"A new retrospective study indicates that, in type 2 diabetes, treatment with insulin is safer when it is used together with metformin.
In the research, recently published in PLoS One, a team from Cardiff University, Wales, sh"...
Mechanism Of Action
Metformin is a biguanide that improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Metformin does not produce hypoglycemia in patients with type 2 diabetes or in healthy subjects except in special circumstances, (see WARNINGS AND 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.
Following a single oral dose of 1000 mg (2x500 mg tablets) GLUMETZA 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 tablets must be administered immediately after a meal to maximize therapeutic benefit.
Single oral doses of GLUMETZA from 500 mg to 2500 mg resulted in less than proportional increase in both AUC and Cmax. Low-fat and high-fat meals increased the systemic exposure (as measured by AUC) from GLUMETZA 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.
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 5μg/mL, even at maximum doses.
Intravenous single-dose studies in healthy 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. Metabolism studies with extended-release metformin tablets have not been conducted.
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.
Following a single dose administration of GLUMETZA 500 mg 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 AND PRECAUTIONS). Metformin peak and systemic exposure was 27% and 61% greater, respectively in mild renal impaired and 74% and 2.36-fold greater in moderate renal impaired patients as compared to healthy subjects. Use of metformin in patients with renal impairment increases the risk for lactic acidosis. GLUMETZA is contraindicated in patients with renal impairment. (See CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS)
No pharmacokinetic studies of GLUMETZA have been conducted in subjects with hepatic impairment. Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. GLUMETZA is not recommended in patients with hepatic impairment. (See WARNINGS AND PRECAUTIONS)
Limited data from controlled pharmacokinetic studies of metformin hydrochloride in healthy elderly subjects suggest that total plasma clearance of metformin is decreased by 35%, the half-life is prolonged by 64% and Cmax is increased by 76%, 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. Metformin treatment should not be initiated in patients of any age unless measurement of creatinine clearance demonstrates that renal function is normal. (See WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION)
In the pharmacokinetic studies in healthy volunteers, there were no important differences between male and female subjects with respect to metformin AUC and t½. However, Cmax for metformin was 40% higher in female subjects as compared to males. 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.
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).
No pharmacokinetic data from studies of GLUMETZA in pediatric subjects are available.
Specific pharmacokinetic drug interaction studies with GLUMETZA have not been performed except for one with glyburide. However, such studies have been performed on metformin.
|Co- administered Drug||Dose of Coadministered Drug1||Dose of .Metformin1||Geometric Mean Ratio (ratio with without coadministered drug)
No effect = 1.00
|No dosing adjustments required for the following:|
|Glybunde||5 mg||500 mg4||0.983||0.993|
|Furosemide||40 mg||850 mg||1.093||1.223|
|Nifedipine||10 mg||850 mg||1.16||1.21|
|Propranolol||40 mg||850 mg||0.90||0.94|
|Ibuprofen||400 mg||850 mg||1.053||1.073|
|Cationic drugs eliminated by renal tubular secretion may reduce metformin elimination: use with caution. (See WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS)|
|Cunetidme||400 mg||850 mg||1.40||1.61|
|C arbonic anhydrase inhibitors may cause metabolic acidosis: use with caution (See WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS)|
|Topiramate||100 mg5||500 mg5||1.255||1.17|
|1 All metformin and coadministered drugs were given as
3. Ratio of anthmetic means
4. GLUMETZA (metformin hydrochloride extended-release tablets) 500 me
5. At steady state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours: AUC “ AUC0-12h
Table 3: Effect of Metformin on Coadministered Drug
|Coadminister ed Drug||Dose of Coadministered Drug1||Dose of Metformin1||Geometric Mean Ratio (ratio trith without coadministered drug) No effect - 1.00|
|No dosing adjustments required for the following|
|Glybunde||5 mg||500 mg4||0.783||0.633|
|Furosemide||40 mg||850 mg||0.873||0.693|
|Nifedipine||10 mg||850 mg||1.104||1.08|
|Propranolol||40 mg||850 mg||1.014||0.94|
|Ibuprofen||400 mg||850 mg||0.975||1.015|
|Cimendine||400 mg||850 mg||0.954||1.01|
|1 All metformin and coadministered drug were given as
2 AUC – AUC0-∞
3 Ratio of anthmetic means, p-value of difference < 0 05
4 AUC0-24hr reported
5 Ratio of anthmetic means
GLUMETZA has been studied as monotherapy and in combination with a sulfonylurea and insulin. Other formulations of metformin have been studied with other classes of antihyperglycemic agents, either as immediate or as extended release tablets.
Double-Blind, Randomized, Parallel Group Clinical Trial to Compare the Efficacy, Safety, and Tolerability of Metformin ER (M-ER) Tablets and Metformin Immediate Release (M-IR) Tablets in the Treatment of Type 2 Diabetes Mellitus
In a multicenter, randomized, double-blind, activecontrolled, dose-ranging, parallel group trial GLUMETZA 1500 mg once daily, GLUMETZA 1500mg per day in divided doses (500 mg in the morning and 1000 mg in the evening), and GLUMETZA 2000 mg once daily were compared to immediate-release metformin 1500 mg per day in divided doses (500 mg in the morning and 1000 mg in the evening). This trial enrolled patients (n = 338) who were newly diagnosed with diabetes, patients treated only with diet and exercise, patients treated with a single antidiabetic medication (sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, or meglinitides ), and patients (n = 368) receiving metformin up to 1500 mg/day plus a sulfonylurea at a dose equal to or less than one-half the maximum dose. Patients who were enrolled on monotherapy or combination anti-diabetic therapy underwent a 6-week washout. Patients randomized to GLUMETZA began titration from 1000 mg/day up to their assigned treatment dose over 3 weeks. Patients randomized to immediate-release metformin initiated 500 mg twice daily for 1week 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. For HbA1c and fasting plasma glucose, each of the GLUMETZA regimens was at least as effective as immediate-release metformin. Additionally, once daily dosing of GLUMETZA was as effective as twice daily dosing of the immediate release metformin formulation.
Table 4: Mean±SE
Changer from Barline to Final Visit in HbA1c, Fasting Plasma Glucose and Body
Weight for the GLUMETZA and Metformin Immediate-Release Treatment Groups (First
|Parameter||GLUMETZA||Metformin immediate- release 1500 mg in dhided doses
|1500 mg once daily
|1500 mg in dhided doses
|2000 mg once daily
(n = 172)
|Baseline||8.2 ± 03||8.5 ± 0.2||8.3 ± 0 2||8.7 ± 0.3|
|Mean Change ± SE at Final Visit||-0.7 ±0.1||-0.7 ± 0.1||-1.1 ± 0.1||-0.7 ± 0.1|
|Mean Difference ± SE from Metformin IR 98 4% CI for Difference||0 ± 0.1
|0 ± 0.1
(-0 .3, 0.3)
|-0.4 ± 0.1
|Fasting Plasma Glucose (mg dL)|
|Baseline||190 ± 10||192.3 ± 10||184 ± 10||197 ± 11|
|Mean Change ± SE at Final Visit||-39 ± 4||-32 ± 4||-42 ± 5||-32 ± 5|
|Mean Difference ± SE from Metformin IR 95% CI for Difference||-6±4 (-15, 2)||0±4 (-8,9)||-10 ± 4 (-19, -1)||N/A|
|Body Weight (kg)|
|Baseline||88.2 ± 3.7||90.5 ± 3.7||87.7 ± 3 7||88.7 ± 3.9|
|Mean Change ± SE at Final Visit||-0.9 ± 0.4||-0.7 ± 0.4||-1.1 ± 0.4||-0 9 ± 0 4|
|Mean Difference ± SE from Metformin IR 95% CI for Difference||-0.1 ± 04
|0.2 ± 0.4
|-0.3 ± 0.4
A Double-Blind, Randomized, Parallel-Group Study to Compare the Safety, Efficacy, and Tolerability of Metformin Extended Release (M-ER) Tablets in Combination with a Sulfonylurea (SU) and SU Alone in the Management of Patients with Type 2 Diabetes Mellitus
In a double-blind, randomized, placebo-controlled (glyburide add-on) multicenter trial, patients with type 2 diabetes mellitus who were newly diagnosed or treated with diet and exercise (n = 144), or who were receiving monotherapy with metformin, sulfonylureas, alphaglucosidase 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) (n = 431) were enrolled. All patients were stabilized on glyburide for a 6-week run-in period, and then randomized to 1 of 4 treatments: placebo + glyburide (glyburide alone); GLUMETZA 1500 mg once a day + glyburide, GLUMETZA 2000 mg once a day + glyburide, or GLUMETZA 1000 mg twice a day + glyburide. A 3-week GLUMETZA titration phase was followed by a 21-week maintenance treatment phase. Use of insulin and oral hypoglycemic agents other than the study drugs were prohibited. The difference in the change from Baseline in HbA1c levels between the combined GLUMETZA + glyburide groups and the glyburide only group was statistically significant at week 24 (p < 0.001). The changes in glycemic control across the three GLUMETZA + glyburide groups were comparable.
Table 5: Mean±SE Changes from Baselie to Final Visit
in HbA1c Fasting Plasma Glucose and Body Weight for the GLUMETZA/ Glyburide
Groups and Placebo /Glyburide Treatment Group (Second 24-Week Study)
|Parameter||GLUMETZA - Glyburide||Placebo/ Ghbaridt*
(n = 141)
|1500 mg QD
(n = 144)
|1000 mg BID
|2000 mg QD
(n = 146)
|Baseline||7.9 ± 0.1||7.8 ± 0.1||7.7 ± 01||81 ± 0.1|
|Mean Change ± SE at Final Visit||-0.7 ± 0.1||-0 8 ± 01||-0.7 ± 01||-0.1 ± 0.1|
|Mean Difference ± SE from Glyburide Alone||-0.8 ± 0.1||-0.9 ± 0.1||-0.8 ± 0.1||N/A|
|95% CI for Difference||(-1.0,-0.6)||(-1.1, -0.7)||(-1.0,- 0.6)|
|p-value for pairwise comparison||- 0 001||< 0.001||< 0.001|
|Fasting Pasma Glucose (mg/dL)|
|Baseline||163 ± 5||163 ± 5||159 ± 5||164 ± 5|
|Mean Change± SE at Final Visit||-14 ± 4||-16 ± 4||-9 ± 4||16 ± 4|
|Mean Difference± SE from Glyburide Alone||-29.2 ± 4. 9||-31.2 ± 40.9||-24.9 ± 4.9||N/A|
|95% CI for Difference||(-39,- 20)||(41,-22)||(-35,- 15)|
|p-value for pairwise comparision||< 0.001||< 0.001||< 0.001|
|Body Weight (kg)|
|Baseline||89.4± 11.2||103.7± 11.2||102.9± 11.2||95.6± 8.0|
|Mean Change± SE at Final Visit||0.3 ± 1.1||0.1 ± 1.1||0 ± 1.1||0.7 ± 1.0|
|Mean Difference± SE from Glyburide Alone||-0.4 ± 0.5||-0.6 ± 0.5||-0.7 ± 0.5||N/A|
|95% CI for Difference||(-1.5, 0.6)||(-1.7,0.4)||(-1.8,0.3)|
|p-value for pairwise comparision||0.410||0.230||0.154|
|* -Glyburide was administered as 10 mg at breakfast and 5mg at dinner.|
A 24-week, double-blind, placebo-controlled trial 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 mean 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: 5/27/2016
This monograph has been modified to include the generic and brand name in many instances.
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