DPP-IV Inhibitors in the Management of Type II Diabetes Mellitus - Essay Example

The Utilization of Incretin Mimetics and DPP-IV Inhibitors in the Management of Type II Diabetes Mellitus The Utilization of Incretin Mimeticsand DPP-IV Inhibitors in the Management of Type II Diabetes Mellitus Abstract This review addresses the introduction of new therapeutic agents in the treatment of Type 2 diabetes mellitus based on the role of incretins in the pathophysiology of the disease. Currently, most patients on classical antidiabetic drug regimens are unable to achieve a satisfactory control of blood glucose levels, as assessed by HbA1c level measurements. Incretin mimetics like exenatide and liraglutide mimic the action of incretin hormones (glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP)), which are found in the gastrointestinal tract and function in insulin secretion. Dipeptidyl peptidase (DPP-IV) inhibitors like sitagliptin and vildagliptin suppress the degradation of the incretins, thus extending their action. The initial results obtained from clinical trials with these new agents indicate a very high promise of achieving better blood glucose control by adding them to the therapeutic arsenal for the management of type 2 diabetes mellitus. Introduction Incretin mimetics are a new class of antidiabetic agents with multiple blood sugar lowering actions that mimic the actions of incretin hormones. Incretins are peptide hormones that originate in the gastrointestinal tract. The two major incretins in humans are glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). These hormones are released during nutrient absorption, when they serve to potentiate the secretion of insulin(Nielsen) Although both GLP-1 and GIP act as incretin hormones in normal subjects, only GLP-1 can be used to treat DM2 because diabetes is often associated with a blunted or absent response to GIP. It has been shown that whereas GLP-1 levels are significantly decreased in DM2, GIP values are normal, suggesting that DM2 patients are resistant to the biological effects of GIP, rendering it relatively ineffective (2A)In mammals, GLP-1 is derived from the proglucagon peptide in mucosal L-cells of the small intestine(Drucker "Glucagon-Like Peptides") Dipeptidyl peptidase (DPP-IV) extends the bioavailability of many peptides by suppressing their break-down. Several incretin mimetics and DPP-IV inhibitors are undergoing late-stage clinical trials for the treatment of type 2 diabetes and results so far have shown some promises. Their mechanisms of action include enhancement of glucose-dependent insulin secretion; suppression of inappropriately elevated glucagon secretion; slowing of gastric emptying; and appetite suppression(Nielsen). Type 2 diabetes is characterized by the emergence of postprandial (post meal) and, subsequently, fasting hyperglycemia (fasting plasma glucose >125 mg/dl) (Nielsen; Drucker "Glucagon-Like Peptides"). Hyperglycemia results from pancreatic -cells secreting inadequate insulin to compensate for insulin-resistance in peripheral tissues(Porte and Sherwin; Weyer). Only about 33 percent of type 2 diabetes mellitus patients in the United States are able to achieve the 7% HbA1c recommended by the American Diabetes Association. However, after the administration of incretin mimetics and DPP-IV inhibitors on some of these patients, there is a significant improvement in their glycemic profile. Their after-meal blood glucose level, and subsequently their HbA1c were better(Freeman). Despite exercise, diet control and some pharmacological intervention in patients with DM 2, control of blood sugar has become increasingly difficult, especially in patients who had been on long term therapy. The progressive deterioration of the beta-cells of the pancreas, which in turn causes deficient insulin (as well as increased glucagon production) is responsible for this failure of treatment. The incretin mimetics and DPP IV inhibitors are thought to offer hope in improving the glycemic profile of patients because they act primarily to both increase insulin secretion and reduce glucagon secretion. The effects of incretins on both insulin levels and glucagon levels are glucose dependent(American Diabetes Association). Unlike sulfonylureas, which may produce insulin-stimulating effects even during periods of hypoglycemia, the effect of incretins on insulin stimulation and glucagon suppression can be suppressed in a hypoglycemic state. This suppression, in turn, may reduce hypoglycemic incidents in patients with type 2 diabetes mellitus(Brandt et al.). The physiologic role of incretins and DPP IV inhibitors in glucose regulations in both healthy and diabetics are considered regarding their use(Freeman). In non diabetic people, the secretion of insulin (insulin response) is greater after the oral administration of glucose than after the intravenous administration of glucose. This difference in insulin secretion is referred to as the "incretin effect". An impaired incretin effect is seen in patients of type 2 diabetes mellitus in response to both oral and intravenous administration of glucose(Nauck et al.). Glucagon-like peptide 1 is a dipeptidyl peptidase IV (DPP IV) inhibitor that is synthesized in the villi of the epithelium of the small intestine. Immediately after synthesis, GLP-1 can be acted on by DPP-IV. The DPP-IV inactivation process causes greater than 50% inactivation of GLP-1 within 1 to 2 minutes-before the GLP1 reaches general circulation.(Hansen et al.; Deacon, Johnsen and Holst) Dipeptidyl peptidase IV inhibitors are drugs that block the action of this degradation pathway. By blocking this action, DPP-IV inhibitors can lead to an increase in endogenous GLP-1 concentration, benefiting patients with T2DM. Several DPP-IV inhibitors are under development (Raz et al.; Pratley et al.; Fonseca et al.) The rationale for the interest in the development of these new drug classes stem from the inadequacy of currently available therapeutic agents. The National Health and Nutrition Examination Survey (NHANES) analyzed T2DM targets in two patient populations-one with 1215 patients studied from 1988 to 1994 and another with 372 patients studied from 1999 to 2000(Koro et al.). After treatment with insulin, oral antidiabetic drugs, or diet, less than 45% of the combined patient population achieved the HbA1c target of less than 7%. The low-density cholesterol (LDL-C) targets of less than 100 mg/dL in both men and women were achieved by about 36% of the patients, while the high-density lipoprotein (HDL-C) targets of 40 mg/dL in men and 55 mg/dL in women were reached by 30% of the patients. Triglyceride concentrations reaching the target of less than 150 mg/dL were achieved by about 65% of the patients. The blood pressure target of 130/80 mm Hg was achieved in about 40% of the population treated with blood pressure-lowering agents(Fan et al.). These results show that apart from glycemic control, other health targets are difficult to reach in many diabetics. Literature Review Several clinical studies have provided data on the potential utility of incretin mimetics and DPP-IV inhibitors in the management of type 2 DM. In three 30-week clinical trials that examined the effects of exenatide (an incretin mimetic that is a receptor agonist) in patients with T2DM who were also using metformin, sulfonylurea (Buse et al.), or metformin plus suThlfonylurea (Kendall et al.), exenatide was given to patients 15 to 60 minutes before two large meals. Patients using metformin who were also treated with exenatide twice a day had a further reduction of HbA1c of approximately 0.8%, compared with patients using metformin and placebo (P Read More