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editoriAL
Metformin: myths, misunderstandings and lessons from history Gillian Shenfield
Clinical trials of new drugs may overstate efficacy and could be minimised by a ‘start low, go slow’ approach not identify adverse effects. It is therefore unusual for the passage of time to reveal that a drug is less Also in 1957 an American group published similar toxic, has greater efficacy and a wider range of results for phenformin (phenylethyl biguanide). uses than first claimed. For decades metformin was Phenformin was energetical y marketed worldwide misunderstood, vilified and banned in many countries, by Ciba-Geigy, but by 1959 an association with lactic but it is now one of the most prescribed drugs in acidosis was reported. Unfortunately, this report the world. In 2010 there were more than 100 mil ion generated little interest. In contrast, metformin was prescriptions worldwide for metformin, alone and in manufactured by a smal French company and, among developed countries, was only the preferred Metformin was developed from a herb, Galega officinalis*, which was used for centuries to treat In the 1970s the number of reports of phenformin- many ailments including polyuria. It is a rich source related lactic acidosis and deaths increased. In 1977 of the toxic substance guanidine. A less toxic it was removed from the market in the USA and also alkaloid, galegine, was identified in France just before withdrawn from many other countries. The Australian World War I. Its pharmacology and toxicology were Drug Evaluation Committee recommended severe studied in Paris and its structure was identified in restrictions on both phenformin and metformin Edinburgh. In 1922 metformin (dimethyl biguanide) in spite of the different pharmacokinetics of the was synthesised in Dublin and shown to lower blood two drugs. Phenformin is metabolised by the liver glucose with fewer gastrointestinal adverse effects than its predecessors. However, in the same year and accumulates in patients with a genetic deficiency insulin was used for the first time, distracting interest of the enzyme cytochrome P450 2D6. Metformin is renal y excreted and all serious reports of its association with lactic acidosis and deaths are in In Paris in 1957 metformin, by then cal ed glucophage overdoses or in people with advanced renal failure.1 (‘glucose eater’), was studied in trials and shown to lower blood glucose in patients with type 2 Endocrinologists in France and Scotland, who had diabetes, but not in people without diabetes. Unlike considerable experience of using metformin safely, sulfonylureas, metformin did not stimulate insulin continued to prescribe it extensively. In 19682 and release, but increased its peripheral uptake and 19773 Scottish studies comparing metformin with also reduced the release of glucose from the liver. chlorpropamide found that glucose control was the Metformin had gastrointestinal adverse effects which same with both drugs, but patients on metformin had less hypoglycaemia and lost weight, while those on the sulfonylurea gained weight. In spite of similar findings published in leading journals, it took the rest of the world a very long time to reach the same conclusions From the editor
because of unwarranted fears of lactic acidosis. In 1995 While prescribers are alert for drug–drug interactions, patients may be more interested to know if they can the benefits of metformin were rediscovered in the drink alcohol with their medicine. Graham Vernon USA4 and restrictions were eased in Australia.
Of the many subsequent studies perhaps the most influential has been the UK Prospective Diabetes Study.5 This was a randomised, multicentre, Many people consume nutritional supplements, but paral el group trial of 3867 patients over 10 years. these are not always necessary. Serena Parker, Patrick Hanrahan and Claire Barrett Independently of blood glucose control, metformin conside.
Concern about the harmful effects of metformin restricted its use for many years. Gil ian Shenfield reflects o * known by many other names including goat’s rue, Spanish sanfoin, false indigo, Italian fitch, French lilac and professor-weed editoriAL
reduced the risks of myocardial infarction and al - cause mortality. As a result metformin became the • it takes a very long time to col ect good population
first-choice treatment for obese patients with type 2 diabetes. Later subgroup analyses showed that it had • medications can produce more benefits and harms
similar vascular protective effects in all patients, but it took another decade for these findings to be translated into official recommendations. In 2012 diabetes experts in the USA and Europe6 declared that metformin is the companies dominate the market9 and using new drug of first choice for all patients with type 2 diabetes. drugs with limited, short-term data from restricted The Australian National Health and Medical Research Council is considering a similar recommendation.
• wider understanding of pharmacodynamics and
The story is not yet over. Nephrologists believe pharmacokinetics could prevent the belief that al metformin is underused in kidney disease. Metformin drugs in a chemical group have the same actions is now also used to treat polycystic ovary syndrome, gestational diabetes and is showing early promise • the long delay of translating evidence into practice
as a treatment for cancer. Recent meta-analyses is occurring with other medicines such as aspirin controversial y suggested that metformin may not prevent macrovascular disease7, however the risk of Conflict of interest: none declared cardiovascular events with metformin may be less than with sulfonylureas8. reFerenCes
6. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). 4. Bailey CJ, Turner RC. Metformin. N Engl J Med 1996;334:574-9.
8. Roumie CL, Hung AM, Greevy RA, Grijalva CG, Liu X, Murff HJ, et al. 5. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose Comparative effectiveness of sulfonylurea and metformin monotherapy on control with sulphonylureas or insulin compared with conventional treatment cardiovascular events in type 2 diabetes mel itus: a cohort study. and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet FUrtHer reAdinG
Bailey CJ, Campbell IW, Chan JCN, Davidson JA, Howlett HCS, Ritz P, editors. Metformin - the gold standard: a scientific handbook. Chichester, UK: Wiley; 2007. Committee welcomes letters, which should be less than 250 words. Before a decision to Complementary medicines
publish is made, letters which refer to a published article Editor, – I work regularly in a large public hospital My concerns regarding complementary medicines anaesthetic preadmission clinic. I am no longer (and I include here all the usual suspects such as surprised at how many patients take expensive sent to an expert for comment. Letters are usual y published complementary medicines with little or no validation • some are expensive and could exhaust patients’ of their efficacy – for example fish oil to improve vision, ginkgo for Alzheimer’s disease, coenzyme Q • some, in fact, may do no good at all or at least for cardiac failure. Some patients are on over 10 discourteous, inaccurate or libel ous statements and different products! Can someone please explain the • some patients maintain adverse lifestyle choices because they felt, or wanted to believe, publication. The Committee's decision on publication is final.

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