"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"...
Mechanism of Action
Metformin is an antihyperglycemic agent, which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. 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 (except in special circumstances, see PRECAUTIONS) and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and daylong plasma insulin response may actually decrease.
Absorption and Bioavailability
The following pharmacokinetic studies were performed with the 500 mg dosage form. Following a single oral dose of 1000 mg (2x500 mg tablets) GLUMETZA (metformin hcl) after a meal, the time to reach maximum plasma metformin concentration (Tmax) is achieved at approximately 7-8 hours. In both single and multiple-dose studies in healthy subjects, once daily 1000 mg (2x500 mg tablets) dosing provides equivalent systemic exposure, as measured by area-under-the-curve (AUC), and up to 35% higher Cmax, of metformin relative to the immediate release given as 500 mg twice daily. GLUMETZA (metformin hcl) tablets must be administered immediately after a meal to maximize therapeutic benefit.
Table 1 : Summary Mean (±SD) of Pharmacokinetic Parameters
after One Day Dosing
2 x 500 mg
1 x 500 mg BID
1 x 500 mg BID
|AUC0-36 (ng•hr/mL)||14182 ± 2415||15260 ± 3496||15342 ± 3398|
|Cmax (ng/mL)||1301.4 ± 285.7||811.9 ± 173.7||959.1 ± 204.0|
|Tmax (hr)||7.5 ± 1.2||7.1 ± 1.2||4.2 ± 1.6|
Single oral doses of GLUMETZA (metformin hcl) from 500 mg to 2500 mg resulted in less than proportional increase in both AUC and Cmax. The mean Cmax values were 473 ± 145, 868 ± 223, 1171 ± 297, and 1630 ± 399 ng/mL for single doses of 500, 1000, 1500, and 2500 mg, respectively. For AUC, the mean values were 3501 ± 796, 6705 ± 1918, 9299 ± 2833, and 14161 ± 4432 ng·hr/mL for single doses of 500, 1000, 1500, and 2500 mg, respectively.
Low-fat and high-fat meals increased the systemic exposure (as measured by AUC) from GLUMETZA (metformin hcl) tablets by about 38% and 73%, respectively, relative to fasting. Both meals prolonged metformin Tmax by approximately 3 hours but Cmax was not affected.
In a two-way, single-dose crossover study in healthy volunteers, the 1000 mg tablet was found to be bioequivalent to two 500 mg tablets under fed conditions based on equivalent Cmax and AUCs for the two formulations (Table 2).
Table 2: Mean (±SD) Pharmacokinetic Parameters for
GLUMETZA (metformin hcl) 1000 mg Tablet and GLUMETZA (metformin hcl) 2x500 mg Tablets
1000 mg Tablet
2 x 500 mg Tablets
|AUC0-ι (ng.hr/mL)||11706 ± 2520||12408 ± 2581|
|AUC0-∞ (ng•hr/mL)||11907 ± 2521||12599 ± 2616|
|Cmax (ng/mL)||1238 ± 271||1116 ± 254|
The apparent volume of distribution (V/F) of metformin following single oral doses of 850 mg immediate release metformin hydrochloride 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 24-48 hours and are generally < 1 μg/mL. During controlled clinical trials, which served as the basis of approval for metformin, maximum metformin plasma levels did not exceed 5 μg/mL, even at maximum doses.
Metabolism and Excretion
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 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.
Renal Impairment: In patients with mild and moderate renal failure (based on measured creatinine clearance) the oral and renal clearance of metformin were decreased by 33% and 50% and 16% and 53%, respectively (see WARNINGS). Metformin peak and systemic exposure were significantly greater in patients with renal failure relative to healthy volunteers with normal renal function. There was a rank-order correlation of metformin AUC and Cmax with degree of renal failure. Since metformin can accumulate to toxic levels in patients with renal impairment, administration of GLUMETZA (metformin hcl) is contraindicated in these patients.
Hepatic Impairment: No pharmacokinetic studies of GLUMETZA (metformin hcl) have been conducted in subjects with hepatic insufficiency.
Geriatrics: Limited data from controlled pharmacokinetic studies of metformin hydrochloride in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged and Cmax is increased, 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 CLINICAL PHARMACOLOGY, Pharmacokinetics). Metformin treatment should not be initiated in patients 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced (see WARNINGS and DOSAGE AND ADMINISTRATION).
Gender: In the pharmacokinetic studies in healthy volunteers, there were no important differences between male and female subjects with respect to metformin AUC (males = 268, females = 293) and t½ (males = 229, females = 260). However, Cmax for metformin were somewhat higher in female subjects (Female/Male Cmax Ratio = 1.4). The gender differences for Cmax are unlikely to be clinically important. Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin hydrochloride tablets was comparable in males and females.
Race: There were no definitive conclusions on the differences between the races with respect to the pharmacokinetics of metformin because of the imbalance in the respective sizes of the racial groups. However, the data suggest a trend towards higher metformin Cmax and AUC values for metformin are obtained in Asian subjects when compared to Caucasian, Hispanic and Black subjects. The differences between the Asian and Caucasian groups are unlikely to be clinically important. In controlled clinical studies of metformin hydrochloride in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n = 249), blacks (n = 51) and Hispanics (n = 24).
Pediatrics: No pharmacokinetic data from studies of GLUMETZA (metformin hcl) in pediatric subjects are available.
GLUMETZA (metformin hcl) has been studied as monotherapy and in combination with a sulfonylurea and insulin. In a multicenter, randomized, double-blind, active-controlled, dose-ranging, parallel group study GLUMETZA (metformin hcl) 1500 mg once a day, GLUMETZA (metformin hcl) 1500 per day in divided doses (500 mg in the morning and 1000 mg in the evening), and GLUMETZA (metformin hcl) 2000 mg once a day were compared to immediate release metformin 1500 mg per day in divided doses (500 mg in the morning and 1000 mg in the evening). (See Table 3.) Newly diagnosed patients, diet-and-exercise-treated (diet/exercise) patients, patients who received combination therapy consisting of metformin up to 1500 mg/day plus a sulfonylurea at a dose equal to or less than one-half the maximum dose allowed (following a 6-week washout), or patients on monotherapy with an antihyperglycemic agent (following a 6week washout) were randomized to treatment and began titration from 1000 mg/day up to their assigned treatment dose over 3 weeks. Metformin IR treatment was initiated as 500 mg BID for 1 week followed by 500 mg with breakfast and 1000 mg with dinner for the second week. The 3-week treatment period was followed by an additional 21-week period at the randomized dose. Each of the GLUMETZA (metformin hcl) regimens, were at least as effective as immediate release metformin in all measures of glycemic control. Additionally, once daily dosing was as effective as the commonly prescribed twice daily dosing of the immediate release metformin formulation.
Table 3 : Mean±SE Changes from Baseline to Final Visit
in HbA1c, Fasting Plasma Glucose and Body Weight for the GLUMETZA (metformin hcl)
and Metformin IR Treatment Groups (First 24-Week Study)
|Parameter||1500 mg QD
(n = 178)
|GLUMETZA (metformin hcl)
1500 mg AM/PM
(n = 182)
|2000 mg QD
(n = 172)
1500 mg AM/PM
(n = 174)
|Baseline||8.22 ± 0.25||8.50 ± 0.24||8.26 ± 0.24||8.70 ± 0.25|
|Mean Change ± SE at Final Visit||-0.73 ± 0.12||-0.74 ± 0.12||-1.06 ± 0.12||-0.70 ± 0.12|
|Mean Difference ± SE from Metformin IR||-0.03 ± 0.12||-0.04 ± 0.12||-0.36 ± 0.12||N/A|
|98.4% CI for Difference||(-0.32, 0.26)||(-0.33, 0.25)||(-0.65, -0.06)|
|Fasting Plasma Glucose (mg/dL)|
|Baseline||190.0 ± 9.9||192.5 ± 9.9||183.9 ± 9.9||196.5 ± 11.2|
|Mean Change ± SE at Final Visit||-38.5 ± 4.4||-31.8 ± 4.4||-42.0 ± 4.5||-32.1 ± 4.5|
|Mean Difference ± SE from Metformin IR||-6.4 ± 4.4||0.2 ± 4.3||-9.9 ± 4.4||N/A|
|95% CI for Difference||(-15.0, 2.1)||(-8.3, 8.7)||(-18.5, -1.3)|
|Body Weight (kg)|
|Baseline||88.17 ± 3.66||90.50 ± 3.66||87.73 ± 3.66||88.72 ± 3.87|
|Mean Change ± SE at Final Visit||-0.93 ± 0.40||-0.68 ± 0.40||-1.10 ± 0.40||-0.85 ± 0.41|
|Mean Difference ± SE from Metformin IR||-0.09 ± 0.40||0.17 ± 0.39||-0.26 ± 0.40||N/A|
|95% CI for Difference||(-0.86, 0.69)||(-0.61, 0.94)||(-1.04, 0.52)|
In a double-blind, randomized, placebo-controlled (glyburide add-on) multicenter study, patients with type 2 diabetes mellitus who were newly diagnosed or treated with diet and exercise, or who were receiving monotherapy with metformin, sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, or meglinitides, or treated with combination therapy consisting of metformin/glyburide at doses up to 1000 mg metformin + 10 mg glyburide per day (or equivalent doses of glipizide or glimepiride up to half the maximum therapeutic dose) were enrolled. They were stabilized on glyburide for a 6-week period, and then randomized to 1 of 4 treatments: placebo + glyburide (glyburide alone); GLUMETZA (metformin hcl) 1500 mg once a day + glyburide, GLUMETZA (metformin hcl) 2000 mg once a day + glyburide, or GLUMETZA (metformin hcl) 1000 mg twice a day + glyburide. A 3-week GLUMETZA (metformin hcl) titration phase was followed by a 21-week maintenance treatment phase. The difference in the change from Baseline in HbA1c levels between the combined M-ER+ SU (sulfonylurea) groups and the SU only group was statistically significant (p < 0.001). The changes in glycemic control across the three GLUMETZA (metformin hcl) +glyburide groups were comparable. (See Table 4.)
Table 4 : Mean±SE Changes from Baseline to Final Visit
in HbA1c, Fasting Plasma Glucose and Body Weight for the GLUMETZA (metformin hcl) /
Glyburide Groups and Placebo/Glyburide Treatment Group (Second 24-Week Study)
|Parameter||GLUMETZA + Glyburide*||Placebo/ Glyburide* (n= 144)|
|1500 mg QD (n = 144)||1000 mg BID (n = 141)||2000 mg QD (n = 146)|
|Baseline||7.93 ± 0.13||7.75 ± 0.13||7.68 ± 0.13||8.08 ± 0.13|
|Mean Change ± SE at Final Visit||-0.72 ± 0.09||-0.82 ± 0.09||-0.71 ± 0.08||-0.07 ± 0.08|
|Mean Difference ± SE from Glyburide Alone||-0.79 ± 0.11||-0.89 ± 0.11||-0.77 ± 0.11||N/A|
|95% CI for Difference||(-1.01, -0.57)||(-1.11, -0.67)||(-0.99, -0.56)|
|p-value for pairwise comparison||< 0.001||< 0.001||< 0.001|
|Fasting Plasma Glucose (mg/dL)|
|Baseline||163.4 ± 4.6||163.2 ± 4.7||158.8 ± 4.7||164.0 ± 4.7|
|Mean Change ± SE at Final Visit||-13.7 ± 3.7||-15.7 ± 3.7||-9.4 ± 3.7||15.5 ± 3.7|
|Mean Difference ± SE from Glyburide Alone||-29.2 ± 4.9||-31.2 ± 40.9||-24.9 ± 4.9||N/A|
|95% CI for Difference||(-38.8, -19.6)||(-40.9, -21.6)||(-34.5, -15.4)|
|p-value for pairwise comparison||< 0.001||< 0.001||< 0.001|
|Body Weight (kg)|
|Baseline||89.38 ± 11.21||103.70 ± 11.21||102.90 ± 11.21||95.56 ± 7.96|
|Mean Change ± SE at Final Visit||0.28 ± 1.05||0.08 ± 1.05||-0.03 ± 1.05||0.71 ± 1.04|
|Mean Difference ± SE from Glyburide Alone||-0.43 ± 0.52||-0.63 ± 0.53||-0.74 ± 0.52||N/A|
|95% CI for Difference||(-1.46, 0.60)||(-1.67, 0.40)||(-1.77, 0.28)|
|p-value for pairwise comparison||0.410||0.230||0.156|
|* -Glyburide was administered as 10 mg at breakfast and 5 mg at dinner.|
A 24-week, double-blind, placebo-controlled study of immediate release metformin plus insulin versus insulin plus placebo was conducted in patients with type 2 diabetes who failed to achieve adequate glycemic control on insulin alone. Patients randomized to receive metformin plus insulin achieved a reduction in HbA1c of 2.10%, compared to a 1.56% reduction in HbA1c achieved by insulin plus placebo. The improvement in glycemic control was achieved at the final study visit with 16% less insulin, 93.0 U/day vs. 110.6 U/day, metformin plus insulin versus insulin plus placebo, respectively, p=0.04. A second double-blind, placebo-controlled study (n=51), with 16 weeks of randomized treatment, demonstrated that in patients with type 2 diabetes controlled on insulin for 8 weeks with an average HbA1c of 7.46 ± 0.97%, the addition of metformin maintained similar glycemic control (HbA1c 7.15 ± 0.61 versus 6.97 ± 0.62 for metformin plus insulin and placebo plus insulin, respectively) with 19% less insulin versus baseline (reduction of 23.68 ± 30.22 versus an increase of 0.43 ± 25.20 units for metformin plus insulin and placebo plus insulin, p < 0.01). In addition, this study demonstrated that the combination of metformin plus insulin resulted in reduction in body weight of 3.11 ± 4.30 lbs, compared to an increase of 1.30 ± 6.08 lbs for placebo plus insulin, p=0.01.
Last reviewed on RxList: 7/6/2009
This monograph has been modified to include the generic and brand name in many instances.
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