Diabetes mellitus is a constantly progressive disease in which:
-cell dysfunction initially leads to impaired glucose tolerance, which in some individuals further progresses to type 2 diabetes;
dysfunction of -cells begins long before the increase in glycemia and worsens after the manifestation of diabetes.
Mechanisms responsible for changes in insulin levels
normal adaptation of -cells to insulin resistance increases the secretion of insulin by each cell and increases the mass
impaired adaptation of -cells in type 2 diabetes develops as a result of a decrease in insulin secretion from each cell and a decrease in the mass of -cells
Thus, one of the main tasks in the treatment of type 2 diabetes is to preserve or slow down the loss of function of -cells.
Insulin therapy has always been considered, and is still considered, the method of choice for this group of patients when diet therapy, exercise, and oral hypoglycemic therapy can no longer maintain normal blood sugar levels. At present, it is believed that earlier administration of insulin helps to preserve and slow down the loss of function and weight
b-cells. Insulin therapy usually begins with the appointment of long-acting insulins or insulin analogues, or with the appointment of ready-made insulin mixtures containing both basal and short-acting insulin components (6, 7, 8). However, the intensification of insulin therapy is often accompanied by weight gain and an increase in the frequency of hypoglycemic conditions, which are known barriers to improving glycemic control (9, 10). For example, approximately 60-90% of patients with type 2 diabetes are overweight or obese at the time of diagnosis. Most options for hypoglycemic therapy, with the exception of biguanide, Metformin hydrochloride, lead to weight gain. Thus, excess weight leads to an increased risk of developing cardiovascular diseases and at the same time is an obstacle to effective treatment of diabetes.
Exenatide is the first drug from the class of incretin mimetics that is recommended for combined administration with Metformin or sulfonylureas, but has never previously been recommended as a substitute for insulin therapy in patients with type 2 diabetes who are indicated for insulin therapy. It is important that the mechanism of action of exenatide differs significantly from the mechanism of action of insulin. Exenatide stimulates the secretion of endogenous insulin by a glucose-dependent mechanism, suppresses the secretion of glucagon, slows down gastric emptying, and reduces food intake (11, 12). Studies involving (13, 14) patients who cannot maintain satisfactory glycemic indicators on oral hypoglycemic therapy have shown that it is possible to achieve similar indicators of improving glycemic control when evaluating HbA1c levels when prescribing both exenatide and insulin. The administration of exenatide also helps to reduce postprandial glycemia and fasting glycemia, but, unlike insulin therapy, is associated with a decrease in body weight. However, there is currently very little evidence to support the possible replacement of insulin with exenatide in patients with type 2 diabetes
(15, 16, 17). Figure 1 (adapted from Keffer et al, J Clin Invest, 1998, 101:515-20) shows two main effects of GPP-1 on the gastrointestinal tract and CNS.
Based on data from preclinical and clinical studies, the following results were obtained when prescribing exenatide. In animal studies, weight loss was observed in rats, pygmy pigs, and rhesus macaques. According to clinical studies, patients with type 2 diabetes mellitus showed a decrease in glycemia and weight, while weight loss was dose-dependent. The effect of exenatide therapy on the weight of patients is an undeniable advantage of therapy. There were questions that weight loss in patients may be due to the development of complications from the gastrointestinal tract, but later it was shown that the administration of exenatide led to weight loss regardless of the development of side effects.
Review of exenatide research based on the materials of the European Congress for the study of diabetes mellitus, which was held in Amsterdam
September 18-21, 2007.
Recently, many new data on exenatide therapy have appeared, some of which were described at the last European Congress on the study of diabetes mellitus and which will be given below. Okerson T. and colleagues (18) presented data on the effect of exenatide on markers of liver function for 3 years in patients with type 2 diabetes. The authors concluded that in patients with diabetes mellitus
2 types that were treated with exenatide showed improvement in biochemical parameters of liver function with simultaneous reduction in HbA1c and weight. The authors suggest conducting further studies on the possibility of improving the course of fat hepatosis of non-alcoholic origin. Gedulin B. and colleagues (19) also conducted a comparative study on the effects of sitagliptin and exenatide on food intake, body weight, glucose-dependent insulin secretion, and gastric emptying in rodents. Data were obtained on the more pronounced in vivo effectiveness of exenatide compared to sitagliptin for the effects of certain physiological parameters that contribute to the improvement of glucoregulation. D. Parkes and colleagues (20) for the first time obtained data on the long-term antihypertensive effect of exenatide on the example of a model of glucocorticoid-induced metabolic syndrome without affecting food intake or body weight. Various suggestions have been made about possible mechanisms of action of exenatide, one of which was suggested by Ionut V. (21), and consisted of hormone-independent glycemia due to pancreatic effect through effects on GPP-1 receptors in the portal liver system. Activation of these portal receptors via a neutral mechanism can increase glucose clearance regardless of islet hormones. The work of MacConell L. and colleagues (22) was devoted to the evaluation of the pharmacokinetics and pharmacodynamics of exenatide with the mechanism of long-term release of the drug after single and multiple dosing. The authors concluded that the pharmacokinetics of the drug with a single administration predetermined the pharmacokinetics of the weekly dose. A weekly dose of exenatide with weekly administration with maintenance of therapeutic doses of the drug in the blood was well tolerated. Dose-dependent effects on postprandial glycemic indicators and body weight, but not on fasting glycemic indicators, indicate differentiated dose-response relationships when evaluating the pharmacology of exenatide. These data show that exenatide with a prolonged release mechanism (Exenatide LAR) provides an adequate concentration in the bloodstream while maintaining the main pharmacodynamic action of exenatide.
According to a number of clinical studies, it has been shown that exenatide monotherapy leads to weight loss and when added to the treatment of hypoglycemic therapy with Metformin, sulfonylureas and thiazolidinediones (24-26). The greatest weight loss was observed with the additional appointment of exenatide to Metformin therapy. Data from two-year open – label studies with extended therapy time showed that the weight loss achieved with exenatide therapy persists, and the weight continues to decrease, which leads to an improvement in risk indicators from the cardiovascular system (27).
Side effects and safety of exenatide therapy
Moderate nausea (33.2%) and vomiting (15%) were observed during exenatide therapy. The frequency of side effects from the gastrointestinal tract in the exenatide therapy group was higher than in the aspart insulin therapy group. The average incidence of side effects was similar between the therapy groups. One of the advantages of exenatide in the treatment of patients with diabetes mellitus