Pharmacotherapeutic group: Oral blood glucose lowering drugs. Biguanides. ATC code: A10BA02.
Pharmacology: Pharmacodynamics: Metformin is a biguanide with antihyperglycaemic effects, lowering both basal and postprandial plasma glucose. It does not stimulate Insulin secretion and therefore does not produce hypoglycaemia.
Metformin may act via 3 mechanisms: reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis.
in muscle, by increasing Insulin sensitivity, improving peripheral glucose uptake and utilization.
and delay of intestinal glucose absorption.
Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase. Metformin increases the transport capacity of all types of membrane glucose transporters (GLUTs) known to date.
In clinical studies, use of Metformin was associated with either a stable body weight or modest weight loss. In humans, independently of its action on glycaemia, Metformin immediate-release has favourable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term clinical studies: Metformin reduces total cholesterol, LDL cholesterol and triglyceride levels.
Clinical Efficacy: The prospective randomised study (UKPDS) has established the long-term benefit of intensive blood glucose control in adult patients with type 2 diabetes. Analysis of the results for overweight patients treated with Metformin after failure of diet alone showed: a significant reduction of the absolute risk of any diabetes-related complication in the Metformin group (29.8 events/1000 patient-years) versus diet alone (43.3 events/1000 patient-years), p=0.0023, and versus the combined Sulfonylurea and Insulin monotherapy groups (40.1 events/1000 patient -years), p=0.0034;
a significant reduction of the absolute risk of diabetes-related mortality: Metformin 7.5 events/1000 patient-years, diet alone 12.7 events/1000 patient-years, p=0.017;
a significant reduction of the absolute risk of overall mortality: Metformin 13.5 events/1000 patient-years versus diet alone 20.6 events/1000 patient-years (p=0.011), and versus the combined Sulfonylurea and Insulin monotherapy groups 18.9 events/1000 patient-years (p=0.021);
a significant reduction in the absolute risk of myocardial infarction: Metformin 11 events/1000 patient-years, diet alone 18 events/1000 patient-years (p=0.01).
Benefit regarding clinical outcome has not been shown for Metformin used as second-line therapy, in combination with a Sulfonylurea.
In type 1 diabetes, the combination of Metformin and Insulin has been used in selected patients, but the clinical benefit of this combination has not been formally established.
Pharmacokinetics: Absorption: After an oral dose of Glucophage XR 500, Metformin absorption is significantly delayed compared to the immediate-release tablet (Tmax at 2.5 hours) with a Tmax at 7 hours. Following a single oral administration of 1500 mg of Glucophage XR 750, a mean peak plasma concentration of 1193 mg/mL is achieved with a median value of 5 hours and a range of 4 to 12 hours. Glucophage XR 750 was shown to be bioequivalent to Glucophage XR 500 at a 1500 mg dose with respect to Cmax and AUC in healthy fed and fasted subjects.
Following a single oral administration in the fed state of one tablet of Glucophage XR 1000, a mean peak plasma concentration of 1214 ng/mL is achieved with a median time of 5 hours (range of 4 to 10 hours). Glucophage XR 1000 was shown to be bioequivalent to Glucophage XR 500 at a 1000 mg dose with respect to Cmax and AUC in healthy fed and fasted subjects.
At steady state, similar to the immediate-release formulation, Cmax and AUC are not proportionally increased to the administered dose. The AUC after a single oral administration of 2000 mg Metformin prolonged-release is similar to that observed after administration of 1000 mg Metformin immediate release twice daily.
Intrasubject variability of Cmax and AUC of Metformin prolonged-release is comparable to that observed with Metformin immediate-release.
When 2 tablets of 500 mg Metformin prolonged-release is administered in fed conditions the AUC is increased by approximately 70% (both Cmax and Tmax are only slightly increased).
When the 1000 mg prolonged release tablet are administered in fed conditions the AUC is increased by 77% (Cmax is increased by 26% and Tmax is slightly prolonged by about 1 hour).
Metformin absorption from the prolonged-release formulation is not altered by meal composition.
No accumulation is observed after repeated administration of up to 2000 mg Metformin prolonged release.
Distribution: 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 between 63-276 L.
Metabolism: Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.
Elimination: Renal clearance of Metformin is >400 mL/min, 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.
Toxicology: Preclinical Safety Data: Preclinical data reveal no special hazard for humans based on conventional studies on safety, pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and reproductive toxicity reproduction.