incretins and Renal-Insufficiency

Incretin-based therapies include pharmacologic agents such as glucagon like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors which exert potent anti-hyperglycemic effects in the diabetic milieu. They are also shown to have extra-pancreatic effects. Renin-angiotensin system is part of the endocrine system which is widely distributed in the body and is closely involved in water and electrolyte homeostasis as well as renal and cardiovascular functions. Hence the renin-angiotensin system is the main target for treating patients with various renal and cardiovascular disorders. There is growing evidence that incretins have modulatory effects on renin-angiotensin system activity; thereby, can be promising therapeutic agents for the management of renal and cardiovascular disorders. But the exact molecular interactions between incretins and renin-angiotensin system are not clearly understood. In this current study, we have reviewed the possible molecular mechanisms by which incretins modulate renin-angiotensin system activity.

Topics: Blood Pressure; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Gene Expression Regulation; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Renal Insufficiency; Renin-Angiotensin System; Treatment Outcome

The continuously increasing incidence of diabetes worldwide has attracted the attention of the scientific community and driven the development of a novel class of antidiabetic drugs that can be safely and effectively used in diabetic patients. Of particular interest in this context are complications associated with diabetes, such as renal impairment, which is the main cause of high cardiovascular morbidity and mortality in diabetic patients. Intensive control of glucose levels and other risk factors associated with diabetes and metabolic syndrome provides the foundations for both preventing and treating diabetic nephropathy. Dipeptidyl peptidase-4 (DPP-4) inhibitors represent a highly promising novel class of oral agents used in the treatment of type 2 diabetes mellitus that may be successfully combined with currently available antidiabetic therapeutics in order to achieve blood glucose goals. Beyond glycemic control, emerging evidence suggests that DPP-4 inhibitors may have desirable off-target effects, including renoprotection. All type 2 diabetes mellitus patients with impaired renal function require dose adjustment of any DPP-4 inhibitor administered except for linagliptin, for which renal excretion is a minor elimination pathway. Thus, linagliptin is the drug most frequently chosen to treat type 2 diabetes mellitus patients with renal failure.

Topics: Blood Glucose; Diabetes Complications; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Incretins; Linagliptin; Renal Insufficiency

This review mainly focuses on metformin, and considers oral antidiabetic therapy in kidney transplant patients and the potential benefits and risks of antidiabetic agents other than metformin in patients with chronic kidney disease (CKD). In view of the debate concerning lactic acidosis associated with metformin, this review tries to solve a paradox: metformin should be prescribed more widely because of its beneficial effects, but also less widely because of the increasing prevalence of contraindications to metformin, such as reduced renal function. Lactic acidosis appears either as part of a number of clinical syndromes (i.e., unrelated to metformin), induced by metformin (involving an analysis of the drug's pharmacokinetics and mechanisms of action), or associated with metformin (a more complex situation, as lactic acidosis in a metformin-treated patient is not necessarily accompanied by metformin accumulation, nor does metformin accumulation necessarily lead to lactic acidosis). A critical analysis of guidelines and literature data on metformin therapy in patients with CKD is presented. Following the present focus on metformin, new paradoxical issues can be drawn up, in particular: (i) metformin is rarely the sole cause of lactic acidosis; (ii) lactic acidosis in patients receiving metformin therapy is erroneously still considered a single medical entity, as several different scenarios can be defined, with contrasting prognoses. The prognosis for severe lactic acidosis seems even better in metformin-treated patients than in non-metformin users.

Topics: Acidosis, Lactic; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Incretins; Insulin; Kidney Transplantation; Metformin; Renal Insufficiency; Sulfonylurea Compounds; Thiazolidinediones

Elderly patients and patients with renal impairment present unique challenges in the management of diabetes mellitus. Impaired renal function is a common comorbidity (or complication) associated with type 2 diabetes, as well as a complicating factor in the treatment of the disease. Renal insufficiency, which can result in elevated plasma concentrations of pharmaceutical agents, may preclude the use of some antihyperglycemic medications and require that the dosages of others be reduced. Failure to select and dose medications carefully in these patients may increase the risk of hypoglycemia and other adverse effects. For example, elevated plasma concentrations of some sulfonylureas may increase the risk of hypoglycemia. Because patients with chronic renal insufficiency tend to retain fluids, treatment with a thiazolidinedione--a class of agents associated with fluid retention--may exacerbate the risk of edema. Older patients with type 2 diabetes--like patients with renal insufficiency an important and populous subgroup--also have issues with therapy selection and dosing regimens. As a result of the effects of aging on kidney function, older patients may also be subject to elevated plasma levels with consequent additional risk of hypoglycemia and other adverse events. Because older patients tend to be treated with multiple medications for multiple comorbidities, it becomes challenging to design regimens that avoid or reduce the risk of drug-drug interactions. For both older patients and patients with chronic renal insufficiency, the most important drug-related adverse effect to avoid is hypoglycemia. Accordingly, incretin-based agents have an advantage because they are unlikely to cause hypoglycemia.

Topics: Diabetes Mellitus, Type 2; Humans; Incretins; Renal Insufficiency; Treatment Outcome