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(Circulation. 1996;94:2297-2301.)
© 1996 American Heart Association, Inc.

Articles

Sulfonylurea K_ATP Blockade in Type II Diabetes and Preconditioning in Cardiovascular Disease

Time for Reconsideration

Robert L. Engler, MD; Derek M. Yellon, PhD, DSc, MRCP (Hon), FESC

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

	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 K_ATP 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 K_ATP. 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.

	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 National Disease and Therapeutic Index estimates that 54% of physician visits by these patients included a prescription for oral hypoglycemic agents and that in 1994 there were 2.5 million patient-years of treatment, accounting for $500 million in sales in the United States alone. Recent insight into the cardiovascular effects of these drugs raises important questions about potentially harmful or fatal effects.

	The Mystery

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The UGDP was a 12-center prospective study to assess the efficacy of oral hypoglycemic treatment in comparison with insulin and diet alone in the prevention of vascular complications of diabetes.² Of the five main sulfonylurea-class agents currently marketed (glyburide, chlorpropamide, glipizide, tolbutamide, and tolazamide), only tolbutamide was used. The results of this study have been very controversial.^{3 4 5 6} The study found that patients treated for 5 to 8 years with tolbutamide had an increased incidence of cardiovascular death compared with those treated with diet alone, and the study was terminated by the monitoring committee. At the study termination, the total mortality curves for tolbutamide and placebo were steadily diverging, although they were not different at the P=.05 level, and it would have been unethical to continue for significance on this secondary end point. The conclusions of the UGDP study were that the combination of diet and tolbutamide was no more effective than diet alone in prolonging life and that diet and tolbutamide may be less effective than diet alone with respect to cardiovascular mortality. The premature termination of the trial may have precluded a finding of increased total mortality with tolbutamide. The subsequent publication of several retrospective trials showed either statistical significance or trends toward increased mortality from cardiovascular disease in patients treated with other sulfonylurea drugs.^{7 8 9} Currently, the package insert on all sulfonylurea drugs carries the warning of increased risk of cardiovascular mortality.

The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the UGDP . . . the use of tolbutamide was discontinued based on the increase in cardiovascular mortality . . . . Although only one drug in the sulfonylurea class (tolbutamide) was included in the study, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.

	Antidiabetic Mechanisms

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Sulfonamides and sulfonylurea drugs as a class inhibit potassium efflux through the K_ATP membrane channel.¹⁰ While regulation of this K⁺ channel is complex, the pertinent aspect for this discussion is activation by low ATP and inhibition by high ATP levels. Opening of the K_ATP hyperpolarizes the cell. Inhibition of K_ATP channels causes membrane depolarization and an influx of calcium via voltage-dependent calcium channels on the ß-cell membrane. Calcium bound to calmodulin acts as the second messenger that signals exocytotic insulin release in the pancreatic ß-cells.¹⁰ Theoretically, glucose also indirectly inhibits these channels by increasing ATP, and on glucose deprivation the channels are activated by decreased concentrations of ATP.

Sulfonylurea drugs have additional experimental actions on glucose metabolism. These peripheral insulinlike actions, such as decreasing phosphorylase A activity and increasing fructose-2,6-bisphosphate,¹¹ however, occur at concentrations not achieved therapeutically; thus, sulfonylurea drugs have no effect in type I diabetic patients.

A third insulinlike effect of sulfonylureas is illustrated by glimepiride, which causes a time- and concentration-dependent release of glycophosphatidyl inositol–anchored membrane proteins such as ecto-5'-nucleotidase, lipoprotein lipase, and a 62-kD cAMP-binding protein.¹² These membrane-anchored proteins are converted from the amphophilic protein form to a hydrophilic version with the inositol attached. Cleavage is by a PI/PLC. Insulin also has the effect of reducing or cleaving these membrane proteins, so both insulin and sulfonylureas may act through activation of a PI/PLC. This effect of glyburide occurs in the upper therapeutic range.

The long-term effects of sulfonylurea drugs in controlling blood glucose are complex, because insulin levels return to baseline after several months but at reduced glucose levels, so insulin levels may in fact be under sulfonylurea stimulation.¹³ Thus, the main antidiabetic action of sulfonylureas is hormone release, and peripheral facilitation of insulin action is not achieved. However, cleavage of glycophosphatidyl inositol–anchored proteins may occur at therapeutic levels in humans.

Preliminary studies have suggested that sulfonylurea agents have other peripheral effects that could affect cardiovascular disease. They may favorably increase tissue plasminogen activator production by endothelial cells, inhibit platelet function, and effect net K⁺ balance in the kidney.^{14 15} Mechanisms of these effects are most likely complex and mediated indirectly through ATP-binding cassette membrane proteins.

The recent discovery that the sulfonylurea receptor is a member of the ATP-binding cassette (ABC) gene family homologous to the CFTR and the multidrug-resistance gene (MDR) raises an additional possible mechanism of action.¹⁶ Since glibenclamide also inhibits CFTR function, it could alter the effects of ischemia on intracellular chloride, sodium, and pH and thus affect viability and arrhythmias by more than one mechanism. Furthermore, it is not clear whether glibenclamide inhibits K_ATP by direct or indirect effects.^{16 17 18} These several effects may explain the observation that sulfonylurea agents are less potent during ischemia¹⁴ and may explain the complex and varied nature of the antiarrhythmic effects of this class of drugs (see below).

	New Discoveries: A Possible Mechanism

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Recent experimental studies in models of myocardial infarction examining the phenomenon of ischemic preconditioning suggest a possible mechanism whereby sulfonylurea drugs might lead to increased mortality. Preconditioning refers to the observation that a brief period of ischemia may render less severe a subsequent, more prolonged episode.¹⁹ For example, a preconditioning episode of 5 minutes of ischemia that causes no cell death followed by reperfusion reduces infarction during a subsequent 30-minute "test" ischemia/reperfusion. Preconditioning has been observed to reduce several types of injury: (1) myocardial infarct size in ischemic and reperfused muscle, (2) myocardial stunning, and (3) arrhythmias.^{20 21 22} Preconditioning occurs in every animal species that has been tested. The protection from ischemic cell death is the most powerful of any adjunct to reperfusion known to date and is sustained after prolonged reperfusion.²¹ For example, in the rabbit model, one preconditioning episode can decrease infarct size during a subsequent test infarction from 40% to 8% of the area at risk.²⁰ Changes in hemodynamics or collateral blood flow do not account for the reduction in infarct size. A key mechanism of preconditioning is thought to involve the release of adenosine formed from net ATP utilization during the preconditioning episode of ischemia. Adenosine stimulation of A₁ or perhaps A₃ adenosine receptors appears to be linked to protein kinase C in most species, which by phosphorylation of unknown targets provides reduction in infarct size during a subsequent test ischemia.^{23 24} Experimentally, stimulation of muscarinic receptors, bradykinin, and catecholamines can mimic preconditioning. Linkage between these receptors and protein kinase C appears to involve, at least in some species, the K_ATP.²⁵ K_ATP channels are also present in vascular smooth muscle cells and ventricular myocytes, and these channels are coupled through G protein to adenosine A₁ receptors.^{26 27 28} Inhibiting these channels inhibits vasodilation in response to hypoxia or ischemia and blocks preconditioning of myocytes. Preconditioning also involves increasing ecto-5'-nucleotidase activity.²⁹ The ecto-5'-nucleotidase enzyme in cardiomyocytes is partially responsible for adenosine production during myocardial ischemia,^{29 30 31} and the reduction in infarct size during the test ischemia appears to be dependent on this adenosine release.³²

Sulfonylurea drugs have two specific actions in this regard. First and foremost, they inhibit the K_ATP. Second, they might activate cleavage of phosphatidyl inositol–linked membrane proteins such as ecto-5'-nucleotidase by activation of a PI/PLC at therapeutic concentrations, thus lowering effective adenosine concentrations near the adenosine receptor.¹² The potential importance of altering ecto-5'-nucleotidase activity in mediating preconditioning has been shown,^{29 33} but the role of glibenclamide in altering ecto-5'-nucleotidase during preconditioning is unclear.³⁴ Glibenclamide has been observed to block ischemic and pharmacological preconditioning in a number of species and tissues, including human cardiac muscle.^{25 35 36 37 38} Thus, augmenting adenosine reduces ischemic injury, and sulfonylureas reduce ecto-5'-nucleotidase activity, reduce the adenosine signal transduction (inhibit K_ATP), prevent preconditioning, and thereby could worsen the impact of acute myocardial ischemia or infarction in humans.^{31 39} Paradoxically, second-generation (glibenclamide, glipizide) sulfonylurea drugs have antiarrhythmic effects during experimental acute ischemia, but tolbutamide does not.^{40 41 42 43 44 45} The antifibrillatory effects had been linked to reduced K⁺ loss³⁸ in some but not all models.⁴⁶ Effects on refractory period, action potential duration, and potassium leak inhomogeneity may all be important mechanisms of reduced arrhythmias.⁴⁷ The finding that glibenclamide blocks the CFTR may be important in its antiarrhythmic actions, because this channel regulator is also expressed in cardiomyocytes.¹⁶ Glibenclamide was found to have antiarrhythmic effects in one double-blind, placebo-controlled crossover trial in diabetic patients.⁴⁸

Thus, experimental results indicate that K_ATPs in ventricular myocytes are activated during ischemia by falling ATP levels and adenosine receptor stimulation. Channel activation results in preconditioning of the myocardium for a subsequent ischemic event and shortens the ventricular action potential by inhibiting depolarization during ischemia, which decreases energy utilization. Activation of K_ATP on vascular smooth muscle contributes to vasodilation. Sulfonylurea drugs experimentally prevent preconditioning, a highly effective mechanism of protection from lethal ischemic injury, and reduce reactive hyperemia and the vasodilator response to ischemia. Furthermore, they do so in a concentration range near that used to treat clinical NIDDM,⁴⁹ although some selectivity may exist and the human pharmacology has had limited testing. Paradoxically, they reduce ischemic arrhythmias and could actually prevent sudden cardiac (arrhythmic) death.

One disappointing aspect of preconditioning is that one episode provides protection for about 1.5 to 2 hours; after this time, a test infarction shows no reduction in injury. Recently, however, a delayed preconditioning phenomenon has been called the second window of protection.⁵⁰ If one waits 24 hours after preconditioning with ischemia or an adenosine agonist, there is again a reduction in injury during a subsequent test infarction.^{51 52 53}

	Does Preconditioning Occur in Humans?

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Ischemic preconditioning is still a laboratory-based phenomenon that has not been conclusively documented in patients. Myocytes from biopsies of human myocardium can be preconditioned against injury by simulated ischemia, providing some ex vivo evidence of preconditioning.⁵⁴ There are several possible clinical scenarios in which ischemic preconditioning might occur that are amenable to experimental scrutiny. These clinical situations offer, in one form or another, a period of ischemia with intermittent reperfusion—precisely what is being undertaken in the laboratory experiments with preconditioning.

(1) Unstable angina preceding myocardial infarction
Unstable angina before myocardial infarction leading to preconditioning has been suggested in several studies. Infarct size, collateral flow, and the timing of the preinfarction angina must all be considered in the analysis of these clinical reports. The first hint that preconditioning may occur in the setting of unstable angina came from the Treatment of Acute Myocardial Infarction (TAMI) study. Patients who had angina for more than 1 week before infarction had a lower rate of reocclusion after reperfusion than those who had no history of angina, and those with angina also had a trend toward a lower mortality while in hospital.⁵⁵ However, neither infarct size nor collateral flow was measured, and the study did not investigate the effect of ischemic episodes occurring within the preceding 24 to 48 hours. Positive results with respect to a reduction of in-hospital mortality could have been due to a number of factors, including a lower reocclusion rate after acute angioplasty.

In the Fourth Thrombolysis in Myocardial Infarction (TIMI-4) study, patients with a history of unstable angina in the preceding 24 to 48 hours before acute myocardial infarction had lower in-hospital death rates, smaller infarcts (assessed by creatine kinase curve analysis), and a lower frequency of congestive heart failure. The 50% reduction of the mortality rate could not be accounted for by changes in collateral blood supply or antianginal medication.⁵⁶ Ottani and colleagues⁵⁷ and Nakagawa and colleagues⁵⁸ also reported that infarct size was smaller in a group of patients who had prodromal angina in the 24 hours preceding the onset of myocardial infarction.

(2) Angioplasty
Angioplasty studies have measured preconditioning for the degree of ischemia rather than infarct size. In one study, the second of two sequential 90-second balloon inflations separated by 5 minutes caused less angina, less ST-segment elevation of the ECG, and less myocardial lactate production, a metabolic indication of ischemia.⁵⁹ In another study, chest pain and ST-segment changes were also attenuated during the second balloon inflation. In contrast to the previous study, however, there was some opening of collateral vessels on the second inflation, suggesting that the opening of these collaterals played a role in the benefit observed.⁶⁰

Is K_ATP involved in preconditioning for ischemia during angioplasty? Tomai and colleagues⁶¹ found that the improvement in chest pain and in ST-segment changes seen during the second balloon inflation (ie, preconditioning) was prevented by glibenclamide. However, one cannot equate preconditioning, as first defined in experimental systems by a reduction in infarct size, with what may be occurring in the setting of angioplasty, in which the second test ischemia is brief and reversible.

(3) Warmup angina
After an episode of angina and a period of rest, patients often find that they are able to exercise freely without further angina, a phenomenon recognized by William Heberden more than two centuries ago. Although this effect is reported by only 20% of patients,⁶² with objective testing it was found to occur in nearly every patient examined.⁶³ The apparent protection after the warmup angina, as with preconditioning, has been shown not to be due to opening of collateral vessels but rather appears to be associated with an enhanced myocardial tolerance that reduces oxygen consumption during the second effort.⁶³

(4) CABG
During CABG, most surgeons arrest and protect the heart, usually by cardioplegia or short periods of aortic cross-clamp fibrillation with intermittent reperfusion. One experimental approach would be to prospectively precondition the myocardium before the bypass procedure by brief coronary occlusion and use of cross-clamp fibrillation during surgery as the "test" ischemia. Routine CABG patients were randomly assigned to either preconditioning using two 3-minute episodes of global ischemia induced by cross-clamping of the aorta during pacing at 90 bpm or to the control group, for which no preconditioning ischemia was induced.⁶⁴ Both groups then underwent 10 minutes of routine cross-clamp fibrillation during the anastomosis of the first vein graft. Biopsies taken before any ischemia and after cross-clamp fibrillation demonstrated a significant preservation of high-energy phosphate levels in the preconditioned group compared with control patients, despite a longer total ischemic time. These results demonstrated that it was possible to directly precondition the human heart and reduce energy utilization during ischemia, as observed in experimental preconditioning.²¹ However, it will ultimately not be desirable to use such means to protect the heart. It will be preferable to find a pharmacological approach to induce the protective effects of preconditioning. In this regard, agents such as adenosine, adenosine-regulating agents, and K_ATP openers are being considered,^{20 39 65 66} and reconsideration of agents that block K_ATP is appropriate.

	No Easy Solutions

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At the time of the UGDP study, the existence of the K_ATP channel was not known. The discovery of the K_ATP channel by Noma,²⁶ the discovery that sulfonylurea drugs inhibit K_ATP,²⁸ and the subsequent development of K_ATP openers⁶⁶ have implicated mechanisms of sulfonylurea therapy in diabetes that cause increased cardiovascular mortality.

What might be the danger of inhibiting the K_ATP channel with sulfonylurea agents? The ability of some oral hypoglycemic agents, such as glyburide, to inhibit the opening of what might be described as the heart's endogenous protective channel (K_ATP) should make us rethink the relative importance of this type of treatment. Patients taking these drugs might have larger myocardial infarctions. If preconditioning is confirmed to be as potent an intervention clinically as it has been in the experimental laboratory, the potential for therapeutic intervention could be immense. This raises an important question as to the use of agents that block this endogenous mechanism and might block potential therapeutic interventions. Nicorandil, a K_ATP opener used for the treatment of angina, is now available in Japan and Europe. Physicians in these areas must weigh the risks and benefits of continuing oral sulfonylurea therapy in their diabetic patients with coronary artery disease or change to other forms of antidiabetic treatment so that this type of agent can be used. Sulfonylureas also block experimental coronary vasodilation, but the effects of these agents on human coronary arteries are unknown. Until recently, alternative treatment for NIDDM has been limited to insulin therapy because the only other available oral agent was phenformin, which is limited by serious side effects. Approval of metformin by the FDA for use in the United States has made an alternative choice available.

An even broader question as to the use of sulfonylurea agents in any patient with diabetes can be raised. At the time of publication, the UGDP finding of increased cardiovascular mortality was questioned because of criticisms of the statistical methods, because of the lack of statistical significance for total mortality, and in part because no physiological basis for the effect was known. The trial was terminated because of cardiovascular mortality, and thus the lack of a significant difference in overall mortality could have been a type II statistical error, ie, insufficient power. Now that a physiological basis for excess cardiovascular mortality has been defined in animal models, clinicians are faced with a difficult choice. They may reconsider the UGDP finding and stop using oral sulfonylurea drugs. Alternatively, NIDDM patients can be screened periodically for cardiovascular disease and risk factors, and sulfonylurea drugs can be used only in those at low risk. The latter approach is limited because current screening techniques lack sensitivity for such subclinical disease. Newer tests, such as ultrafast computed tomography, are as yet of unknown sensitivity and specificity for asymptomatic subjects, and diabetes per se is a significant risk factor for developing ischemic heart disease. Furthermore, the UGDP study enrolled all type II diabetics, not just those with cardiovascular disease, so the finding should apply to all type II diabetics. We would advocate another prospective trial of sulfonylurea agents in diabetics that would include screening for cardiovascular disease. Further retrospective or epidemiological studies of cardiovascular disease in sulfonylurea-treated diabetics might be helpful. In light of current understanding of the cardiovascular effects of sulfonylurea drugs, especially on preconditioning, more cautious use of these agents in patients at risk for cardiovascular disease seems warranted.

	Selected Abbreviations and Acronyms

 

CABG = coronary artery bypass graft surgery CFTR = cystic fibrosis transmembrane regulator KATP = ATP-regulated potassium channel NIDDM = non–insulin-dependent diabetes mellitus PI/PLC = phosphatidyl inositol–specific phospholipase C UGDP = University Group Diabetes Program

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Top Introduction Oral Hypoglycemics: The... The Mystery Antidiabetic Mechanisms New Discoveries: A Possible... Does Preconditioning Occur in... No Easy Solutions References

 

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