"The U.S. Food and Drug Administration today approved Invokana (canagliflozin) tablets, used with diet and exercise, to improve glycemic control in adults with type 2 diabetes.
Type 2 diabetes is the most common form of the disease, affe"...
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Mechanism of Action
GLUCOVANCE combines glyburide and metformin hydrochloride, 2 antihyperglycemic agents with complementary mechanisms of action, to improve glycemic control in patients with type 2 diabetes.
Glyburide 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. The mechanism by which glyburide lowers blood glucose during long-term administration has not been clearly established. With chronic administration in patients with type 2 diabetes, the blood glucose-lowering effect persists despite a gradual decline in the insulin secretory response to the drug. Extrapancreatic effects may be involved in the mechanism of action of oral sulfonylurea hypoglycemic drugs.
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
Glucovance (glyburide and metformin)
In bioavailability studies of GLUCOVANCE (glyburide and metformin) 2.5 mg/500 mg and 5 mg/500 mg, the mean area under the plasma concentration versus time curve (AUC) for the glyburide component was 18% and 7%, respectively, greater than that of the Micronase® brand of glyburide coadministered with metformin. The glyburide component of GLUCOVANCE (glyburide and metformin) , therefore, is not bioequivalent to Micronase®. The metformin component of GLUCOVANCE (glyburide and metformin) is bioequivalent to metformin coadministered with glyburide.
Following administration of a single GLUCOVANCE (glyburide and metformin) 5 mg/500 mg tablet with either a 20% glucose solution or a 20% glucose solution with food, there was no effect of food on the Qnax and a relatively small effect of food on the AUC of the glyburide component. The Tmax for the glyburide component was shortened from 7.5 hours to 2.75 hours with food compared to the same tablet strength administered fasting with a 20% glucose solution. The clinical significance of an earlier Tmax for glyburide after food is not known. The effect of food on the pharmacokinetics of the metformin component was indeterminate.
Single-dose studies with Micronase® tablets in normal subjects demonstrate significant absorption of glyburide within 1 hour, peak drug levels at about 4 hours, and low but detectable levels at 24 hours. Mean serum levels of glyburide, as reflected by areas under the serum concentration-time curve, increase in proportion to corresponding increases in dose. Bioequivalence has not been established between GLUCOVANCE (glyburide and metformin) and single-ingredient glyburide products.
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.
Sulfonylurea drugs are extensively bound to serum proteins. Displacement from protein binding sites by other drugs may lead to enhanced hypoglycemic action. In vitro, the protein binding exhibited by glyburide is predominantly non-ionic, whereas that of other sulfonylureas (chlorpropamide, tolbutamide, tolazamide) is predominantly ionic. Acidic drugs, such as phenylbutazone, warfarin, and salicylates, displace the ionic-binding sulfonylureas from serum proteins to a far greater extent than the non-ionic binding glyburide. It has not been shown that this difference in protein binding results in fewer drug-drug interactions with glyburide tablets in clinical use.
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 c ontrolled clinical trials, maximum metformin plasma levels did not exceed 5 µg/mL, even at maximum doses.
Metabolism and Elimination
The decrease of glyburide in the serum of normal healthy individuals is biphasic; the terminal half-life is about 10 hours. The major metabolite of glyburide is the 4-trans-hydroxy derivative. A second metabolite, the 3-cis-hydroxy derivative, also occurs. These metabolites probably contribute no significant hypoglycemic action in humans since they are only weakly active (1/400 and 1/40 as active, respectively, as glyburide) in rabbits. Glyburide is excreted as metabolites in the bile and urine, approximately 50% by each route. This dual excretory pathway is qualitatively different from that of other sulfonylureas, which are excreted primarily in the urine.
Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted 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 is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.
Patients With Type 2 Diabetes
Multiple-dose studies with glyburide in patients with type 2 diabetes demonstrate drug level concentration-time curves similar to single-dose studies, indicating no buildup of drug in tissue depots.
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.
No pharmacokinetic studies have been conducted in patients with hepatic insufficiency for either glyburide or metformin.
No information is available on the pharmacokinetics of glyburide in patients with renal insufficiency.
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 glyburide 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
|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)|
|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
After administration of a single oral GLUCOPHAGE® (metformin hydrochloride) 500 mg tablet with food, geometric mean metformin Qnax 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.
After administration of a single oral GLUCOVANCE (glyburide and metformin) tablet with food, dose-normalized geometric mean glyburide C^x and AUC in pediatric patients with type 2 diabetes (11-16 years of age, n=28, mean body weight of 97 kg) differed < 6% from historical values in healthy adults.
There is no information on the effect of gender on the pharmacokinetics of glyburide.
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 glyburide.
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 20-week, double-blind, multicenter U.S. clinical trial, a total of 806 drug-naive patients with type 2 diabetes, whose hyperglycemia was not adequately controlled with diet and exercise alone (baseline fasting plasma glucose [FPG] < 240 mg/dL, baseline hemoglobin AIC [HbA1c] between 7% and 11%), were randomized to receive initial therapy with placebo, 2.5 mg glyburide, 500 mg metformin, GLUCOVANCE (glyburide and metformin) 1.25 mg/250 mg, or GLUCOVANCE (glyburide and metformin) 2.5 mg/500 mg. After 4 weeks, the dose was progressively increased (up to the 8-week visit) to a maximum of 4 tablets daily as needed to reach a target FPG of 126 mg/dL. Trial data at 20 weeks are summarized in Table 2.
Table 2: Placebo- and Active-Controlled Trial of GLUCOVANCE (glyburide and metformin)
in Patients with Inadequate Glycemic Control on Diet and Exercise Alone: Summary
of Trial Data at 20 Weeks
2.5 mg tablets
500 mg tablets
1.25 mg/250 mg tablets
2.5 mg/500 mg tablets
|Mean Final Dose||0 mg||5.3 mg||1317mg||2.78 mg/557 mg||4.1 mg/824 mg|
|Baseline Mean (%)||8.14||8.14||8.23||8.22||8.20|
|Mean Change from Baseline||-0.21||-1.24||-1.03||-1.48||-1.53|
|Difference from Placebo||-1.02||-0.82||-1.26a||-1.31a|
|Difference from Glyburide||-0.24b||-0.29b|
|Difference from Metformin||-0.44b||-0.49b|
|Fasting Plasma Glucose||N=159||N=158||N=156||N=153||N=154|
|Baseline Mean FPG (mg/dL)||177.2||178.9||175.1||178||176.6|
|Mean Change from Baseline||4.6||-35.7||-21.2||-41.5||-40.1|
|Difference from Placebo||-40.3||-25.8||-46.1a||-44.7a|
|Difference from Glyburide||-5.8c||-4.5c|
|Difference from Metformin||-20.3c||-18.9c|
|Body Weight Mean Change from Baseline||-0.7kg||+1.7 kg||-0.6kg||+1.4 kg||+1.9 kg|
|Final HbA1c Distribution (%)||N=147||N=142||N=141||N=149||N=152|
|≥ 7%and < 8%||37.4%||26.1%||29.8%||25.5%||19.1%|
| a p < 0.001
b p < 0.05
Treatment with GLUCOVANCE (glyburide and metformin) resulted in significantly greater reduction in HbAic and postprandial plasma glucose (PPG) compared to glyburide, metformin, or placebo. Also, GLUCOVANCE (glyburide and metformin) therapy resulted in greater reduction in FPG compared to glyburide, metformin, or placebo, but the differences from glyburide and metformin did not reach statistical significance.
Changes in the lipid profile associated with GLUCOVANCE (glyburide and metformin) treatment were similar to those seen with glyburide, metformin, and placebo.
The double-blind, placebo-controlled trial described above restricted enrollment to patients with HbA1c < 11% or FPG < 240 mg/dL. Screened patients ineligible for the first trial because of HbA1c and/or FPG exceeding these limits were treated directly with GLUCOVANCE (glyburide and metformin) 2.5 mg/500 mg in an open-label, uncontrolled protocol. In this study, 3 out of 173 patients (1.7%) discontinued because of inadequate therapeutic response.
Across the group of 144 patients who completed 26 weeks of treatment, mean HbAic was reduced from a baseline of 10.6% to 7.1%. The mean baseline FPG was 283 mg/dL and reduced to 164 and 161 mg/dL after 2 and 26 weeks, respectively. The mean final titrated dose of GLUCOVANCE (glyburide and metformin) was 7.85 mg/1569 mg (equivalent to approximately 3 GLUCOVANCE (glyburide and metformin) 2.5 mg/500 mg tablets per day).
Patients with Inadequate Glycemic Control on Sulfonylurea Alone
In a 16-week, double-blind, active-controlled U.S. clinical trial, a total of 639 patients with type 2 diabetes not adequately controlled (mean baseline HbAic 9.5%, mean baseline FPG 213 mg/dL) while being treated with at least one-half the maximum dose of a sulfonylurea (eg, glyburide 10 mg, glipizide 20 mg) were randomized to receive glyburide (fixed dose, 20 mg), metformin (500 mg), GLUCOVANCE (glyburide and metformin) 2.5 mg/500 mg, or GLUCOVANCE (glyburide and metformin) 5 mg/500 mg. The doses of metformin and GLUCOVANCE (glyburide and metformin) were titrated to a maximum of 4 tablets daily as needed to achieve FPG < 140 mg/dL. Trial data at 16 weeks are summarized in Table 3.
Table 3: GLUCOVANCE (glyburide and metformin) in Patients with Inadequate Glycemic
Control on Sulfonylurea Alone: Summary of Trial Data at 16 Weeks
|Glyburide 5mg tablets|| Metformin
500 mg tablets
2.5 mg/500 mg tablets
5 mg/500 mg tablets
|Mean Final Dose||20 mg||1840 mg||8.8 mg/1760 mg||17 mg/1740 mg|
|Baseline Mean (%)||9.63||9.51||9.43||9.44|
|Difference from Glyburide||-1.69a||-1.70a|
|Difference from Metformin||-1.90a||-1.91a|
|Fasting Plasma Glucose||N=163||N=152||N=160||N=160|
|Baseline Mean (mg/dL)||218.4||213.4||212.2||210.2|
|Difference from Glyburide||-51.3a||-59.9a|
|Difference from Metformin||-64.2a||-72.7a|
|Body Weight Mean Change from Baseline||+0.43 kg||-2.76kg||+0.75 kg||+0.47 kg|
|Final HbA1c Distribution (%)||N=158||N=142||N=154||N=159|
|≥ 7% and < 8%||9.5%||11.3%||33.1%||37.1%|
|ap < 0.001|
After 16 weeks, there was no significant change in the mean HbAic in patients randomized to glyburide or metformin therapy. Treatment with GLUCOVANCE (glyburide and metformin) at doses up to 20 mg/2000 mg per day resulted in significant lowering of HbAic, FPG, and PPG from baseline compared to glyburide or metformin alone.
Addition of Thiazolidinediones to GLUCOVANCE (glyburide and metformin) Therapy
In a 24-week, double-blind, multicenter U.S. clinical trial, patients with type 2 diabetes not adequately controlled on current oral antihyperglycemic therapy (either monotherapy or combination therapy) were first switched to open label GLUCOVANCE (glyburide and metformin) 2.5 mg/500 mg tablets and titrated to a maximum daily dose of 10 mg/2000 mg. A total of 365 patients inadequately controlled (HbA1c > 7.0% and ≤ 10%) after 10 to 12 weeks of a daily GLUCOVANCE (glyburide and metformin) dose of at least 7.5 mg/1500 mg were randomized to receive add-on therapy with rosiglitazone 4 mg or placebo once daily. After 8 weeks, the rosiglitazone dose was increased to a maximum of 8 mg daily as needed to reach a target mean daily glucose of 126 mg/dL or HbA1c < 7%. Trial data at 24 weeks or the last prior visit are summarized in Table 4.
Table 4: Effects of Adding Rosiglitazone or Placebo in Patients
Treated with GLUCOVANCE (glyburide and metformin) in a 24-Week Trial
|Placebo + GLUCOVANCE||Rosiglitazone + GLUCOVANCE|
|Mean Final Dose GLUCOVANCERosiglitazone||10mg/1992mg 0 mg||9.6 mg/1914 mg 7.4 mg|
|Baseline Mean (%)||8.09||8.14|
|Difference from Placeboa||-1.02b|
|Fasting Plasma Glucose||N=181||N=176|
|Baseline Mean (mg/dL)||173.1||178.4|
|Difference from Placeboa||-48.5b|
|Body Weight Mean Change from Baseline||+0.03 kg||+3.03 kg|
|Final HbA1c Distribution (%)||N=178||N=177|
|≥ 7%and < 8%||32.0%||38.4%|
|a Adjusted for the baseline mean difference
b p < 0.001
For patients who did not achieve adequate glycemic control on GLUCOVANCE (glyburide and metformin) , the addition of rosiglitazone, compared to placebo, resulted in significant lowering of HbA1c and FPG.
Last reviewed on RxList: 1/11/2011
This monograph has been modified to include the generic and brand name in many instances.
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