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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.
Therapeutic Use in Non—Insulin-Dependent Diabetes Mellitus
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.
Dosage and Administration
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.
KeywordsMetformin Glycaemic Control Glibenclamide Sulphonylurea Gliclazide
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- 2.Bailey CJ, Nattrass M. Treatment-metformin. Baillieres Clin Endocrin Metab 1988; 2: 455–76Google Scholar
- 6.DeFronzo RA. The triumvirate: β-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes 1988; 37: 667–87Google Scholar
- 9.Beck-Nielsen H, Hother-Nielsen O, Vaag A, et al. Pathogenesis of type 2 (non-insulin-dependent) diabetes mellitus: the role of skeletal muscle uptake and hepatic glucose production in the development of hyperglycaemia. A critical comment. Diabetologia 1994; 37: 217–21Google Scholar
- 11.Karam JH. Type II diabetes and syndrome X. Pathogenesis and glycemic management. Endocrinol Metab Clin North Am 1992; 21: 329–50Google Scholar
- 14.Bailey CJ. Metformin and intestinal glucose handling [abstract]. NIDDM: prevention and treatment. Glucophage International Symposium, Heidelberg, Germany, September 25–26, 1994: 18.Google Scholar
- 15.Hermann LS. Metformin as monotherapy and combined with glibenclamide in patients with non-insulin dependent diabetes mellitus. Lund: Department of Community Health Sciences, Lund University, 1994Google Scholar
- 16.Hermann LS, Melander A. Biguanides: basic aspects and clinical use. In: Alberti KGMM, DeFronzo RA, Keen H, et al., editors. International textbook of diabetes mellitus. New York: John Wiley & Sons, 1992: 773–95Google Scholar
- 17.Althoff P-H, Haupt E, Pichel C, et al. Metformin increases insulin sensitivity and first phase of the arginin-induced insulin response in type 2 diabetes [abstract]. Diabetes 1991 May; 40 Suppl. 1: 342Google Scholar
- 30.Nagi DK, Mohamed AV, Yudkin JS. Effects of metformin on intact and des 31, 32 proinsulin in subjects with non-insulin-dependent diabetes [abstract]. Diabetic Med 1994 Apr; 11 Suppl. 1: 25–6Google Scholar
- 45.DeFronzo RA. Mechanism of metformin action: clinical studies in NIDDM [abstract]. NIDDM: prevention and treatment. Glucophage International Symposium, Heidelberg, Germany, September 25–26, 1994: 15.Google Scholar
- 46.Radziuk J. Glucose production, gluconeogenesis and metformin [abstract]. NIDDM: prevention and treatment. Glucophage International Symposium, Heidelberg, Germany, September 25–26, 1994: 21-2.Google Scholar
- 49.Sarabia V, Lam L, Burdett E, et al. Glucose transport in human skeletal muscle cells in culture. Stimulation by insulin and metformin. J Clin Invest 1992 Oct; 90: 1386–95Google Scholar
- 54.Mendoza SG, Faieta A, Carrasco H, et al. Metformin lowers blood pressure, insulin resistance, triglycerides, and endogenous estradiol in hypertensive men [abstract]. Clin Res 1994; 42: 338AGoogle Scholar
- 55.Goodman AM, Metformin Investigator Group. Efficacy and safety of metformin in NIDDM: results of a multicenter trial [abstract]. Diabetes 1993 May; 42 Suppl. 1: 57AGoogle Scholar
- 63.Gregorio F, Ambrosi F, Filliponi P, et al. Metformin and haemostatic variables in Type II non-insulin dependent diabetes mellitus. Diabetes Nutr Metab 1995; 8: 1–8Google Scholar
- 70.Rudnichi A, Fontbonne A, Safar M, et al. The effect of metformin on the metabolic anomalies associated with android type body fat distribution. Results of the BIGPRO trial [abstract]. Diabetes 1994; 43 Suppl. 1: 150AGoogle Scholar
- 76.Matthaei S, Hamann A, Klein HH, et al. Association of metformin’s effect to increase insulin-stimulated glucose transport with potentiation of insulin-induced translocation of glucose transporters from intracellular pool to plasma membrane in rat adipocytes. Diabetes 1991 Jul; 40: 850–7PubMedGoogle Scholar
- 78.Matthaei S, Hamann A, Klein HH, et al. Evidence that metformin increases insulin-stimulated glucose transport by potentiating insulin-induced translocation of glucose transporters from an intracellular pool to the cell surface in rat adipocytes. Horm Metab Res 1992; 26 Suppl.: 34–41Google Scholar
- 80.Matthaei S, Reibold JP, Hamann A, et al. In vivo metformin treatment ameliorates insulin resistance: evidence for potentiation of insulin-induced translocation and increased functional activity of glucose transporters in obese (fa/fa) Zucker rat adipocytes. Endocrinology 1993 Jul; 133: 304–11PubMedGoogle Scholar
- 85.Arafat T, Kaddoumi A, Shami M. Pharmacokinetics and pharmacodynamics of two oral formulations of metformin hydrochloride. Adv Ther 1994 Jan–Feb; 11: 21–33Google Scholar
- 86.Benzi L, Marchetti P, Cecchetti P, et al. Determination of metformin and phenformin in human plasma and urine by reversed-phase high-performance liquid chromatography. J Chromatogr 1986; 375: 184–9Google Scholar
- 87.Brookes LG, Sambol NC, Lin ET, et al. Effect of dosage form, dose and food on the pharmacokinetics of metformin [abstract]. Pharm Res 1991 Oct; 8 Suppl.: 320Google Scholar
- 88.Sambol NC, O’Connor MD, Lin ET, et al. Pharmacokinetics and pharmacodynamics of metformin HCl in healthy individuals and individuals with noninsulin-dependent diabetes mellitus (NIDDM) [abstract]. Clin Pharmacol Ther 1993 Feb; 53: 211Google Scholar
- 98.United Kingdom Prospective Diabetes Study Group. United Kingdom prospective diabetes study (UKPDS) 13: relative efficacy of randomly allocated diet, sulphonylurea, insulin, or metformin in patients with newly diagnosed non-insulin dependent diabetes followed for three years. BMJ 1995; 310: 83–8Google Scholar
- 100.Campbell IW, Menzies DG, Chalmers J, et al. One year comparative trial of metformin and glipizide in type 2 diabetes mellitus. Diabete Metab 1994; 21: 394–400Google Scholar
- 101.National Diabetes Data Group. Classification and diagnosis of diabetes mellitus and other categories of glucose tolerance. Diabetes 1979; 28: 1039–57Google Scholar
- 102.WHO Study Group. Diabetes mellitus. Geneva: World Health Organization, 1985 (WHO Technical Report Series; 727)Google Scholar
- 104.United Kindom Prospective Diabetes Study Group. UK Prospective Diabetes Study (UKPDS): VIII. Study design, progress and performance. Diabetologia 1992; 34: 877–90Google Scholar
- 105.Watkins PJ. Guidelines for good practice in the diagnosis and treatment of non-insulin-dependent diabetes mellitus. J R Coll Physicians Lond 1993 Jul; 27: 259–66Google Scholar
- 119.DeFronzo RA, Goodman A, Metformin IG. Combined metformin/glyburide treatment in NIDDM patients not optimally responding to maximum dose sulfonylurea: results of a multicenter trial [abstract]. Diabetes 1993 May; 42 Suppl. 1: 146AGoogle Scholar
- 133.Campbell IW. Metformin and the sulphonylureas: the comparative risk. Horm Metab Res 1985; 15 Suppl.: 105–11Google Scholar
- 134.Berger W. Incidence of severe side effects during therapy with sulphonylureas and biguanides. Horm Metab Res 1985; 15 Suppl.: 111–5Google Scholar
- 137.Chalmers J, McBain AM, Brown IRF, et al. Metformin: is its use contraindicated in the elderly?. Pract Diabetes 1992 Mar/Apr; 9: 51–3Google Scholar