"The US Food and Drug Administration (FDA) has approved a once-daily oral combination of linagliptin and metformin hydrochloride (Jentadueto XR, Boehringer Ingelheim and Eli Lilly & Co) for treating adults with type 2 diabetes."...
Mechanism of Action
METAGLIP combines glipizide and metformin hydrochloride, 2 antihyperglycemic agents with complementary mechanisms of action, to improve glycemic control in patients with type 2 diabetes.
Glipizide appears to lower blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. Extrapancreatic effects may play a part in the mechanism of action of oral sulfonylurea hypoglycemic drugs. The mechanism by which glipizide lowers blood glucose during long-term administration has not been clearly established. In man, stimulation of insulin secretion by glipizide in response to a meal is undoubtedly of major importance. Fasting insulin levels are not elevated even on long-term glipizide administration, but the postprandial insulin response continues to be enhanced after at least 6 months of treatment.
Metformin hydrochloride is an antihyperglycemic agent that improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin hydrochloride decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
Absorption and Bioavailability
Metaglip (glipizide and metformin)
In a single-dose study in healthy subjects, the glipizide and metformin components of METAGLIP (glipizide and metformin) 5 mg/500 mg were bioequivalent to coadministered GLUCOTROL® and GLUCOPHAGE®. Following administration of a single METAGLIP (glipizide and metformin) 5 mg/500 mg tablet in healthy subjects with either a 20% glucose solution or a 20% glucose solution with food, there was a small effect of food on peak plasma concentration (Cmax) and no effect of food on area under the curve (AUC) of the glipizide component. Time to peak plasma concentration (Tmax) for the glipizide component was delayed 1 hour with food relative to the same tablet strength administered fasting with a 20% glucose solution. Cmax for the metformin component was reduced approximately 14% by food whereas AUC was not affected. Tmax for the metformin component was delayed 1 hour after food.
Gastrointestinal absorption of glipizide is uniform, rapid, and essentially complete. Peak plasma concentrations occur 1 to 3 hours after a single oral dose. Glipizide does not accumulate in plasma on repeated oral administration. Total absorption and disposition of an oral dose was unaffected by food in normal volunteers, but absorption was delayed by about 40 minutes.
The absolute bioavailability of a 500 mg metformin hydrochloride tablet given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of metformin tablets of 500 mg and 1500 mg, and 850 mg to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower peak concentration and a 25% lower AUC in plasma and a 35-minute prolongation of time to peak plasma concentration following administration of a single 850 mg tablet of metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.
Protein binding was studied in serum from volunteers who received either oral or intravenous glipizide and found to be 98% to 99% 1 hour after either route of administration. The apparent volume of distribution of glipizide after intravenous administration was 11 liters, indicative of localization within the extracellular fluid compartment. In mice, no glipizide or metabolites were detectable autoradiographically in the brain or spinal cord of males or females, nor in the fetuses of pregnant females. In another study, however, very small amounts of radioactivity were detected in the fetuses of rats given labeled drug.
The apparent volume of distribution (V/F) of metformin following single oral doses of 850 mg averaged 654±358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin, steady state plasma concentrations of metformin are reached within 24 to 48 hours and are generally < 1 μg/mL. During controlled clinical trials, maximum metformin plasma levels did not exceed 5 μg/mL, even at maximum doses.
Metabolism and Elimination
The metabolism of glipizide is extensive and occurs mainly in the liver. The primary metabolites are inactive hydroxylation products and polar conjugates, and are excreted mainly in the urine. Less than 10% unchanged glipizide is found in the urine. The half-life of elimination ranges from 2 to 4 hours in normal subjects, whether given intravenously or orally. The metabolic and excretory patterns are similar with the 2 routes of administration, indicating that first-pass metabolism is not significant.
Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted 4 unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. Renal clearance (see Table 1) is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life isapproximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.
Patients With Type 2 Diabetes
In the presence of normal renal function, there are no differences between single- or multiple-dose pharmacokinetics of metformin between patients with type 2 diabetes and normal subjects (see Table 1), nor is there any accumulation of metformin in either group at usual clinical doses.
The metabolism and excretion of glipizide may be slowed in patients with impaired hepatic function (see PRECAUTIONS). No pharmacokinetic studies have been conducted in patients with hepatic insufficiency for metformin.
The metabolism and excretion of glipizide may be slowed in patients with impaired renal function (see PRECAUTIONS).
In patients with decreased renal function (based on creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance (see Table 1; also, see WARNINGS).
There is no information on the pharmacokinetics of glipizide in elderly patients.
Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total plasma clearance is decreased, the half-life is prolonged, and Cmax is increased, when compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see Table 1). Metformin treatment should not be initiated in patients ≥ 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced.
Table 1: Select Mean (±SD) Metformin Pharmacokinetic
Parameters Following Single or Multiple Oral Doses of Metformin
|Subject Groups: Metformin Dosea (Number of Subjects)||Cmaxb (μg/mL)||Tmaxc (hrs)||Renal Clearance (mL/min)|
|Healthy, Nondiabetic Adults:|
|500 mg SDd (24)||1.03 (±0.33)||2.75 (±0.81)||600 (±132)|
|850 mg SD (74)e||1.60 (±0.38)||2.64 (±0.82)||552 (±139)|
|850 mg t.i.d. for 19 dosesf (9)||2.01 (±0.42)||1.79 (±0.94)||642 (±173)|
|Adults with Type 2 Diabetes:|
|850 mg SD (23)||1.48 (±0.5)||3.32 (±1.08)||491 (±138)|
|850 mg t.i.d. for 19 dosesf (9)||1.90 (±0.62)||2.01 (±1.22)||550 (±160)|
|Elderlyg, Healthy Nondiabetic Adults:|
|850 mg SD (12)||2.45 (±0.70)||2.71 (±1.05)||412 (±98)|
|Renal-impaired Adults: 850 mg SD|
|Mild (CLcrh 61-90 mL/min) (5)||1.86 (±0.52)||3.20 (±0.45)||384 (±122)|
|Moderate (CLcr 31-60 mL/min) (4)||4.12 (±1.83)||3.75 (±0.50)||108 (±57)|
|Severe (CLcr 10-30 mL/min) (6)||3.93 (±0.92)||4.01 (±1.10)||130 (±90)|
|a All doses given fasting except
the first 18 doses of the multiple-dose studies
b Peak plasma concentration
c Time to peak plasma concentration
d SD=single dose
e Combined results (average means) of 5 studies: mean age 32 years (range 23-59 years)
f Kinetic study done following dose 19, given fasting
g Elderly subjects, mean age 71 years (range 65-81 years)
h CLcr=creatinine clearance normalized to body surface area of 1.73 m²
No data from pharmacokinetic studies in pediatric subjects are available for glipizide.
After administration of a single oral GLUCOPHAGE 500 mg tablet with food, geometric mean metformin Cmax and AUC differed < 5% between pediatric type 2 diabetic patients (12-16 years of age) and gender- and weight-matched healthy adults (20-45 years of age), all with normal renal function.
There is no information on the effect of gender on the pharmacokinetics of glipizide.
Metformin pharmacokinetic parameters did not differ significantly in subjects with or without type 2 diabetes when analyzed according to gender (males=19, females=16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin was comparable in males and females.
No information is available on race differences in the pharmacokinetics of glipizide.
No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51), and Hispanics (n=24).
Patients with Inadequate Glycemic Control on Diet and Exercise Alone
In a 24-week, double-blind, active-controlled, multicenter international clinical trial, patients with type 2 diabetes, whose hyperglycemia was not adequately controlled with diet and exercise alone (hemoglobin A1c [HbA1c] > 7.5% and ≤ 12%, and fasting plasma glucose [FPG] < 300 mg/dL) were randomized to receive initial therapy with glipizide 5 mg, metformin 500 mg, METAGLIP (glipizide and metformin) 2.5 mg/250 mg, or METAGLIP (glipizide and metformin) 2.5 mg/500 mg. After 2 weeks, the dose was progressively increased (up to the 12-week visit) to a maximum of 4 tablets daily in divided doses as needed to reach a target mean daily glucose (MDG) of ≤ 130 mg/dL. Trial data at 24 weeks are summarized in Table 2.
Table 2: Active-Controlled Trial of METAGLIP (glipizide and metformin) in Patients
with Inadequate Glycemic Control on Diet and Exercise Alone: Summary of Trial
Data at 24 Weeks
|Glipizide 5 mg tablets||Metformin 500 mg tablets||METAGLIP 2.5 mg/250 mg tablets||METAGLIP 2.5 mg/500 mg tablets|
|Mean Final Dose||16.7 mg||1749 mg||7.9 mg/791 mg||7.4 mg/1477 mg|
|Hemoglobin A1c (%)||N=168||N=171||N=166||N=163|
|Adjusted Mean Change from Baseline||-1.77||-1.46||-2.15||-2.14|
|Difference from Glipizide||-0.38a||-0.37a|
|Difference from Metformin||-0.70a||-0.69a|
|% Patients with Final HbA1c < 7%||43.5%||35.1%||59.6%||57.1%|
|Fasting Plasma Glucose (mg/dL)||N=169||N=176||N=170||N=169|
|Adjusted Mean Change from Baseline||-46.2||-42.9||-54.2||-56.5|
|Difference from Glipizide||-8.0||-10.4|
|Difference from Metformin||-11.3||-13.6|
|a p < 0.001|
After 24 weeks, treatment with METAGLIP (glipizide and metformin) 2.5 mg/250 mg and 2.5 mg/500 mg resulted in significantly greater reduction in HbA1c compared to glipizide and metformin therapy. Also, METAGLIP (glipizide and metformin) 2.5 mg/250 mg therapy resulted in significant reductions in FPG versus metformin therapy.
Increases above fasting glucose and insulin levels were determined at baseline and final study visits by measurement of plasma glucose and insulin for 3 hours following a standard mixed liquid meal. Treatment with METAGLIP (glipizide and metformin) lowered the 3-hour postprandial glucose AUC, compared to baseline, to a significantly greater extent than did the glipizide and the metformin therapies. Compared to baseline, METAGLIP (glipizide and metformin) enhanced the postprandial insulin response, but did not significantly affect fasting insulin levels.
There were no clinically meaningful differences in changes from baseline for all lipid parameters between METAGLIP (glipizide and metformin) therapy and either metformin therapy or glipizide therapy. The adjusted mean changes from baseline in body weight were: METAGLIP (glipizide and metformin) 2.5 mg/250 mg, -0.4 kg; METAGLIP (glipizide and metformin) 2.5 mg/500 mg, -0.5 kg; glipizide, -0.2 kg; and metformin, -1.9 kg. Weight loss was greater with metformin than with METAGLIP (glipizide and metformin) .
Patients with Inadequate Glycemic Control on Sulfonylurea Monotherapy
In an 18-week, double-blind, active-controlled U.S. clinical trial, a total of 247 patients with type 2 diabetes not adequately controlled (HbA1c ≥ 7.5% and ≤ 12%, and FPG < 300 mg/dL) while being treated with at least one-half the maximum labeled dose of a sulfonylurea (eg, glyburide 10 mg, glipizide 20 mg) were randomized to receive glipizide (fixed dose, 30 mg), metformin (500 mg), or METAGLIP (glipizide and metformin) 5 mg/500 mg. The doses of metformin and METAGLIP (glipizide and metformin) were titrated (up to the 8-week visit) to a maximum of 4 tablets daily as needed to achieve MDG ≤ 130 mg/dL. Trial data at 18 weeks are summarized in Table 3.
Table 3: METAGLIP (glipizide and metformin) in Patients with Inadequate Glycemic Control
on Sulfonylurea Alone: Summary of Trial Data at 18 Weeks
|Glipizide 5 mg tablets||Metformin 500 mg tablets||METAGLIP 5 mg/500mg tablets|
|Mean Final Dose||30.0 mg||1927 mg||17.5 mg/ 1747 mg|
|Hemoglobin A1c (%)||N=79||N=71||N=80|
|Final Adjusted Mean||8.45||8.36||7.39|
|Difference from Glipizide||-1.06a|
|Difference from Metformin||-0.98a|
|% Patients with Final HbA1c < 7%||8.9%||9.9%||36.3%|
|Fasting Plasma Glucose (mg/dL)||N=82||N=75||N=81|
|Adjusted Mean Change from Baseline||7.0||6.7||-30.4|
|Difference from Glipizide||-37.4|
|Difference from Metformin||-37.2|
|a p < 0.001|
After 18 weeks, treatment with METAGLIP (glipizide and metformin) at doses up to 20 mg/2000 mg per day resulted in significantly lower mean final HbA1c and significantly greater mean reductions in FPG compared to glipizide and metformin therapy. Treatment with METAGLIP (glipizide and metformin) lowered the 3-hour postprandial glucose AUC, compared to baseline, to a significantly greater extent than did the glipizide and the metformin therapies. METAGLIP (glipizide and metformin) did not significantly affect fasting insulin levels.
There were no clinically meaningful differences in changes from baseline for all lipid parameters between METAGLIP (glipizide and metformin) therapy and either metformin therapy or glipizide therapy. The adjusted mean changes from baseline in body weight were: METAGLIP (glipizide and metformin) 5 mg/500 mg,-0.3 kg; glipizide, -0.4 kg; and metformin, -2.7 kg. Weight loss was greater with metformin than with METAGLIP (glipizide and metformin) .
Last reviewed on RxList: 1/26/2017
This monograph has been modified to include the generic and brand name in many instances.
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