Glipizide-Metformin (glipizide/metformin HCl)

Glipizide is a sulfonylurea antidiabetic agent.

Metformin hydrochloride is a biguanide antidiabetic agent.

The precise mechanism(s) of hypoglycemic action of sulfonylurea antidiabetic agents has not been clearly established, but the drugs, including glipizide, initially appear to lower blood glucose concentration principally by binding to the sulfonylurea receptor in the pancreatic beta cell plasma membrane, leading to closure of the ATP-sensitive potassium channel and stimulating the release of insulin. Glipizide also appears to enhance peripheral insulin action at postreceptor (probably intracellular) site(s) during short-term therapy. Like other sulfonylureas, glipizide alone is ineffective in the absence of functioning beta cells.

The glipizide-induced increase in glucose- or meal-stimulated secretion of endogenous insulin appears to be sustained during prolonged administration and has persisted in most diabetic patients for up to at least 2 years. The prolonged effect of glipizide on secretion of endogenous insulin is unlike that of most other sulfonylureas, but its clinical importance in the long-term efficacy of the drug remains to be clearly determined; while this effect likely contributes to the improvement in glucose tolerance in many patients during prolonged glipizide therapy, it alone does not appear to be sufficient for a long-term, effective response to the drug and glucose tolerance can improve in some patients without an increase in insulin secretion. Fasting plasma insulin concentrations are usually not increased during prolonged glipizide therapy but have been reported to be slightly increased in some patients.

The drug generally does not appear to alter glucagon secretion. During prolonged administration of sulfonylureas, including glipizide, extrapancreatic effects appear to substantially contribute to the hypoglycemic action of the drugs. Many extrapancreatic effects of the drugs have been proposed and/or studied, but the principal effects appear to include enhanced peripheral sensitivity to insulin and reduction of basal hepatic glucose production; however, the nature of the long-term hypoglycemic effect and the mechanism(s) involved remain to be fully elucidated.

There is evidence that glipizide enhances the peripheral action of insulin at postreceptor (probably intracellular) site(s) during long-term administration, and this appears to be a principal mechanism of action during prolonged therapy. An increase in insulin binding in erythrocytes obtained from diabetic patients receiving long-term therapy with the drug has also been reported. On a weight basis, glipizide is one of the most potent of the sulfonylurea antidiabetic agents; although an exact dosage relationship does not exist, a daily glipizide dose of 5 mg controls blood glucose concentration to approximately the same degree as daily doses of glyburide 2.5-5 mg.

Glipizide is rapidly and essentially completely absorbed from the GI tract. First-pass metabolism of glipizide appears to be minimal, and the absolute oral bioavailability of the drug is reported to be 80-100%. Food delays the absorption of glipizide but does not affect peak serum concentrations achieved or the extent of absorption of the drug.

Following oral administration of a single 5-mg dose of glipizide as conventional (immediate-release) tablets in fasting and nonfasting individuals, the drug appears in plasma within 15-30 minutes and average peak plasma concentrations are attained within 1-3 hours (range: 1-6 hours). Peak serum concentrations generally are delayed 20-40 minutes in the nonfasting state compared with the fasting state. A few reports indicate that biphasic peak serum concentrations may occur in some patients, suggesting that the drug may undergo enterohepatic circulation.

The AUC for glipizide increases in proportion to increasing doses. Following single oral doses in fasting healthy individuals, the hypoglycemic action of glipizide generally begins within 15-30 minutes and is maximal within 1-2 hours. In nonfasting diabetic patients, the hypoglycemic action of a single morning dose of the drug may persist for up to 24 hours.

Distribution of glipizide into human body tissues and fluids has not been fully characterized. In humans, small amounts of glipizide are apparently distributed into bile and very small amounts are distributed into erythrocytes and saliva. It is not known if glipizide is distributed into milk in humans.

Glipizide is approximately 92-99% bound to plasma proteins. Unlike the protein binding of some other sulfonylurea antidiabetic agents and like that of glyburide, the protein binding of glipizide appears to be principally nonionic; consequently, glipizide may be less likely to be displaced from binding sites by, or displace from binding sites, other highly protein-bound drugs whose protein binding is ionic in nature. Following oral administration in healthy individuals or diabetic patients with normal renal and hepatic function, the terminal elimination half-life of glipizide averages 3-4.7 hours (range: 2-7.3 hours).

The terminal elimination half-life of total glipizide metabolites reportedly ranges from 2-6 hours in patients with normal renal and hepatic function. Serum glipizide concentrations may be increased in patients with renal or hepatic insufficiency. The terminal elimination half-life of total glipizide metabolites may be prolonged to greater than 20 hours in patients with impaired renal function; however, since glipizide metabolites are considered essentially inactive, this is probably of little clinical importance, at least in patients with moderate renal impairment.

Glipizide is almost completely metabolized, mainly in the liver. The drug is metabolized principally at the cyclohexyl ring to 4-trans-hydroxyglipizide; the drug is also metabolized to the 3-cis-hydroxy derivative, N-(2-acetylaminoethylphenylsulfonyl)-N'-cyclohexyl urea (DCDA), and at least 2 unidentified metabolites. There is no information regarding the effects of hepatic impairment on the disposition of glipizide.

However, since glipizide is highly protein bound and hepatic biotransformation is the predominant route of elimination, the pharmacokinetics and/or pharmacodynamics of glipizide may be altered in patients with hepatic impairment. Glipizide and its metabolites are excreted principally in urine. The drug and its metabolites are also excreted in feces, apparently almost completely via biliary elimination; only small amounts may be excreted in feces as unabsorbed drug following oral administration.

Most urinary excretion occurs within the first 6-24 hours after oral administration of the drug. Following oral administration of a single 5-mg dose of glipizide in individuals with normal renal and hepatic function, approximately 60-90% of the dose is excreted in urine as unchanged drug and metabolites within 24-72 hours and about 5-20% is excreted in feces within 24-96 hours; less than 10% of a dose is excreted in urine as unchanged drug within 24 hours, about 20-60% as the 4-trans-hydroxy metabolite, 10-15% as the 3-cis-hydroxy metabolite, 1-2% as DCDA, and the remainder as unidentified metabolites. The effects have not been fully evaluated, but elimination of glipizide may be reduced in patients with impaired renal and/or hepatic function.

Limited data indicate that renal excretion and terminal elimination half-life of glipizide metabolites are substantially decreased and increased, respectively, in patients with severe renal impairment. Following single-dose administration in older diabetic patients, there were no differences in glipizide pharmacokinetics compared with that in younger healthy individuals.

Metformin a biguanide antidiabetic agent, lowers both basal (fasting) and postprandial glucose concentrations in patients with type 2 diabetes mellitus. Biguanides usually do not produce hypoglycemia in patients with diabetes and do not affect normal blood glucose concentrations in nondiabetic individuals; metformin, even in excessive dosage, normally does not lower glucose concentrations below euglycemia, although hypoglycemia occasionally may occur with overdosage. Although the precise mechanism(s) by which metformin exerts its antihyperglycemic effect has not been fully established, current evidence suggests that the medication 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. 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). 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 medication'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.

Metformin is slowly and incompletely absorbed from the GI tract, mainly from the small intestine; absorption is complete within 6 hours. The absolute oral bioavailability of the medication under fasting conditions is reported to be approximately 50-60% with metformin hydrochloride doses of 0.5-1.5 g; binding of the medication to the intestinal wall may explain the difference between the amount of medication absorbed (as determined by the urinary and fecal excretion of unchanged drug) and the amount bioavailable in some studies. In single-dose studies with metformin hydrochloride immediate-release tablets at doses of 0.5-1.5 g or 0.85-2.55 g, plasma metformin concentrations did not increase in proportion to increasing doses, suggesting an active saturable absorption process.

Food decreases and slightly delays the absorption of metformin immediate-release tablets; the clinical importance of these effects is unknown. Administration of metformin hydrochloride immediate-release tablets with food reportedly has decreased peak plasma concentrations of the medication by 35-40%, reduced area under the plasma concentration-time curve (AUC) by 20-25%, and delayed time to peak plasma concentration by 35-40 minutes compared with these parameters in fasting individuals receiving this metformin preparation. However, in one study, concomitant administration of the medication as immediate-release tablets with food had a less pronounced effect (average reduction in bioavailability of 10%) on absorption.

Following oral administration of metformin hydrochloride as an extended-release tablet preparation with food, the extent of absorption (as measured by AUC) increased by approximately 50%, but peak plasma concentrations and time to achieve peak plasma concentrations were not altered. However, following administration of another metformin hydrochloride extended-release preparation (Glumetza(R)) with low-fat and high-fat meals, the AUCs increased by 38 and 73%, respectively, compared with those in the fasting state. Following oral administration of metformin hydrochloride as an immediate-release oral solution with food, the extent of absorption (as measured by AUC) increased by approximately 17-21% compared with administration in the fasted state.

Food delayed the time to achieve peak plasma concentrations by 1.4 hours compared with administration in the fasted state. The pharmacokinetics of immediate-release metformin oral solution were not appreciably affected by the fat content of meals. Following administration of a single 500-mg dose of metformin hydrochloride as immediate-release tablets with food in pediatric patients (12-16 years of age) with type 2 diabetes mellitus, mean peak plasma concentrations and AUC differed less than 5% compared with those values in healthy adults; all patients had normal renal function.

In pediatric patients 11-16 years of age receiving a single dose of metformin in fixed combination with glyburide, mean dose-normalized glyburide peak plasma concentration and AUC differed less than 6% from historical values in healthy adults.

Following oral administration of 0.5-1.5 g of metformin hydrochloride as immediate-release tablets in healthy individuals or in patients with type 2 diabetes mellitus, peak plasma drug concentrations usually are attained within 2-4 hours. Following oral administration of a single dose of metformin hydrochloride as extended-release tablets, peak plasma drug concentrations usually are attained within a median of 7 hours. Following administration of a single dose (0.5-2.5 g) of another extended-release preparation (Glumetza(R)), peak plasma drug concentrations usually are attained within 7-8 hours.

Peak plasma concentrations following administration of metformin extended-release tablets are approximately 20% lower than those following administration of the same dose as immediate-release tablets. The extent of absorption of metformin hydrochloride 2 g once daily as extended-release tablets is similar to that following administration of 1 g of the drug twice daily as immediate-release tablets. Steady-state plasma concentrations with usual dosages of metformin hydrochloride as immediate-release tablets (e.g., 1.5-2.55 g daily in 1 to 3 divided doses) are attained within 24-48 hours.

Satisfactory control of blood or plasma glucose concentration may occur within a few days to 1 week following initiation of metformin therapy in patients with type 2 diabetes mellitus, but the maximum antihyperglycemic effect may be delayed for up to 2 weeks. Following discontinuance of metformin therapy, blood glucose concentration increases within 2 weeks.

Bioequivalence has been demonstrated between the fixed combination of metformin and sitagliptin and each agent given concurrently. Bioequivalence also has been demonstrated between the fixed combination of immediate-release metformin and pioglitazone (ActoPlus Met(R)) and each agent (immediate-release metformin (Glucophage(R)) and pioglitazone (Actos(R))) given concurrently. Results of a bioequivalence study indicate that the fixed-combination tablets of immediate-release metformin hydrochloride and canagliflozin are bioequivalent to the corresponding doses of metformin hydrochloride and canagliflozin given as individual tablets under fed conditions.

Bioequivalence between the fixed combination of extended-release metformin hydrochloride and dapagliflozin (Xigduo(R) XR) and each agent (extended-release metformin hydrochloride and dapagliflozin) given concurrently as separate tablets has been demonstrated; however, the relative bioavailability of the fixed combination of extended-release metformin hydrochloride and dapagliflozin (Xigduo(R) XR) and concomitantly administered dapagliflozin and immediate-release metformin hydrochloride has not been established. Bioequivalence between the fixed-combination tablets of immediate-release metformin hydrochloride and empagliflozin and the corresponding doses of metformin hydrochloride and empagliflozin as individual tablets also has been established. In healthy individuals who received the extended-release metformin hydrochloride preparation (Glumetza(R)) in a single-dose crossover study, a 1-g tablet has been shown to be bioequivalent to two 500-mg tablets based on peak plasma concentrations and AUC.

Metformin is distributed rapidly in animals and humans into peripheral body tissues and fluids, particularly the GI tract; the medication also appears to distribute slowly into erythrocytes and into a deep tissue compartment (probably GI tissues). The highest tissue concentrations of metformin (at least 10 times the plasma concentration) occur in the GI tract (e.g., esophagus, stomach, duodenum, jejunum, ileum), with lower concentrations (twice the plasma concentration) occurring in kidney, liver, and salivary gland tissue. The medication distributes into salivary glands with a half-life of about 9 hours.

Metformin concentrations in saliva are 10-fold lower than those in plasma and may be responsible for the metallic taste reported in some patients. Any local effect of metformin on glucose absorption in the GI tract may be associated with the relatively high GI concentrations of the medication compared with those in other tissues. Limited data indicate that metformin is distributed into breast milk in humans.

Metformin is negligibly bound to plasma proteins.

Following oral administration of metformin hydrochloride (0.5-1.5 g) as immediate-release tablets in healthy individuals or in patients with type 2 diabetes mellitus, plasma concentrations decline in a triphasic manner. The principal plasma elimination half-life of metformin averages approximately 6.2 hours; 90% of the medication is cleared within 24 hours in patients with normal renal function. The decline in plasma metformin concentrations is slower after oral than after IV administration, indicating that elimination is absorption rate-limited.

Urinary excretion data and data from whole blood indicate a slower terminal-elimination phase half-life of 8-20 hours (e.g., 17.6 hours) suggesting that the erythrocyte mass may be a compartment of distribution. Metformin is not metabolized in the liver or GI tract and is not excreted in bile; no metabolites of the medication have been identified in humans. Renal elimination of metformin involves glomerular filtration and secretion by the proximal convoluted tubules as unchanged drug.

Renal clearance is approximately 3.5 times greater than creatinine clearance, indicating that tubular secretion is the principal route of metformin elimination. Renal impairment results in increased peak plasma concentrations of metformin, a prolonged time to peak plasma concentration, and a decreased volume of distribution. Renal clearance is decreased in patients with renal impairment (as measured by decreases in creatinine clearance) and, because of reduced renal function with age, in geriatric individuals.

In geriatric individuals, decreased renal and plasma clearance of metformin results in increased plasma concentrations of metformin; volume of distribution remains unaffected. The pharmacokinetics of metformin in patients with normal renal function do not appear to be affected by sex, race, or the presence of diabetes mellitus.

USES: This diabetes medication is a combination of 2 drugs (glipizide and metformin). It is used along with a diet and exercise program to control high blood sugar in patients with type 2 diabetes. Glipizide is a sulfonylurea and works by stimulating the release of your body's natural insulin and by decreasing the amount of sugar that your liver makes.

Metformin is a biguanide and works by decreasing the amount of sugar that your liver makes and that your stomach/intestines absorb. Both of these medications work by helping to restore your body's proper response to the insulin you naturally produce. Controlling high blood sugar helps prevent kidney damage, blindness, nerve problems, loss of limbs, and sexual function problems.

Proper control of diabetes may also lessen your risk of a heart attack or stroke.

Generic name: glipizide/metformin HCl
Pronunciation: (GLIP-i-zide/met-FOR-min)

The following indications are listed for Glipizide-Metformin:

• Type 2 Diabetes Mellitus

Also known as: Adult Onset Diabetes, Adult Onset Diabetes Mellitus, Adult Onset Dm, Diabetes Mellitus Type 2, Diabetes Mellitus Type Ii, Ketosis-Resistant Diabetes Mellitus, Ketosis-Resistant Dm, Maturity Onset Diabetes, Maturity Onset Diabetes Mellitus, Non-Insulin Dependent Diabetes Mellitus, Non-Insulin-Dependent Diabetes Mellitus, Type Ii Diabetes Mellitus.

No ICD codes are available for this drug.