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(Circulation. 1996;94:2297-2301.)
© 1996 American Heart Association, Inc.
Articles |
Sulfonylurea KATP Blockade in Type II Diabetes and Preconditioning in Cardiovascular Disease
Time for Reconsideration
the Division of Cardiology, Department of Medicine, Department of Veterans Affairs Medical Center, San Diego, and University of California, San Diego, School of Medicine, La Jolla (R.L.E.), and the Division of Cardiology, Hatter Institute, University College London Medical School, UK (D.M.Y.).
Correspondence to Robert L. Engler, MD, Professor of Medicine, UCSD School of Medicine, and Associate Chief of Staff/Research, Department of Veterans Affairs Medical Center, 3350 La Jolla Village Dr, San Diego, CA 92161.
Key Words: diabetes mellitus • ischemia • sulfonylurea
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Introduction |
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In the early 1970s, the UGDP assessed the efficacy of oral hypoglycemic treatment in comparison with insulin and diet alone in the prevention of vascular complications. The surprising finding was the appearance of a significantly higher cardiovascular mortality in patients on oral hypoglycemic agents (sulfonylureas) compared with those on diet alone. Nonetheless, these agents are used extensively because, one suspects, of a lack of a plausible mechanism for the UGDP study results. In 1983, the KATP was discovered and was demonstrated to be sensitive to the sulfonylurea class of drugs; ie, these agents block the opening of this channel. In 1986, the phenomenon of ischemic preconditioning was discovered, which demonstrated the unique ability of a sublethal period of ischemia (angina) to protect the heart from a subsequent lethal ischemic insult. In the 1990s, it became clear that one of the probable mechanisms through which this preconditioning phenomenon worked was via the opening of the KATP. New discoveries often shed light on old mysteries, and this may be the case with the sulfonylurea class of oral hypoglycemic agents. Therefore, it is timely to rethink the seemingly paradoxical result of the UGDP study.
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Oral Hypoglycemics: The Sulfonylureas |
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In 1942, Janbon et al1 found that sulfonamide derivatives used to treat typhoid fever caused hypoglycemia, which led to the development of a new treatment for NIDDM. Diabetes is a significant problem worldwide. For example, six million people in the United States have NIDDM (85% of all diabetics) and are eligible for treatment with these drugs. The
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