Original articleMetformin in patients with type 2 diabetes mellitus: reconsideration of traditional contraindications
Introduction
Metformin has been used as a glucose-lowering agent in type 2 diabetes mellitus since 1957. Nearly 40 years later, it was approved in the United States and rapidly gained wide acceptance [1], [2], [3]. A series of clinical studies on both sides of the Atlantic established the pivotal role of metformin as an effective glucose-lowering agent with some lipid-lowering [4] and blood pressure-lowering [5], [6] potential, especially in obese patients. The use of metformin is not associated with weight gain. Its main mechanisms of action are to suppress basal hepatic glucose output by the inhibition of hepatic glycogenolysis and probably also to improve peripheral insulin sensitivity [7], [8], [9], [10]. Metformin has been effectively used as a single drug as well as in combination with sulfonylurea preparations, insulin and, recently, also with repaglinide and thiazolidine diones [11], [12], [13], [14].
The most serious complication of metformin—lactic acidosis—is very rare; the estimated incidence is 0.03 cases per 1000 patient years [15], [16]. Yet, the possibility exists, and the use of metformin has thus far dictated strict adherence to the recommendations concerning the exclusion of patients with even preliminary renal impairment (serum creatinine≥130 μmol/l), evidence of liver damage, or the common clinical conditions associated with hypoxemia, congestive heart failure (CHF), and chronic obstructive pulmonary disease (COPD) [1], [17]. Editorials published recently have warned against flexibility in the application of contraindications [18]. On the other hand, reduced compliance with the recommendations was apparently not associated with a rise in the incidence of lactic acidosis [19], [20].
In order to evaluate the validity of the time honored, strict criteria for metformin use, we have prospectively followed a large series of patients who had initially been treated with metformin as part of their glucose-lowering regimen and who developed one or more of the contraindications to metformin. These patients were randomly assigned to either stop or continue metformin. A comparison between the relevant end points of the two groups may help to re-evaluate the contraindications to the use of metformin.
Section snippets
Subjects
The study comprised 471 patients with type 2 diabetes mellitus who were admitted to our hospital during the years 1995–1996, who had been treated with metformin, alone or in combination with other hypoglycemic agents, and who were found to have one or more contraindications to metformin according to accepted recommendations [17], [18]. Patients were included in the study if they were 40–75 years old, if diabetes mellitus had been diagnosed after age 40, if they had a body mass index of 24–40
Results
The baseline characteristics of the patients who stopped and those who continued metformin are outlined in Table 1. There were no differences in any of the baseline parameters between the two groups. The mean age was 64 and 65 years, the body mass index 28.4 and 28.7 kg/m2, respectively. The mean HbA1c was 8.6% in both groups and the serum creatinine 161 and 163 μmol/l, respectively. The mean and distribution of blood levels of lactic acid were also very similar in both groups (1.5±0.3 and
Discussion
This study demonstrates the relative safety of metformin in a fairly large group of patients with formal contraindications to this agent. Discontinuation of metformin resulted in weight gain, worsening of glucose control as evidenced by a rise in HbA1c, and a modest rise in LDL compared to those patients who continued the drug (Table 4). These disadvantages were balanced by no advantage. Patients with coronary artery disease including those defined as severe or unstable angina pectoris and
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