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METFORMIN HCL ORAL
Antidiabetic Effects
Metformin, a biguanide antidiabetic agent, is chemically and pharmacologically unrelated to sulfonylurea antidiabetic agents. Unlike sulfonylureas, biguanides such as metformin lower blood glucose concentrations in patients with type 2 (noninsulin-dependent) diabetes mellitus (NIDDM) without increasing insulin secretion from pancreatic beta cells;however, metformin is ineffective in the absence of some endogenous or exogenous insulin. Biguanides usually do not produce hypoglycemia in diabetic patients and do not affect normal blood glucose concentrations in nondiabetic individuals; metformin, even in excessive dosage, normally does not lower glucose concentrations below euglycemia.(See Acute Toxicity.) Therefore, while biguanides as well as sulfonylureas historically have been referred to as oral hypoglycemic agents,biguanides such as metformin are more appropriately referred to as antihyperglycemic agents.Type 2 diabetes mellitus is characterized by insulin resistance (impaired uptake and disposal of glucose by peripheral tissues and excessive glucose production by the liver), and abnormal insulin secretion, which may result in insulin deficiency (impaired secretion of insulin from pancreatic beta cells) during the late stage of the disease.(See Uses.) Although the underlying pathophysiology of type 2 diabetes mellitus may be similar in obese and nonobese patients with the disease, severe peripheral and hepatic insulin resistance appears to predominate in obese patients, while nonobese patients tend to have milder degrees of insulin resistance but more marked insulin deficiency; however, both abnormalities eventually occur in the course of the disease.Obesity itself often is associated with insulin resistance and an elevated rate of fatty acid oxidation, which may contribute to the glucose intolerance observed in obese patients with type 2 diabetes mellitus.Metformin lowers both basal (fasting) and postprandial glucose concentrations in patients with type 2 diabetes mellitus. Although the precise mechanism(s) by which metformin exerts its antihyperglycemic effect has not been fully established, current evidence suggests that the drug improves both peripheral and hepatic sensitivity to insulin.Improved insulin sensitivity occurs principally as a result of decreased hepatic glucose production and enhanced insulin-stimulated uptake and utilization of glucose by peripheral tissues (e.g., skeletal muscle, adipocytes);the relative contribution of these mechanisms to the antihyperglycemic effect of metformin has not been fully elucidated. Increases of 18—29% in the rate of insulin-stimulated glucose uptake (principally by skeletal muscle) have been reported in patients with type 2 diabetes mellitus with metformin hydrochloride and in normoglycemic insulin-resistant individuals in whom glucose utilization during therapy (0.5—3 g daily) generally was evaluated using a euglycemic, hyperinsulinemic clamp technique (a high-dose, continuous IV infusion of insulin administered concurrently with a glucose infusion titrated to maintain euglycemia).However, some studies in which insulin and/or glucose concentrations were not regulated during metformin therapy have reported no increases and/or even decreases in glucose uptake,possibly because of the nonphysiologic conditions inherent in the euglycemic, hyperinsulinemic clamp technique.The apparent improvement in peripheral glucose disposal with metformin therapy has been attributed principally to improved metabolism of glucose via nonoxidative (anaerobic) pathways (e.g., glycogen formation in skeletal muscle, postprandial lactate production in splanchnic tissues, lipogenesis in adipose tissue).Studies in animals and humans indicate that metformin, unlike phenformin, enhances glucose oxidation and does not affect fasting lactate production in peripheral tissues.While increases in postprandial plasma lactate concentrations have been demonstrated in type 2 diabetic patients receiving metformin alone or in combination with a sulfonylurea (e.g., glyburide), plasma lactate concentrations generally remain within the normal range during metformin therapy.Postprandial increases in serum lactate concentration observed with metformin therapy may occur as a result of increased conversion of glucose to lactate and glycogen in the splanchnic bed by metformin.While most of the lactate from the portal circulation serves as a substrate for gluconeogenesis and is thus cleared, some may escape into the systemic circulation as increased amounts are presented to the liver after a meal.Metformin does not increase lactate production or alter lactate uptake or release from skeletal muscle.Metformin reduces basal hepatic glucose production by decreasing gluconeogenesis and possibly glycogenolysis, thereby lowering fasting plasma glucose concentrations. Although some investigators have suggested that reduction of hepatic glucose production may be the drug’s principal antihyperglycemic mechanism,this effect has not been demonstrated in all studies. In vitro studies in hepatocytes indicate that metformin, at concentrations similar to or higher than those observed with therapeutic dosages, enhances insulin-induced suppression of gluconeogenesis and decreases glucagon-stimulated gluconeogenesis.Insulin secretion usually remains unchanged during metformin therapy; fasting insulin concentrations and day-long plasma insulin response remain the same or may even decrease.The magnitude of the decrease in fasting blood glucose concentrations generally is proportional to the level of fasting baseline hyperglycemia.Metformin also may decrease plasma glucose concentrations by enhancing basal glucose disposal through insulin-independent mechanisms (e.g., a decrease in free fatty acid oxidation), but such effects appear to be modest.Receptor binding of insulin is decreased in patients with type 2 diabetes mellitus, and some studies using radiolabeled insulin in rat and human cell cultures have demonstrated improved insulin binding with metformin.However, conflicting data also have been reported,and a direct correlation between increases in insulin binding and decreases in blood glucose concentration has not been observed.In in vitro studies in animal and human skeletal muscle cells or adipocytes, metformin has increased glucose uptake through enhancement of insulin-stimulated recruitment of specific glucose transporters (e.g., GLUT-1, GLUT-4) to the plasma membrane of insulin target cells (e.g., adipose tissue, skeletal muscle) and through increases in the activity of these glucose transporters.In in vitro studies using metformin concentrations within the therapeutic range, metformin has not consistently enhanced basal glucose uptake, which is noninsulin-mediated; however, in vitro data may not accurately reflect in vivo actions of the drug, and further study is needed to determine whether metformin acts through insulin-dependent or -independent pathways, or both, to affect basal glucose uptake.Metformin accumulates in the walls of the intestine but does not appear to have clinically important effects on glucose absorption.
Antilipemic Effects
Metformin has demonstrated modest favorable effects on serum lipids, which are often abnormal in patients with type 2 diabetes mellitus.In clinical studies, particularly in patients with elevated baseline serum lipid concentrations (e.g., patients with type II, type III, or type IV hyperlipoproteinemia), metformin alone or combined with a sulfonylurea antidiabetic agent lowered fasting serum triglyceride concentrations and total and LDL-cholesterol concentrations without adversely affecting other serum lipids.Modest reductions (e.g., 10—20%) in serum triglyceride concentrations noted with metformin therapy generally have been attributed to decreased hepatic synthesis of VLDL-cholesterol, particularly in patients with elevated baseline triglyceride concentrations.Characteristics of patients who are likely to exhibit a decrease in serum triglycerides with metformin therapy have not been determined, and correlation of potential antilipemic effect with the degree of glycemic control has been inconsistent.Small reductions (e.g., 5—10%) in serum total cholesterol also have been reported in some studies;these effects may be attributed to decreased LDL- or VLDL-cholesterol concentrations.Increases in HDL-cholesterol also have been reported with metformin therapy in nondiabetic patientsand in those with type 2 diabetes mellitus.Consistent changes in plasma glycerol and free fatty acid concentrations have not been reported during metformin therapy in patients with NIDDM or in nondiabetic individuals.A reduction in free fatty oxidation has been suggested as a possible mechanism for the decrease in plasma free fatty acids observed in some studies with metformin therapy.
Hematologic Effects
Metformin may exert potentially beneficial effects on the fibrinolytic system by increasing the activity of tissue-type plasminogen activator (t-PA) and/or reducing concentrations of plasminogen activator inhibitor-1 (PAI-1) in nondiabetic, hypertensive patients and in patients with type 2 diabetes mellitus; serum fibrinogen concentrations do not appear to be affected by metformin therapy.Patients with type 2 diabetes mellitus, hypertension, and obesity often have hyperinsulinemia and a high incidence of vascular disease.PAI-1 concentrations, which are regulated by insulin, may be substantially increased in patients with type 2 diabetes mellitus and in obese individuals,and it has been suggested that the reduced fibrinolytic activity associated with elevated PAI-1 concentrations may be important in the pathogenesis of vascular disease in these individuals.Metformin has been shown to increase fibrinolytic activity (as measured by blood clot lysis time, euglobulin fibrinolytic activity, and by increases in t-PA activity) in patients with coronary artery disease, obese individuals, and in patients with mild hypertension; increases in fibrinolytic activity with metformin therapy generally occur in patients who have low fibrinolytic activity at baseline.Reduced platelet density, activation, and/or aggregation;decreased blood pressure; and decreased peripheral arterial resistancealso have been reported in some normotensive patients with type 2 diabetes mellitus and in nondiabetic, mildly hypertensive patients receiving metformin; however, whether these effects are associated with the drug or are secondary to improvement in glycemic control or a reduction in body weight has not been determined.
Other Effects
Therapy with metformin may be associated with weight stabilizationor loss. Although the exact mechanism associated with such alterations in weight has not been established,suggested mechanisms include the absence of a hyperinsulinemic effect (which if present may increase appetite and/or lipogenesis)and decreased dietary intake associated with adverse GI effects of metformin. The antihyperglycemic effect of the drug does not appear to be related to weight loss in patients with type 2 diabetes mellitus receiving metformin, nor does weight loss appear to be dose related. Limited data from studies comparing metformin therapy with oral sulfonylurea (e.g., glyburide, chlorpropamide, tolbutamide) therapy indicate that patients with type 2 diabetes mellitus receiving oral sulfonylureas gained weight or lost less weight than patients receiving metformin.Metformin has little or no effect on fasting plasma glucagon, somatostatin, serum growth hormone, or serum cortisol concentration in patients with normal renal function; glucagon, growth hormone, and cortisol concentrations are elevated in patients with lactic acidosis and renal failure who have been receiving metformin.
Antidiabetic Effects
Metformin, a biguanide antidiabetic agent, is chemically and pharmacologically unrelated to sulfonylurea antidiabetic agents. Unlike sulfonylureas, biguanides such as metformin lower blood glucose concentrations in patients with type 2 (noninsulin-dependent) diabetes mellitus (NIDDM) without increasing insulin secretion from pancreatic beta cells;however, metformin is ineffective in the absence of some endogenous or exogenous insulin. Biguanides usually do not produce hypoglycemia in diabetic patients and do not affect normal blood glucose concentrations in nondiabetic individuals; metformin, even in excessive dosage, normally does not lower glucose concentrations below euglycemia.(See Acute Toxicity.) Therefore, while biguanides as well as sulfonylureas historically have been referred to as oral hypoglycemic agents,biguanides such as metformin are more appropriately referred to as antihyperglycemic agents.Type 2 diabetes mellitus is characterized by insulin resistance (impaired uptake and disposal of glucose by peripheral tissues and excessive glucose production by the liver), and abnormal insulin secretion, which may result in insulin deficiency (impaired secretion of insulin from pancreatic beta cells) during the late stage of the disease.(See Uses.) Although the underlying pathophysiology of type 2 diabetes mellitus may be similar in obese and nonobese patients with the disease, severe peripheral and hepatic insulin resistance appears to predominate in obese patients, while nonobese patients tend to have milder degrees of insulin resistance but more marked insulin deficiency; however, both abnormalities eventually occur in the course of the disease.Obesity itself often is associated with insulin resistance and an elevated rate of fatty acid oxidation, which may contribute to the glucose intolerance observed in obese patients with type 2 diabetes mellitus.Metformin lowers both basal (fasting) and postprandial glucose concentrations in patients with type 2 diabetes mellitus. Although the precise mechanism(s) by which metformin exerts its antihyperglycemic effect has not been fully established, current evidence suggests that the drug improves both peripheral and hepatic sensitivity to insulin.Improved insulin sensitivity occurs principally as a result of decreased hepatic glucose production and enhanced insulin-stimulated uptake and utilization of glucose by peripheral tissues (e.g., skeletal muscle, adipocytes);the relative contribution of these mechanisms to the antihyperglycemic effect of metformin has not been fully elucidated. Increases of 18—29% in the rate of insulin-stimulated glucose uptake (principally by skeletal muscle) have been reported in patients with type 2 diabetes mellitus with metformin hydrochloride and in normoglycemic insulin-resistant individuals in whom glucose utilization during therapy (0.5—3 g daily) generally was evaluated using a euglycemic, hyperinsulinemic clamp technique (a high-dose, continuous IV infusion of insulin administered concurrently with a glucose infusion titrated to maintain euglycemia).However, some studies in which insulin and/or glucose concentrations were not regulated during metformin therapy have reported no increases and/or even decreases in glucose uptake,possibly because of the nonphysiologic conditions inherent in the euglycemic, hyperinsulinemic clamp technique.The apparent improvement in peripheral glucose disposal with metformin therapy has been attributed principally to improved metabolism of glucose via nonoxidative (anaerobic) pathways (e.g., glycogen formation in skeletal muscle, postprandial lactate production in splanchnic tissues, lipogenesis in adipose tissue).Studies in animals and humans indicate that metformin, unlike phenformin, enhances glucose oxidation and does not affect fasting lactate production in peripheral tissues.While increases in postprandial plasma lactate concentrations have been demonstrated in type 2 diabetic patients receiving metformin alone or in combination with a sulfonylurea (e.g., glyburide), plasma lactate concentrations generally remain within the normal range during metformin therapy.Postprandial increases in serum lactate concentration observed with metformin therapy may occur as a result of increased conversion of glucose to lactate and glycogen in the splanchnic bed by metformin.While most of the lactate from the portal circulation serves as a substrate for gluconeogenesis and is thus cleared, some may escape into the systemic circulation as increased amounts are presented to the liver after a meal.Metformin does not increase lactate production or alter lactate uptake or release from skeletal muscle.Metformin reduces basal hepatic glucose production by decreasing gluconeogenesis and possibly glycogenolysis, thereby lowering fasting plasma glucose concentrations. Although some investigators have suggested that reduction of hepatic glucose production may be the drug’s principal antihyperglycemic mechanism,this effect has not been demonstrated in all studies. In vitro studies in hepatocytes indicate that metformin, at concentrations similar to or higher than those observed with therapeutic dosages, enhances insulin-induced suppression of gluconeogenesis and decreases glucagon-stimulated gluconeogenesis.Insulin secretion usually remains unchanged during metformin therapy; fasting insulin concentrations and day-long plasma insulin response remain the same or may even decrease.The magnitude of the decrease in fasting blood glucose concentrations generally is proportional to the level of fasting baseline hyperglycemia.Metformin also may decrease plasma glucose concentrations by enhancing basal glucose disposal through insulin-independent mechanisms (e.g., a decrease in free fatty acid oxidation), but such effects appear to be modest.Receptor binding of insulin is decreased in patients with type 2 diabetes mellitus, and some studies using radiolabeled insulin in rat and human cell cultures have demonstrated improved insulin binding with metformin.However, conflicting data also have been reported,and a direct correlation between increases in insulin binding and decreases in blood glucose concentration has not been observed.In in vitro studies in animal and human skeletal muscle cells or adipocytes, metformin has increased glucose uptake through enhancement of insulin-stimulated recruitment of specific glucose transporters (e.g., GLUT-1, GLUT-4) to the plasma membrane of insulin target cells (e.g., adipose tissue, skeletal muscle) and through increases in the activity of these glucose transporters.In in vitro studies using metformin concentrations within the therapeutic range, metformin has not consistently enhanced basal glucose uptake, which is noninsulin-mediated; however, in vitro data may not accurately reflect in vivo actions of the drug, and further study is needed to determine whether metformin acts through insulin-dependent or -independent pathways, or both, to affect basal glucose uptake.Metformin accumulates in the walls of the intestine but does not appear to have clinically important effects on glucose absorption.
Antilipemic Effects
Metformin has demonstrated modest favorable effects on serum lipids, which are often abnormal in patients with type 2 diabetes mellitus.In clinical studies, particularly in patients with elevated baseline serum lipid concentrations (e.g., patients with type II, type III, or type IV hyperlipoproteinemia), metformin alone or combined with a sulfonylurea antidiabetic agent lowered fasting serum triglyceride concentrations and total and LDL-cholesterol concentrations without adversely affecting other serum lipids.Modest reductions (e.g., 10—20%) in serum triglyceride concentrations noted with metformin therapy generally have been attributed to decreased hepatic synthesis of VLDL-cholesterol, particularly in patients with elevated baseline triglyceride concentrations.Characteristics of patients who are likely to exhibit a decrease in serum triglycerides with metformin therapy have not been determined, and correlation of potential antilipemic effect with the degree of glycemic control has been inconsistent.Small reductions (e.g., 5—10%) in serum total cholesterol also have been reported in some studies;these effects may be attributed to decreased LDL- or VLDL-cholesterol concentrations.Increases in HDL-cholesterol also have been reported with metformin therapy in nondiabetic patientsand in those with type 2 diabetes mellitus.Consistent changes in plasma glycerol and free fatty acid concentrations have not been reported during metformin therapy in patients with NIDDM or in nondiabetic individuals.A reduction in free fatty oxidation has been suggested as a possible mechanism for the decrease in plasma free fatty acids observed in some studies with metformin therapy.
Hematologic Effects
Metformin may exert potentially beneficial effects on the fibrinolytic system by increasing the activity of tissue-type plasminogen activator (t-PA) and/or reducing concentrations of plasminogen activator inhibitor-1 (PAI-1) in nondiabetic, hypertensive patients and in patients with type 2 diabetes mellitus; serum fibrinogen concentrations do not appear to be affected by metformin therapy.Patients with type 2 diabetes mellitus, hypertension, and obesity often have hyperinsulinemia and a high incidence of vascular disease.PAI-1 concentrations, which are regulated by insulin, may be substantially increased in patients with type 2 diabetes mellitus and in obese individuals,and it has been suggested that the reduced fibrinolytic activity associated with elevated PAI-1 concentrations may be important in the pathogenesis of vascular disease in these individuals.Metformin has been shown to increase fibrinolytic activity (as measured by blood clot lysis time, euglobulin fibrinolytic activity, and by increases in t-PA activity) in patients with coronary artery disease, obese individuals, and in patients with mild hypertension; increases in fibrinolytic activity with metformin therapy generally occur in patients who have low fibrinolytic activity at baseline.Reduced platelet density, activation, and/or aggregation;decreased blood pressure; and decreased peripheral arterial resistancealso have been reported in some normotensive patients with type 2 diabetes mellitus and in nondiabetic, mildly hypertensive patients receiving metformin; however, whether these effects are associated with the drug or are secondary to improvement in glycemic control or a reduction in body weight has not been determined.
Other Effects
Therapy with metformin may be associated with weight stabilizationor loss. Although the exact mechanism associated with such alterations in weight has not been established,suggested mechanisms include the absence of a hyperinsulinemic effect (which if present may increase appetite and/or lipogenesis)and decreased dietary intake associated with adverse GI effects of metformin. The antihyperglycemic effect of the drug does not appear to be related to weight loss in patients with type 2 diabetes mellitus receiving metformin, nor does weight loss appear to be dose related. Limited data from studies comparing metformin therapy with oral sulfonylurea (e.g., glyburide, chlorpropamide, tolbutamide) therapy indicate that patients with type 2 diabetes mellitus receiving oral sulfonylureas gained weight or lost less weight than patients receiving metformin.Metformin has little or no effect on fasting plasma glucagon, somatostatin, serum growth hormone, or serum cortisol concentration in patients with normal renal function; glucagon, growth hormone, and cortisol concentrations are elevated in patients with lactic acidosis and renal failure who have been receiving metformin.
