycemia. The same does not seem to apply in the presence of hyperinsulinemia, unless concentrations are not well above physiologic levels.

A key role seems to be played by growth factors: stimulated by hyperglycemia growth factors increase in the blood and stimulate the proliferation of smooth muscle cells and the production of extracellular matrix. The pathophysiologic mechanisms behind the growth of smooth muscle cells are numerous. Hyperglycaemia, via the hexosamine biosynthetic pathway, leads to an increase in the production of platelet derived growth factor (PDGF), basic fibroblast growth factor (bFGF) and transforming growth factor-beta (TGF-ß). An increase in glucose levels also induces the end-products of advanced glycosylation which in turn enhance the production of TGF- ß‚ in the myofibroblasts and PDGF in the mesangial cells. Hyperglycemia also induces the activation of protein kinase C which causes an increased production of PDGF by the smooth muscle cells.
 
Another important mechanism is the increase in oxidative stress via the polyol pathway, which leads to increased activation of the PDGF receptor. Once atherosclerosis has set in, there can be different effects on the heart, with the presentation of angina or infarction, or with even lethal consequences. Ischemia can be particularly damaging in diabetic subjects. Oxidation of fatty acids decreases markedly during ischemia, but it does nonetheless remain an important source of residual energy. Pyruvate oxidation is decreased, thus rendering the oxidation of fatty acids the main source of acetyl-Co-A. At reperfusion, the oxidation of fatty acids rapidly becomes the main source of energy, following the high levels of fatty acids which accumulate in proportion to the intensity of the ischemia and also the direct increase in their oxidation. The main consequence is that glucose oxidation is significantly inhibited. As a result there is an excess of glycolysis and a low amount of glucose oxidation, a condition which can lead to an uncoupling between glycolysis and glucose oxidation. All of this translates, during reperfusion, into the formation of protons deriving from glucose metabolism which contribute to enhancing the ischemic damage.

Studies have demonstrated how inflammation plays a key role in the genesis and progression of atherosclerosis. Vascular damage begins when the endothelium suffers insults which render it unable to maintain the normal homeostasis of the coagulation system: this is the case of endothelial dysfunction, which is closely linked to insulin resistance. Through the interaction with its receptor, insulin is able to stimulate both nitric oxide synthesis and glucose disposal. In particular two different signalling pathways are activated: phosphatidylinositolo 3-kinase pathway, which is antiatherogenic since it induces both glucose uptake and nitric oxide production, and miogen activated protein kinase pathway, which is proatherogenic, since it regulates both cell growth and endothelin-1 production.

Metabolic insulin resistance is characterised by pathway-specific impairment in phosphatidylinositol 3-kinase-dependent signaling, which in endothelium may cause not only increased mitogenesis, but also an imbalance between production of nitric oxide and secretion of endothelin-1, leading to decreased blood flow, which worsens insulin resistance. Therefore, the defects in the translation of metabolic messages can predict defects in the translation of hemodynamic messages and vice versa. Studies in humans suggest that endothelial dysfunction plays a pivotal role in the genesis of insulin resistance: altered flow-mediated vasodilatation has been demonstrated in normotensive first-degree family members of type 2 diabetic subjects; abnormalities in micro- and macrovascular reactivity have been reported in individuals at risk of type 2 diabetes with a glucose load curve still within normal limits.

A need for intensive treatment

As early as 1998 the UKPDS study noted that intensive blood-glucose control offers one certain advantage: a 1% reduction in glycosylated hemoglobin equivalent to a 1% reduction in macro- and microvascular complications in type II diabetes.

The STENO study, published in 2003, demonstrates how the intensive treatment of all risk factors present in the diabetic patient iimportant. In this prospective study, one group received conventional treatment (all risk factors treated, but not particularly intensively) whereas another received intensive treatment (all risk factors treated more intensively). At the end of the 7-year observational period 50% less cardiovascular events were recorded in the study group than in the control group. The conclusions of the study were that diabetic patients should receive intensive
treatment, particularly patients with type II diabetes and microalbuminuria.

The administration of an insulin-glucose infusion during acute coronary syndromes reduces the level of circulating free fatty acids and improves ventricular performance.
The DIGAMI study reported a 30% decrease in mortality at one year in diabetic patients with myocardial infarction who had received the infusion for 24 h, followed by multidose subcutaneous injections of insulin 4 times per day for 3 months, compared with patients who received standard care.

Van den Berghe’s study, published in 2001, highlights that intensive insulin therapy to maintain blood glucose at or below 110 mg per deciliter reduces morbidity and mortality among critically ill patients in the intensive care unit. On admission, patients were randomly assigned to receive intensive insulin therapy (maintenance of blood glucose at a level between 80 and 110 mg per deciliter) or conventional treatment (infusion of insulin only if the blood glucose level exceeded 215 mg per deciliter and maintenance of glucose at a level between 180 and 200 mg per deciliter). At 12 months, intensive insulin therapy reduced mortality during intensive care from 8.0 percent with conventional treatment to 4.6 percent and overall in-hospital mortality by 34 percent. However the better treatment of patient with diabetes during the in-hospital stay for ACS is still controversial. In fact the DIGAMI 2 study, a follow up to the first DIGAMI trial, has given different results: it confirmed that subjects with hyperglycaemia at hospital admission had an increased mortality risk, but it didn’t find advantage with a glucose-insulin-potassium (GIK) infusion followed by standard metabolic control or even routine metabolic management according to local practice. But probably this was a very difficult study to perform and the study design could be considered a reason, with other several factors that account for the results (age of patients, cardiac treatment, etc).

So, although these recent studies don’t negate the findings of the first DIGAMI study, it will require further studies to understand the better treatment for diabetic patients admitted for suspected myocardial infarction.

Cardiovascular risk assessment

Diabetic patients have an increased risk of developing cardiovascular diseases. The aim of the physician should therefore be to identify diabetic patients to assess their real risk of cardiovascular events, thus stratifying the population to suggest appropriate prevention strategies and advice on performing tests for the early diagnosis of diseases which are often underestimated but also potentially very dangerous.

Global cardiovascular risk should take into account the following features:

1. Age;
2. Gender (prior to menopause);
3. Family history of CAD or sudden death (positive if CAD or sudden death is present in first-degree family member younger than 55 years);
4. Physical activity: activity level both at work and not;
5. Smoking, including passive smoking;
6. BMI;
7. Diabetes (including family history of diabetes);
8. Microalbuminuria: albuminuria/creatininuria ratio;
9. Arterial blood pressure (including family history of hypertension):
10. Plasma lipid profile (including family history and thyroid, renal, hepatic function
11. Tests to exclude secondary dyslipidemia).

In recent decades other factors have been studied for a complete assessment of cardiovascular risk: fibrinogen, C-reactive protein, plasminogen activator inhibitor, homocysteine, lipoprotein (a) and uricemia.

Once these factors have been examined, risk stratification is essential. Patients have high cardiovascular risk if they have a probability greater than 20% of developing an event at 10 years:

• Primary prevention includes those
  – aged >55 years + 1 risk factor;
  – aged between 45 and 54 years + 2 risk factors;
  – aged between 35 and 44 + 3 risk factors.
  The risk factors are presented in Table 1.
• Secondary prevention includes ischemic cardiovascular disease, even if asymptomatic but instrumentally demonstrated:
  – all patients.

In all diabetic subjects, regardless of the risk, a number of tests should be performed for the early diagnosis of cardiovascular disease: 

Table 1

Diagnostic strategy for cardiovascular risk assessment in the diabetic patients

Physical examination, including ABI evaluation

Electrocardiogram, at rest and during exercise, above all in high risk patients

Echocolor-Doppler examination of the peripheral arteries

Laboratory examinations, including dose of markers of inflammation and homocysteine

Prevention strategies

Previously we discussed the importance of diet and physical activity as an initial approach for blood glucose control. If this is not enough, pharmacologic treatment should begin. It has been shown that maintaining low blood glucose levels reduces the likelihood of patients suffering cardiovascular events. According to recent evidence, the addition of the new hypoglycaemic agent exenatide to an existing treatment regimen in patients with type II diabetes and metabolic syndrome results in significant reductions in HbA1c along with decline in lipids, abdominal girth and body weight; furthermore, since blood pressure, C-reactive protein, and insulin resistance may improve in patients treated with exenatide, exenatide would get better cardiovascular control in diabetic patients

Several studies, as already discussed, redefine the role of thiazolidinediones in the treatment of type II diabetes; data from the CHICAGO study suggest that, independently of its glycaemic effect, pioglitazone particularly produces benefit on cardiovascular risk factors, including an increase of 14% in HDL-C, reducing atherosclerosis progression.

Furthermore, data from a current meta-analysis show that intensive glucose-lowering treatment has cardiovascular benefit compared to standard treatment for individuals with type 2 diabetes. During approximately 5 years of treatment, reduction in HbA1c concentration by 0.9% resulted in a significant 17% reduction in events of non-fatal myocardial infarction, a significant 15% reduction in events of coronary heart disease, and a non-significant 7% reduction in events of stroke.

However, this is not enough: assessing global cardiovascular risk means taking into account all the factors that can lead to disease and correcting them. This is why prevention in the diabetic patient also includes close monitoring of the lipid profile together with appropriate antihypertensive therapy. The ADA has provided evidence of a further priority for the treatment of the diabetic patient: a goal of LDL cholesterol <100 mg/dL should be achieved. Added to this is close monitoring of arterial blood pressure, a correct diet and physical activity.