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The Uses of Biguanides in Diabetesmellitus Postgrad. med. J. (June 1968) 44, 466-471. Postgrad Med J: first published as 10.1136/pgmj.44.512.466 on 1 June 1968. Downloaded from CURRENT SURVEYS The uses of biguanides in diabetes mellitus H. KEEN R. J. JARRETT M.B., M.R.C.P. M.A., M.D. Department of Medicine, Guy's Hospital, London, S.E.1 IN 1918, Watanabe first demonstrated the hypo- theoretical and practical bases for their use in glycaemic properties of guanidine. After nearly treatment. 40 years of sporadic investigation of its deriva- tives, including the misadventures with synthalin Mode of (Frank, Nothmann & Wagner, 1926), this ob- action servation bore clinical fruit in the first of the The anti-diabetic effect of the biguanides ap- biguanides, phenylethylbiguanide (phenformin) see pears to be distinct from their hypoglycaemic effect. In non-diabetic animals, the blood-sugar Protected by copyright. Fig. 1). Other biguanides have since appeared lowering dose of the biguanides is close to the including dimethylbiguanide (metformin, 'Gluco- lethal dose (Sterne, 1964); at clinically appro- phage') and butylbiguanide. In the 10 years since priate dose levels in man, blood sugar lowering their introduction into therapeutics the precise is seen only in diabetic subjects. The anti-dia- mode of action of these compounds has not been betic effect is to be due to increased elucidated nor is there complete agreement on unlikely the indications for their use. Research and clini- insulin secretion for in obese and diabetic sub- cal both jects, the administration of phenformin reduced experience have, however, provided the circulating insulin response to a glucose load (Grodsky et al., 1963; Abramson & Arky, 1967). Furthermore, in human diabetics and in experi- BIGUANIDES mental animals, the administration of a biguanide reduces the quantity of insulin required to con- CH3 trol hyperglycaemia (Sterne, 1964). In some way, http://pmj.bmj.com/ H H - HN - C - N -C - NH therefore, the to the II biguanides appear augment NH H NH I~CH3 hypoglycaemic effectiveness of circulating insulin, IDimethyl possibly by enhancing its stimulation of glucose utilization in muscle (Butterfield & Whichelow, H - HN - C - N - C-NH I- (CH)2. - 1962). While this effect is most clearly apparent NH HIH NH Phenylethyl when the glucose/insulin interrelation is disturbed as in diabetes, it may, under special conditions, also be demonstrated in normals (Pereira, Waj- on September 24, 2021 by guest. chenberg & Schnaider, 1967). DIGUANIDINES In adult diabetics, the biguanides may also effect a reduction in body weight, in serum tri- glycerides and in serum cholesterol (Schwartz, HN - C - N - -N - C - II (CH2)n II NH2 Mirsky & Schaefer, 1966). Phenformin may owe NH H H NH these effects partly to its anorexigenic properties (Patel & Stowers, 1964) and partly to reduced insulin in to the lowered n = 10 Synthalin A circulating response n = 12 blood sugar, thus diminishing lipogenic and anti- Syntholin B lipolytic activity. Metformin has also been shown to have an antidiuretic effect in idiopathic dia- FIG. 1. Structure of guanidine derivatives. betes insipidus (Katsuki & Ito, 1966). Current 467 surveys Postgrad Med J: first published as 10.1136/pgmj.44.512.466 on 1 June 1968. Downloaded from Side-effects combination if the blood sugar response is in- The commonest side-effects of the biguanides adequate or if an initial response is lost. are upon the gastro-intestinal tract, causing a An additional claim for the biguanides is their metallic taste in the mouth, loss of appetite, usefulness as an adjunct to insulin in diabetics nausea, diarrhoea and abdominal cramps. By (sometimes called 'brittle') who show violent starting with small doses and increasing the dose swings in blood sugar level. Pomeranze et al. level slowly, the incidence of these side effects (1959) claimed that there was improvement in can be reduced (Pomeranze et al., 1959); in overall control and a reduction in the frequency obese patients, particularly, a degree of anorexia of hypoglycaemic attacks when phenformin was may be a useful side-effect. Phenformin is avail- added to the regime. However, this improvement able in timed-disintegration capsules, with which is usually attended by a reduction in the total the incidence of gastro-intestinal side effects is insulin dosage which is itself likely to iron out said to be lower (Breidahl, 1961) or which permit the major swings from hypoglycaemia to re- higher doses before side-effects occur (Jakobson, actionary hyperglycaemia and ketonaemia (Som- Kahampaa & Berglund, 1965). ogyi, 1959). Indeed, later reports are more There is controversy about the possible meta- critical of the value of phenformin in these diffi- bolic side-effects of the biguanides. Earlier re- cult patients (Jakobson et al., 1965; Pedersen, ports that phenformin therapy was associated 1964), but there remains a strong clinical feeling with dangerous episodes of lactic acidosis (see among some physicians that on a few occasions, Davidson et al., 1966 for references) cannot be when alteration of insulin dosage, correction of accepted unreservedly, for in the majority of diet, control of exercise or stabilization of emo- cases hypoxaemia or circulatory collapse, both tional lability have failed to restore euglycaemia, potent causes of lactic acidosis, were also pre- the addition of biguanides may succeed. sent. Nevertheless, a recent case report (Proctor The aim of normalizing the blood sugar in the Protected by copyright. & Stowers, 1967) suggests that, in rare cases, lac- diabetic has the long-term purpose of postpon- tic acidosis may be provoked by phenformin. ing or preventing the so-called complications of Suspicion is based largely on in vitro tissue ex- the disease. There is no evidence that the bigu- periments where high concentrations of phen- anides are better or worse than the other oral formin stimulate anaerobic glycolysis and hence agents in their effects upon retinopathy, nephro- increased lactate production (Sterne, 1964). Gut- pathy and neuropathy; there is, however, some tler, Petersen & Kjeldsen (1963) found in man cause to suppose that the course of the accel- that therapeutic doses of phenformin only in- erated atherosclerosis of the diabetic might be constantly lead to small rises in circulating levels favourably influenced. In a series of studies over of lactic acid. According to Sterne (1964), met- the past 5 years Fearnley, Chakrabarti and their formin does not inhibit tissue respiration in vitro colleagues have shown that phenformin increases and he quotes Debry to support the view that fibrinolytic activity, decreases platelet adhesive- the blood lactic acid is not raised in diabetics ness and lowers the blood cholesterol (Fearnley receiving metformin therapy. It was concluded & Chakrabarti, 1964; Fearnley et al., 1967; Chak- http://pmj.bmj.com/ by an expert committee (Special Communication, rabarti, Fearnley & Evans, 1967; Fearnley, 1968). 1963) that biguanides alone probably do not Serum triglycerides and the pattern of circulat- cause lactic acidosis. ing lipoproteins are also restored towards the normal by the biguanides (Schwartz, et al., 1966). Therapeutic indications All of this lends weight to the view that the The prime aim of treatment in the diabetic is biguanides might confer some protection upon to normalize the blood sugar; to effect this, the vulnerable major arteries of the diabetic; on September 24, 2021 by guest. several oral hypoglycaemic preparations are there is as yet, however, no sound evidence that now available. They include the sulphonylureas, these desirable ends are actually attained. the sulphapyrimidines and the biguanides. The Finally, Wilansky & Hahn (1967) have pub- indications for their use are generally similar lished the provocative results of a study of the and lie mainly in the management of the dia- effect of a 6 weeks' course of phenformin upon betic who is not insulin dependent, not prone to the subsequent development of diabetes in a ketosis and who is inadequately controlled by group of relatives of diabetics who had abnormal dietary carbohydrate restriction. The initial use cortisone-glucose tolerance curves. In a 3-year of oral preparations or their combinations is follow-up, they fared significantly better than a largely a matter of personal preference, though control group treated with placebo. If this ob- currently most clinicians would opt first for the servation is confirmed, phenformin might well sulphonylureas, using the biguanides alone or in have an important prophylactic role. 468 Current surveys Postgrad Med J: first published as 10.1136/pgmj.44.512.466 on 1 June 1968. Downloaded from References JAKOBSON, T., KAHANPAA, A. & BERGLUND, B. (1965) ABRAMSON, E. & ARKY, R.A. (1967) Treatment of the obese Experience with phenethylbiguanide (DBI) tablets and diabetic-a comparative study of placebo, sulfonylurea timed-disintegration capsules (DBI-TD) administered as and phenformin. Metabolism, 16, 204. an adjunct to insulin or sulfonylurea drugs in previously treated diabetic patients. Ann. Med. int. Fenn. 54, 109. BREIDAHL, H.D. (1961) Phenformin (phenethylbiguanide) in KATSUKI, S. & ITO, M. (1966) Antidiuretic effect ofdiguanides. the treatment of diabetes mellitus: a preliminary report. Lancet, ii, 530. Med. J. Aust. 2, 1041. PATEL, D.P. & STOWERS, J.M. (1964) Phenformin in weight BUTTERFIELD, W.J.H. & WHICHELOW, M.J. (1962) The hypo- reduction of obese diabetics. Lancet, ii, 282. glycaemic action of phenformin. Effect of phenformin on PEREIRA, V.G., WAJCHENBERG, B.L. & SCHNAIDER, J. (1967) glucose metabolism in peripheral tissues. Diabetes, 11, 281. Mechanism of action of phenethylbiguanide in normal CHAKRABARTI, R., FEARNLEY, G.R. & EVANS, J.F. (1967) subjects. Diabetes, 16, 302. Reduction of platelet stickiness by phenformin plus PEDERSEN, J. (1964) Treatment of diabetes mellitus with ethyloestrenol. Lancet, i, 1012. dimethylbiguanide (metformin). Ugeskr. Laeg. 126, 1635. DAVIDSON, M.B., BOZARTH, W.R., CHALLONER, D.R. & POMERANZE, J., MOURATOFF, G.T., GADEK, R.J. & KING, GOODNER, C.J. (1966) Phenformin, hypoglycaemia and E.J. (1959) Phenethylbiguanide, a new orally given hypo- lactic acidosis. New Engl. J.
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