Correspondence
Efficacy of Metformin in Non-Insulin-Dependent Diabetes Mellitus
N Engl J Med 1996; 334:269-270January 25, 1996
- Article
To the Editor:
After the completion of the studies reported by DeFronzo et al. (Aug. 31 issue),1 metformin was introduced into use in the United States. As of October 30, 1995, the Food and Drug Administration (FDA) Medwatch reporting program (1-800-FDA-1088) had received 10 reports of possible metformin-associated lactic acidosis. Of the three deaths attributed to lactic acidosis (Table 1Table 1
Clinical and Biochemical Data on Patients Whose Deaths Were Attributed to Metformin-Associated Lactic Acidosis.), the diagnosis was substantiated in only two. Even in these two patients, factors other than metformin probably contributed to the development of lactic acidosis. Of the seven nonfatal cases of lactic acidosis attributed to metformin therapy, the diagnosis was probably correct in only two. The diagnosis of lactic acidosis requires the measurement of blood pH and lactate.2,3 The value of reporting cases to the FDA is increased by including these values and information about any contributing conditions that may have been present.In considering whether to prescribe metformin, physicians should keep the following points in mind. Lactic acidosis occurs in nondiabetic3 as well as diabetic patients. When lactic acidosis is associated with metformin therapy, other conditions such as sepsis, hypoxia, heart failure, or renal insufficiency may be contributory or even causal. On the basis of an estimated 500,000 new patient prescriptions (information provided by Bristol-Myers Squibb), the finding of two cases of fatal lactic acidosis is consistent with data on fatal lactic acidosis in metformin-treated patients in Europe and on fatal hypoglycemia during sulfonylurea-drug therapy.4
Metformin is contraindicated in diabetic patients with impaired renal function and should not be given to patients with cardiac or hepatic dysfunction or during periods of hypoxia or poor tissue perfusion. Caution should also be exercised in patients with blood glucose concentrations of more than 300 mg per deciliter, because this degree of hyperglycemia often leads to impaired renal function as a result of volume depletion from polyuria. The increased risk of lactic acidosis militates against the use of metformin in these patients.
4 ReferencesJohn Gueriguian, M.D.
Lanh Green, R.Ph., M.P.H.
Robert I. Misbin, M.D.
Bruce Stadel, M.D.
G. Alexander Fleming, M.D.
Food and Drug Administration, Rockville, MD 208571
DeFronzo RA, Goodman AM, Multicenter Metformin Study Group
Full Text | Web of Science | Medline2
Misbin RI . Phenformin-associated lactic acidosis: pathogenesis and treatment. Ann Intern Med 1977;87:591-595
Web of Science | Medline3
Stacpoole PW ,Harman EM ,Curry SH ,Baumgartner TG ,Misbin RI . Treatment of lactic acidosis with dichloroacetate. N Engl J Med 1983;309:390-396
Full Text | Web of Science | Medline4
Berger W . Incidence of severe side effects during therapy with sulfonylureas and biguanides. Horm Metab Res Suppl 1985;15:111-115
Medline
To the Editor:
With respect to the article by DeFronzo et al., we are concerned about the risks of vitamin B12 deficiency in metformin-treated patients. The serum vitamin B12 concentrations fell by 22 percent in the metformin-treated patients in protocol 1 and by 29 percent in those in protocol 2, although no patient became anemic. Metformin is associated with malabsorption of vitamin B12.1 Potentially irreversible neurologic disease due to vitamin B12 deficiency can develop without anemia.2 Furthermore, vitamin B12 deficiency can lead to hyperhomocyst(e)inemia,2 which is associated with accelerated vascular disease.3 Since diabetic patients are at risk for both accelerated vascular disease and neuropathy, should not patients taking metformin receive supplemental vitamin B12?
3 ReferencesJ.C. Deutsch, M.D.
C.R. Santhosh-Kumar, M.D.
J.F. Kolhouse, M.D.
University of Colorado Health Sciences Center, Denver, CO 802621
Adams JF ,Clark JS ,Ireland JT ,Kesson CM ,Watson WS . Malabsorption of vitamin B12 and intrinsic factor secretion during biguanide therapy. Diabetologia 1983;24:16-18
CrossRef | Web of Science | Medline2
Lindenbaum J ,Healton EB ,Savage DG , et al. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med 1988;318:1720-1728
Full Text | Web of Science | Medline3
Selhub J ,Jacques PF ,Bostom AG , et al. Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis. N Engl J Med 1995;332:286-291
Full Text | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Because of concern about metformin-induced lactic acidosis, fasting plasma lactate concentrations were closely monitored during the two protocols. There were no significant changes from base line and no cases of lactic acidosis. This experience is similar to that reported in the worldwide literature, which has shown that lactic acidosis is very rare in diabetic patients treated with metformin.1-3
When lactic acidosis has been reported, it has almost always been associated with some severe underlying medical condition that itself can cause lactic acidosis. One or more of these conditions were present in the two patients described by Gueriguian et al., making it as reasonable to attribute the lactic acidosis to the underlying condition as to metformin. As they point out, physicians should take particular care not to prescribe metformin for patients with cardiac, pulmonary, or hepatic disease; renal disease (serum creatinine, >1.5 mg per deciliter), because the drug is excreted by the kidneys; or severe symptomatic hyperglycemia. Patients with severe symptomatic hyperglycemia should be treated with insulin to achieve glycemic control quickly. After several weeks of good glycemic control, a trial with metformin can be attempted.
Gueriguian et al. also point out the difficulty in establishing the diagnosis of lactic acidosis. In suspected cases of lactic acidosis, physicians should measure serum bicarbonate and electrolytes and blood pH and lactic acid. If the lactate concentration is elevated (>5 mmol per liter), the diagnosis of lactic acidosis is established and appropriate therapy for the underlying cause should be initiated. In anyone with suspected lactic acidosis who is taking metformin, the drug should be stopped until the diagnosis is confirmed or clearly excluded.
Deutsch et al. raise the possibility that neurologic dysfunction may occur in metformin-treated patients with subclinical vitamin B12 deficiency in the absence of anemia. It is unclear how often this might occur in the absence of evidence of overt vitamin B12 deficiency. However, physicians should be aware of this possibility; hemoglobin and serum vitamin B12 should be measured in any patient with unexplained neurologic symptoms, and a therapeutic trial of vitamin B12 should be considered. To date, only five cases of vitamin B12–deficiency anemia have been reported in the literature worldwide.
3 ReferencesRalph A. DeFronzo, M.D.
University of Texas Health Science Center, San Antonio, TX 78284Anita M. Goodman, M.D.
Lipha Pharmaceuticals, New York, NY 100191
Campbell IW . Metformin and the sulphonylureas: the comparative risk. Horm Metab Res Suppl 1985;15:105-111
Medline2
Bailey CJ . Biguanides and NIDDM. Diabetes Care 1992;15:755-772
CrossRef | Web of Science | Medline3
Wiholm BE ,Myrhed M . Metformin-associated lactic acidosis in Sweden 1977-1991. Eur J Clin Pharmacol 1993;44:589-591
CrossRef | Web of Science | Medline
- Citing Articles (3)
Citing Articles
1
S Halimi. (2006) Metformin: 50 years old, fit as a fiddle, and indispensable for its pivotal role in type 2 diabetes management. Diabetes & Metabolism 32:6, 555-556
CrossRef2
Alan J. Garber. 2004. Metformin and Other Biguanides: Pharmacology and Therapeutic Usage. .
CrossRef3
Irl B. Hirsch. (1997) Approach to the Patient with Diabetes Undergoing a Vascular or Interventional Procedure
. Journal of Vascular and Interventional Radiology 8:3, 329-336
CrossRef
