NDT Advance Access originally published online on April 3, 2008
Nephrology Dialysis Transplantation 2008 23(7):2436-2438; doi:10.1093/ndt/gfn152
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Metformin-associated lactic acidosis in type 2 diabetes mellitus: incidence and presentation in common clinical practice
Correspondence and offprint requests to: E-mail: jalmirall{at}cspt.esMetformin is an oral antihyperglycaemic agent used in the treatment of type 2 diabetes mellitus. In 1998, the results of the UK Prospective Diabetes Study [1] indicated that metformin treatment is associated with a reduction in total mortality compared to other antihyperglycaemic treatments. These and other results led to its progressive widespread use. In the recent ADA-EASD consensus on management of hyperglycaemia in type 2 diabetes, metformin plus lifestyle intervention is the initial recommended therapeutic step [2].
Metformin is considered to be contraindicated in many chronic hypoxaemic conditions that may be associated with lactic acidosis (LA), such as cardiovascular, renal, hepatic, pulmonary disease and advancing age. Nevertheless, this has been a controversial matter. In a recent Cochrane review [3], pooled data from 206 comparative trials and cohort studies revealed no cases of fatal and nonfatal LA in 47 846 patient-years of metformin use. Thus, the causal relationship between metformin use and LA has been questioned. Some authors have even stated that ‘metformin's contraindications should be contraindicated in people with type 2 diabetes’ [4].
In the past several years an increasing number of LA associated with metformin use has been appreciated. The aim of this brief report is to perform a clinical description of metformin-associated LA in our reference area, triggering medical conditions, possible contraindications and evolution. An epidaemiologic study is made in order to determine the incidence of LA and its relation with metformin administration.
A retrospective analysis of all cases defined by hospital discharge with a diagnosis of metabolic acidosis (International Classification of Diseases, ninth revision code), attended in the emergency department of our hospital during the period 2001–2005, was performed. This is a general hospital with a reference population area of 390 000 inhabitants. LA was accepted on the basis of an arterial blood sample with a pH <7.35 and circulating lactate values >5 mmol/l. Demographic information, clinical presentation and evolution, biochemical data and risk factors were obtained. During the same period, the metformin consumption in the general population was analysed (dose/1000 inhabitants/day: DHD) in our reference area, this information was obtained from the Pharmacology Department of Catalonian Health Institute (Serveis Centrals de l’ICS).
Out of 226 attended cases in which the diagnosis of metabolic acidosis was made, 21 were diagnosed of LA; 13 of them (5.7%) were related to metformin administration. Severe sepsis or septic shock was ruled out in all of them.
There were 10 women and 3 men, between 65 and 77 years. Main biochemical results at admission are shown in Table 1. The trigger factor was an acute gastrointestinal process with relevant dehydration in 85% of cases; 15% (two cases) had overt congestive heart failure. Interestingly, despite a clear worsening of their clinical condition, none of the patients had discontinued metformin treatment in the days preceding admission. All had renal insufficiency at different stages at admission. Five patients (39%) needed immediate renal replacement therapy, and four (31%) died a few hours after admission in spite of advanced medical support in a context of severe acidosis, profound hypotension and multiple organ failure.
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The analysis of clinical information obtained from medical charts before the episode of LA disclosed several possible contraindications for metformin administration: nine patients (70%) had pre-existing renal insufficiency (creatinine clearance <60 ml/min), five patients (38%) had congestive heart failure and four (31%) had more than one risk factor.
Case distribution throughout the years has been: period 2001: 1; 2002: 0; 2003: 2; 2004: 6; 2005: 4 cases. This tendency to increase runs in parallel with metformin DHD administered in the general population: 2001: 4.8; 2002: 6.6; 2003: 8.8; 2004: 10.8; 2005: 13.1 (Fig. 1). Incidences of metformin associated with LA during years 2004 and 2005 are 1.38 and 0.76/1000 patient-years.
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Comments
The clinical efficacy of metformin in the treatment of overweight type 2 diabetes mellitus patients is well established. It has been shown to reduce cardiovascular and total mortality rates compared with insulin or sulfonylurea use [1]. As with all pharmacological agents, there are limitations and contraindications to the use of metformin. Some side effects have been described, the most frequent being gastrointestinal, but the main concern remains over the possible risk of associated LA, a rare but serious side effect with a mortality of up to 50%.
The real incidence is not fully known. Population-based studies have estimated a rate of 0.02–0.09 cases of LA in metformin users per 1000 patient-years, but results vary.
In a recent systematic review study by Salpeter and co-authors from the Cochrane Library [3], pooled data from 206 comparative trials and cohort studies revealed no cases of fatal or nonfatal LA in 47 846 patient-years of metformin use. The authors concluded that treatment with metformin was not associated with an increased risk of LA.
Nevertheless, other studies have been more cautious in their appreciation of the security of metformin. Safety monitoring in Canada revealed 0.64 cases of LA per 1000 patient-years [5]. A population-based study from Scotland reported one case of LA among 1847 patients given metformin over 30 months, 25% of whom had contraindications. This implies an annual rate of LA of 0.22 per 1000 patient-years but 0.87 per 1000 patients when the drug is administered inappropriately [6]. These results are quite similar to those obtained in our present study.
These conflicting results may be due to several factors. Because LA is so uncommon, obtaining reliable data from controlled studies would require a large patient population studied over a longer period of time. Another reason could be biased data obtained from published trials, which could not reflect the real clinical situation when applied in normal clinical practice. Another confounding factor could be related to imprecision in admitted relative contraindications, in which terms such as ‘renal or hepatic insufficiency’ or ‘advanced age’ could be unclear.
Pharmacokinetic data suggest that metformin levels increase only when creatinine clearance is reduced to <60 ml/min. This aspect can be hypothetically controlled, but there is no prevision in cases with acute renal failure in the setting of severe haemodynamic compromise. In the cases described previously, as in our series, the antecedent of abdominal discomfort for some days and a diarrhoeic episode causing dehydration that precipitate the metabolic ‘disaster’ [7] are not uncommon.
The question is how to balance the benefits of metformin prescription with the potential exposition to the risk of LA. A reasonable approach is to recommend to patients that and/or relatives that if unexplained symptoms develop such as nausea or vomiting, abdominal pain, diarrhoea or other clinical impairment, metformin administration must be discontinued and prompt medical attention should be seeked. In the present series, none of the patients discontinued metformin administration before admission in spite of a clear worsening of their clinical condition.
Although no causal relation has been convincingly proved, circumstantial evidence shows that treatment with metformin may be linked to LA. In our series, the increase in metformin prescription has been associated with an increase in the number of LA diagnosis. Registered cases are higher than what can be expected under study conditions. Without questioning the benefits of metformin in reducing cardiovascular mortality, we wish to emphasize that there are some contraindications to its use, stressing the importance of renal clearance (instead of the creatinine level) and the possibility of an unpredictable acute renal impairment as a result of a dehydration episode.
It is important to be aware of this complication, identify people at risk (correct estimation of renal function), and inform and warn patients and/or relatives about symptoms and management as we observed that many patients had not been informed.
Conflict of interest statement. None declared.
1 Nephrology Service 2 Endocrinology Service Corporació Parc Taulí, Institut Universitari Parc Taulí (UAB) Spain
References
- UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS). Lancet (1998) 352:854–865.[CrossRef][Web of Science][Medline]
- Nathan DM, Buse JB, Davidson MB, et al. Management of hyperglycemia in Type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care (2006) 29:1963–1972.
[Free Full Text] - Salpeter S, Greyber E, Pasternak G, et al. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev (2006) CD002967.
- McCormack J, Johns K, Tildesley H. Metformin's contraindications should be contraindicated. CMAJ (2005) 173:502–504.
[Free Full Text] - Lucis OJ. The status of metformin in Canada. Can Med Assoc J (1983) 128:24–26.[Abstract]
- Emslie-Smith AM, Boyle DI, Evans JM, et al. Contraindications to metformin therapy in patients with Type 2 diabetes—a population-based study of adherence to prescribing guidelines. Diabet Med (2001) 18:483–488.[CrossRef][Web of Science][Medline]
- Brassoe R, Elkmann T, Hempel M, et al. Fulminant lactic acidosis in two patients with Type 2 diabetes treated with metformin. Diabet Med (2005) 22:1451–1453.[CrossRef][Web of Science][Medline]
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