LETTERS TO THE EDITOR
Reply
Kirk N. Garratt, MDa
a Mayo Clinic and Foundation, Cardiovascular Diseases and Internal Medicine, 200 First Street SW, Rochester, Minnesota 55905, USA
We appreciate the comments made by Drs. Lin and Wright. The essence of their letter seems to be that clarification of the mechanisms whereby sulfonylurea drug use confers increased risk could prove helpful in determining our best course of patient care. We agree completely, but unfortunately available data are not yet sufficient.
A sensible, although unproven, mechanistic explanation for increased mortality during profound ischemia blames sulfonylurea interference with K+ATP channel function. This action, as demonstrated in many studies (1), impairs endogenous cardioprotective mechanisms and may enhance arrhythmogenesis. In our study (2), the cause of in-hospital mortality for sulfonylurea-treated patients was chiefly cardiogenic shock plus a few arrhythmic deaths. We sought a relation between sulfonylurea use and malignant arrhythmias, but none was found, suggesting that any such effect must be small relative to interference with other endogenous cardioprotective mechanisms. As noted in our report, however, mechanisms other than interference with K+ATP channel function could explain increased risk of death with sulfonylurea drug use.
Late all-cause and cardiac mortality rates were described in our report, and, as expected, these patients died chiefly of cardiovascular causes. Obviously, only hospital survivors were eligible for continued monitoring, but it does not follow, as suggested by Drs. Lin and Wright, that an early increased mortality risk would necessarily translate into lower late risk for these patients. Indeed, if the postulate regarding this class of drugs is correct, the survivors continuing on sulfonylurea drugs may have been at continued increased risk. However, it was not known how many survivors continued taking sulfonylurea drugs after hospital discharge.
As Drs. Lin and Wright point out, our report is consistent with a large body of indirect clinical evidence implicating sulfonylurea drugs with increased risk. Alternative hypoglycemic drugs are available, but existing data are not yet sufficient to make a blanket recommendation to switch patients from sulfonylurea drugs. Newer agents, such as the insulin-sensitizing thiazolidinediones (e.g., troglitazone) and the biguanide compounds (e.g., metformin), do not appear to have the deleterious cardiac properties of the sulfonylurea drugs, but may cause other troubles: troglitazone may cause significant hepatotoxicity and is not recommended as first-line therapy (3), and metformin may cause lethal lactic acidosis, especially in patients with renal insufficiency who are exposed to radiologic contrast agents (4). Furthermore, many patients will require combined drug therapy for optimal diabetic control (5).
More research is needed before a policy statement in this matter can be justified. In this regard, corroboration of our findings from larger data sets, data generated by several ongoing studies that tabulate diabetic drug therapies and especially prospective studies such as the planned Bypass Angioplasty Revascularization Investigation (BARI II) trial, will be of great importance.
We would be happy to support the work of Drs. Lin and Wright by providing information on our patients that might be of use in their meta-analysis.
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References
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- Brady PA, Terzic A. The sulfonylurea controversy: more questions from the heart. J Am Coll Cardiol. 1998;31:950–956[Abstract/Free Full Text]
- Garratt KN, Brady PA, Hassinger NL, Grill DE, Terzic A, Holmes DR Jr. Sulfonylurea drugs increase early mortality in patients with diabetes mellitus after direct angioplasty for acute myocardial infarction. J Am Coll Cardiol. 1999;33:119–124[Abstract/Free Full Text]
- Johnson MD, Campbell LK, Campbell RK. Troglitazone: review and assessment of its role in the treatment of patients with impaired glucose tolerance and diabetes mellitus. Ann Pharmacother. 1998;32:337–348[Abstract]
- Bailey CJ, Turner RC. Metformin. N Engl J Med. 1996;334:574–579[Free Full Text]
- U.K. Prospective Diabetes Study (UKPDS) GroupTurner RC, Cull CA, Frighi V, Holman RR. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). J Am Med Assoc. 1999;281:2005–2012[Abstract/Free Full Text]
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S. H. Simpson, S. R. Majumdar, R. T. Tsuyuki, D. T. Eurich, and J. A. Johnson
Dose-response relation between sulfonylurea drugs and mortality in type 2 diabetes mellitus: a population-based cohort study
Can. Med. Assoc. J.,
January 17, 2006;
174(2):
169 - 174.
[Abstract]
[Full Text]
[PDF]
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