Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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Creatinine clearance
- Matthew P Doogue (3 January 2003)
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Metformin and Hepatic Impairment
- Richard Quinton (3 January 2003)
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metformin drug of choice
- dr.manan vasenwala (3 January 2003)
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What is advanced renal failure?
- Richard Ganz (5 January 2003)
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Metformin and coronary angiography
- Kiran C Patel, Rectory Rd, Sutton Coldfield,West Midlands, B75 7RR (5 January 2003)
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Metformin and iodinated contrast media
- James D Birchall (5 January 2003)
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Is Managed Chronic Renal failure a Contraindication to metformin?
- Dr Neil D Burman (6 January 2003)
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Metformin and measuring renal function
- Andrew F Orange (6 January 2003)
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Re: Metformin and iodinated contrast media
- Michal T Kluger (6 January 2003)
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Metformin and surgery
- Alan G Conn, Max Allen, SHO General Medicine / Anaesthesia (7 January 2003)
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RCTs needed
- Dan Hackam (7 January 2003)
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Metformin usage and holidaying in the tropics
- Nadarajah Sreeharan (7 January 2003)
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Stopping metformin before surgery
- Philip Jones, Paul Yate, Consultant anaesthetist (7 January 2003)
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Metformin, "lactic acidosis" and renal failure
- Richard G Fiddian-Green (7 January 2003)
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Metformin as OHA
- Ganapathy Chidambaram Chidambaram (8 January 2003)
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Metformin in patients aged over 65 years.
- Andrew T Elder (9 January 2003)
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Lactic acidosis and implicated metformin: why good information about risk factors?
- Gérard MACHET (10 January 2003)
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Contraindications to the use of metformin
- William M Hague, Peter Davoren, J Oliver, J Rowan (21 January 2003)
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Use of metformin in endocrinopathies other than Diabetes
- HONEY M MATHEW, KIRK CHIN (Consultant Obstetrician and Gynaecologist) (27 January 2003)
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When to stop Metformin
- Mordchai Ravid, Rita Rachmani (29 January 2003)
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Hip patients love to call drugs by trade names
- Phillip J. Colquitt (30 January 2003)
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Contraindications to metformin - a reply
- Maria Valois, Ivy Fettes, Gideon Koren (22 February 2003)
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Re: metformin drug of choice
- Eduardo Naranjo (10 October 2003)
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Matthew P Doogue, Medical Registrar Christchurch Hospital, New Zealand
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The data relating to the risk benefits of Metformin is now well documented. It has been clear for some time that stopping metformin in many patients does them harm. To propose a serum creatinine as a basis of decision making is equally foolish. Creatinine clearance using the Cockcroft and Gault equation, is an appropriate decison making tool. I hope the authors use Cockcroft and Gault in adjusting doses of renally cleared medicines. This aside the proposals of the authors are pragmatic and will go along way to aleviating the harm done by doctors stopping metformin inappropriately for fear of the consequences to their patients (and themselves) Competing interests: None declared |
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Richard Quinton, Consultant & Senior Lecturer in Endocrinology Royal Victoria Infirmary, Newcastle-upon-Tyne. NE3 2NJ
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The editorial by Jones et al (1) is extremely timely and and illustrates just how easily pharmacotherapeutic dogma can still become entrenched in the BNF and similar publications, despite a paucity of evidence. Patients with type 2 diabetes are routinely encouraged to lose weight so as to improve insulin-sensitivity and, hence, glycaemic control, yet metformin remains the only available anti-hyperglycaemic agent reliably shown not to promote weight gain. Non-alcoholic steatohepatitis (NASH) accounts for the great majority of cases of "liver function test" dysfunction in type 2 diabetes. NASH appears to be yet another manifestation of the insulin-resistant metabolic syndrome X, and a proportion of cases eventually evolve into liver cirrhosis. Weight loss remains the only proven treatment for NASH, but emerging data increasingly suggest metformin to be of significant therapeutic benefit (2). As a result of published prescribing guidance on metformin, many overweight patients with type 2 diabetes and NASH may well not be receiving the most appropriate drug for both these diseases. 1 Jones GC, Macklin JP, Alexander WD. Contraindications to the use of metformin: evience suggests that it is time to amend the list. BMJ 2003;326:4-5. 2 Marchesini G, Brizi M, Bianchi G, Tomassetti S, Zoli M, Melchionda N. Metformin in non-alcoholic steatohepatitis. Lancet 2001;358:893-4 [Comment in Lancet 2002;359:355-6.] Competing interests: None declared |
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dr.manan vasenwala, consultant-cardiologist (non-invasive) k.k.heart center, aligarh.202002,INDIA
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the bnf says that metformin is the drug of choice in obesity with diabetes. lactic acidosis is a potential contraindication in the situations cited by the author. bnf says that metformin may provoke lactic acidosis in renal imapairment, severe dehydration, infection, shock, ccf, resp. failure, recent mi etc. it also includes pregnancy and breast feeding in the contraindications.i think these warnings cannot be faulted. it would be prudent to withhold metformin in these situations, albeit temporarily. it does not place any restriction on the prescriber.it is our current practice to reintroduce metformin in mi patients after they recover from the acute episode. i agree with the author about less ambigous guidelines, including GFR or transaminases at which drug should be withdrawn rather than just saying renal impairment or hepatic insufficiency (Cr>133umol/l for men, .124umol/l for women) Competing interests: None declared |
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Richard Ganz, private practice Healdsburg,CA 96558
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Is there a concensus about what creatinine clearance should be a cutoff for the use of metformin? Using 1.5 mg/dl as a cutoff for creatinine would eliminate many stable diabetics. Competing interests: None declared |
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Kiran C Patel, SpR in Cardiology Good Hope Hospital, Rectory Rd, Sutton Coldfield,West Midlands, B75 7RR
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Dear Editor, I read with interest the editorial on metformin (1) in the BMJ. It still baffles me however, why there is such a variation in attitudes towards metformin use either prior to or following coronary angiography. Whilst some institutions prefer patients to cease taking the drug up to 48 hours prior to the procedure, others prefer cessation of therapy for up to 48 hours following the procedure. Should we follow the advice given in the editorial, surely the latter approach is correct? In patients best interests, one would welcome uniformity across the NHS to avoid the unneccesary cancellation, postponement or delay of coronary (and probably other forms of) angiography in diabetic patients who are prescribed metformin. 1. Contraindications to the use of metformin G C Jones, J P Macklin, and W D Alexander BMJ 2003; 326: 4-5 Competing interests: None declared |
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James D Birchall, Specialist Regsitrar in Radiology Directorate of Imaging, Queens Medical Centre< Nottigham NG7 2UH
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The editorial of Jones et al regarding contraindications to the use of metformin [1], was interesting as a radiologist for they suggest the withdrawal of metformin for 72 hours following the administration of intravenous iodinated contrast media due to the potential ominous complication of lactic acidosis. Our college 4 years ago, with the advice of the British Diabetic Association and the Medicine Control Agency, recommended discontinuing metformin at the time of the study requiring iodinated contrast for 48 hours with assessment of renal function prior to the metformin being restarted [2]. It would be intriguing to know Jones et al comments regarding this? [1] Jones GC, Macklin JP, Alexander WD ‘Contraindications to the use of metformin’ BMJ 2203;326:4-5 [2] Board of the Faculty of Clinical Radiology Guidelines with Regard to Metformin-Induced Lactic Acidosis and X-ray Contrast Medium Agents’ The Royal College of Radiologists 1999 BFCR (99)2 http://www.rcr.ac.uk/pubtop.asp?PublicationID=70 Competing interests: None declared |
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Dr Neil D Burman, Research Internist Monism Health Planning Foundation,PO Box 44285 , Claremont 7735, Cape Town, RSA
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DEAR SIR, well said the Editorial on forty-year-old metformin as firstline drug for increasingly common diabetes. Reasons for its underuse surely include that it is no longer a profitable, marketed patent - it is the last NEW synthetic designer drug which, as a generic, has proven both safe and effective when used as LONGTERM prevention of the common major degenerative diseases of lifestyle/aging. Much literature, and experience, shows that metformin is the ONLY anti-diabetic, antilipidemic and anti-obesity synthetic which, with sense, has negligible if not useful dose-related risks (anorexia, loose bowels), without hypoglycemia (up to 40% pa on sulphonylureas), while significantly improving survival quality, reducing all-cause mortality by 36%, over 15 years. Unlike phenformin and sulphonylureas, it improves peripheral and myocardial perfusion, as does testosterone. (Jens Moller) Metformin (and testosterone) are the only physiological agents which favour exercise and thus lean>fat body content, avoiding ageing’s weight gain and thus reducing the chronic major premature degenerative diseases (vascular-renal, mood, mental, osteoarthritic, infective, malignant, fractures etc). But Quetelet weight-height index says nothing about the crucial lean-fat ratio, ageing’s inexorable fat gain as we lose lean mass.. Only testosterone proves safer, better and cheaper - combination with metformin optimizes eg fibrinolysis and eulipidemia, healthier lean:fat mass. As you say, where is evidence to justify listing managed chronic renal failure as a contra-indication? Lalau showed that, if anything, (in contrast to phenformin) higher meformin level minimizes skeletal muscle lactate production while improving tissue perfusion and cardiac output, and thus reduces mortality from lactic acidosis IN treated acute or chronic renal failure of whatever degree. So why should metformin -a nontoxic drug - be the ONLY current useful drug which is banned with renal failure? No-one should use any drugs for long without occasional checkup, if only of body fat and lean mass, bloodpressure, and urine multistix test for sugar and hepatorenal problems. Legion commonly used chronic drugs need such consideration: ethanol; tobacco; minerals including salt, calcium, lithium, aluminium; antibiotics; analgesics/ anti-inflammatories; diuretics, digitalis; sulphonylureas, anti-asthma- and anti- hypertensives. So why ban a vulnerable group - those with managed diabetic renal impairment - from taking the best, key baseline prohormone drug for limiting tissue glycogenation and lipidemia in the commonest diseases of affluence? As Wulffele et al have just shown, witholding metformin because of renal failure increased insulin requirement (ie insulin resistance) by 40% - drastically increasing the risk of lethal hypoglycemias let alone ischemic lactic acidosis. All patients should be sensibly advised when to reduce or stop any drugs including metformin; and monitored appropriately for bloodlevels as would be eg lithium, digoxin, thyroid, warfarin, theophyline, estradiol, testosterone, calcium, etc. Why should metformin be restricted more than all other chronic drugs? as opposed to starting with conservative dose in proportion to renal function (eg 250 if not 125mg/day) and gradual titration; due dose reduction for needs, age, body build and renal function; and in due course symptoms, response, and appropriate monitoring of usual blood parameters including venous acid-base balance and metformin bloodlevels?? Yours sincerely, NEIL D BURMAN MRCP(UK)
ref: Jens Moller: Testosterone and Cardiovascular Diseases; Springer; Berlin; 1984. Jean-Daniel Lalau and Jean-Michael Race: Lactic Acidosis in Metformin therapy: Drugs 1999:58 supp 1:55-60. Wulffele MG, Kooy A, Lehert P, Bets D, Oom JA, Borger van der Burg B, Donker AJ, Stehouwer CD: Discontinuation of metformin in type 2 diabetes patients treated with insulin Neth J Med. 2002 Jul;60(6):228-30, 249-252 Competing interests: None declared |
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Andrew F Orange, Pharmacist Facilitator Manawatu Independent Practice Association, Palmerston North, New Zealand
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The editorial by Jones and colleagues provides compelling arguments for a review of the contraindications to metformin use.(1) However, it is difficult to understand the rationale behind their advocacy of serum creatinine concentration in determining the appropriateness of therapy with metformin; creatinine clearance is a much better objective assessment of renal function. Creatinine clearance is considered superior to a serum creatinine concentration as it is a more accurate assessment of renal function. In addition, creatinine clearance reduces the arbitrary nature of the cut off point for renal failure described by Jones et al, and allows some guidance for metformin use in elderly patients, some of whom may have significant renal impairment but a serum creatinine concentration within the normal range. Guidelines on the use of oral hypoglycaemic agents recently published in the Australian Family Physician employ creatinine clearance as a measure of renal function in determining an appropriate dose of metformin.(2) These guidelines present a practical alternative to the view of Jones et al, that the term "renal impairment" is vague and unhelpful. There is one certainty in all of this: more research is needed in order to optimise the medicines-related health outcomes that metformin can provide. References: (1) Jones GC, Macklin JP, Alexander WD. Contraindications to the use of metformin. BMJ 2003; 326: 4-5 (2) Phillips P, Braddon J. Oral hypoglycaemics. When not to use what. Australian Family Physician 2002; 31: 637-43 Competing interests: None declared |
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Michal T Kluger, Specialist Anaesthetist, North Shore Hospital, Auckland NDept Anaesthesiology and Perioperative Medicine, North Shore Hospital, AUckland
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The editorial by Jones and Macklin [1] appears to make an appeal to re-evaluate the contraindications for the use of metformin in the treatment of diabetes. The authors cite guidelines and references to support their statements, yet make a generalised statement relating to the perioperative use of metformin. They state that metformin should be stopped for 2 days preoperatively and reinstated when renal function returns to normal. This is not referenced and I would be surprised to find one that supported such a notion. Whilst I would agree that metformin should be witheld for those operations that are at risk of significant alterations in renal function, there can be little support for this guideline in most other procedures. Knowledege of the potential risk factors for the development of lactic acidosis are important, but managed by the perioperative team. Care must be taken to avoid stopping any medication in the perioperative period; this often leads to failure of this medication to be restarted after the procedure. Moreover, close control of blood glucose in this period may be of greater importance in the prevention of both metabolic and haemodynamic sequelae than a theoretical risk from lactic acidosis. I would suggest that this is not a rationale component of this otherwise exceelent guideline and should be withdrawn until evidence arises that supports its inclusion. 1. Contraindications to the use of metformin G C Jones, J P Macklin, and W D Alexander BMJ 2003; 326: 4-5 Competing interests: None declared |
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Alan G Conn, Consultant Anaesthetist Wansbeck Hospital NE63 9JJ, Max Allen, SHO General Medicine / Anaesthesia
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The immensely helpful editorial by Jones et al gives suggested revised contraindications to and guidelines for withdrawing metformin. The last bullet point is “withdraw two days before general anaesthesia”. Given the authors’ stated intention this is unintentionally misleading since it is not general anaesthesia per se which leads to tissue hypoxia but concomitant major surgery. In this context there is a world of difference between (say) a brief surgical procedure such as carpal tunnel release and a hip replacement. We suggest that to stop metformin two days before minor surgery (merely on the basis of "general anaesthesia") is both impractical and unnecessary. Competing interests: None declared |
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Dan Hackam, Dept. of Medicine McMaster University
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Unfortunately, the only way to settle the debate and provide rational guidelines on absolute/relative contraindications to the use of metformin is to conduct RCT's in diabetics with higher-risk conditions (for lactic acidosis) such as renal insufficiency, CHF, COPD, and chronic liver disease. Because this may be unethical, and because there is little industry support in demonstrating that metformin might be safe in these populations, such controlled studies are unlikely to be done. Therefore we are forced to rely on retrospective case-control and prospective pharmacy database studies as have recently been published on the subject, which is a distant second-best in terms of standards of clinical evidence.
To be a devil's advocate (!), there are certainly other options than metformin in patients with comorbidity and diabetes: insulin, acarbose, sulfonylureas, TZD's, not to mention lifestyle modification (exercise and diet). Until the published recommendations change, I am certainly reluctant to prescribe metformin in these high-risk groups, if not because of theoretical risk of lactic acidosis, then at least because of the medicolegal risks! Competing interests: None declared |
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Nadarajah Sreeharan, Senior Vice President and European Medical Director GlaxoSmithKline R&D, New Frontiers Science Park,3rd Avenue,Harlow,Essex,CM19 5AW
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Jones et al conclude that metformin is now considered as the initial therapy of choice in overweight patients with Type II diabetes(1). However, it is important to note that over 80% of patients treated with metformin alone will not maintain target glycaemic control over a long period as defined by an HbA1C level below 7% (2). Use of additional agents in combination with metformin will be necessary to achieve recommended target levels. Jones et al are however right to urge the adoption of 'simplified and pragmatic set of guidelines' to facilitate the expanded use of metformin,either alone or in combination. Based on my experience of managing lactic acidosis in Sri Lanka, an area that needs greater focus is the provision of sound medical advice to metformin users travelling on holiday to the tropics. Care should be taken to avoid or limit activities that lead to excessive dehydration,which predisposes to intravascular volume loss resulting in tissue hypoxia and reduced renal clearance. The 'holiday pastime' of excessive consumption of alcohol should be moderated as its diuretic properties further exaggerate the dehydration. Ethanol is also well documented to increase serum lactate production via its oxidative metabolism to acetate and NADH resulting in a shift in favour of the conversion of pyruvate to lactate(3). Dehydration and excessive alcoholic consumption remain a potentially lethal pathophysiological combination for the development of lactic acidosis in metformin users travelling to the tropics. (1) Jones GC,Macklin JP,Alexander WD. Contraindications to the use of metformin. BMJ,2003;326;4-5. (2)Turner RC,Cull CA,Frighi V,Holman RR. Glycaemic control with diet,sulfonylurea,metformin or insulin in patients with type 2 diabetes mellitus:progressive requirements for multiple therapies(UKPDS 49). JAMA,1999;281(21);2005-12. (3)Lieu D,Mader TJ.Survival from profound alcoholic related lactic acidosis. J of Emergency Medicine,1999;17(5);841-6 Competing interests: GlaxoSmithkline markets Avandia for the treatment of Type II diabetes |
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Philip Jones, Specialist registrar in anaesthetics Bart's and The London NHS Trust, Whitechapel, London E1 1BB, Paul Yate, Consultant anaesthetist
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EDITOR – The editorial by Jones, Macklin and Alexander makes several excellent and welcome recommendations regarding better prescribing of metformin. It is a pity then that they advised stopping metformin two days before general anaesthesia when there is no evidence to suggest this is warranted, or even safe. We conducted a search of the Medline database using the keywords “metformin”, “an(a)esthesia”, “an(a)esthetics”, “pre-operative” and “diabetes”. We could find no evidence supporting the unreferenced statement in their editorial. They rightly point out that tissue hypoxia is commonly the trigger for metformin-associated lactic acidosis, and that metformin has a short half life except in advanced renal failure. It follows that it is illogical to suspend metformin earlier than the evening before most surgery, unless a degree of tissue hypoxia already exists. Avoiding metformin in patients with established or expected tissue hypoxia, or when substantial impairment of hepato-renal function perioperatively may be anticipated, is perfectly sensible. May we suggest the recommendations reflect this? Emergency surgery, cardiac surgery, operations requiring deliberate hypotension, and major vascular surgery would be examples where this modified advice would apply. Much elective surgery however does not fit this description, and their recommendation will, necessarily, only be applicable to elective surgical patients. In our view a blanket recommendation to stop metformin two days before going to theatre is neither necessary, safe, nor practical. Paul Yate Philip Jones Competing interests: None declared |
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Richard G Fiddian-Green, None None
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That metformin can cause a “lactic acidosis” on occasions suggests that it may either induce or compound the severity of anaerobic metabolism (1). This is important for the development of a tissue acidosis may have an adverse effect upon outcome (2). The term “lactic acidosis” is misleading for being a base, not an acid, an elevated blood lactate per se does not establish the presence of a tissue acidosis or of anaerobic metabolism. Conversely inhibiting the generation of lactate with iodoacetate in vitro does not prevent the development of a tissue acidosis in anerobiosis and any lactate present in blood in vivo may be removed very rapidly and used as a fuel by the heart or converted into glucose and hence glycogen by the liver. Thus the finding of a normal blood lactate does not exclude the presence of anaerobic metabolism which may exist chronically and only become evident when the demand for energy from ATP hydrolysis exceeds the capacity for ATP resynthesis by mitochondrial oxidative phosphorylation (2,3). A fall in gastric intramucosal pH is a very sensitive predictor of adverse outcome from the translocation of gut toxins, cytokine release, and hence organ dysfunctions, nosocomial infections, and organ failures (2,3). Patients with chronic renal failure on haemodialysis have an abnormally low gastric intramucosal pH but a normal arterial pH (4). This means that patients with chronic renal failure are more likely to develop gut mucosal injury and suffer from the adverse consequences of the translocation of bacterial toxins, notably endotoxin, the release of cytokines and the increase in permeability of the mitochondrial membrane they may induce (5). An increase in permeability of mitochondrial membranes causes a proton leak which dissipates the proton gradient thus uncoupling oxidative phosphorylation. This induces or compounds the severity of any impairment of mitochondrial oxidative phosphorylation present. The presence of a compensated metabolic acidosis in patients with chronic renal failure makes them more likely to develop an uncompensated gastric intramucosal acidosis and even a systemic tissue acidosis. The metabolic acidosis might even represent an adaptation by enzymes regulating ATP hydrolysis and resynthesis to an unappreciated presence of an impairment of mitochondrial oxidative phosphorylation in patients with chronic renal failure (6). Given this pathophysiologic scenario it would seem appropriate to withhold metformin from any patient who has a gastric intramucosal acidosis or develops a gastric intramucosal acidosis after the administration of metformin regardles of whether they have renal failure. A negative exercise stress test whilst on metformin should increase the confidence in prescribing metformin without precipitating anaerobiosis. A negative stress test might not, however, avoid compounding the severity of a gastric intramucosal acidosis and having an adverse effect upon outcome should it develop for other reasons during the course of a critical illness (7). 1. "Lactic acidosis": the common denominator? Richard G Fiddian-Green bmj.com/cgi/eletters/325/7374/1202#28322, 2 Jan 2003 2. Fiddian-Green RG. Gastric intramucosal pH, tissue oxygenation and acid- base balance. Br J Anaesth. 1995 May;74(5):591-606. Review. 3. Fiddian-Green RG. Monitoring of tissue pH: the critical measurement. Chest. 1999 Dec;116(6):1839-41. 4. Diebel L, Kozol R, Wilson RF, Mahajan S, Abu-Hamdan D, Thomas D. Gastric intramucosal acidosis in patients with chronic kidney failure. Surgery. 1993 May;113(5):520-6. 5. Lassus P, Opitz-Araya X, Lazebnik Y. Requirement for caspase-2 in stress-induced apoptosis before mitochondrial permeabilization. Science. 2002 Aug 23;297(5585):1352-4. 6. Hochachka PA, Somero GW. Biochemical adaptation. Oxford University Press, New York, NY, 2002 7. Kolkman JJ, Groeneveld AB, van der Berg FG, Rauwerda JA, Meuwissen SG. Increased gastric PCO2 during exercise is indicative of gastric ischaemia: a tonometric study. Gut. 1999 Feb;44(2):163-7. Competing interests: None declared |
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Ganapathy Chidambaram Chidambaram, General Practioner Chennai,India-600020
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Sir, Thank you very much for the excellent article on Metformin. I have been using this drug for the last fiftten years in my practice to treat type II DM with or without CAD & HTN & I have experienced very good results without a single case of Lactic Acidosis.It is a good drug in the sense that it rarely causes hypoglycemic episodes.Combination with Glybenclamide is ideal. DrG.Chidambaram Competing interests: None declared |
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Andrew T Elder, Consultant Physician WesternGeneral Hospital,Crewe Road,Edinburgh,Scotland.EH4 2XU
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Contraindications to the use of metformin. Jones et al (1) criticise current guidelines, which highlight possible contraindications to the use of metformin, as too vague and potentially leading to underuse in patients with type 2 diabetes. Although their desire for a “less ambiguous” approach seems sensible, their own guidelines still lack clarity. They note that any specific value of serum creatinine chosen as a cut -off for prescription of metformin will be arbitrary, because of variations in muscle mass and protein turnover. Despite this they then select – for undefined reasons- a serum creatinine value of 150 micromols/L as the cut-off point in their guideline. They then suggest “caution should therefore be used in prescribing metformin for elderly patients”. This is a vague statement, which could be interpreted as meaning that metformin shouldn’t be prescribed at all in the elderly; that specialist opinion should be sought or creatinine clearance calculated before it is prescribed; or that renal function or serum lactate should be monitored after it is prescribed.(2) In addition, we are not informed of the authors' own definition of “elderly”. Given that the growing majority of patients with type 2 diabetes are over the age of 65 years,and that there is already evidence of undertreatment of such patients (3), it would seem particularly desirable to be as clear as is possible about this age group, if the full benefits of treatment are to be attained. Although the simple formulae that can be used to estimate creatinine clearance(4) are not completely reliable it may be preferable to suggest that prescription is related to such a calculated estimate of clearance, which takes into account patient age, rather than the serum creatinine value alone. Andrew T. Elder
1.Jones GC, Macklin JP, Alexander WD. Contraindications to the use of metformin. BMJ 2003; 326: 4-5 2.Chehade JM, Mooradian AD in Diabetes in old age eds Sinclair AJ,Finucane P. John Wiley,Chichester. 2001 p 202-3. 3.Hendra TJ,Sinclair AJ (1997) Improving the care of elderly diabetic patients ; the final report of the St Vincent Joint Task Force for Diabetes. Age and Ageing, 26 , 3-6. 4.Cockcroft, D.W. and Gault, M.H. (1976). Prediction of creatinine clearance from serum creatinine. Nephron 16, 31. Competing interests: None declared |
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Gérard MACHET, Pharmacist Hôpital Paul Doumer Labruyère B.P. 10239 60332 Liancourt Cedex FRANCE
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After an analysis of the editorial “Contraindications to the use of metformin Evidence suggests that it is time to amend the list” BMJ 2003;326:4-5 (4 January), we want to precise that just after the period of cited review of cases (May 1995 and January 2000) with “no mortality was associated with metformin alone”, we notified one case of death with metformin alone in France in October 1995, this case was published (with two other different cases of lactic acidosis and metformin implicated) in : Machet G, Coudray JM. “Lactic acidosis and metformin implicated: why better information about risk factors?” Therapie 2000 Mar-Apr;55(2):283- 94. We declared these three cases between October 1995 and May 1997 in the same General Hospital (Longjumeau, Essonne, France). Metformin was implicated by plasma and intra-erythrocyte levels. A woman (68 years old) died with :
Another patient who died have had an infection problem. The third patient was saved, she had contraindication of age and three drug interactions with metformin but she was rapidly in the hospital after symptoms beginning (she was living in a house for old people). Using information given by these cases, we analysed available information about this risk for healthcare professionals and for patients (in 1999). A comparison was made of approved labelling information on Glucophage and its patient leaflets in France and in the USA and an analysis made of the differences. We concluded that : “In France, Information given to physicians, pharmacists and patients on the risk of lactic acidosis where Glucophage is implicated must be improved, and on the interest of the metformin plasma level in this case. These are primary points because the issue for the few patients concerned may be fatal. Advice on self- medication may be introduced. The evolution of information provided on these risks depends on the pharmaceutical laboratory, government authorities and healthcare professionals.” In this article, we wrote on an important point: adverse drug reactions notifications are usually neglected. In “Adverse drug reactions in a hospital general medical unit meriting notification to the Committee on Safety of Medicines.Br J Clin Pharmacol 1996; 42: 429-429. Smith CC, Bennett PM, Pearce HM et al.” the authors precise that for admissions in a hospital medical unit during three years (20695 patients) only 30 (6.3 %) of 477 notifications to do were, in fact, done. So is the estimated prevalence of lactic acidosis associated with metformin the real one ? An other difficulty : with a lactic acidosis, healthcare professionals must act rapidly for a vital problem. With a patient taking metformin, the implication is given by a plasma level corresponding to an accumulation. This determination is not usual in hospital laboratories and may be not see as an important element, useful for possible notification but without interest to take care. In conclusion, different effects of metformin have a great interest for many patients but it is very important to prevent by a good information the risk of metformin and lactic acidosis, a rare adverse reaction, fatal in approximately 50 per cent of cases. To amend the list of contraindications to use metformin is possible but is it the better way to give a contribution to inform on the good use of this drug and about its’ possible fatal adverse reaction ? Competing interests: None declared |
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William M Hague, Consultant Physician in Obstetric Medicine Queen Elizabeth Hospital, Woodville SA 5011 Australia, Peter Davoren, J Oliver, J Rowan
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Your recent editorial on contraindications to the use of metformin1 did not mention pregnancy, according to the British National Formulary (http://bnf.org/), another contraindication to its use. In women with gestational diabetes (GDM), or pre-gestational type 2 diabetes, whose blood glucose values cannot be controlled by lifestyle measures, insulin therapy is usually recommended. Given that pregnancy is a state of insulin resistance, metformin might be a logical alternative: it reduces hepatic glucose output, improves peripheral glucose uptake and suppresses fatty acid oxidation, cardinal features of both GDM and type 2 diabetes. Cohort data support use of metformin in pregnancy2. In a recent report of women with polycystic ovary syndrome who had become pregnant while taking metformin, its continuation through pregnancy reduced the incidence of GDM as well as the frequency of early miscarriage3. One retrospective study4 has reported an increased rate of pre-eclampsia in pregnant women treated with metformin, but this study was weakened by the lack of matched controls, while the perinatal losses reported in the metformin group cannot be attributed to the treatment: two were in non-compliant women treated with metformin at the end of pregnancy, one was in a woman treated at 28 weeks who changed to insulin, and one was in a woman treated from 36 weeks who had a stillbirth weighing 1700g at 38 weeks. We (WMH, PMD, JO) have recently completed a pilot study (The MiG Pilot trial - MiG = Metformin in Gestational diabetes) in 30 women with GDM diagnosed by Australasian Diabetes in Pregnancy Society (ADIPS) criteria, matched for age, parity, BMI, and gestation at entry (Table 1), and randomised to metformin or insulin treatment. Our hypotheses were that metformin would be as effective as insulin in reducing maternal hyperglycaemia and therefore fetal hyperinsulinism, and that perinatal outcome would be similar. The trial was approved by the local Ethics Committees and women gave written informed consent. Cord C-peptide concentration was used as a measure of fetal beta-cell activity: no difference was detected in the results from the 17 women whose cord blood was stored (P=0.31: Mann-Whitney) (Figure 1). Perinatal outcomes were not different between the two groups (Table 1) but numbers are too small to comment further5. A larger trial has now been initiated (the MiG Study), with adequate power to test the hypothesis that, in women with GDM, metformin treatment, compared with insulin, will have similar perinatal outcomes, improve insulin sensitivity in both mother and baby, and be associated with improved treatment acceptability. Funding and ethical approval has been obtained, and recruitment has commenced (details: WMH/JR). A follow up study of the offspring is planned, to study potential effects of metformin in relation to later insulin sensitivity and subsequent health5. 1. Jones GC, Macklin JP, Alexander WD. Contraindications to the use of metformin BMJ 2003;326(7379):4-5. 2. Coetzee E, Jackson W. The management of non-insulin-dependent diabetes during pregnancy. Diab Res Clin Pract 1986;1:281-287. 3. Glueck CJ, Wang P, Kobayashi S, Phillips H, Sieve-Smith L. Metformin therapy throughout pregnancy reduces the development of gestational diabetes in women with polycystic ovary syndrome. Fertility and Sterility 2002;77(3):520-525. 4. Hellmuth E, Damm P, Molsted-Pedersen L. Oral hypoglycaemic agents in 118 diabetic pregnancies. Diabetic Medicine 2000;17:507-511. 5. Barker D. Mothers, babies and health in later life. Edinburgh: Churchill, Livingstone, 1998.
Table 1. Baseline characteristics and Outcome data. No significant differences were found
1 Mean (SD); 2Median (range)
Distribution of cord blood C-peptide concentrations from pregnant women treated with either insulin or metformin. (P for difference = 0.31: Mann-Whitney) W M Hague1
1Consultant Physician in Obstetric Medicine,
Department of Obstetrics,
University of Adelaide,
The Queen Elizabeth Hospital,
Woodville, SA 5011,
Australia
2Consultant Physician,
Department of Medicine,
Gold Coast Hospital,
University of Queensland,
Southport, QLD 4215,
Australia
3Associate Professor,
Department of Physiology,
School of Medicine,
Flinders University,
Bedford Park, SA 5042,
Australia
4Consultant Physician in Obstetric Medicine,
National Women's Hospital,
Green Lane,
Auckland,
New Zealand
Corresponding Author: Dr WM Hague, Department of Obstetrics, Women's and Children's Hospital, North Adelaide, SA 5006, Australia Competing interests: None declared |
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HONEY M MATHEW, Specialist Registrar Stafford general Hospital, ST16 3SA, KIRK CHIN (Consultant Obstetrician and Gynaecologist)
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We would like to congratulate Jones et al on their timely reminder of the inappropriately strict contraindications to the use of metformin(1).The authors have emphasised the justification for using metformin in patients with type 2 diabetes and its proven effect in reducing cardiovascular risk in such patients. For many years Gynaecologists have also found favour with metformin and its emerging role in the treatment of polycystic ovary syndrome despite not being licensed for this. Metformin improves insulin sensitivity and decreases hyperinsulinaemia,reduces serum androgen levels,restores menstrual cyclicity and increases the ovulatory and pregnancy rates in patients with polycystic ovary syndrome who are resistant to clomiphene citrate(2).When administered during pregnancy it decreases the occurence of first trimester pregnancy loss(3),and reduces the development of gestational diabetes in women with polycystic ovary syndrome(4). Furthermore it has also been suggested as a useful treatment for obesity(5). We feel that these proven uses have to be formally recognised in addition to amending the published contraindications list,thereby eliminating ambiguity in its usage,especially considering the value of metformin in endocrinopathies like polycystic ovary syndrome. REFERENCES 1)Jones GC, Macklin JP, Alexander WD. Contraindications to the use of metformin.BMJ 2003;326:4-5 (4 January) 2)Nestler JE, Stovall D, Akhtar N, Iuorno MJ, Jakubowicz DJ. strategies for the use of insulin-sensitising drugs to treat infertility in women with polycystic ovary syndrome. Fertil Steril 2002;77(2):209-15. 3)Jakubowicz DJ,Iuorno MJ,Jakubowicz S,Roberts KA,Nestler JE Effects of metformin on early pregnancy loss in the poycystic ovary syndrome.J Clin Endocrinol Metab 2002;87(2):524-9. 4)Glueck CJ, Wang P, Kobayashi S,Philips H, Sieve-Smith L. Metformin therapy throughout pregnancy reduces the development of gestational diabetes in women with polycystic ovary syndrome.Fertil Steril 2002;77(3):520-5. 5)Glokcel A, Gumurdulu Y, Karakose H, Melek Ertorer E, Tanaci N,Bascil TutncuN, Guvener N. Evaluation of the safety and efficacy of sibutramine,orlistat and metformin in the treatment of obesity.Dibetes Obes Metab 2002;4(1):49-55 Competing interests: None declared |
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Mordchai Ravid, Professor of Medicine Meir Hospital, Kfar Sava 44281 Israel, Rita Rachmani
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The authors should be congratulated on their review of the relevant literature about the side effects of metformine. However,their suggestions for the guidelines about discontinuation of metformin do not stem from the literature they quote. The arbitrary limit of serum creatinine ,150 micmol/L for example,is not born out by the data. In a randomized prospective study(1) we have followed up, for 4 years, nearly 400 elderly patients with diabetes mellitus and serum creatinine values of 130-220 micmol/L who had been treated with metformin . The drug was discontinued in half of the patients. Analysis by intention to treat showed a rise in BMI and in HbA1c in in the patients who stopped metformin as compared to those who continued the drug. Serum levels of lactic acid were equal in the two groups. There were no cases of lactic acidosis.Cardiovascular morbidity and mortality were identical in the two groups. More than 200 of the patients had conditions associated with hypoxemia (e.g. chroic obstructive pulmonary disease ,congestive heart failure). We have concluded that diabetic patients treated with metformin who tolerate the drug well my contnue metformin also when mild renal filure develops possibly to a limit of 220 micmol/L of Serum creatinine. The limit set by Jones, Macklin and Alexander is arbitrary and may deprive a substantial number of patients of the benefits of this medication.They did not find a rise in the rate of side effects in patients with serum creatinine values of 150-220 micmol/L as compared to thse with values lower than 150. Reference 1.Rachmani R, Slavachevski I,Kedar Y, Ravid M Metformin in patients with type 2 diabetes mellitus:reconsiderations of traditional contraindications. Eur J Intern Med 2002;13:428-33 Competing interests: None declared |
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Phillip J. Colquitt, RN Independent
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Prescribing practices of doctors may affect outcomes, as follows: I escorted the patient from the ward to radiology for a CAT scan. In the preamble, it took about half an hour of “discussion” for the ward nursing staff to feel comfortable with the “new” idea that Metformin should have been discontinued. They satisfied themselves that the patient wasn’t on Metformin anyway, but still didn’t like the new idea - created by some “researcher” no doubt, merely to interrupt an otherwise healthy schedule. On arrival, radiology re-explained the new approach to Metformin being discontinued, and had a look at the patient’s medication sheet, just in case. The scan went ahead. On return to the ward, in order to clarify the above-mentioned "discussion", some computer searching was done via PubMed. This revealed the usual duplicate names for the same drug – Metformin is also called Glucophage, though rarely prescribed in the hospital in question as such. The patient was in fact on Glucophage, and it had not been withheld in the last 24 hours. No adverse outcome on that occasion, but using drug names consistently may help. Sometimes, doctors prescribe existing medications for new admissions, by writing down exactly what the patient tells them. And patients love trade names. PS. Please feel free to comment on any errors. Competing interests: None declared |
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Maria Valois, Motherisk Clinic Scarborough Grace Hospital, Ivy Fettes, Gideon Koren
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The contraindications to the use of metformin have been reviewed in a recent article by Jones et al[1], focusing primarily on the type II diabetes cohort. However, pregnancy is one contraindication missing from their table, and we predict it will gain more importance in the near future. Shifts in profile of morbidity of type II diabetes will lead to changes in the use of metformin, as this syndrome is seen in younger people, particularly in the United States of America. Indeed, recent trends show that younger adults now declare a non-insulin dependent diabetes, and this trend includes women in reproductive years. Polycystic ovary syndrome is the most common endocrinopathy in women of reproductive years and is the most common cause of endocrine infertility[2-4]. Central, but not unique, in its physiopathology is insulin resistance[2, 5], which leads to a rate of obesity, type II diabetes, and premature coronary disease several folds above that of the general population[6]. NIDDM in PCOS patients declares itself at a younger age than in the general population[4, 7]. Despite the fact that oral hypoglycemic agents have been contraindicated in pregnancy for over twenty years[8-11], metformin has been used off label by the fertility community to induce ovulatory menstrual cycles in women with polycystic ovary syndrome[12-16]. This practice has led to unavoidable fetal exposure. The Motherisk Clinic in Toronto, Canada has focused on documenting pregnancy outcome in women with polycystic ovary syndrome exposed to metformin. Our preliminary data show that metformin does not increase the risk of major malformations above that of the general population, and is not associated with an increased rate of obstetrical complications such as peri-natal hypoglycemia. Other studies have also shown similar results, although data are still too scarce in the literature to revise the status of metformin yet[17-20]. As insulin resistance gets growing recognition for its central role in polycystic ovary syndrome, we predict that metformin will be used more and more in women of reproductive years, and this cohort should not be overlooked when we issue recommendations regarding the use of insulin sensitizers. Bibliography 1. Jones, G.C., J.P. Macklin, and W.D. Alexander, Contraindications to the use of metformin. Brit J Med, 2003. 326: p. 4-5. 2. Lobo, R.A. and E. Carmina, The importance of diagnosing the polycystic ovary syndrome. Ann Intern Med, 2000. 132(12): p. 989-993. 3. Yen, S.S.C., Polycystic ovary syndrome (Hyperandrogenic chronic anovulation), in Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management., S.S.C. Yen, Jaffe, and Babieri, Editors. 1999. p. 436-478. 4. Legro, R.S., et al., Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: A prospective, controlled study in 254 affected women. J Clin Endocrinol Metab, 1999. 84(1): p. 165-169. 5. Ciaraldi, T.P., et al., Cellular mechanisms of insulin resistance in polycystic ovarian syndrome. J Clin Endocrinol Metab, 1992. 75(2): p. 577- 583. 6. Ovalle, F. and R. Azziz, Insulin resistance, polycystic ovary syndrome, and type 2 diabetes mellitus. Fertility and Sterility, 2002. 77(2): p. 1095-1105. 7. Dunaif, A., Hyperandrogenic anovulation (PCOS): A unique disorder of insulin action associated with an increased risk of non-insulin-dependent diabetes mellitus. Amer J Med, 1995. 98(suppl 1A): p. 33S-39S. 8. Meltzer, S., et al., 1998 clinical practice guidelines for the management of diabetes in Canada. Can Med Ass Jour, 1998. 159(8 suppl): p. S1-S29. 9. Piacquadio, K., D.R. Hollingsworth, and H. Murphy, Effects of in-utero exposure to oral hypoglyceamic drugs. The Lancet, 1991. 338(Oct 5): p. 866 -869. 10. Briggf, G., R. Freeman, and S. Yaffe, A reference guide to fetal and neonatal risk. Drugs in Pregnancy and Lactation. 6th ed. 2002: Lippincott, Williams, and Wilkins. 11. ASRM, A.S.o.R.M., Use of insulin sensitizing agents in the treatment of polycystic ovary syndrome - A Practice Committee Report (A Committee Opinion). 2000. 12. Velazquez, E., et al., Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism, 1994. 43(5 (May)): p. 647-654. 13. Glueck, C.J., et al., Metformin-induced resumption of normal menses in 39 of 43 (91%) previously amenorrheic women with the polycystic ovary syndrome. Metabolism, 1999. 48(4 (April)): p. 511-519. 14. Morin-Papunen, L.C., et al., Metformin therapy improves the menstrual pattern with minimal endocrine and metabolic effects in women with polycystic ovary syndrome. Fertility and Sterility, 1998. 69(4): p. 691- 696. 15. Nestler, J.E., et al., Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. New Eng J Med, 1998. 338(April 29): p. 1314-1320. 16. Fleming, R., et al., Ovarian function and metabolic factors in women with oligomenorrhaea treate with metformin in a randomized double blind placebo-controlled trial. J Clin Endocrinol Metab, 2002. 87(2): p. 569- 574. 17. Glueck, C.J., et al., Pregnancy outcomes among women with polycystic ovary syndrome treated with metformin. Human Reprod, 2002. 17(11): p. 2858 -2864. 18. Glueck, C.J., et al., Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first- trimester spontaneous abortion: A pilot study. Fertility and Sterility, 2001. 75(Jan): p. 46-52. 19. Heard, M.J., et al., Pregnancies following use of metformin for ovulation induction in patients with polycystic ovary syndrome. Fertility and Sterility, 2002. 77(4): p. 669-673. 20. Pinto, A.B., et al., Pregnancy outcome in clomiphene citrate (CC)- resistant polycystic ovary syndrome (PCOS) patients treated with and without metformin (abstr). Fertility and Sterility, 2001. 76(3, suppl 1): p. S 186. Competing interests: None declared |
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Eduardo Naranjo, Metformin Mexico city 03410
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I have 10 years to use metformin in my patients and I have not had a single case of lactic acidosis or another complication. Metformin is a drug of choice to conserve the pancreatic answer of diabetic patients. Competing interests: None declared |
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