Source: Pharmaceutical Benefits Scheme (AU) Revision Year: 2022 Publisher: Alphapharm Pty Ltd trading as Viatris, Level 1, 30 The Bond, 30-34 Hickson Road, Millers Point NSW 2000, www.viatris.com.au, Phone: 1800 274 276
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:
Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase.
Metformin increases the transport capacity of all types of membrane glucose transporters (GLUT).
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 or long-term clinical studies: metformin reduces total cholesterol, LDL cholesterol and triglyceride levels.
The prospective randomised (UKPDS) study has established the long-term benefit of intensive blood glucose control in type 2 diabetes.
Analysis of the results for overweight patients treated with metformin after failure of diet alone showed:
Benefit regarding clinical outcome has not been shown for metformin hydrochloride 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.
In a double blind, placebo-controlled study in 82 paediatric patients aged 10 to 16 years with type 2 diabetes (mean FPG 10.1 mmol/L), 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 3.6 mmol/L, compared with placebo.
After oral administration, metformin hydrochloride is absorbed along the entire gastrointestinal mucosa. Studies using single oral doses of metformin tablets indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an increase in elimination. After oral administration, metformin absorption is saturable and incomplete. It is assumed that the pharmacokinetics of metformin absorption are non-linear.
At usual clinical doses and dosing schedules of metformin tablets, steady-state plasma concentrations are reached in 24 to 48 hours and are generally less than 1 µg/mL. During controlled clinical trials, maximum metformin plasma levels did not generally exceed 5 µg/mL, even at maximum doses.
Metformin is not bound to plasma proteins.
Metformin is excreted unchanged in the urine and does not undergo hepatic metabolism.
In patients with significantly decreased renal function (based on measured creatinine clearance), the plasma halflife of metformin is prolonged and renal clearance is decreased in proportion to the decrease in creatinine clearance, e.g. if creatinine clearance is 10-30 mL/min, renal clearance is reduced to 20% of normal.
Following an oral dose, children 12 years and older, have shown similar pharmacokinetic profile of metformin to that observed in adults. Pharmacokinetic data in children between 10 and 12 years are not available.
Long term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively. These doses are both approximately two to three times the recommended human 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 treated with 900mg/kg/day.
No evidence of a mutagenic potential of metformin was found in the Ames test (S.typhimurium), gene mutation test (mouse lymphoma cells), chromosomal aberrations test (human lymphocytes), or in vivo micronuclei formation test (mouse bone marrow).
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