cise in a patient with type 2 diabetes taking met Diabetes Centre and Department of metformin monotherapy in diabetes was described as a cause of …
The British Journal of Diabetes Vascular Disease
http://dvdsagepubcom Exercise, metformin and hypoglycaemia: a neglected entity
Abdullah Omari, Dennis K Yue and Stephen M Twigg British Journal of Diabetes Vascular Disease 2005; 5; 106 DOI: 101177/14746514050050021001 The online version of this article can be found at: http://dvdsagepubcom/cgi/content/abstract/5/2/106
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Exercise, metformin and hypoglycaemia: a neglected entity
ABDULLAH OMARI,1 DENNIS K YUE,1,2 STEPHEN M TWIGG1,2
Abstract
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Aspirin Folic acid
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e
describe a case of hypoglycaemia induced by exercise in a patient with type 2 diabetes taking metformin, who was not taking insulin or sulphonylurea medication The hypoglycaemia resolved after the dosage of metformin was reduced, despite increased physical activity A brief review of the literature identifying the frequency of and risk factors for hypoglycaemia during treatment with metformin is discussed
Table 1 Ramipril Metoprolol
Medication at initial presentation 10 mg nocte
D LT
25 mg bid 15 mg mane 40 mg daily 100 mg daily 5 mg daily
Indapamide slow release Omeprazole
Introduction
Metformin is an insulin sensitising agent and its role in therapy continues to expand1 Well recognised potential adverse effects of metformin include common gastrointestinal symptoms and rare life-threatening lactic acidosis1,2 Whilst hypoglycaemia risk is clearly increased when metformin is added as combination therapy in patients taking pre-existing sulphonylurea or insulin,3 that metformin monotherapy can also be associated with symptomatic hypoglycaemia may not be appreciated4-6 We now describe a case of hypoglycaemia precipitated by increased physical activity in a patient on metformin
monotherapy and address its clinical relevance
History and examination
A 57-year-old white female was seen for management of type 2 diabetes of two years duration Despite ongoing efforts with lifestyle management, her home capillary fasting blood glucose readings were 6575 mmol/L and 70112 mmol/L two hours after her evening meal Glycaemic control was suboptimal with a HbA1C of 76 normal range to 60 She had documented macrovascular but not microvascular disease, with an inferior myocardial infarction and coronary stent insertion two years earlier, followed by a coronary artery by-pass graft 12 months later, due to persistent angina Intercurrent stable doses of medications are listed in table 1
1 Diabetes Centre and Department of Endocrinology, Royal Prince Alfred Hospital, Missenden Road, Camperdown NSW 2005, Australia 2 Discipline of Medicine, University of Sydney, NSW 2006, Australia
Correspondence to: Dr Stephen Twigg Discipline of Medicine, University of Sydney, NSW 2006, Australia Tel: 1 612 9515 6150; Fax: 1 612 9516 1273 E-mail: stwigg@medusydeduau Br J Diabetes Vasc Dis 2005;5:10608
Her weight was 725 kg with BMI 283 kg/m2 Blood pressure was 128/74 mmHg with no
cardiovascular abnormalities to examination There was no peripheral vascular disease, retinopathy or neuropathy Respiratory and gastrointestinal examinations were unremarkable Metformin was commenced at 425 mg bid for one week after meals, then increasing to 850 mg bid This was well tolerated and the dose was subsequently increased to 850 mg tds On review after a further three months, she had lost 25 kg in weight with reduced caloric intake, with stable home fasting capillary glucose readings of 5062 mmol/L, and up to 84 mmol/L two hours after the evening meal After six months of metformin monotherapy her HbA1C level had fallen to 66 She commenced a graded supervised cardiovascular exercise program and within one week, began to develop predictable symptoms of hypoglycaemia less than 30 minutes after commencing exercise, characterised by sweating, tremor and increasing confusion Neither angina or arrhythmia were precipitated by the episodes Capillary glucose levels at the time of symptoms were between 28 and 35 mmol/L Seven episodes were documented and two equivalent events also occurred after 1 hour intervals of gardening She was able to reproducibly self-treat the symptoms with
simple carbohydrate intake, and in parallel on each occasion, the low 40 mmol/L blood capillary glucose levels were reversed No other person was required to help in the treatments, indicating that the episodes were mild, rather than severe in type She subsequently found she was able to prevent most but not all episodes by consumption of 15 to 30 g of absorbable carbohydrate before exertion The dose of metformin was then decreased to 425 mg bid and other medications were unchanged Over the succeeding two months, despite increased physical activity in the structured
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Abbreviations ACE bid HbA1C tds angiotensin-converting enzyme twice a day haemoglobin A1C thrice a day
Table 2
Changes in glycaemic control Home FPG mmol/L Home 2-hour postmeal mmol/L 70112 HbA1C
Initial presentation
6575
76
exercise program, episodes of hypoglycaemia have not recurred Daily glucose readings and HbA1C have increased see table 2
Metformin 850 tds Metformin 425 bid
5062 6672
84 66109
66 71
Investigation
Other potential causes of hypoglycaemia such as end-organ
impairment, pituitary hypofunction or insulinoma were excluded Serum sodium and potassium, bicarbonate, and hepatic function tests were normal and renal function showed a serum creatinine of 009 mmol/L normal to 011 mmol/L, calculated creatinine clearance of 674 ml/min and normal microalbumin excretion rate of 154 g/min Pituitary hormones were normal with a normal morning serum cortisol of 356 nmol/L, normal serum prolactin and thyroid function, and post-menopausal range gonadotropins Insulin antibodies were absent
On exercising symptomatic hypoglycaemia not requiring third party assistance
Discussion
This case describes the development of hypoglycaemia in a patient with type 2 diabetes; metformin is implicated as the hypoglycaemia occurred when exercise was added to maximal metformin therapy These exercise-associated hypoglycaemic episodes resolved when the metformin dose was markedly reduced 850 tds to 425 bid, despite increased physical activity Whilst metformin induced hypoglycaemia occurs in a minority of patients on metformin monotherapy mild self-limiting and self-treated episodes are most common when they occur However, isolated cases of severe episodes of
hypoglycaemia with neuroglycopaenic effects of confusion, erratic behaviour and reduction in level and loss of consciousness have been reported, in each case in the presence of major co-morbidity7,8 In the United Kingdom Prospective Diabetes Study UKPDS, metformin monotherapy in diabetes was described as a cause of hypoglycaemia in 63 of patients, compared with 12 on diet alone, 20 on sulphonylurea alone glibenclamide or chlorpropamide and 33 of patients taking insulin therapy alone9,10 All but one of these episodes in the metformin treated group were of mild hypoglycaemia, defined as symptoms reported consistent with hypoglycaemia without routine requirement for biochemical confirmation that did not require third party assistance or hospital admission9 Whilst the UKPDS was not blinded to medication type, it does appear that hypoglycaemia due to metformin treatment alone, is more common than with lifestyle management by diet and exercise alone In contrast to the UKPDS, whether hypoglycaemia occurred in the placebo controlled Diabetes Prevention Program,4 where a middle range median dose 1,700 mg daily was used, was not reported Case reports to the voluntary registry of Adverse
Drug
Reactions in Australia ADRAC, show that since 1998, five cases of hypoglycaemia ascribed to metformin monotherapy were documented, with some reportedly causing reduced level of consciousness and leading to hospitalisation The mechanism of action of metformin is complex and still being fully elucidated; its ability to increase peripheral insulin sensitivity and decrease hepatic glucose output through its potentiation of hepatic insulin sensitivity,11 may partly account for its ability to cause hypoglycaemia Recently metformin has been shown to potentiate insulin mediated signalling in skeletal muscle through AMP-kinase,11 a pathway which when excessively activated can induce hypoglycaemia in rodents12 Certain medications such as ACE inhibitors,8,13,14 and NSAID therapy,8,15 may potentiate metformin induced hypoglycaemia In some cases physical activity as in the current case, and nutritional deprivation, presumably causing low hepatic glycogen stores, have also been associated8 Beta-blockade therapy may impair the counterregulatory response to hypoglycaemia,15 and such intercurrent therapy may also have contributed to the development of this patients hypoglycaemia Higher range
doses of metformin may be more likely to be associated with hypoglycaemia,8 although it is reported that the maximal glucose-lowering efficacy of the drug is usually achieved at about 2,000 mg/day16 Hypoglycaemia due to therapy for diabetes is a significant clinical concern Even when mild it can reduce quality of life, and when it is severe, it can be life-threatening, and can cause seizure, major trauma, precipitate major cardiovascular and cerebrovascular events, and when recurrent and severe, result in chronic cognitive disturbance17 It should be remembered that insulin sensitising agents, such as metformin, improve the response to physiological endogenous insulin secretion as does exercise However, in type 2 diabetes, in particular, counter-regulatory responses to falling glucose concentrations are often blunted and these delayed responses may result in symptomatic hypoglycaemia although this is usually mild and self-limiting Ideally in type 2 diabetes antidiabetic medication is added to existing weight loss and exercise strategies both of which improve insulin sensitivity However, to maximise the benefit:risk ratio of using medication to control hyperglycaemia, we reinforce
that patients prescribed such agents, including metformin,
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should be made aware of the risk of hypoglycaemia, particularly when commencing aerobic exercise, and methods to minimise its occurrence Medication dose may need to be reduced as exercise is intensified Patients should know how to treat hypoglycaemia, and should be asked about the presence of hypoglycaemic symptoms at each routine follow-up assessment
References
1 Bailey CJ, Turner RC Metformin N Engl J Med 1996;334:574-9 2 UK Prospective Diabetes Study UKPDS Group Effect of intensive bloodglucose control with metformin on complications in overweight patients with type 2 diabetes UKPDS 34 Lancet 1998;352:854-65 3 Fruehwald-Schultes B, Kern W, Oltmanns KM et al Metformin does not adversely affect hormonal and symptomatic responses to recurrent hypoglycemia J Clin Endocrinol Metab 2001;86:4187-92 4 Knowler WC, Barrett-Connor E, Fowler SE et al Diabetes Prevention Program
Research Group Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin N Engl J Med 2002;346:393403 5 Campbell RK, White JR Jr, Saulie BA Metformin: a new oral biguanide Clin Ther 1996;18:360-71 6 Wiernsperger NF, Bailey CJ The antihyperglycaemic effect of metformin: therapeutic and cellular mechanisms Drugs 1999;58suppl 1:31-9 7 UK Prospective Diabetes Study UKPDS Group United Kingdom Prospective Diabetes Study UKPDS 13: Relative efficacy of randomly allocated diet, sulphonylurea, insulin, or metformin in patients with newly diagnosed non-insulin dependent diabetes followed for three years BMJ 1995;310:83-8 8 Zitzmann S, Reimann IR, Schmechel H Severe hypoglycemia in an elderly patient treated with metformin Int J Clin Pharmacol Ther 2002;40: 108-10 9 UK Prospective Diabetes Study UKPDS Group UK prospective diabetes study 16 Overview of 6 years therapy of type II diabetes: a progressive disease Diabetes 1995;44:1249-58 10 UK Prospective Diabetes Study UKPDS Group United Kingdom Prospective Diabetes Study 24: a 6-year, randomized, controlled trial comparing sulfonylurea, 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 11 Radziuk J, Bailey CJ, Wiernsperger NF, Yudkin JS Metformin and its liver targets in the treatment of type 2 diabetes Curr Drug Targets Immune Endocr Metabol Disord 2003;3:151-69 12 Zou MH, Kirkpatrick SS, Davis BJ et al Activation of the AMP-activated protein kinase by the anti-diabetic drug metformin in vivo: Role of mitochondrial reactive nitrogen species J Biol Chem 2004;279:43940-51 13 Ferriere M, Lachkar H, Richard JL, Bringer J, Orsetti A, Mirouze J Captopril and insulin sensitivity Ann Intern Med 1985;102:134-5 14 Herings RM, de Boer A, Stricker BH, Leufkens HG, Porsius A Hypoglycaemia associated with use of inhibitors of angiotensin converting enzyme[see comment] Lancet 1995;345:1195-8 15 White JR Jr, Hartman J, Campbell RK Drug interactions in diabetic patients The risk of losing glycemic control Postgrad Med 1993;93:131-2 16 Garber AJ, Duncan TG, Goodman AM, Mills DJ, Rohlf JL Efficacy of metformin in type II diabetes: results of a double-blind, placebo-controlled, dose-response trial Am J Med 1997;103:491-7 17 Cryer PE Hypoglycemia is the limiting factor in the management of diabetes
Diabetes Metab Res Rev 1999;15:42-6
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