IMPORTANCE OF METFORMIN WITH REPAGLINIDE IN THE TREATMENT OF TYPE II DIABETES MELLITUS: A DECADEL REVIEW

Objectives of this work is to summarize the consequent development of dosage form from clinical evidence to market and its combination to control the both, insulin deficiency and resistance, to achieve the minimal hypoglycemia, repaglinide shows that no cardiac and vascular effect, antioxidant effect, no increase in blood pressure and improved lipid profile. Also shows glucose concentration dependent response, combination to exert additive/synergistic effect to achieve near normal glycemia. Most of the patients are with stimulated insulin deficiency and insulin resistance. The former can manifest the post prandial hyperglycemia and later as fasting hyperglycemia. Higher failures are from long term monotherapies and uncontrolled post prandial glucose excursions in progression of microvascular complications. Metformin monotherapy3 can reduce fasting plasma glucose levels by approximately 1.5% and gradual deterioration of glycemic control is commonly observed due to progressive s cell failure. To overcome such failures of monotherapy, a combined therapy of oral anti-diabetic agents should be considered, the recently used oral anti-diabetic agents are sulphonylureas, biguanidines & thiazolidinediones and non-sulphonylureas. The former three categories were mainly target the fasting hyperglycemia and had a limited effect on post prandial glucose levels. Later one can control both fasting plasma glucose and post prandial glucose levels. Metformin, N, N-dimethylimido dicarbonimidic diamide hydrochloride, a biguanidines derivative, is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents has been used in the treatment of type2 diabetes for nearly 50 years as insulin sensitizer, lowers fasting plasma glucose but increase in use of metformin results in lactic acidosis can occurs by accumulation of metformin. May be the factors are renal impairment, old age doses more than 2g per day. The secondary reason may be due to metformin excreted unchanged in the urine was decreased. The chronic impairment associated with acute dehydration, shock and tissue hypoxia, acute myocardial infarction, pulmonary embolism, cardiac failure and chronic liver disease. Between 1985& 2001, total 48 cases of lactic acidosis with metformin were reported to Australian adverse drug reactions advisory committee (ADRAC). The dose of the metformin should be significantly reduced under these circumstances. MECHANISM OF ACTION OF METFORMIN Metformin improves glucose tolerance in patients with type 2 diabetes; its pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease. Without doubt, metformin is the drug of choice for most of the patients with type 2 diabetes mellitus. The combination therapies can correct the metabolic defects. Long term monotherapies lost the early phase of insulin secretion, leads to increased post prandial glucose and increased insulin resistance also frequently occurs in people, who are obese and associated with metabolic syndrome. For example good treatments are achieved by only about 25% of patients treated with monotherapies such is metformin monotherapy with a mean baseline HbA1c of 8.2 to 8.44,5. Most of oral anti-hyperglycemic agents were mainly to reduce fasting plasma glucose, but controlling of both post prandial and fasting glycemia are important for improvement of metabolic disorder. Most of the studies did not mention about post prandial glycemia and glycosylated haemoglobin (HbA1c) was found to be a strong predictor of major cardiovascular events. Sulphonylureas provide optimal efficiency and few side effects at low dosages but apart from their tendency to cause hypoglycemia. £- glucosidase inhibitors can reduce the post prandial hyperglycemia but gastrointestinal side effects limits their use in combination. The best example for insulin sensitizer is metformin. Addition of acarbose to metformin, patients inadequately control decreases the post prandial glucose levels but however the complications are git side effects, bloating, abdominal discomfort, diarrhorea and