Original article
Metformin in patients with type 2 diabetes mellitus: reconsideration of traditional contraindications

https://doi.org/10.1016/S0953-6205(02)00131-0Get rights and content

Abstract

Background: The strict limiting criteria for the use of metformin in diabetes mellitus stem largely from reports, in the 1970s, of mortality and lactic acidosis associated with phenformin. Data about metformin are less clear and are based mainly on case reports. The aim of this study was to evaluate the safety of continued use of metformin in patients with contraindications to this agent. Patients: Some 393 patients with type 2 diabetes mellitus (serum creatinine 130–220 μmol/l) were studied. Among them were 266 patients with coronary heart disease (CHD), 94 with congestive heart failure (CHF), and 91 with chronic obstructive pulmonary disease (COPD), all of whom had been treated with metformin. The patients were randomized to either continue or to stop metformin and were then followed for 4 years. Results: Analysis was by intention-to-treat. The patients who stopped taking metformin showed a rise in body mass index and in hemoglobin A1c significantly greater than those who continued the drug. There were no cases of lactic acidosis. Lactic acid values did not differ in the two groups and correlated only with serum creatinine and body mass index. Microvascular diabetic complications, cardiovascular events, and cardiovascular and total mortality were identical in the two groups. Conclusions: Diabetic patients who are treated with metformin and who tolerate the drug well may continue taking it, even when mild renal impairment develops, possibly up to serum creatinine levels of 220 μmol/l. There is also no apparent reason why patients with CHD, CHF, and COPD should discontinue metformin.

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

References (29)

  • M. Stumvoll et al.

    Metabolic effects of metformin in non-insulin-dependent diabetes mellitus

    N Engl J Med

    (1995)
  • N.F. Wiernsperger

    Preclinical pharmacology of biguanides

    Handbook Exp Pharmacol

    (1996)
  • R.A. DeFronzo et al.

    Mechanism of metformin action in obese and lean noninsulin-dependent diabetic subjects. The Multicenter Metformin Study group

    J Clin Endocrinol Metab

    (1991)
  • V. Trischitta et al.

    Efficacy of combined treatments in NIDDM patients with secondary failure to sulphonylureas. Is it predictable?

    J Endocrinol Invest

    (1998)
  • Cited by (129)

    • Toxicity of Metformin and Hypoglycemic Therapies

      2020, Advances in Chronic Kidney Disease
    View all citing articles on Scopus
    View full text