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Metformin is a biguanide with antihyperglycaemic effects, lowering both basal and postprandial plasma glucose. It increases insulin sensitivity but does not stimulate insulin secretion. Metformin reduces blood glucose levels probably via:
Metformin also increases glycogen synthase activity and stimulates intracellular glycogen synthesis.
In humans, independently of its action on glycaemia, metformin has favourable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term and long-term clinical studies: metformin reduces total cholesterol, LDL-cholesterol and triglyceride levels.
Glibenclamide is a second generation sulfonylurea with a medium half-life: it causes acute lowering of blood glucose by stimulating the release of insulin by the pancreas, this effect being dependent on the presence of functioning beta cells in the islets of Langerhans. The administration of glibenclamide to diabetics induces an increase in the postprandial insulin-stimulating response. The increased postprandial responses in insulin and C-peptide secretion persist after at least 6 months of treatment.
Metformin and glibenclamide have different mechanisms and sites of action, but their action is complementary. Glibenclamide stimulates the pancreas to secrete insulin, while metformin reduces cell resistance to insulin by acting on peripheral (skeletal muscle) and hepatic sensitivity to insulin.
Results from controlled, double blind clinical trials versus reference products in the treatment of type II diabetes inadequately controlled by monotherapy with metformin or glibenclamide combined with diet and exercise, have demonstrated that the combination had an additive effect on glucose regulation.
In a 16-week, double-blind, active-controlled U.S. clinical trial, a total of 639 patients with type II diabetes not adequately controlled (mean baseline HbA1c 9.5%, mean baseline FPG 11.8 mmol/L) while being treated with at least one-half the maximum dose of a sulfonylurea (e.g., glibenclamide 10 mg, glipizide 20 mg) were randomized to receive glibenclamide (fixed dose, 20 mg), metformin (500 mg), Glucovance 500 mg/2.5 mg, or Glucovance 500 mg/5 mg. The doses of metformin and Glucovance were titrated to a maximum of four tablets daily as needed to achieve FPG<7.8 mmol/L. Trial data at 16 weeks are summarised in Table 3.
Table 3. Glucovance as Second-Line Therapy in Patients Not Adequately Controlled with Sulfonylurea: Summary of Trial Data at 16 Weeks:
| Glibenclamide 5 mg tablets | Metformin 500 mg tablets | Glucovance 500 mg/2.5 mg tablets | Glucovance 500 mg/5 mg tablets | |
|---|---|---|---|---|
| Mean Final Dose | 20 mg | 1840 mg | 8.8 mg/1760 mg | 17 mg/1740 mg |
| Haemoglobin A1c | N=158 | N=142 | N=154 | N=159 |
| Baseline Mean (%) | 9.6 | 9.5 | 9.4 | 9.4 |
| Final Mean | 9.6 | 9.8 | 7.9 | 7.9 |
| Difference from Glibenclamide | -1.7a | -1.7a | ||
| Difference from Metformin | -1.9a | -1.9a | ||
| Fasting Plasma Glucose | N=163 | N=152 | N=160 | N=160 |
| Baseline Mean (mmol/L) | 12.1 | 11.8 | 11.8 | 11.7 |
| Final Mean | 12.3 | 13 | 9.4 | 8.9 |
| Difference from Glibenclamide | -2.8a | -3.3a | ||
| Difference from Metformin | -3.6a | -4a | ||
| Body Weight Mean Change from Baseline | +0.4 kg | -2.8 kg | +0.8 kg | +0.5 kg |
| Final HBA1c Distribution | N=158 | N=142 | N=154 | N=159 |
| <7% | 2.5% | 2.8% | 24.7% | 22.6% |
| ≥7% | 97.5% | 97.2% | 75.3% | 77.4% |
a p<0.001
After 16 weeks, there was no significant change in the mean HbA1c in the patients randomized to glibenclamide or to metformin therapy. Treatment with Glucovance at doses up to 20 mg/2000 mg per day resulted in significant lowering of HbA1c, FPG, and PPG from baseline compared to glibenclamide or metformin alone.
In a 16-week, double-blind, active-controlled European clinical trial, a total of 411 patients with type II diabetes not adequately controlled (mean baseline HbA1c 7.9%, mean baseline FPG 10.8 mmol/L) while being treated with metformin (at least 850 mg b.i.d. or 500 mg t.i.d.) in addition to diet and exercise were randomized to receive glibenclamide 5 mg, metformin 500 mg, Glucovance 500 mg/2.5 mg, or Glucovance 500 mg/5 mg. The doses of metformin and Glucovance were titrated to a maximum of four tablets daily as needed to achieve FPG <7 mmol/L. Trial data at 16 weeks are summarised in Table 4.
Table 4. Glucovance as Second-Line Therapy in Patients Not Adequately Controlled with Metformin: Summary of Trial Data at 16 Weeks:
| Glibenclamide 5 mg tablets | Metformin 500 mg tablets | Glucovance 500 mg/2.5 mg tablets | Glucovance 500 mg/5 mg tablets | |
|---|---|---|---|---|
| Mean Final Dose | 13.4 mg | 1660 mg | 6.1 mg/1225 mg | 11.7mg/1170mg |
| Haemoglobin A1c | N=103 | N=104 | N=100 | N=103 |
| Baseline Mean (%) | 7.9 | 8.1 | 7.9 | 7.6 |
| Final Mean | 7.5 | 7.8 | 6.7 | 6.8 |
| Difference from Glibenclamide | -0.9a | -0.6a | ||
| Difference from Metformin | -1.0a | -0.7b | ||
| Fasting Plasma Glucose | N=103 | N=104 | N=100 | N=103 |
| Baseline Mean (mmol/L) | 10.4 | 11.0 | 10.7 | 10.6 |
| Final Mean | 9.6 | 10.4 | 8.1 | 8.2 |
| Difference from Glibenclamide | -1.9a | -1.6a | ||
| Difference from Metformin | -2.1a | -1.8a | ||
| Body Weight Mean Change from Baseline | +0.9 kg | -0.8 kg | +0.6 kg | +1 kg |
| Final HBA1c Distribution | N=103 | N=104 | N=100 | N=103 |
| <7% | 41.9% | 37.6% | 75.5% | 63.8% |
| ≥7% | 58.1% | 62.4% | 24.5% | 36.2% |
a p<0.001
b p<0.01
No clinical trial has been performed in type II diabetes patients already on combination therapy whose glycaemia is well controlled.
In a 26-week, active controlled, double-blind, clinical study performed in 167 paediatric patients aged 9 to 16 years with type 2 diabetes not adequately controlled with diet and exercise, with or without an oral antidiabetic treatment, a fixed combination of metformin hydrochloride 250 mg and glibenclamide 1.25 mg was not shown more effective than either metformin hydrochloride or glibenclamide in reducing HbA1c from baseline.
After an oral dose of metformin, Tmax is reached in 2.5 hours. Absolute bioavailability of a 500 mg or 850 mg metformin tablet is approximately 50 to 60 % in healthy subjects. After an oral dose, the non-absorbed fraction recovered in faeces is 20 to 30 %.
After oral administration, metformin absorption is saturable and incomplete. It is assumed that the pharmacokinetics of metformin absorption is non-linear. At the usual metformin doses and dosing schedules, steady state plasma concentrations are reached within 24 to 48 hours and are generally less than 1 µg/mL. In controlled clinical trials, maximum metformin plasma levels (Cmax) did not exceed 5 µg/mL, even at maximum doses.
Following administration of a single combination of a Glucovance 500 mg/5 mg tablet with food, there is no effect of food on the bioavailability of metformin.
Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak is lower than the plasma peak and appears at approximately the same time. The red blood cells most likely represent a secondary compartment of distribution. The mean volume of distribution Vd ranged from 63 to 276 L.
Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.
Renal clearance of metformin is > 400 mL/minute, indicating that metformin is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 hours. When renal function is impaired, renal clearance is decreased in proportion to that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of metformin in plasma.
Glibenclamide is very readily absorbed (>95%) following oral administration. The peak plasma concentration is reached in about 4 hours.
Glibenclamide is extensively bound to plasma albumin (99%), which may account for certain drug interactions.
Glibenclamide is completely metabolised in the liver to 2 metabolites. Hepatocellular failure decreases glibenclamide metabolism and appreciably slows down its excretion.
Glibenclamide is excreted in the form of metabolites via biliary route (60%) and urine (40%), elimination being complete within 45 to 72 hours. Its terminal elimination half-life is 4 to 11 hours. Biliary excretion of the metabolites increases in cases of renal insufficiency, according to the severity of renal impairment until a creatinine clearance of 30 mL/minute. Thus, glibenclamide elimination is unaffected by renal insufficiency as long as the creatinine clearance remains above 30 mL/minute.
The metformin component of Glucovance is strictly bio-equivalent to metformin co-administered with glibenclamide. In bioavailability studies, the glibenclamide component of Glucovance showed a higher peak plasma concentration as well as an earlier time to peak. No difference in total area under the curve was noted between Glucovance and the co-administered glibenclamide and metformin.
The bioavailability of metformin is unaffected by the ingestion of food whereas the effect of food on the glibenclamide component of Glucovance is indeterminate. Thus, Glucovance can be safely administered at the beginning of the meals.
In this setting, the magnitude of the differences in the pharmacokinetic properties between Glucovance and the reference preparations is not outside the range of differences between individuals and day-to-day variations. These slight pharmacokinetic differences are easily overcome by titration and are not expected to result in clinically relevant modifications on the long-term outcome of diabetes management.
Paediatric patients: There were no differences in pharmacokinetics of glibenclamide and metformin between adolescents and weight and gender-matched healthy adults. There are no reliable data in children (12 years or younger).
No animal studies have been conducted with the combination of metformin and glibenclamide.
Metformin was not genotoxic in assays for gene mutations (S. typhimurium, mouse lymphoma cells) or chromosomal damage (chromosomal aberrations test in human lymphocytes or in vivo micronuclei formation test).
Glibenclamide was not genotoxic in a limited set of in vitro assays for gene mutations (S. typhimurium) and other genotoxic effects (DNA damage/alkaline elution assay). The clastogenic potential of glibenclamide has not been investigated.
Long-term carcinogenicity studies with metformin alone have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at oral doses up to 900 mg/kg/day and 1,500 mg/kg/day, respectively. These doses are approximately 3 to 4 times the maximum recommended daily dose on a body surface area basis. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumourigenic potential observed with metformin in male rats. However, an increased incidence of benign stromal uterine polyps was seen in female rats at 900 mg/kg/day.
A study with glibenclamide alone in a small number of rats (15/sex/group) at doses up to 300 mg/kg/day (approximately 136 times the maximum recommended daily dose on a body surface area basis) for 18 months showed no carcinogenic effects.
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