Metformin

Abstract

The biguanide metformin (dimethylbiguanide) is an oral antihyperglycaemic agent used in the management of non—insulin-dependent diabetes mellitus (NIDDM). It reduces blood glucose levels, predominantly by improving hepatic and peripheral tissue sensitivity to insulin without affecting the secretion of this hormone. Metformin also appears to have potentially beneficial effects on serum lipid levels and fibrinolytic activity, although the long term clinical implications of these effects are unclear. Metformin possesses similar antihyperglycaemic efficacy to sulphonylureas in obese and nonobese patients with NIDDM. Additionally, interim data from the large multicentre United Kingdom Prospective Diabetes Study (UKPDS) indicated similar antihyperglycaemic efficacy for metformin and insulin in newly diagnosed patients with NIDDM. Unlike the sulphonylureas and insulin, however, metformin treatment is not associated with increased bodyweight. Addition of metformin to existing antidiabetic therapy confers enhanced antihyperglycaemic efficacy. This may be of particular use in improving glycaemic control in patients with NIDDM not adequately controlled with sulphonylurea monotherapy, and may serve to reduce or eliminate the need for daily insulin injections in patients with NIDDM who require this therapy. The acute, reversible gastrointestinal adverse effects seen with metformin may be minimised by administration with or after food, and by using lower dosages, increased slowly where necessary. Lactic acidosis due to metformin is rare, and the risk of this complication may be minimised by observance of prescribing precautions and contraindications intended to avoid accumulation of the drug or lactate in the body. Unlike the sulphonylureas, metformin does not cause hypoglycaemia. Thus, metformin is an effective antihyperglycaemic agent which appears to improve aberrant plasma lipid and fibrinolytic profiles associated with NIDDM. Possible long term clinical benefits of this drug with regard to cardiovascular mortality and morbidity are not yet established but are being assessed in a major ongoing study. Since metformin does not promote weight gain or hypoglycaemia it should be considered first-line pharmacotherapy in obese patients with NIDDM inadequately controlled by nonpharmacological measures. Metformin appears similarly effective for the pharmacological management of NIDDM in nonobese patients. Metformin appears to act principally by improving the sensitivity of peripheral tissue (chiefly skeletal muscle) and the liver to insulin, thus opposing the insulin resistance of non—insulin-dependent diabetes mellitus (NIDDM). Metformin does not increase pancreatic insulin secretion and does not induce hypoglycaemia. Improved glucose disposal has been observed in both patients with NIDDM and normoglycaemic hyperinsulinaemic individuals, under fasting and hyperinsulinaemic euglycaemic clamp conditions. Studies of up to 12 weeks’ duration typically demonstrated increases in insulin-stimulated glucose disposal of 18 to 29% after metformin 0.5 to 3 g/day. In vitro data also suggest a metformin-associated improvement in glucose uptake and storage by erythrocytes from patients with NIDDM. Results of studies of the effect of metformin on plasma levels of insulin and related products are consistent with the view that metformin improves peripheral and hepatic sensitivity to insulin. Furthermore, treatment with metformin 1000 to 2550 mg/day for up to 3 months resulted in reductions in hepatic glucose production of 9 to 30% relative to baseline or placebo. Evidence is conflicting with regard to the effect of metformin on insulin binding to cell membranes, but the drug appears to increase the rate of insulin-stimulated glucose transport across cell membranes. Metformin has beneficial effects on serum lipid profiles in obese and lean patients with NIDDM, and in other patients with concomitant NIDDM, hypertension and/or hyperlipidaemia. In particular, reduced circulating levels of free fatty acids, triglycerides and low density lipoprotein cholesterol, and increased high density lipoprotein cholesterol levels have been reported. Potentially beneficial vascular properties, such as increased fibrinolytic activity and decreased platelet density and aggregability, have also been observed in nondiabetic volunteers and patients with NIDDM after treatment with metformin ≤3 g/day for up to 6 months. Metformin has an absolute oral bioavailability of 50 to 60%, and gastrointestinal absorption is apparently complete within 6 hours of ingestion. Higher oral doses are proportionately less bioavailable than lower doses (observed with doses ranging from 500 to 1500mg). Metformin is rapidly distributed following absorption and does not bind to plasma proteins. No metabolites or conjugates of metformin have been identified. The drug undergoes renal excretion and has a mean plasma elimination half-life after oral administration of between 4.0 and 8.7 hours. This is prolonged in patients with renal impairment and correlates with creatinine clearance. In placebo-controlled trials in patients with NIDDM, metformin (0.5 to 3 g/day for up to 8 months) was associated with a significantly greater reduction in fasting blood glucose (22 to 26% of baseline) and glycated haemoglobin (12 to 17% of baseline) levels than placebo. No changes in mean bodyweight were reported for any patient group, and glycaemic improvement was not restricted to obese patients. The antihyperglycaemic efficacy of metformin was shown to be similar to that of the sulphonylureas chlorpropamide, glibenclamide (glyburide) and gliclazide in studies of up to 3 years’ duration, while a single 1-year study suggested superior antihyperglycaemic efficacy for metformin over glipizide. Reductions in fasting blood glucose levels from baseline ranged from 7 to 45% for metformin, and from 8 to 43% for sulphonylureas. Bodyweight was not adversely affected by metformin, but was increased by sulphonylurea therapy in some trials. Furthermore, similar glycaemic control was documented with metformin and insulin after 3 years of treatment in an interim report of the large multicentre United Kingdom Prospective Diabetes Study (UKPDS). Metformin may also be used in combination with other antihyperglycaemic agents, particularly sulphonylureas. This may be used to good effect in patients who demonstrate an unsatisfactory response to previously effective sulphonylurea monotherapy (secondary sulphonylurea failure). In these patients, metformin may obviate the need for insulin injections. Two trials of patients with NIDDM no longer adequately controlled by maximal sulphonylurea dosages showed mean reductions in fasting blood glucose levels of 4.6 to 31% after the addition of metformin 1 g/day for up to 6 weeks. Results from other studies have shown metformin in combination with a sulphonylurea to possess similar antihyperglycaemic efficacy to insulin, and insulin plus a sulphonylurea, without the increase in bodyweight that may occur with insulin therapy. Treatment with metformin 1.7 g/day for 6 months reduced the mean insulin requirement of 50 obese patients with NIDDM by 25%. Acute, reversible adverse effects, mainly of gastrointestinal origin, occur in 5 to 20% of patients treated with metformin. These may be minimised by taking the drug with or after food, and starting therapy with low dosages which may be increased slowly. Diarrhoea may occur in up to 20% of patients and may respond to a reduction in dosage. It is estimated that less than 5% of patients are unable to tolerate metformin. Lactic acidosis is the biguanide-related adverse effect of most concern. Although serious, it is rare, and may be minimised during metformin therapy by strict adherence to prescribing guidelines and contraindications (particularly the presence of renal or hepatic failure, and medical conditions which increase tissue production of lactate). Hypoglycaemia does not occur with metformin, and the incidence of metformin-associated lactic acidosis is lower than that of sulphonylurea-induced hypoglycaemia. Therapy with metformin should be initiated with a dosage of 0.5 to 1 g/day, in divided doses with or after meals. This may be gradually increased as necessary to a maximum of five 500mg or three 850mg tablets daily in the USA, although dosages of up to 3 g/day are used in other countries. The drug may be coadministered with a sulphonylurea if desired. Metformin should not be administered to patients with renal or hepatic impairment, cardiovascular disease or hypoxic conditions which cause lactate accumulation.