|ISSN No. 1606-7754 Vol.16 No.2 August 2008|
Do contraindications to metformin therapy deprive type 2 diabetic patients of its benefits?
SS Al Awadhi,1,3 RM Clifford,2 VB Sunderland,3 LRP. Hackett,4 H Farah,5 TM Shareef 6
Fujairah Medical Zone, Ministry of Health, United Arab Emirates1; School of Biomedical and Chemical Sciences, University of Western Australia, WA, Australia2; School of Pharmacy, Curtin University of Technology, Australia3; MRC, Path West, WA, Australia4; Department of Health, WA, Australia5; Fujairah Hospital, Ministry of Health, UAE6
Background: Metformin is considered to be the drug of choice in overweight, newly diagnosed type 2 diabetes. Lactic acidosis is stated to be the most serious side effects of metformin therapy. Current available guidelines contain so many ambiguous terms in describing the contraindications to metformin use that they do little to assist in addressing this problem. Moreover, these ambiguous contraindications may deprive many diabetic patients from the benefit of metformin. Objectives: The aim of the current study was to evaluate the safety of metformin use in the presence of “standard” contraindications to its use. Research design and methods: This was a cross sectional study that involved type 2 diabetic patients who were on chronic treatment with metformin. A fasting blood sample was taken from each subject to determine levels of serum creatinine levels, bicarbonate, fasting blood sugar, lactate, insulin, C-Peptide, and metformin plasma concentration. Results: 106 patients were recruited in the study with 68 (64%) females. The mean age was 58 ± 13 years. The results illustrate that metformin has been prescribed for patients who are listed in the guidelines as having standard contraindications to its use. There were 30 (28%) patients with impaired renal function (Clcr < 60ml/min.) and five with Clcr < 30ml/min. Moreover, 30 (28%) had ischemic heart disease, six (5%) patients were diagnosed as having congestive heart failure, five (4%) with chronic obstruction pulmonary disease, and three (2%) with peripheral vascular disease. Although the numbers of those patients were not large enough to establish and confirm the safety of metformin in the presence of these standard contraindications and precautions, there were no cases of lactic acidosis observed. Conclusions: This study along with other studies has revealed that there is vagueness in the available guidelines in prescribing metformin, which led to the different observed practices. This study revealed that metformin is still prescribed to patients with listed contraindications. Clearer guidelines are needed for prescribing metformin with more specific contraindications. For example it would be more beneficial if the degree of heart failure, classified according to the New York Heart Association is specified.
Keywords: Diabetes, metformin, lactic acidosis, creatinine clearance, guideline, contraindications
Metformin is a biguanide (1, 1-dimethylbiguanide) used as an oral hypoglycaemic agent in the treatment of type 2 diabetes mellitus (DM).1,2 It improves insulin sensitivity, as shown by a reduction in hepatic glucose production.1,3 It undergoes rapid renal excretion through active secretion.4,5
According to United Kingdom Prospective Diabetes Study (UKPDS) 1 metformin is now considered to be the drug of choice for the treatment of overweight in newly diagnosed type 2 diabetic subjects. Two factors limit the use of metformin, with both factors relating to its adverse effects. The first is its gastrointestinal adverse effect. 6,7 However, in order to minimize this effect, metformin should be taken with meals and, as the symptoms are dose related, metformin should be started at a lower dose. More than half of the patients can tolerate the maximal dose, but about 5% cannot tolerate any dose of metformin. 5,8 The second effect is rare but potentially fatal lactic acidosis.9 The true incidence of metformin associated lactic acidosis is unknown.10 The Food and Drug Administration (FDA) has estimated the rate of fatal or non-fatal lactic acidosis to be five cases per 100,000 persons treated with metformin over the course of one year.11 However, almost all of the reported cases of lactic acidosis associated with metformin therapy have occurred in the presence of other conditions, which can themselves potentially precipitate lactic acidosis, such as renal impairment, congestive heart failure and sepsis.12,13
Despite this low incidence, guidelines are still using ambiguous terms in describing contraindications and precautions for metformin use. Moreover, these terms are not absolutely matching, which might result in depriving a significant number of diabetics of its use. Table 1 shows the contraindications and precautions of metformin as given by National Institute for Clinical Excellence (NICE) guidelines,14 Australian Medical Handbook (AMH),15 manufacturers, and International Diabetes Federation (IDF).16 As shown, the guidelines are not consistent in describing contraindications to metformin use. For example, in case of impaired renal function, the manufacturers package insert specified creatinine clearance (Crcl) of <60ml/ min as a contraindication versus < 30ml/ min in Australian Medical Handbook (AMH). Moreover, the guidelines employ undefined and confusing terms in describing metformin use. For example, almost all available guidelines contraindicate metformin use in congestive heart failure (CHF) patients without specifying the degree of heart failure as classified by the New York Heart Association (NYHA).17
Clearer guidelines for metformin use and contraindications are recommended. As an example, it would be more useful for prescribing practitioners to be provided with detailed dosage adjustment in certain subgroups, particularly in conditions such as renal impairment.
The aims of this study were to assess risks and benefits of metformin use in diabetics with various clinical backgrounds, and to determine the degree of lactic acidosis, if detected.