Abstract
Metformin has been used for over 40 years as an effective glucose-lowering agent in type 2 (noninsulin-dependent) diabetes mellitus. Typically it reduces basal and postprandial hyperglycaemia by about 25% in more than 90% of patients when either given alone or coadministered with other therapies including insulin during a programme of managed care.
Metformin counters insulin resistance and offers benefits against many features of the insulin resistance syndrome (Syndrome X) by preventing body weight gain, reducing hyperinsulinaemia and improving the lipid profile. In contrast to sulphonylureas, metformin does not increase insulin secretion or cause serious hypoglycaemia. Treatment of type 2 diabetes mellitus with metformin from diagnosis also offers greater protection against the chronic vascular complications of type 2 diabetes mellitus.
The most serious complication associated with metformin is lactic acidosis which has an incidence of about 0.03 cases per 1000 patients years of treatment and a mortality risk of about 0.015 per 1000 patient-years. Most cases occur in patients who are wrongly prescribed the drug, particularly patients with impaired renal function (e.g. serum creatinine level >130μmol/Lor >1.5 g/L). Other major contraindications include congestive heart failure, hypoxic states and advanced liver disease. Serious adverse events with metformin are predictable rather than spontaneous and are potentially preventable if the prescribing guidelines are respected.
Gastrointestinal adverse effects, notably diarrhoea, occur in less than 20% of patients and remit when the dosage is reduced.
The life-threatening risks associated with metformin are rare and could mostly be avoided by strict adherence to the prescribing guidelines. Given the 4 decades of clinical experience with metformin, its antihyperglycaemic efficacy and benefits against Syndrome X, metformin offers a very favourable risk-benefit assessment when compared with the chronic morbidity and premature mortality among patients with type 2 diabetes mellitus.
Similar content being viewed by others
References
Amos AF, McCarthy DJ, Zimmet P. The rising global burden of diabetes and its complications: estimates and projections to the year 2010. Diabetic Med 1997; 14 Suppl. 5: S7–85
Panzram G. Mortality and survival in type 2 (non-insulin dependent) diabetes mellitus. Diabetologia 1987; 30: 123–31
Fuller J. Mortality trends and causes of death in diabetic patients. Diabete Metab 1993; 19: 96–9
Eschwege E, Balkau B, Fontbonne A. The epidemiology of coronary heart disease in glucose-intolerant and diabetic subjects. J Intern Med 1994; 236: 5–11
Geiss LS, Hermann WH, Smith PJ. Mortality in non-insulin dependent diabetes: diabetes in America. National Institute of Diabetes and Digestive and Kidney Disease. 2nd ed. Bethesda (MD): US Department of Health and Human Services. 1995 NIH publication. Report no.: 95-1468: 233-58
National Institute of Diabetes and Digestive and Kidney Diseases. Diabetes statistics. Bethesda (MD): US Department of Health and Human Services. 1994 NIH publication. Report no.: 94-3822
United Kingdom Prospective Diabetes Study Group. UK Prospective diabetes study 6: complications in newly diagnosed type 2 diabetic patients and their association with different clinical and biochemical risk factors. Diabetes Res 1990; 13: 1–11
Walters DP, Gatling W, Mullee R, et al. The distribution and severity of diabetic foot disease: a community study with a comparison to a non-diabetic group. Diabetic Med 1992; 9: 354–8
Hasslacher CH. Similar risks of nephropathy in patients with type 1 or type 2 diabetes mellitus. Nephrol Dial Transpl 1989; 4: 859–63
Rubin RJ, Altaian WM, Mendelson DN. Health care expenditure for people with diabetes 1992. J Clin Endocrinol Metab 1994; 78: 809A–F
British Diabetic Association. Counting the cost: the real impact of non-insulin dependent diabetes. King’s Fund Policy Institute; London: British Diabetic Association Publications, 1996
Costa B, Arroyo J, Sabate A. The economics of pharmaco-therapy for diabetes mellitus. Pharmacoeconomics 1997; 11: 139–58
UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837–53
Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomised prospective 6 year study. Diabetes Res Clin Pract 1995; 28: 103–17
Klein R. Hyperglycaemia and microvascular and macrovascular disease in diabetes. Diabetes Care 1995; 18: 258–68
Reaven GM. Role of insulin resistance in human disease. Diabetes 1988; 37: 1595–607
De Fronzo RA, Ferrannini E. Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidaemia, and atherosclerotic cardiovascular disease. Diabetes Care 1991; 14: 173–94
Haffner SM, Miettinen H. Insulin resistance implications for type II diabetes mellitus and coronary heart disease. Am J Med 1997; 103: 152–62
Bailey CJ, Turner RC. Metformin. N Engl J Med 1996; 334: 574–9
Hermann LS, Melander A. Biguanides: basic aspects and clinical uses. In: Alberti KGMM, DeFronzo RA, Keen H, et al., editors. International textbook of diabetes mellitus. 2nd ed. Chichester: John Wiley & Sons Ltd 1997: 841–64
Bailey CJ. Biguanides and NIDDM. Diabetes Care 1992; 15: 755–72
Hermann LS. Metformin. Areview of its pharmacological properties and therapeutic use. Diabete Metab 1979; 5: 233–45
Balfour JA, Clissold SP. Management of non-insulin-dependent diabetes mellitus: defining the role of metformin. Dis Manage Health Outcomes 1997; 1: 49–59
Davidson MB, Peters AL. An overview of metformin in the treatment of type 2 diabetes mellitus. Am J Med 1997; 102: 99–110
Dunn CJ, Peters DH. Metformin: a review of its pharmacological properties and therapeutic use in non-insulin dependent diabetes mellitus. Drugs 1995; 49: 721–49
De Fronzo RA, Goodman AM, Multicentre study group. Efficacy of metformin in patients with non-insulin dependent diabetes mellitus. N Engl J Med 1995; 333: 541–9
Campbell IW, Howlett HCS. Worldwide experience of metformin as an effective glucose-lowering agent: a meta-analysis. Diabetes Metab Rev 1995; 11 Suppl. 1: S57–62
United Kingdom Prospective Diabetes Study Group. UK Prospective diabetes study 24: a 6 year, randomised, controlled trial comparing sulphonylurea, insulin and metformin therapy in patients with newly diagnosed type 2 diabetes that could not be controlled with diet therapy. Ann Intern Med 1998; 128: 165–75
Chan JC, Tomlinson B, Critchley JA, et al. Metabolic and hemodynamic effects of metformin and glibenclamide in normotensive NIDDM patients. Diabetes Care 1993; 16: 1035–8
Giugliano D, De Rosa N, Di Mario G, et al. Metformin improves glucose lipid metabolism, and reduces blood pressure in hypertensive, obese women. Diabetes Care 1993; 16: 1387–90
Campbell IW, Duncan CD, Patton NW, et al. The effect of metformin on glycaemic control, intermediary metabolism and blood pressure in non-insulin dependent diabetes mellitus. Diabetic Med 1987; 4: 337–41
Marfella R, Acampora R, Verrazzo G, et al. Metformin improves hemodynamic and rheological responses to L-arginine in NIDDM patients. Diabetes Care 1996; 19: 934–9
Sundaresan P, Lykos D, Daher A, et al. Comparative effects of glibenclamide and metformin on ambulatory blood pressure and cardiovascular reactivity in NIDDM. Diabetes Care 1997; 20: 692–7
Dorella M, Giusto M, Da Tos V, et al. Improvement of insulin sensitivity by metformin treatment does not lower blood pressure of non-obese insulin-resistant hypertensive patients with normal glucose tolerance. J Clin Endocrinol Metab 1996; 81: 1568–74
Gudbjornsdottir HS, Friberg P, Elam M, et al. The effect of metformin and insulin on sympathetic nerve activity, norepinephrine spillover and blood pressure in obese, insulin resistant, normoglycemic, hypertensive men. Blood Press 1994; 3: 394–403
Snorgaard O, Kober L, Carlsen J. The effect of metformin on blood pressure and metabolism in non-diabetic hypertensives. J Intern Med 1997; 242: 407–12
Grant PJ. The effects of high and medium dose metformin therapy on cardiovascular risk factors in patients with type II diabetes. Diabetes Care 1996; 19: 64–6
Nagi DK, Yudkin JS. Effects of metformin on insulin resistance, risk factors for cardiovascular disease, and plasminogen activator inhibitor in NIDDM subjects. Diabetes Care 1993; 16: 621–9
Jansson PE, Anderson OK, Gudbjornsdottir HS, et al. The effect of metformin on adipose tissue metabolism and peripheral blood flow in subjects with NIDDM. Diabetes Care 1996; 19: 160–4
Sirtori CR, Franceschini G, Gianfranceschi G, et al. Metformin improves peripheral vascular flow in non hyperlipidemic patients with arterial disease. J Cardiovasc Pharmacol 1984; 6: 914–23
Montanari G, Bondioli A, Rizzato G, et al. Treatment with low dose metformin in patients with peripheral vascular disease. Pharmacol Res 1992; 25: 63–73
United Kingdom Prospective Diabetes Study Group. UK prospective diabetes study 16: overview of 6 years therapy of type II diabetes: a progressive disease. Diabetes 1995; 44: 1249–58
Sattar N, Hopkinson ZEC, Greer IA. Insulin sensitising agents inpolycystic ovary syndrome. Lancet 1998; 351: 305–7
Velazquez EM, Mendoza S, Hamer T, et al. Metformin therapy in women with polycystic ovary syndrome reduces hyperinsulinaemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating menstrual regularity and pregnancy. Metabolism 1994; 43: 647–55
Velazquez EM, Mendoza SG, Wang P, et al. Metformin therapy is associated with a decrease in plasma plasminogen activator inhibitor-1, lipoprotein(a), and immunoreactive insulin levels in patients with the polycystic ovary syndrome. Metabolism 1997; 46: 454–7
Nestler JE, Jakubowicz DJ. Decreases in ovarian cytochrome p450c17 alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. N Engl J Med 1996; 335: 617–23
Lee PJ, Cranston I, Amiel SA. Effect of metformin on glucose disposal and hyperinsulinaemia in a 14 year old boy with acanthosis nigricans. Horm Res 1997; 48: 88–92
Fontbonne A, Aline-Charles M, Juhan-Vague I. The effect of metformin on the metabolic abnormalities associated with upper body fat distribution. Diabetes Care 1996; 19: 920–6
Hermann LS. Combination therapy with insulin and metformin. Endocr Practice 1998; 4: 404–12
Giugliano D, Quatraro A, Consoli G, et al. Metformin for obese insulin treated diabetic patients: improvement in glycaemic control and reduction of metabolic risk factors. Eur J Clin Pharmacol 1993; 44: 107–12
Yki-Jarvinen H, Nikkila K, Ryysy L, et al. Comparison of bedtime insulin regimens in patients with type 2 diabetes. Ann Intern Med 1999; 130: 389–96
Bell DSH, Mayo MS. Outcome of metformin-facilitated reinitiation of oral diabetic therapy in insulin-treated patients with non-insulin-dependent diabetes mellitus. Endocr Practice 1997; 3: 73–6
Robinson AC, Burke J, Robinson S, et al. The effects of metformin on glycaemic control and serum lipids in insulin-treated NIDDM patients with suboptimal metabolic control. Diabetes Care 1998; 21: 701–5
Daniel JR, Hagmeyer KO. Metformin and insulin: is there a role for combination therapy? Ann Pharmacother 1997; 31: 474–80
Golay A, Guillet-Dauphiné N, Fendel A, et al. The insulin sparing effect of metformin in insulin-treated diabetic patients. Diabetes Metab Rev 1995; 11 Suppl. 1: S63–7
Pagano G, Taguaferro V, Carta Q, et al. Metformin reduces insulin requirement in type 1 (insulin dependent) diabetes. Diabetologia 1983; 24: 351–4
Gin H, Messerchmitt C, Brottier E, et al. Metformin improved insulin resistance in type 1, insulin-dependent diabetic patients. Metabolism 1985; 34: 923–5
Schafer G. Biguanides: molecular mode of action. Res Clin Forums 1979; 1: 21–32
Scheen AJ. Clinical pharmacokinetics of metformin. Clin Phar-macokin 1996; 30: 359–71
Sambol NC, Chiang J, O’Connor M, et al. Pharmacokinetics and pharmacodynamics of metformin in healthy subjects and patients with non-insulin-dependent diabetes mellitus. J Clin Pharmacol 1996; 36: 1012–21
Sirtori CR, Franceschini G, Galli-Kienie M, et al. Disposition of metformin (N, N-dimethyl biguanide) in man. Clin Pharmacol Ther 1978; 24: 683–93
Pentakainen PJ, Neuvonen PJ, Penttila A. Pharmacokinetics of metformin after intravenous and oral administration to man. Eur J Clin Pharmacol 1979; 16: 195–202
Tucker GT, Casey C, Philiips PJ, et al. Metformin kinetics in healthy subjects and in patients with diabetes mellitus. Br J Clin Pharmacol 1981; 12: 235–46
Wilcock C, Bailey CJ. Accumulation of metformin by tissues of the normal and diabetic mouse. Xenobiotica 1994; 24: 49–57
Wiernsperger NF. Preclinical pharmacology of biguanides. Oral antidiabetics. In: Puls W, editor. Handbook of experimental pharmacology. Berlin: Springer Verlag, 1996: 305–58
Rossetti L, DeFronzo RA, Gherzi R, et al. Effect of metformin treatment on insulin action in diabetic rats: in vivo and in vitro correlations. Metabolism 1990; 39: 425–35
Santos RF, Nomizo R, Wajhenberg BL, et al. Changes in insulin receptor tyrosine kinase activity associated with metformin treatment of type 2 diabetes. Diabete Metab 1995; 21: 274–80
Dominguez LJ, Davidoff AJ, Srinivas PR, et al. Effects of metformin on tyrosine kinase activity, glucose transport and intracellular calcium in rat vascular smooth muscle. Endocrinology 1996; 137: 113–21
Stith BJ, Goalstone ML, Espinoza R, et al. The antidiabetic drug metformin elevates receptor tyrosine kinase activity and inositol 1,4,5-triphosphate mass in Xenopus oocytes. Endocrinology 1996; 137: 2990–9
Johnson AB, Webster JM, Sum CF, et al. The impact of metformin therapy on hepatic glucose production and skeletal muscle glycogen synthase activity in overweight type II diabetic patients. Metabolism 1993; 42: 1217–22
Detaille D, Wiernsperger N, Devos P. Potentiating effect of metformin on insulin-induced glucose uptake and glycogen metabolism within xenopus oocytes. Diabetologia 1998; 41: 2–8
Matthei 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; 40: 850–7
Hundal HS, Ramlal T, Reyes R, et al. Cellular mechanism of metformin action involves glucose transporter translocation from an intracellular pool to the plasma membrane in L6 muscle cells. Endocrinol 1992; 131: 1165–73
Kozka U, Holman GD. Metformin blocks down regulation of cell surface GLUT4 caused by chronic insulin treatment of rat adipocytes. Diabetes 1993; 42: 1159–65
Hamann A, Benecke H, Greten H, et al. Metformin increases glucose transporter protein and gene expression in human fibroblasts. Biochem Biophys Res Commun 1993; 196: 382–7
Cuber JC, Bosshard A, Vidal H, et al. Metabolic and drug distribution studies do not support direct inhibitory effects of metformin on intestinal glucose absorption. Diabete Metab 1994; 20: 532–9
Bailey CJ. Metformin and intestinal glucose handling. Diabete Metab Rev 1995; 11: S23–S32
Bailey CJ, Wilcock C, Day C. Effect of metformin on glucose metabolism in the splanchnic bed. Br J Pharmacol 1992; 105: 1009–13
Yoa RG, Rapin JR, Wiernsperger NF, et al. Demonstration of defective glucose uptake and storage in erthrocytes from non-insulin dependent diabetic patients and effects of metformin. Clin Exp Pharmacol Physiol 1993; 20: 563–7
Cusi K, Consoli A, DeFronzo RA. Metabolic effects of metformin on glucose and lactate metabolism in non-insulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1996; 81: 4059–67
Stumvoll M, Nurjhan N, Perriello G, et al. Metabolic effects of metformin in non-insulin dependent diabetes mellitus. N Engl JMed 1995; 333: 550–4
Perriello G, Misericordia P, Volpi E, et al. Acute antihyperglycaemic mechanisms of metformin in NIDDM. Diabetes 1994; 43: 920–8
Riccio A, Del Prato S, Vigili de Kreutzenberg S, et al. Glucose and lipid metabolism in non-insulin dependent diabetes. Effect of metformin. Diabete Metab 1991; 17: 180–4
McIntyre HD, Paterson CA, Ma A, et al. Metformin increases insulin sensitivity and basal glucose clearance in type 2 (non-insulin dependent) diabetes mellitus. Aust NZ J Med 1991; 21: 714–9
Nosadini R, Avogaro A, Trevison R, et al. Effect of metformin on insulin stimulated plasma turnover and insulin binding to receptors in type II diabetes. Diabetes Care 1987; 10: 62–7
Jackson RA, Hawa MI, Jaspan JB, et al. Mechanism of metformin action in non-insulin-dependent diabetes. Diabetes 1987; 36: 532–40
De Fronzo RA, Barzilai N, Simonson DC. Mechanism of metformin action in obese and lean non-insulin dependent diabetic subjects. J Clin Endocrinol Metab 1991; 73: 1294–301
Dornan TL, Heller SR, Peck GM. Double-blind evaluation of efficacy and tolerability of metformin in NIDDM. Diabetes Care 1991; 14: 342–4
Josephkutty S, Potter JM. Comparison of tolbutamide and metformin in elderly diabetic patients. Diabetic Med 1990; 7: 510–4
Gregorio F, Ambrosi F, Filipponi P, et al. Is metformin safe enough for ageing type 2 diabetic patients. Diabete Metab 1996; 22: 43–50
Jennings PE. Oralantihyperglycaemics: considerations in older patients with non-insulin-dependent diabetes mellitus. Drugs Aging 1997; 10: 323–31
Garber AJ, Duncan TG, Goodman AM, et al. Efficacy of metformin in type II diabetes: results of a double-blind placebo controlled, dose response trial. Am J Med 1997; 102: 491–7
Hermann LS, Schersten B, Melander A. Antihyperglycaemic efficacy response prediction and dose-response relations of treatment with metformin and sulphonylureas, alone and in primary combination. Diabetic Med 1994; 11: 953–60
Campbell IW, Menzies DG, Chalmers J, et al. One year comparative trial of metformin and glipizide in type 2 diabetes mellitus. Diabetes Metab 1994; 20: 394–400
McAlpine LG, McAlpine CH, Waclawski ER, et al. A comparison of treatment with metformin and gliclazide in patients with non-insulin dependent diabetes. Eur J Clin Pharmacol 1988; 34: 129–32
Collier A, Watson HHK, Patrick AW, et al. Effect of glycaemic control, metformin and gliclazide on platelet density and aggregability in recently diagnosed type 2 (non-insulin dependent) diabetic patients. Diabete Metab 1989; 15: 420–5
Clarke BF, Duncan LJP. Comparison of chlorpropamide and metformin treatment on weight and blood glucose response of uncontrolled obese diabetics. Lancet 1968; I: 123–6
Hermann LS, Scheresten B, Bitzen P-O. Therapeutic comparison of metformin and sulphonylureas, alone and in various combinations. Diabetes Care 1994; 17: 1100–9
United Kingdom Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998; 352: 854–65
Holman RR, Steemson J, Turner RC, et al. Sulphonylurea failure in type 2 diabetes: treatment with a basal insulin supplement. Diabetic Med 1987; 4: 457–62
United Kingdom Prospective Diabetes Study Group. UKPDS 28: a randomized trial of efficacy of early addition of metformin in sulphonylurea-treated type 2 diabetes. Diabetes Care 1998; 21: 87–92
Trishitta V, Italia S, Mazzarino S, et al. Comparison of combined therapies in treatment of secondary failure to glyburide. Diabete Care 1992; 15: 539–42
Klein W. Sulphonylurea-metformin combination versus sulphonylurea-insulin combination in secondary failure of sulphonylurea monotherapy. Diabete Metab 1991; 17: 235–40
Groop L, Widen E, Franssila-Kallunki A, et al. Different effects of insulin and oral antidiabetic agents on glucose and energy metabolism in type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 1989; 32: 599–605
Marena S, Tagliaferro V, Montegrosso G, et al. Metabolic effects of metformin addition to chronic glibenclamide treatment in type 2 diabetes. Diabete Metab 1994; 20: 15–9
Hermann LS. Biguanides and sulphonylureas as combination therapy in NIDDM. Diabetes Care 1990; 13 Suppl. 3: 37–41
Clarke BF, Campbell IW. Comparison of metformin and chlorpropamide in non-obese, maturity onset diabetics uncontrolled by diet. BMJ 1977; 2: 1576–8
Noury J, Nandeuil A. Comparative three month study of the efficacies of metformin and gliclazide in the treatment of NIDD. Diabete Metab 1991; 17: 209–212
Chong PK, Jung RT, Rennie MJ, et al. Energy expenditure in type 2 diabetic patients on metformin and sulphonylurea therapy. Diabetic Med 1995; 12: 401–8
De Fronzo RA, Bonadonna RC, Ferrannini E. Pathogenesis of NIDDM. Abalanced overview. Diabetes Care 1992; 15: 318–68
Garancini MP, Calori G, Ruotolo G, et al. Prevalence of NIDDM and impaired glucose tolerance in Italy: an OGTT-based population study. Diabetologia 1995; 38: 306–13
Tuomilehto J, Knowler WC, Zimmet P. Primary prevention of non-insulin-dependent diabetes mellitus. Diabetes Metab Rev 1992; 8: 339–53
Harris MI. Impaired glucose tolerance: prevalence and progression to NIDDM. IDF Bulletin 1996; 41: 12–5
Alberti KGMM. The clinical implications of impaired glucose tolerance. Diabetic Med 1996; 13: 927–37
Chiasson JL. Possible therapeutic approaches to impaired glucose tolerance. IDF Bull 1996; 41: 16–20
Abbasi F, Kamath V, Rizvi AA, et al. Results of a placebo controlled study of the metabolic effects of the addition of metformin to sulphonylurea-treated patients. Diabetes Care 1997; 20: 1863–9
Gregorio F, Ambrosi F, Manfrini S. Metformin, plasma glucose and free fatty acids in type II diabetic out-patients: results of a clinical study. Diabetes Res Clin Pract 1997; 37: 21–33
Reaven G, Johnston P, Hollenbeck C, et al. Combined metformin-sulphonylurea treatment of patients with non-insulin-dependent diabetes mellitus in fair to poor glycaemic control. J Clin Endocrinol Metab 1992; 74: 1024–6
Del Prato S, Marchetto S, Pipitone A, et al. Metformin and free fatty acid metabolism. Diabetes Metab Rev 1995; 11 Suppl. 1: S33–41
Wu M-S, Johnston P, Sheu WH-H, et al. Effect of metformin on carbohydrate and lipoprotein metabolism in NIDDM patients. Diabetes Care 1990; 13: 1–8
Rains SGH, Wilson GA, Richmond W, et al. The effect of glibenclamide and metformin on serum lipoproteins in type 2 diabetes. Diabetic Med 1988; 5: 653–8
Rains SGH, Wilson GA, Richmond W, et al. The reduction of low density lipoprotein cholesterol by metformin is maintained with long-term therapy. J R Soc Med 1989; 82: 93–4
Taylor KG, John WG, Matthews KA, et al. A prospective study of the effect of 12 months treatment on serum lipids and apolipoproteins A-1 and B in type 2 (non-insulin-dependent) diabetes. Diabetologia 1982; 23: 507–10
Carlsen SM, Rossvoll O, Bjerve KS, et al. Metformin improves blood lipid pattern in non-diabetic patients with coronary heart disease. J Intern Med 1996; 239: 227–33
Montaguti U, Celin D, Ceredi C. Efficacy of the long-term administration of metformin in hyperlipidaemic patients. Res Clin Forum 1979; 1: 95–103
Gustafson A, Bjorntorp P, Fahlen M. Metformin administration in hyperlipidaemic states. Acta Med Scand 1971; 190: 491–4
Jeppeson J, Zhou M-Y, Chen Y-DI, et al. Effect of metformin on post-prandial lipemia in patients with fair to poorly controlled NIDDM. Diabetes Care 1994; 17: 1093–9
Grosskopf I, Ringel Y, Charach G, et al. Metformin enhances clearance of chylomicrons and chylomicron remnants in non-diabetic mildly overweight glucose-tolerant subjects. Diabetes Care 1997; 20: 1598–602
Marquie G. Effect of metformin on lipid metabolism in the rabbit aortic wall. Atherosclerosis 1978; 30: 165–75
Marquie G. Metformin action on lipid metabolism in lesions of experimental aortic atherosclerosis of rabbits. Atherosclerosis 1983; 47: 7–17
Intaglietta M, Sirtori CR, Standi E, et al., editors. Vascular disease and diabetes mellitus — a new approach. Proceedings of an international workshop; 1988 Feb 4-5: Switzerland. Diabete Metab 1988; 14: 473–617
Vague P, Juhan Vague I, Alessi MC, et al. Metformin decreases the high plasminogen activator inhibitor capacity, plasma insulin and triglyceride levels in non-diabetic obese subjects. Thromb Haemost 1987; 57: 326–8
Landin K, Tengborn T, Smith U. Metformin and metoprolol CR treatment in non-obese men. J Intern Med 1994; 235: 335–41
Weichert W, Breddin HK. Antithrombotic effects of metformin in laser injured arteries. Diabete Metab 1988; 14: 540–3
Massad L, Plotkine M, Allux M, et al. Antithrombotic drugs in a carotid occlusion model: beneficial effect of the antidiabetic agent, metformin. Diabete Metab 1988; 14: 544–8
Barnes AJ, Willars EJ, Clark PA, et al. Effects of metformin on haemorheological indices in diabetes. Diabete Metab 1988; 14: 608–9
Data on file. Merck-Lipha, Lyon, France, 1999
Berger W. Incidence of severe side effects during therapy with sulphonylureas and biguanides. Horm Metab Res 1985; 15 Suppl.: 111–5
Campbell IW. Metformin and the sulphonylureas: the comparative risk. Horm Metab Res 1985; 15 Suppl.: 105–11
Cohen RD. The relative risks of different biguanides in the causation of lactic acidosis. Res Clin Forums 1979; 1: 126–34
Lucis OJ. The status of metformin in Canada. Can Med Assoc J 1983; 128: 24–6
Bailey CJ, Nattrass M. Treatment — metformin. Baillieres Clin Endocrinol Metab 1988; 2: 455–76
Wiholm BE, Myrhed M. Metformin — associated lactic acidosis in Sweden 1977–1991. Eur J Clin Pharmacol 1993; 44: 589–91
Data on file. French National Drug Adverse Effect Surveillance Commission, Paris, 1998
Misbin RI, Green L, Stadel BV, et al. Lactic acidosis in patients with diabetes treated with metformin. N Engl J Med 1998; 338: 265
Brown JB, Pedula K, Barzilay J, et al. Lactic acidosis rates in type 2 diabetes. Diabetes Care 1998; 21: 1659–1663
Sirtori CR, Pasik C. Re-evaluation of a biguanide metformin: mechanism of action and tolerability. Pharmacol Res 1994; 30: 187–228
Lalau JD, Lacroix C, Compagnon P, et al. Role of metformin accumulation in metformin-associated lactic acidosis. Diabetes Care 1995; 18: 779–84
Arieff AI. Pathogenesis of lactic acidosis — current concepts. Diabetes Rev 1994; 2: 168–76
Cohen RD. Lactic acidosis. Diabetes Rev 1994; 2: 86–97
Turner RC, Bailey CJ. Lactic acidosis associated with Glucophage use in a man with normal renal and hepatic function. Diabetes Care 1997; 20: 233
Cusi K, Consoli A. Alcoholic ketoacidosis and lactic acidosis. Diabetes Rev 1994; 2: 195–208
Luft D, Schmulling RM, Eggstein M. Lactic acidosis in biguanide-treated diabetes: a review of 330 cases. Diabetologia 1978; 14: 75–87
Assan R, Heuclin C, Ganeval D, et al. Metformin-induced lactic acidosis in the presence of acute renal failure. Diabetologia 1977; 13: 211–7
Jalling O, Olsen C. The effects of metformin compared to the effects of phenformin on the lactate production and the metabolism of isolated parenchymal rat liver cell. Acta Pharmacol Toxicol 1984; 54: 327–32
Gill GV, Alberti KGMM. Lactic acidosis. Pract Diabetes 1985; 2: 15–9
Cohen RD, Woods HF Clinical and biochemical aspects of lactic acidosis. Oxford; Blackwell Scientific, 1976
Ryder REJ. Lactic acidotic coma with multiple medication including metformin in a patient with normal renal function. Br J Clin Pract 1984; 38: 229–30
Hutchinson SMW, Catterall JR. Metformin and lactic acidosis — a reminder. Br J Clin Pract 1987; 41: 673–4
Gan SC, Bar J, Arieff AI, et al. Biguanide-associated lactic acidosis. Case report and review of the literature. Arch Intern Med 1992; 152: 2333–6
Chan NN, Brain HPS, Feher MD. Metformin associated lactic acidosis: a rare or very rare clinical entity? Diabet Med 1999; 16: 273–81
Lalau JD, Andrejak M, Moriniere P, et al. Hemodialysis is the treatment of lactic acidosis in diabetics treated by metformin: a study of metformin elimination. Int J Clin Pharmacol Ther Toxicol 1989; 27: 285–8
Krentz AJ, Ferner RE, Bailey CJ. Comparative tolerability profiles of oral antidiabetic agents. Drug Saf 1994; 11: 223–41
Ferner RE, Neil HAW. Sulphonylureas and hypoglycaemia. BMJ 1988; 296: 949–50
Seltzer HS. Drug-induced hypoglycaemia: a review of 1418 cases. Endocrinol Metab Clin North Am 1989; 18: 163–83
Frier BM. Hypoglycaemia and diabetes. Diabetic Med 1986; 3: 513–25
Gerich JE. Oral hypoglycaemic agents. N Engl J Med 1989; 321: 1231–45
Cryer PE, Frier BM. Hypoglycaemia. In: Alberti KGMM, DeFronzo RA, Keen H, et al., editors. International textbook of diabetes mellitus. 2nd ed. Chichester: John Wiley & Sons Ltd, 1997; 1193–214
Dandona P, Fonseca VA, Mier A, et al. Diarrhoea and metformin in a diabetic clinic. Diabetes Care 1983; 6: 472–4
Scarpello JHB, Hodgson E, Howlett HCS. Effect of metformin on bile salt circulation and intestinal motility in type 2 diabetes mellitus. Diabet Med 1998; 15: 651–6
Haupt E, Knick B, Koschinsky T, et al. Oral antidiabetic combination therapy with sulphonylureas and metformin. Diabete Metab 1991; 17 Suppl. 1: 224–31
Tomkin GH. Malabsorption of vitamin B12 in diabetic patients treated with phenformin: a comparison with metformin. BMJ 1973; 3: 673–5
Bergman U, Boman G, Wiholm BE. Epidemiology of adverse drug reactions to phenformin and metformin. BMJ 1978; 2: 464–6
Klapholz L, Leitersdorf E, Weinrauch L. Leucocytoclastic vasculitis and pneumonitis induced by metformin. BMJ 1986; 293: 483
Alberti KGMM, Gries FA. Management of non-insulin-dependent diabetes mellitus in Europe: a consensus view. Diabetic Med 1988; 5: 275–81
American Diabetes Association. Clinical Practice Recommendations 1996. The pharmacological treatment of hyperglycaemia in NIDDM. Diabetes Care 1996; 19 Suppl. 1: S54–S61
Vannasaeng S, Nitiyanant W, Vichayannat A, et al. Effects of alpha-glucosidase inhibitor (acarbose) combined with sulphonylureas or sulphonylurea and metformin in treatment of non-insulin-dependent diabetes mellitus. J Med Assoc Thai 1995; 78: 578–84
Josse RG. Acarbose for the treatment of type II diabetes: the results of a Canadian multi-centre trial. Diabetes Res Clin Pract 1995; 28 Suppl.: S167–72
Stout RW. Insulin and atheroma: 20 year perspective. Diabetes Care 1990; 13: 631–54
Despres JP, Lamarche B, Mauriege P, et al. Hyperinsulinaemia as an independent risk factor for ischaemic heart disease. N Engl J Med 1996; 334: 952–7
Sambol NC, Chiang J, Lin ET, et al. Kidney function and age are both predictors of pharmacokinetics of metformin. J Clin Pharmacol 1995; 35: 1094–102
Petrides AS. Liver disease and diabetes mellitus. Diabetes Rev 1994; 2: 2–17
Somogyi A, Stockley C, Keal J. Reduction of metformin renal tubular secretion by cimetidine in man. Br J Clin Pharmacol 1987; 23: 545–51
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Howlett, D.H.C.S., Bailey, C.J. A Risk-Benefit Assessment of Metformin in Type 2 Diabetes Mellitus. Drug-Safety 20, 489–503 (1999). https://doi.org/10.2165/00002018-199920060-00003
Published:
Issue Date:
DOI: https://doi.org/10.2165/00002018-199920060-00003