Metformin Hydrochloride (Page 2 of 7)

CLINICAL STUDIES

METFORMIN HYDROCHLORIDE TABLETS

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 hydrochloride tablets (up to 2550 mg/day) for 29 weeks resulted in significant mean net reductions in fasting and postprandial plasma glucose (PPG) and hemoglobin A 1c (HbA 1c ) of 59 mg/dL, 83 mg/dL, and 1.8%, respectively, compared to the placebo group (see Table 2 ).

Table 2: Metformin Hydrochloride Tablets vs Placebo Summary of Mean Changes from Baseline* in Fasting Plasma Glucose, HbA 1c , and Body Weight, at Final Visit (29-week study)
Metformin Hydrochloride Tablets Placebo p-Value
(n=141) (n=145)
FPG (mg/dL)
Baseline 241.5 237.7 NS**
Change at FINAL VISIT -53 6.3 0.001
Hemoglobin A 1c (%)
Baseline 8.4 8.2 NS**
Change at FINAL VISIT -1.4 0.4 0.001
Body Weight (lbs)
Baseline 201 206 NS**
Change at FINAL VISIT -1.4 -2.4 NS**

*All patients on diet therapy at Baseline

**Not statistically significant

A 29-week, double-blind, placebo-controlled study of metformin hydrochloride tablets 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 hydrochloride tablets 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 hydrochloride tablets 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 hydrochloride tablets 2500 mg. Patients in the metformin hydrochloride tablets 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 hydrochloride tablets 2000 mg/glyburide 20 mg or metformin hydrochloride tablets 2500 mg/glyburide 20 mg. Patients randomized to continue on glyburide experienced worsening of glycemic control, with mean increases in FPG, PPG, and HbA 1c of 14 mg/dL, 3 mg/dL, and 0.2%, respectively. In contrast, those randomized to metformin hydrochloride tablets (up to 2500 mg/day) experienced a slight improvement, with mean reductions in FPG, PPG, and HbA 1c of 1 mg/dL, 6 mg/dL, and 0.4%, respectively. The combination of metformin hydrochloride tablets and glyburide was effective in reducing FPG, PPG, and HbA 1c 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 Hydrochloride Tablets/Glyburide (Comb) vs Glyburide (Glyb) or Metformin Hydrochloride Tablets (MET) Monotherapy: Summary of Mean Changes from Baseline* in Fasting Plasma Glucose, HbA 1c , and Body Weight, at Final Visit (29-week study)
Comb (n=213) Glyb (n=209) MET (n=210) p-values
Glyb vs Comb MET vs Comb Glyb
Fasting Plasma Glucose (mg/dL)
Baseline 250.5 247.5 253.9 NS** NS** NS**
Change at FINAL VISIT -63.5 13.7 -0.9 0.001 0.001 0.025
Hemoglobin A 1c (%)
Baseline 8.8 8.5 8.9 NS** NS** 0.007
Change at FINAL VISIT -1.7 0.2 -0.4 0.001 0.001 0.001
Body Weight (lbs)
Baseline 202.2 203 204 NS** NS** NS**
Change at FINAL VISIT 0.9 -0.7 -8.4 0.011 0.001 0.001

*All patients on glyburide, 20 mg/day, at Baseline **Not statistically significant

The magnitude of the decline in fasting blood glucose concentration following the institution of metformin hydrochloride tablets 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 hydrochloride tablets, 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 Hydrochloride Tablets vs Placebo Combined Metformin Hydrochloride Tablets/Glyburide vs Monotherapy
Metformin Hydrochloride Tablets Placebo Metformin Hydrochloride Tablets Metformin Hydrochloride Tablets/ Glyburide Glyburide
(n=141) (n=145) (n=210) (n=213) (n=209)
Total Cholesterol (mg/dL)
Baseline 211 212.3 213.1 215.6 219.6
Mean % Change at FINAL VISIT -5% 1% -2% -4% 1%
Total Triglycerides (mg/dL)
Baseline 236.1 203.5 242.5 215 266.1
Mean % Change at FINAL VISIT -16% 1% -3% -8% 4%
LDL-Cholesterol (mg/dL)
Baseline 135.4 138.5 134.3 136 137.5
Mean % Change at FINAL VISIT -8% 1% -4% -6% 3%
HDL-Cholesterol (mg/dL)
Baseline 39 40.5 37.2 39 37
Mean % Change at FINAL VISIT 2% -1% 5% 3% 1%

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

A 24-week, double-blind, placebo-controlled study of metformin hydrochloride tablets 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 hydrochloride tablets plus insulin achieved a reduction in HbA 1c of 2.10%, compared to a 1.56% reduction in HbA 1c 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 hydrochloride tablets plus insulin versus insulin plus placebo, respectively, p=0.04.

Table 5: Combined Metformin Hydrochloride Tablets/Insulin vs Placebo/Insulin Summary of Mean Changes from Baseline in HbA 1c and Daily Insulin Dose
Metformin Hydrochloride Tablets/ Insulin (n=26) Placebo/ Insulin (n=28) Treatment difference Mean ± SE
Hemoglobin A 1c (%)
Baseline 8.95 9.32
Change at FINAL VISIT -2.1 -1.56 -0.54 ± 0.43 a
Insulin Dose (U/day)
Baseline 93.12 94.64
Change at FINAL VISIT -0.15 15.93 -16.08 ± 7.77 b

a Statistically significant using analysis of covariance with baseline as covariate (p=0.04)

Not significant using analysis of variance (Values shown in table)

b Statistically significant for insulin (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 HbA 1c of 7.46 ± 0.97%, the addition of metformin hydrochloride tablets maintained similar glycemic control (HbA 1c 7.15 ± 0.61 versus 6.97 ± 0.62 for metformin hydrochloride tablets 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 hydrochloride tablets 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 ± 4.30 lbs, compared to an increase of 1.30 ± 6.08 lbs for placebo plus insulin, p=0.01.

A 24-week, double-blind, randomized study of metformin hydrochloride tablets, taken twice daily (with breakfast and evening meal), was conducted in patients with type 2 diabetes who had been treated with metformin hydrochloride 500 mg tablets twice daily for at least 8 weeks prior to study entry. The metformin hydrochloride tablets dose had not necessarily been titrated to achieve a specific level of glycemic control prior to study entry. Patients qualified for the study if HbA1c was ≤8.5% and FPG was ≤200 mg/dL. Changes in glycemic control and body weight are shown in Table 7.

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Changes in lipid parameters in the previously described study of metformin hydrochloride tablets and metformin hydrochloride extended release tablets are shown in Table 9.

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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 hydrochloride tablets (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 10 ).

Table 10: Metformin Hydrochloride Tablets vs Placebo (Pediatrics a) Summary of Mean Changes from Baseline* in Plasma Glucose and Body Weight at Final Visit
Metformin Hydrochloride Tablets Placebo p-Value
FPG (mg/dL) (n=37) (n=36)
Baseline 162.4 192.3 <0.001
Change at FINAL VISIT -42.9 21.4
Body Weight (lbs) (n=39) (n=38)
Baseline 205.3 189 NS**
Change at FINAL VISIT -3.3 -2

a Pediatric patients mean age 13.8 years (range 10 to 16 years)

* All patients on diet therapy at Baseline

** Not statistically significant

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