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Diabetes Care 29:751-752, 2006
DOI: 10.2337/diacare.29.03.06.dc05-2259
© 2006 by the American Diabetes Association
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Letters: Comments and Responses

Metformin and Heart Failure: Innocent Until Proven Guilty

Response to Inzucchi

Sergio Muntoni, MD, PHD

1 From the Center for Metabolic Diseases and Atherosclerosis of Cagliari, The ME.DI.CO. Association, Cagliari, Italy

Address correspondence to Sergio Muntoni, MD, PhD, 29 Viale Merello, 09123 Cagliari, Italy. E-mail: sergiomuntoni{at}hotmail.com

The editorial by Inzucchi (1) in the October 2005 issue of Diabetes Care on the effects of metformin in type 2 diabetic patients with heart failure deals in a masterly manner with the choice of the most suitable treatment of this condition. Since both diabetic heart failure and mechanism of metformin action are not completely understood, it is difficult, in the author’s opinion, to find a convincing explanation of the benefit from the use of this drug. However, as the contracting heart gets most of its energy from nonesterified fatty acids (FFAs), and even does so more in the insulin-resistant state of diabetes, the author correctly states that a drug that enhances the uptake of the more metabolically efficient glucose instead of FFA may improve the function of the failing heart.

What the author is not aware of is that the mechanism of shift from one substrate to another has just been demonstrated for metformin and the other biguanides. In fact, dose-dependent inhibition of long-chain fatty acid oxidation in red muscle restores the glucose oxidation when depressed by concurrent oxidation of palmitic acid; hence, the proposed definition of biguanides as drugs of the Randle’s cycle (2,3).

Fischer et al. (4) describe increased content of glucose transporters GLUT1 and GLUT4 produced by metformin in heart cells.

Essop and Opie (5) stress the concept that high blood FFAs, especially in the presence of a hyperadrenergic state, can damage the ischemic myocardium and that agents that inhibit myocardial FFA oxidation should improve the work efficiency of the failing heart.

In conclusion, in my opinion there is good evidence that the beneficial effect of metformin in heart failure in type 2 diabetic patients rests on the same underlying mechanism shared by other well-known effects of the drug, i.e., increased utilization of glucose by red muscle and hindered gluconeogenesis in liver, as consequences of depressed fatty acid oxidation (2,3).

References

  1. Inzucchi SE: Metformin and heart failure: innocent until proven guilty (Editorial). Diabetes Care 28:2585–2587, 2005[Free Full Text]
  2. Muntoni S: Inhibition of fatty acid oxidation by biguanides: implications for metabolic physiopathology. Adv Lipid Res 12:311–377, 1974[Medline]
  3. Muntoni S: Metformin and fatty acids. Diabetes Care 22:179–180, 1999[Free Full Text]
  4. Fischer Y, Thomas J, Rosen P, Kammermeier H: Action of metformin on glucose transporter GLUT1 and GLUT4 in heart muscle cells from healthy and diabetic rats. Endocrinology 136:412–420, 1995[Abstract]
  5. Essop MF, Opie LH: Metabolic therapy for heart failure. Eur Heart J 25:1765–1769, 2004[Free Full Text]

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This Article
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