PHARMACOLOGIC TREATMENT OF DIABETES

  

PHARMACOLOGIC TREATMENT OF DIABETES

INTRODUCTION

Diabetes mellitus is a chronic disease with one of the highest social and healthcare costs and is associated with a 3-fold to 4-fold increment in cardiovascular morbidity and mortality. In fact, ischemic heart disease is the main cause of death in diabetic patients. This article places special emphasis on the therapeutic management of type 2 diabetes, which is the most prevalent type and, consequently, the modality that will cause the greatest cardiovascular morbidity and mortality in absolute figures.

The treatment of diabetes must be based on an understanding of its pathophysiology. Thus, in type 1 diabetes mellitus a severe insulin secretion deficit exists and the only treatment, at present, is the administration of insulin or insulin analog. However, type 2 diabetes mellitus is a much more complex disease, in which insulin resistance predominates in the early stages. In more advanced stages, insulin resistance persists but the deficit in insulin secretion is more evident. Therefore, the therapeutic approach will depend on the stage of the disease and characteristics of the patient.

GOALS OF TREATMENT

The general goals of the treatment of diabetes are to avoid acute decompensation, prevent or delay the appearance of late disease complications, decrease mortality, and maintain a good quality of life. As for chronic complications of the disease, it is clear that good control of glycemia makes it possible to reduce the incidence of microvascular complications (retinopathy, nephropathy, and neuropathy), whereas good control of glycemia per se does not seem to be as determinant in the prevention of macrovascular complications (ischemic heart disease, cerebrovascular disease, peripheral arteriopathy).4 In this sense, the treatment of hyperglycemia should be contemplated as part of an integral approach to the combined risk factors present in these patients (arterial hypertension [AHT], dyslipidemia, smoking). Thus, a treatment designed to obtain optimal glycemic control that neglects other cardiovascular risk factors is not very rational. In fact, it will surely be more beneficial to the diabetic patient to address cardiovascular risk factors overall, even if goals are not strictly reached for any of them.. Glycosylated hemoglobin (HbA1c) is the best index of the control of diabetes, since it provides information about the degree of glycemic control in the last two to three months and should remain below 7%. Nevertheless, in older patient or persons with a very limited life expectancy, it is not necessary to reach this therapeutic target since it entails a high risk of causing severe hypoglycemia. As for the target values for the lipid profile and blood pressure, it should be remembered that ischemic heart disease is the main cause of mortality in diabetic patients and that the cardiovascular risk of diabetic patients is similar to that of nondiabetic patients who already have ischemic heart disease. Therefore, the target values required in the diabetic population should be strict and similar to those demanded in patients with established coronary artery disease.

GENERAL PRINCIPLES OF TREATMENT

Diet and exercise are fundamental in the treatment of diabetes. Dietary recommendations must be customized for each individual to achieve the general objectives of treatment. It should be remembered that obesity is common in type 2 diabetics so one of the main objectives should be weight reduction. The calorie content of the diet should be adjusted in each individual in accordance with the body mass index and regular physical activity. As far as the nutrient proportions of the diet, it is recommended that proteins should constitute 10%-20% of calorie intake and fats less than 30%, with less than 10% saturated fats. With regard to carbohydrates, emphasis should be placed on total intake rather than on their origin, although rapidly absorbed carbohydrates should be avoided.

Physical exercise, aside from constituting a mainstay of the treatment of diabetic patients, helps to prevent the development of diabetes in adult life. In patients with type 2 diabetes, moderate regular exercise (30 min/day) is very beneficial, since it reduces glycemia by increasing sensitivity to insulin, improves the lipid profile, lowers blood pressure, contributes to weight loss, and improves cardiovascular state (decreased heart rate at rest, increased systolic volume, and decreased cardiac work). In addition, it gives the patient a sense of well being and better quality of life. The main disadvantage of exercise in diabetic patients is hypoglycemia, which can occur several hours later and should condition adjustments in the therapeutic regimen. In addition, in patients with type 1 diabetes and poor metabolic control, especially after anaerobic exercise, hyperglycemic decompensation or even ketosis can take place. Aside from disturbing glucose metabolism, physical exercise can entail other risks. Therefore, the patient´s exercise program must be planned individually taking into consideration physical capacity and potential risks.

The diabetological education that the patient receives from qualified healthcare personnel is essential in achieving therapeutic objectives. For example, self-testing of capillary blood glucose informs the patient about the time of day when glycemic control is worse and helps to identify undetected hypoglycemia. Therefore, self-tests are fundamental for making opportune modifications in therapy. In addition, the patient who knows how to modify treatment based on capillary blood glucose measurements and has received advice on how to handle various situations, such as hypoglycemia or hyperglycemic-ketotic decompensation, will require fewer hospital admissions and have a better quality of life.

Pharmacological treatment

Sulfonylureas

In the mid-1950s the first sulfonylureas (SU) were developed for commercial use (carbutamide and tolbutamide). In the mid-1960s there were already four SUs on the market (tolbutamide, acetohexamide, tolazamide and chlorpropamide), which are currently known as the first-generation SUs. At the end of the 1960s, second-generation SUs were introduced (glibenclamide, glipizide, gliquidone, and gliclazide). In 1970, the results of the University Group Diabetes Program (UGDP) were published, where it was concluded that tolbutamide was ineffective in the treatment of the diabetes and also increased cardiovascular mortality. This study had a major impact not only in the U.S., but also in various European countries, and resulted in a considerable decrease in the use of SUs. Nevertheless, since the results of the UGDP were much criticized regarding the methodology of the study, and there was evidence of its clinical effectiveness, in 1979 the American Diabetes Society decided to end restrictions of the use of SUs and they have been marketed in the U.S. since 1984. More recently, a new long-acting SU has been introduced: glimepiride.

Mechanism of action

The SUs stimulate the second phase of insulin secretion by pancreatic beta cells, that is to say, the release of preformed insulin. Therefore, the SUs require the presence of a critical mass of beta cells with insulin secretory capacity in order to act. Therefore, the SUs will not be effective in patients who are pancreatectomized or have type 1 diabetes mellitus. The SUs act through high-affinity receptors located in the pancreatic beta cells. Binding to these receptors inhibits the opening of ATP-sensitive potassium channels and avoids potassium outflow from the cell, thus triggering cell membrane depolarization. As a result, the calcium channels open, increasing intracellular calcium content and calcium binding to calmodulin, which produces microfilament contraction and the exocytosis of insulin granules.

In the heart and throughout the cardiovascular system there are also SU receptors and ATP-sensitive potassium channels, which have an important cardioprotective effect against ischemia. Closure of these channels by SUs could contribute to ischemia. Nevertheless, although this possible harmful effect seems evident in experimental studies in which high doses of SUs are administered acutely, this does not seem to be clinically relevant, as has been shown in the UKDPS study.

Clinical pharmacology. 

The SU differ in potency, duration of action, metabolism, undesirable effects, and other pharmacological properties. The second-generation SUs are more potent and have less toxicity than the first-generation SUs. All the SUs are absorbed quickly in the digestive tract, reaching peak plasma level 2-4 h after ingestion. They bind mainly to albumin, from which they can be displaced by other drugs. The metabolism is fundamentally hepatic and its metabolites are eliminated in urine and, to a lesser extent, in bile. Gliquidone is eliminated mainly in bile, so it can be used in cases of moderate kidney failure.