Treatment of type 2 diabetes mellitus by drugs modulating the incretin system
Resumen
Diabetes, specifically type 2 diabetes mellitus (T2DM), one of the most common non-communicable diseases,poses a major health problem throughout the world.T2DM is characterized by insulin resistance, impaired glucose-induced insulin secretion and inappropriately regulated glucagon secretion which in combination eventually result in hyperglycemia and in the longer term microvascular and macrovascular complications of diabetes.Traditional treatment modalities, even multidrug approaches, for T2DM are often inadequate in getting patients to achieve glycemic goals as the disease progresses due to a steady, relentless decline in pancreatic β-cell /number/function. Furthermore, current treatment modalities are often limited by inconvenient dosing regimens, safety and tolerability issues, the latter including hypoglycemia, body weight gain, edema and gastrointestinal side effects. A novel category of antihyperglycemic therapy based on modulation of the endogenous incretin system has recently evolved. The incretins, specifically glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), are gut-derived peptides secreted in response to meals, specifically the presence and absorption of nutrients in the intestinal lumen. The incretins potentiate meal-induced insulin secretion and trophic effects on the β-cell; the GLP-1 also inhibits glucagon secretion, and suppresses food intake and appetite.The activity/level of the incretins is diminished in T2DM. Both GLP-1 and GIP are rapidly degraded by the endogenous dipeptidyl-peptidase-4 (DPP-4). Hence, stable long-acting GLP-1 analogs/GLP-1 receptor agonists (incretin mimetics) have been developed. Since, the incretin mimetics have to be injected, orally active inhibitors of DPP-4, the incretin enhancers, have also been introduced for the treatment of T2DM. The GLP-1 receptor agonists and DPP-4 inhibitors are useful in the management of T2DM because they provide effective reductions in levels of fasting plasma glucose (FPG) and postprandial glucose (PPG), partly through their actions on pathogenic causes of T2DM that are not addressed by other glucoselowering agents. In addition, the GLP-1 receptor agonists promote weight loss, whereas the DPP-4 inhibitors are mostly weight neutral, and there is a low risk of symptomatichypoglycemia with both type of agents. The GLP- 1 receptor agonists and DPP-4 inhibitors are effective as monotherapy in drug-naive patients as well as in those in whom other treatments (for example with metformin, sulfonylureas, thiazolinediones, etc.) have been inadequate to achieve glycemic control. When combined with other glucose-lowering agents, the GLP-1 receptor agonists and DPP-4 inhibitors further lower FPG and PPG levels,and hemoglobin A1c. Consequently, these agents can be used for all stages of T2DM. However, the durability and long-term safety of these drugs remains to be determined.This review focuses on the therapeutic potential of the incretin mimetics and incretin enhancers in treating T2DM.In addition, the review also presents some information on the mechanism of action(s), efficacy, pharmacokinetics, pleiotropic effects, drug interactions and adverse effects of the main drugs which modulate levels and activity ofendogenous incretins.Descargas
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