CLINICAL RESEARCH: CORONARY ARTERY DISEASE: EDITORIAL COMMENT
The sulfonylurea controversy
Much ado about nothing or cause for concern?*
Peter A. Brady, MD, FRCP, FACC ,* and
Aleksandar Jovanovic, MD, PhD
From the Mayo Clinic, Rochester, MN, USA
Tayside Institute of Child Health, Ninewells hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom
* Reprint requests and correspondence: Dr. Peter A. Brady, Division of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA.
brady.peter{at}mayo.edu
The dictum "Primum non nocere" remains axiomatic of modern clinical practice, yet adverse drug reactions are accepted as a consequence of drug use despite estimates that morbidity and mortality resulting from adverse reactions to drugs is not insignificant (1). At the bedside, an accurate assessment of a potential adverse drug reaction relies on a precise diagnosis that in many cases is difficult or impossible because of several competing risk factors, especially in patients with complex and/or chronic illness. Thus, a diagnosis of an adverse drug reaction is often presumptive. In cardiology, one example of this problem is in determining whether sulfonylurea drugs (SUDs), used in the treatment of patients with type 2 diabetes mellitus (T2DM), may have harmful cardiovascular effects, especially in patients with coronary artery disease (CAD) (i.e., two complex and chronic diseases in association with a poorly defined drug effect). This is an important issue because T2DM is the most common chronic disease affecting Western populations, with an increasing incidence, and is associated with a high prevalence of CAD (2–4). Moreover, hyperglycemia per se is an independent risk factor in patients presenting with acute coronary syndromes (5,6). Therefore, if the use of SUDs to control hyperglycemia causes only a fractional increase in absolute risk this would translate into a marked increase in cardiovascular morbidity and mortality when spread across such a large number of patients.
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The sulfonylurea controversy
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Uncertainty regarding the safety of SUDs arose more than 30 years ago after publication of the University Group Diabetes Program (UGDP) trial (7), which randomized patients with T2DM to a sulfonylurea agent (phenformin or tolbutamide), fixed- and variable-dose insulin, and placebo, and found an increase in mortality as a result of cardiovascular causes among patients taking SUD-type medication compared with patients treated with insulin or placebo (in whom rates were similar).
Within a decade, advances in single-cell patch-clamp electrophysiologic techniques led to the discovery of a metabolism-sensitive channel that was inhibited from opening by high levels of intracellular adenosine triphosphate (ATP) (8). The channel, known as the ATP-sensitive K+ (KATP) channel, also is inhibited from opening by SUDs. In the pancreas, this is the mechanism through which SUDs induce the release of insulin (9). However, the KATP channel also plays an essential role in myocardial resistance towards metabolic stress (9–16). By also preventing opening of myocardial KATP channels, SUDs could increase the consequences of ischemia in the heart. Several lines of evidence, including many clinical studies, have suggested this mechanism as a basis for the UGDP findings (9).
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Opening of KATP channels underlies ST-segment elevation during ischemia
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Beyond a role in protecting the myocardium from ischemic insult, the efflux of K+ through the opening of KATP channels also is thought to underlie elevation of the ST-segment of the surface electrocardiogram (ECG) as a consequence of myocardial injury. Evidence for this initially came from experiments using epicardial recordings in open-chest dogs (17) and in humans during coronary angioplasty (18). More definitively, in an elegant series of experiments, Suzuki et al. (19) "knocked-out" the gene that encodes for Kir6.2, the pore-forming subunit of sarcolemmal KATP (sKATP, through which K+ cross the lipophilic cell membrane), in mouse cardiomyocytes and demonstrated that homozygous knockout (resulting in functional absence of sKATP channels) was associated with the loss of manifest ST-segment elevation, in response to repeated coronary ligation, readily apparent in wild-type (control) mice in which the pore-forming region of the KATP channel was intact. Of note, pretreatment of control mice with glibenclamide (a SUD) resulted in near-identical attenuation of the magnitude of ST-segment elevation to that observed in knockout mice.
Currently, in this issue of the Journal, Huizar et al. (20) provide, for the first time, evidence that SUDs may attenuate the magnitude of ST-segment elevation in patients presenting with acute myocardial infarction (AMI), leading to less frequent use of thrombolytic therapy. Because precise recognition of ST-segment elevation is central to accurate and efficient triage of patients with chest pain syndromes, any reduction in its magnitude, for a given degree of ischemia, limits the power of the ECG as a diagnostic tool. If proven, the findings of Huizar et al. (20) are important and should be cause for concern because, whether because of delayed or misdiagnosis, diabetic patients admitted to MetroWest Medical Center while on SUDs were much less likely to receive thrombolytic therapy compared with diabetics not taking SUDs (26% vs. 47%) (20).
The study by Huizar et al. (20) does, however, suffer from several limitations, many of which are acknowledged. First, it is small and retrospective. Second, all data were derived from chart review with the assumption that patients assigned to the SUD group had taken the drug close enough to admission, when the index ECG was performed, to have any measurable effect (drug levels were not drawn). Third, on the basis of demographic data presented in Table 1 of Huizar et al. (20), the control group is far more heterogeneous when compared with the study group, especially in terms of gender distribution (see the following text): more than one-half the patients were on no therapy or controlled with diet alone whereas the remainder were mostly taking insulin (presumably because they were not adequately controlled on oral agents or had type 1 [insulin-dependent] diabetes). Such differences are important because diabetes mellitus is a complex disease and not merely a disorder of elevated blood sugar. As a consequence, intrinsic differences between the groups are difficult to adjust for (even in much larger studies) and thus limit meaningful comparison despite broadly similar demographics, blood glucose, and glycosylated Hb levels at the time of admission. Fourth, close to 40% of patients initially eligible were excluded from further analysis. However, all were due to conditions known to distort the surface ECG, in particular the ST/T portion (such as bundle branch block, fully paced rhythm, left ventricular hypertrophy with "strain pattern," and digoxin therapy), making ECG interpretation in any case difficult or impossible and, therefore, are reasonable. It would, however, have been interesting to know whether the use of more sensitive markers of myocardial injury, such as cardiac troponins, or comparison of serial ECG recordings, as is common in clinical practice, could have impacted on the low rate of reperfusion therapy administered to study group patients. Finally, differences in the magnitude of ST-segment elevation in the control and study groups, although statistically significant, are, at least in clinical terms, small (1.1 ± 1.0 mm vs. 2.1 ± 2.7 mm) with a considerable overlap, making it difficult to see how this alone could account for the much less frequent use of thrombolysis in patients treated with SUDs.
To further analyze and compare each group, patients were arbitrarily grouped according to peak creatine phosphokinase (CPK) (CPK <500, 500 to 1,000, and >1,000 mg/dl) levels. When stratified in this way, differences in the number of nondiagnostic ST-segment elevations were significant only in those patients who had moderate infarcts (CPK 500 to 1,000 mg/dl; p = 0.04). This observation, however, was based on data from only 16 patients (7 in the SUD group and 9 in the control group). No differences were found in the number of nondiagnostic ECGs in patients with small infarcts (CPK <500 mg/dl) or large infarcts (CPK >1,000 mg/dl). Leaving aside the poor specificity of CPK as an index of infarct size, looked at another way, 80% of patients in the SUD group had a peak CPK <1,000 mg/dl (mostly in the range of <500 mg/dl) compared with 58% of patients in the control group. Moreover, patients not on SUDs were more than twice as likely to suffer a large infarct (CPK >1,000 mg/dl) compared with patients on SUDs (41% vs. 20%). Although the authors offer their own interpretation, our view is that these data, at best, contradict the notion that SUDs are harmful but more likely simply expose the pitfalls in drawing conclusions using data derived from "soft" end points in small groups of patients.
The preponderance of females in the study group (52% vs. 25%) also deserves comment. Recently, in animal studies it has been reported that the density of sKATP channels is significantly higher in females and that this gender difference declines with ageing (21,22). If this is also the case in humans, it could, at least in part, account for the greater attenuation of the ST-segment observed in the SUD group. One intriguing possibility is whether differences in the density of sKATP might play some part in gender differences in regards to outcome after AMI.
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Outcomes in T2DM: impact of SUDs?
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Therefore, given the hypothesis that SUD may abolish important cardioprotective mechanisms as well as decrease the magnitude of ST-segment elevation leading to less frequent use of thrombolysis, especially in a group of patients known to benefit from reperfusion therapy (23,24), it is perhaps logical to assume that SUD use would be associated with worse outcome, as was observed in the UGDP trial (7). For the most part, however, available literature does not bear this out. For example, the United Kingdom Prospective Diabetes Study Group (UKPDS) followed-up 3,867 newly diagnosed patients with T2DM randomly assigned to intensive treatment (with a SUD or insulin) or conventional treatment (25). Over more than 10 years, the use of SUDs was not associated with increased mortality (a caveat is all patients enrolled in UKPDS were <65 years of age [median age 54 years] and none had a history of cardiac disease). Similarly, in a study of patients discharged after AMI, the use of a SUD was not associated with increased mortality, although most underwent complete revascularization before dismissal (26). Several other clinical studies have reported similar findings (9).
In contrast, Garratt et al. (27) reported that SUDs did adversely affect outcome among diabetics undergoing direct angioplasty in the setting of AMI (27). In that study, the risk of death was found to be 2.77 times higher in the diabetics taking SUDs, and SUDs were independently predictive of worse outcome (odds ratio 2.53, 95% confidence interval 1.13 to 5.66). Indeed, the impact of SUD use in that study was similar to an ejection fraction <30% or the presence of congestive heart failure at admission. However, in all patients in whom revascularization was successful, long-term outcome was not affected by SUD use (27). One explanation for these findings is that KATP channel activation also protects against microvascular injury, a cause of the "no-reflow" phenomenon (28). Therefore, exacerbation of the no-reflow phenomenon by SUDs during coronary interventions could contribute to worse outcome.
Based on these, as well as other data (9), the cardiovascular consequences of SUDs seem paradoxical. However, such a dual action of SUD is consistent with several lines of evidence that suggest that the efficacy with which SUDs inhibit KATP channels is altered by the extent of cellular hypoxia (29–31). Putting this in clinical terms, the consequence of SUD use appears to be determined in large part by the presence or absence of myocardial ischemia.
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Optimal management of T2DM, CAD, and SUDs in 2003?
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Using this model, whereby the harmful cardiovascular effects of SUDs relate to the presence or absence of myocardial ischemia, together with the findings of Huizar et al. (20), what is then the most appropriate management of diabetic patients who present with suspected acute coronary syndrome while taking SUDs? Unfortunately, a definitive answer to this question is not yet possible, especially in light of the fact that the issues surrounding the management of the diabetic patient are complex and often controversial (24). Clearly, given the potential for SUDs to reduce the sensitivity of the ECG, as reported by Huizar et al (20), increased awareness, along with greater vigilance when assessing diabetic patients, is important. In regards to controlling hyperglycemia, our view, in the spirit of "first do no harm" and until more definitive data are available, is that SUDs should immediately be discontinued and insulin infusion substituted where necessary. This may also have beneficial effects beyond stopping the SUDs (24,32). Subsequently, after myocardial ischemia has been ruled out, or treated, the SUDs can safely be restarted. Such an approach is safe, simple, and inexpensive.
In response to the question, "the sulfonylurea controversy: much ado about nothing or cause for concern?," our view is that this important issue has yet to be satisfactorily resolved. Until then, and in light of the potential for harm, the cardiovascular effects of SUDs should remain a cause for concern to cardiologists as well as to other physicians caring for patients with T2DM and CAD. The study by Huizar et al. (20) surely adds to the debate, as well as highlighting the urgent need for adequately powered randomized trials, in hopes of putting to rest more than a quarter century of uncertainty regarding the safe use of SUDs (9).
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
|
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1. Brown SDJ, Landry FJ. Recognizing, reporting, and reducing adverse drug reactions. South Med J. 2001;94:370–373[Medline]
2. Harris MI, Hadden WC, Knowler WC, Bennett PH. Prevalence of diabetes and impaired glucose tolerance and plasma glucose levels in U.S. population aged 20 to 74 years. Diabetes. 1987;36:523–554
3. Wingard DL, Barrett-Connors E. Heart Disease and Diabetes. 2nd edition. Bethesda, MD: National Institutes of Health; 1995.
4. National Diabetes Information Clearing House. Washington, DC: NIH Publications 1999:99–3926
5. Wahab NN, Cowden EA, Pearce NJ, Gardner MJ, Merry H, Cox JL. Is blood glucose an independent predictor of mortality in acute myocardial infarction in the thrombolytic era? J Am Coll Cardiol. 2002;40:1748–1754[Abstract/Free Full Text]
6. Malmberg K, Norhammar A, Wedel H, Ryden L. Glycometabolic state at admission: important risk marker of mortality in conventionally treated patients with diabetes mellitus and acute myocardial infarction: long-term results from the Diabetes and Insulin-Glucose infusion in Acute Myocardial Infarction (DIGAMI) study. Circulation. 1999;99:2626–2632[Abstract/Free Full Text]
7. Klimt CR, Knatterud GL, Meinert CL, Prout TE. A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes (UGDP). Diabetes. 1970;19:747–830
8. Noma A. ATP-regulated K+ channel in cardiac muscle. Nature. 1983;305:147–148[CrossRef][Medline]
9. Brady PA, Terzic A. The sulfonylurea controversy: more questions from the heart. J Am Coll Cardiol. 1998;31:950–956[Abstract/Free Full Text]
10. Brady PA, Zhang S, Lopez JR, Jovanovic A, Alekseev AE, Terzic A. Dual effect of glyburide, an antagonist of KATP channels, on metabolic inhibition-induced Ca2+ loading in cardiomyocytes. Eur J Pharmacol. 1996;308:343–349[CrossRef][Medline]
11. Jovanovic A, Jovanovic S, Lorenz E, Terzic A. Recombinant cardiac ATP-sensitive K+ channel subunits confer resistance towards chemical hypoxia-reoxygenation injury. Circulation. 1998;98:1548–1555[Abstract/Free Full Text]
12. Jovanovic S, Jovanovic A. Pinacidil prevents membrane depolarisation and intracellular Ca2+ loading in single cardiomyocytes exposed to metabolic stress. Int J Mol Med. 2001;7:639–643[Medline]
13. Carrasco AJ, Dzeja PP, Alekseev AE, et al. Adenylate kinase phosphotransfer communicates cellular energetic signals to ATP-sensitive potassium channels. Proc Natl Acad Sci USA. 2001;98:7623–7628[Abstract/Free Full Text]
14. Crawford RM, Ranki HJ, Botting CH, Budas GR, Jovanovic A. Creatine kinase is physically associated with the cardiac ATP-sensitive K+ channel in vivo. FASEB J. 2002;16:102–104[Abstract/Free Full Text]
15. Crawford RM, Budas GR, Jovanovic S, et al. M-LDH serves as a sarcolemmal KATP channel subunit essential for cell protection against ischemia. EMBO J. 2002;21:3936–3948[CrossRef][Medline]
16. Zingman LV, Hodgson DM, Bast PH, et al. Kir6.2 is required for adaptation to stress. Proc Natl Acad Sci USA. 2002;99:13278–13283[Abstract/Free Full Text]
17. Kubota I, Yamaki M, Shibata T, Ikeno E, Hosoya Y, Tomoike H. Role of ATP-sensitive K+ channel on ECG ST-segment elevation during a bout of myocardial ischemia. A study on epicardial mapping in dogs. Circulation. 1993;88:1845–1851[Abstract/Free Full Text]
18. Tomai F, Crea F, Gaspardone A, et al. Ischemic preconditioning during coronary angioplasty is prevented by glibenclamide, a selective ATP-sensitive K+ channel blocker. Circulation. 1994;90:700–705[Abstract/Free Full Text]
19. Suzuki M, Sasaki N, Miki T, et al. Role of sarcolemmal KATP channels in cardioprotection against ischemia/reperfusion injury in mice. J Clin Invest. 2002;109:509–516[CrossRef][Medline]
20. Huizar JF, Gonzalez LA, Alderman J, Smith HS. Sulfonylureas attenuate electrocardiographic ST-segment elevation during an acute myocardial infarction in diabetics. J Am Coll Cardiol 2003;42:1017–21
21. Ranki HJ, Budas GR, Crawford RM, Jovanovic A. Gender-specific difference in cardiac ATP-sensitive K+ channels. J Am Coll Cardiol. 2001;38:906–915[Abstract/Free Full Text]
22. Ranki HJ, Crawford RM, Budas GR, Jovanovic A. Ageing is associated with decrease in number of sarcolemmal ATP-sensitive K+ channels in a gender-dependent manner. Mech Ageing Dev. 2002;123:695–705[CrossRef][Medline]
23. Mak KH, Moliterno DJ, Granger CB, et al. Influence of diabetes mellitus on clinical outcome in the thrombolytic era of acute myocardial infarction. GUSTO-I Investigators. Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries. J Am Coll Cardiol. 1997;30:171–179[Abstract]
24. Mak KH, Topol EJ. Emerging concepts in the management of acute myocardial infarction in patients with diabetes mellitus. J Am Coll Cardiol. 2000;35:563–568[Abstract/Free Full Text]
25. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837–853[CrossRef][Medline]
26. Brady PA, Al-Suwaidi J, Kopecky SL, Terzic A. Sulfonylureas and mortality in diabetic patients after myocardial infarction. Circulation. 1998;97:709–710[Free Full Text]
27. Garratt KN, Brady PA, Hassinger NL, Grill DE, Terzic A, Holmes DRJ. 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]
28. Genda S, Miura T, Miki T, Ichikawa Y, Shimamoto K. KATP channel opening is an endogenous mechanism of protection against the no-reflow phenomenon but its function is compromised by hypercholesterolemia. J Am Coll Cardiol. 2002;40:1339–1346[Abstract/Free Full Text]
29. Terzic A, Kurachi Y. Actin microfilament disrupters enhance KATP channel opening in patches from guinea-pig cardiomyocytes. J Physiol (Lond). 1996;492:395–404[Abstract/Free Full Text]
30. Brady PA, Alekseev AE, Terzic A. Operative condition-dependent response of cardiac ATP-sensitive K+ channels towards sulfonylureas. Circ Res. 1998;82:272–278[Abstract/Free Full Text]
31. Jovanovic S, Jovanovic A. Diadenosine tetraphosphate-gating of cardiac KATP channels requires intact actin cytoskeleton. Naunyn Schmiedebergs Arch Pharmacol. 2001;364:276–280[CrossRef][Medline]
32. Fath-Ordoubadi F, Keatt KJ. Glucose-insulin-potassium therapy for treatment of acute myocardial infarction. An overview of randomized placebo-controlled trials. Circulation. 1997;96:1152–1156[Abstract/Free Full Text]
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The sulfonylurea controversy
Opening of KATP channels...