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Metformin (Metformin Hydrochloride) - Description and Clinical Pharmacology

 
 



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DESCRIPTION

Metformin hydrochloride is an oral antihyperglycemic drug used in the management of type 2 diabetes. Metformin hydrochloride (N,N -dimethylimidodicarbonimidic diamide hydrochloride) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. The structural formula is as shown:

Metformin hydrochloride is a white to off-white crystalline compound with a molecular formula of C4H11N5 • HCl and a molecular weight of 165.63. Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68.

Metformin hydrochloride tablets, for oral administration, contain 500 mg, 850 mg or 1000 mg of metformin hydrochloride. Each tablet contains the inactive ingredients povidone and magnesium stearate. In addition, the coating for the 500-mg, 850-mg and 1000-mg tablets contains hypromellose and polyethylene glycol.

CLINICAL PHARMACOLOGY

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 day-long plasma insulin response may actually decrease.

Pharmacokinetics

Absorption and Bioavailability

The absolute bioavailability of a metformin hydrochloride 500 mg tablet given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of metformin hydrochloride tablets of 500 mg to 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 mean peak plasma concentration (Cmax), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35-minute prolongation of time to peak plasma concentration (Tmax) 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.

Distribution

The apparent volume of distribution (V/F) of metformin following single oral doses of metformin 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin hydrochloride tablets, steady-state plasma concentrations of metformin are reached within 24 to 48 hours and are generally <1 mcg/mL. During controlled clinical trials of metformin, maximum metformin plasma levels did not exceed 5 mcg/mL, even at maximum doses.

Metabolism and Elimination

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.

Special Populations

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.

Renal Insufficiency

In patients with decreased renal function (based on measured 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).

Hepatic Insufficiency

No pharmacokinetic studies of metformin have been conducted in patients with hepatic insufficiency.

Geriatrics

Limited data from controlled pharmacokinetic studies of metformin 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 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 (see WARNINGS and DOSAGE AND ADMINISTRATION).

Table 1. Select Mean (± S.D.) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of Metformin
Subject Groups: metformin dosea
(number of subjects)
Cmaxb
(mcg/mL)
Tmaxc
(hrs)
Renal Clearance
(mL/min)
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–Combined results (average means) of five studies: mean age 32 years (range 23-59 years).
e–Kinetic study done following dose 19, given fasting.
f–Elderly subjects, mean age 71 years (range 65-81 years).
g–CLcr = creatinine clearance normalized to body surface area of 1.73 m2.          
Healthy, nondiabetic adults:
    500 mg single dose (24)
    850 mg single dose (74) d
    850 mg three times daily for 19
    dosese (9)

1.03 (± 0.33)
1.60 (± 0.38)
2.01 (± 0.42)

2.75 (± 0.81)
2.64 (± 0.82)
1.79 (± 0.94)

600 (± 132)
552 (± 139)
642 (± 173)
Adults with type 2 diabetes:
    850 mg single dose (23)
    850 mg three times daily for 19
    dosese (9)

1.48 (± 0.5)
1.90 (± 0.62)

3.32 (± 1.08)
2.01 (± 1.22)

491 (± 138)
550 (± 160)
Elderlyf, healthy nondiabetic adults:
   850 mg single dose (12)

2.45 (± 0.70)

2.71 (± 1.05)

412 (± 98)
Renal-impaired adults: 850 mg
single dose
   Mild (CLcrg 61-90 mL/min) (5)
    Moderate (CLcr 31-60 mL/min) (4)
    Severe (CLcr 10-30 mL/min) (6)


1.86 (± 0.52)
4.12 (± 1.83)
3.93 (± 0.92)


3.20 (± 0.45)
3.75 (± 0.50)
4.01 (± 1.10)


384 (± 122)
108 (± 57)
130 (± 90)

Pediatrics

After administration of a single oral metformin hydrochloride 500 mg tablet with food, geometric mean metformin Cmax and AUC differed less than 5% between pediatric type 2 diabetic patients (12 to 16 years of age) and gender- and weight-matched healthy adults (20 to 45 years of age), all with normal renal function.

Gender

Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with 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 hydrochloride tablets was comparable in males and females.

Race

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).

CLINICAL STUDIES

In a double-blind, placebo-controlled, multicenter U.S. clinical trial involving obese patients with type 2 diabetes whose hyperglycemia was not adequately controlled with dietary management alone (baseline fasting plasma glucose [FPG] of approximately 240 mg/dL), treatment with metformin (up to 2550 mg/day) for 29 weeks resulted in significant mean net reductions in fasting and postprandial plasma glucose (PPG) and hemoglobin A1c (HbA1c) of 59 mg/dL, 83 mg/dL, and 1.8%, respectively, compared to the placebo group (see Table 2).

Table 2. Metformin vs Placebo Summary of Mean Changes from Baseline* in Fasting Plasma Glucose, HbA1c and Body Weight, at Final Visit (29-week study)
Metformin
(n = 141)
Placebo
(n = 145)
p-Value
*   All patients on diet therapy at Baseline
** Not statistically significant
FPG (mg/dL)
  Baseline
  Change at FINAL VISIT

241.5
-53.0

237.7
6.3

NS **
0.001
Hemoglobin A1c (%)
  Baseline
  Change at FINAL VISIT

8.4
-1.4

8.2
0.4

NS **
0.001
Body Weight (lbs)
  Baseline
  Change at FINAL VISIT

201.0
-1.4

206.0
-2.4

NS **
NS **

A 29-week, double-blind, placebo-controlled study of metformin and glyburide, alone and in combination, was conducted in obese patients with type 2 diabetes who had failed to achieve adequate glycemic control while on maximum doses of glyburide (baseline FPG of approximately 250 mg/dL) (see Table 3). Patients randomized to the combination arm started therapy with metformin 500 mg and glyburide 20 mg. At the end of each week of the first four weeks of the trial, these patients had their dosages of metformin increased by 500 mg if they had failed to reach target fasting plasma glucose. After week four, such dosage adjustments were made monthly, although no patient was allowed to exceed metformin 2500 mg. Patients in the metformin only arm (metformin plus placebo) followed the same titration schedule. At the end of the trial, approximately 70% of the patients in the combination group were taking metformin 2000 mg/glyburide 20 mg or metformin 2500 mg/glyburide 20 mg. Patients randomized to continue on glyburide experienced worsening of glycemic control, with mean increases in FPG, PPG and HbA1c of 14 mg/dL, 3 mg/dL and 0.2%, respectively. In contrast, those randomized to metformin (up to 2500 mg/day) experienced a slight improvement, with mean reductions in FPG, PPG and HbA1c of 1 mg/dL, 6 mg/dL and 0.4%, respectively. The combination of metformin and glyburide was effective in reducing FPG, PPG and HbA1c levels by 63 mg/dL, 65 mg/dL and 1.7%, respectively. Compared to results of glyburide treatment alone, the net differences with combination treatment were –77 mg/dL, –68 mg/dL and –1.9%, respectively (see Table 3).

Table 3.  Combined Metformin/Glyburide (Comb) vs Glyburide (Glyb) or Metformin (MET) Monotherapy: Summary of Mean Changes from Baseline* in Fasting Plasma Glucose, HbA1c and Body Weight, at Final Visit (29-week study) 
p-values

Comb
(n = 213)

Glyb
(n = 209)

MET
(n = 210)

Glyb vs
Comb

MET vs
Comb

MET vs
Glyb
*   All patients on glyburide, 20 mg/day, at Baseline
** Not statistically significant
Fasting Plasma
Glucose (mg/dL)

  Baseline
  Change at FINAL VISIT


250.5
-63.5


247.5
13.7


253.9
-0.9


NS**
0.001


NS**
0.001


NS**
0.025
Hemoglobin A1c (%)
  Baseline
  Change at FINAL VISIT

8.8
-1.7

8.5
0.2

8.9
-0.4

NS**
0.001

NS**
0.001

0.007
0.001
Body Weight (lbs.)
   Baseline
   Change at FINAL VISIT

202.2
0.9

203.0
-0.7

204.0
-8.4

NS**
0.011

NS**
0.001

NS**
0.001

The magnitude of the decline in fasting blood glucose concentration following the institution of metformin hydrochloride tablet therapy was proportional to the level of fasting hyperglycemia.  Patients with type 2 diabetes with higher fasting glucose concentrations experienced greater declines in plasma glucose and glycosylated hemoglobin.

In clinical studies, metformin, alone or in combination with a sulfonylurea, lowered mean fasting serum triglycerides, total cholesterol and LDL cholesterol levels and had no adverse effects on other lipid levels (see Table 4).

Table 4. Summary of Mean Percent Change from Baseline of Major Serum Lipid Variables at Final Visit (29-week studies) 

Metformin vs Placebo
Combined Metformin/Glyburide
        vs Monotherapy
Metformin
(n = 141)
Placebo
(n = 145)
Metformin
(n = 210)
Metformin/
Glyburide
(n = 213)
Glyburide
(n = 209)
Total Cholesterol
(mg/dL)

   Baseline

   Mean %   
   change at
   FINAL VISIT


211.0


-5%


212.3


1%


213.1


-2%


215.6


-4%


219.6


1%
Total
Triglycerides
(mg/dL)

   Baseline

   Mean %
   change at
   FINAL VISIT



236.1


-16%



203.5


1%



242.5


-3%



215.0


-8%



266.1


4%
LDL-Cholesterol
(mg/dL)

   Baseline
   
  
   Mean %
   change at
   FINAL VISIT


135.4



-8%


138.5



1%


134.3



-4%


136.0



-6%


137.5



3%
HDL-Cholesterol
(mg/dL)

   Baseline

  Mean %
  change at
  FINAL VISIT


39.0


2%


40.5


-1%


37.2


5%


39.0


3%


37.0


1%

In contrast to sulfonylureas, body weight of individuals on metformin tended to remain stable or even decrease somewhat (see Tables 2 and 3).

A 24-week, double-blind, placebo-controlled study of 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 (see Table 5).  Patients randomized to receive metformin plus insulin achieved a reduction in HbA1c of 2.1%, 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 U/day vs 110.6 U/day, metformin plus insulin versus insulin plus placebo, respectively, p=0.04.

Table 5. Combined Metformin/Insulin vs Placebo/Insulin Summary of Mean Changes from Baseline in HbA1c and Daily Insulin Dose
Metformin/
Insulin
(n = 26)
Placebo/
Insulin,
(n = 28)
  Treatment
     Difference   
   Mean ± SE
a Statistically significant using analysis of covariance with baseline as covariate (p=0.04) Not significant using analysis of variance (values shown in table)
Statistically significant for insulin (p=0.04)
Hemoglobin A1c (%)
   Baseline
   Change at FINAL VISIT

8.95
-2.10

9.32
-1.56


-0.54 ± 0.43a
Insulin Dose (U/day)
   Baseline
   Change at FINAL VISIT

93.12
-0.15

94.64
15.93


-16.08 ± 7.77b

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 ± 25.2 units for metformin plus insulin and placebo plus insulin, p<0.01). In addition, this study demonstrated that the combination of metformin hydrochloride tablets plus insulin resulted in reduction in body weight of 3.11 ± 4.3 lbs, compared to an increase of 1.3 ± 6.08 lbs for placebo plus insulin, p=0.01.

Pediatric Clinical Studies

In a double-blind, placebo-controlled study in pediatric patients aged 10 to 16 years with type 2 diabetes (mean FPG 182.2 mg/dL), treatment with metformin (up to 2000 mg/day) for up to 16 weeks (mean duration of treatment 11 weeks) resulted in a significant mean net reduction in FPG of 64.3 mg/dL, compared with placebo (see Table 6).

Table 6. Metformin vs Placebo (Pediatricsa) Summary of Mean Changes from Baseline* in Plasma Glucose and Body Weight at Final Visit  
 Metformin Placebo p–Value
a Pediatric patients mean age 13.8 years (range 10-16 years)
* All patients on diet therapy at Baseline
** Not statistically significant
   FPG (mg/dL)
  Baseline
  Change at FINAL VISIT
(n = 37)
162.4
-42.9
(n = 36)
192.3
21.4


<0.001
   Body Weight (lbs)
  Baseline
  Change at FINAL VISIT
(n = 39)
205.3
  -3.3
(n = 38)
189.0
-2.0


NS**

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