CLINICAL RESEARCH: CORONARY ARTERY DISEASE
Sulfonylureas attenuate electrocardiographic ST-segment elevation during an acute myocardial infarction in diabetics
Jose F. Huizar, MD* ,*,
Luis A. Gonzalez, MD*,
James Alderman, MD, FACC  and
Harton S. Smith, MD, FACC
* MetroWest Medical Center, Framingham, Massachusetts, USA
State University of New York, Upstate Medical University Hospital, Syracuse, New York, USA
Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
Heart Center of MetroWest, Framingham, Massachusetts, USA
* Reprint requests and correspondence: Dr. Jose F. Huizar, Upstate Medical University Hospital, State University of New York, Cardiovascular Division, 750 East Adams Street, Syracuse, New York 13210, USA.
jfhuizar{at}massmed.org
huizarj{at}upstate.edu
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Abstract
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OBJECTIVES: The aim of this study was to determine whether sulfonylureas attenuate ST-segment elevation in diabetics during acute myocardial infarction (AMI).
BACKGROUND: Sulfonylureas block adenosine triphosphate-sensitive potassium channels found in the pancreas and heart. Animal studies have demonstrated that opening of these cardiac channels results in ST-segment elevation during AMI, and pretreatment with sulfonylureas blunts these ST-segment changes.
METHODS: We performed a retrospective study of diabetic patients hospitalized with AMI over a four-year period in Framingham, Massachusetts. Electrocardiograms obtained on arrival were analyzed for standard ST-segment criteria for thrombolytic therapy (>1 mm in two or more contiguous leads). Results were compared between the study group (40 patients taking sulfonylureas) and control group (48 patients taking alternative hypoglycemic agent).
RESULTS: Demographics were similar for both groups apart from a female preponderance in the study group. A significantly higher percentage of patients in the study group did not meet ST-segment criteria for thrombolytic therapy as compared with the control group (53% vs. 29%, p = 0.02). This difference was most prominent in patients with peak creatinine phosphokinase levels between 500 and 1,000 mg/dl (86% vs. 22%, p = 0.04). The magnitude of ST-segment elevation and the frequency of thrombolytic therapy were significantly lower in the sulfonylurea group than in the control group (1.1 ± 1.0 mm vs. 2.1 ± 2.7 mm, p = 0.02 and 20% vs. 40%, p = 0.04, respectively).
CONCLUSIONS: Sulfonylurea therapy appears to attenuate the magnitude of ST-segment elevation during an AMI, resulting in failure to meet criteria for thrombolytic therapy and as a consequence leading to inappropriate withholding therapy in this subset of diabetic patients.
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Abbreviations and Acronyms
| | ADP | | adenosine diphosphate | | AMI | | acute myocardial infarction | | ATP | | adenosine triphosphate | | CPK | | creatinine phosphokinase | | ECG | | electrocardiogram | | K+ | | potassium | | KATP | | adenosine triphosphate-sensitive potassium |
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Diabetes mellitus is a major risk factor for the development of coronary artery disease, conferring more than a three-fold increased risk for acute coronary syndromes and congestive heart failure (1). Sulfonylureas are commonly used as first-line drugs for glycemic control.
These agents stimulate insulin release from pancreatic beta cells via blocking of adenosine triphosphate-sensitive potassium (KATP) channels (2–4). These channels are also found in the heart and smooth muscle. The channels are normally closed during steady state in heart muscle, inhibited by adenosine triphosphate (ATP). During ischemia, when ATP falls and adenosine diphosphate (ADP) increases, the channels open (2–8). Animal studies have shown that opening of these channels results in ST-segment elevation on the electrocardiogram (ECG) during an acute ischemic event (5–7).
Experimental studies have demonstrated that ST-segment elevation during acute myocardial injury can be blunted by pretreating animals with the sulfonylurea, glyburide (5–7,9); however, there are no human studies that address this issue. The purpose of this study was to discern whether sulfonylurea drugs affect ST-segment elevation in diabetics with an acute myocardial infarction (AMI), because the underuse of thrombolytics in diabetics has important implications.
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Methods
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We retrospectively reviewed the charts of all diabetic patients admitted to the coronary care unit of our community hospital, MetroWest Medical Center (Framingham, Massachusetts), with the diagnosis of AMI from October 1996 through August 2000. Patients with no more than 24 h of symptoms and a positive creatinine phosphokinase (CPK) elevation were selected for the study. All diabetic patients were included for study purposes regardless of the hypoglycemic regimen, from diet control only and no medical therapy, to any kind of sulfonylureas, biguanides, glitazones, and/or insulin.
Patients presenting with a left or right bundle-branch block, fully paced rhythm, left ventricular hypertrophy with strain pattern by ECG, or digoxin therapy were excluded from analysis.
We reviewed demographic data as well as the ECG on presentation to the emergency department. The population was divided into two groups: those taking sulfonylurea drugs (study group) and those treated with non-sulfonylurea hypoglycemic agents (control group). Each group was further categorized into three subgroups based on peak CPK level (as a surrogate for size of myocardial infarction): group 1 = peak CPK <500 mg/dl; group 2 = peak CPK 500 to 1,000 mg/dl; and group 3 = peak CPK >1,000 mg/dl.
The first ECG obtained in the emergency room was chosen for ST-segment analysis. A single physician was assigned to blindly analyze all ECGs for ST-segment changes. A baseline was traced horizontally in all leads, and ST-segment elevation and/or depression was measured at 20 to 40 ms after the J point in all affected leads. An average ST-segment elevation and/or depression was obtained in all affected contiguous leads. Each patient had an average ST-segment elevation and depression that was used for statistical analysis. The ECGs were classified as either meeting or not (non-diagnostic ST-segment elevation) the standard ST-segment elevation criteria for thrombolytic therapy for AMI (>1 mm ST-segment elevation in two or more contiguous leads). The prevalence of non-diagnostic ST-segment elevation was analyzed for each group (study group vs. control group).
Statistical analysis.
Data were analyzed with SAS software (SAS Institute, Cary, North Carolina). Chi-square was used to compare all demographic data, ST-segment characteristics, and non-diagnostic ECG between the control and the sulfonylurea groups. The Fisher exact test was used for subgroup analysis. Differences were considered statistically significant at p < 0.05.
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Results
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A total of 147 diabetics were admitted to MetroWest Medical Center with AMI from October 1996 to August 2000. Only 88 diabetic patients met the criteria for inclusion in the study, 40 patients taking sulfonylurea drugs (study group) and 48 patients taking other hypoglycemic agents (control group). The remaining 59 patients were excluded (18 patients on digoxin, 8 and 17 patients with right and left bundle-branch block, respectively, 3 patients with a fully paced rhythm, 2 patients with left ventricular hypertrophy-strain pattern, and 11 patients with more than 24 h of symptoms). Demographic data and baseline characteristics were similar for both groups (Table 1) except for gender, with a clear preponderance of females in the study group.
The sulfonylurea group had 25 patients (63%) with peak CPK <500 mg/dl, 7 patients (17%) with peak CPK 500 to 1,000 mg/dl, and 8 patients (20%) with peak CPK >1,000 mg/dl. The control group had 19 patients (40%) with peak CPK <500 mg/dl, 9 patients (18%) with peak CPK 500 to 1,000 mg/dl, and 20 patients (41%) with peak CPK >1,000 mg/dl.
The prevalence of ECGs not meeting ST-segment elevation criteria for thrombolytics (non-diagnostic ST-segment elevation) in both groups is depicted in Figure 1. Overall, we found a significantly greater number of non-diagnostic ST-segment elevation in the sulfonylurea group as compared with the control group (53% vs. 29%, p = 0.02). This difference was most pronounced for patients with a peak CPK level between 500 and 1,000 mg/dl (86% vs. 22%, p = 0.04). There was no significant difference in the frequency of non-diagnostic ST-segment elevation in patients with a peak CPK <500 mg/dl (59% vs. 64%, p = NS) or >1,000 mg/dl (25% vs. 15%, p = NS). The magnitude of ST-segment elevation in the sulfonylurea group was significantly less than in the control group (mean 1.1 ± 1.0 mm vs. 2.1 ± 2.7 mm, p = 0.02), whereas there was no difference in average ST-segment depression (0.8 ± 0.7 mm vs. 1.0 ± 1.0 mm, p = NS). Thrombolytic therapy was administered less frequently in the sulfonylurea group as compared with the control group (20% vs. 40%, p = 0.04), with no difference in the duration of symptoms or contraindications to thrombolytic therapy between groups (Table 2).
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Figure 1 Non-diagnostic ST-segment elevation during acute myocardial infarction, subdivided by infarct size (total of 88 patients). White bars = control; black bars = sulfonylureas. CPK = creatinine phosphokinase.
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Table 2 Results: Electrocardiographic ST-Segment Changes and Thrombolytic Therapy in the Overall Study Population and in Males Alone
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Analysis of the male population (55 patients) alone demonstrated significantly less magnitude of ST-segment elevation in the sulfonylurea group when compared with the control group (mean 1.2 ± 0.9 mm vs. 2.3 ± 2.9 mm, p = 0.04) (Table 2). However, the trend of non-diagnostic ST-segment elevation in the sulfonylurea and control groups (47% vs. 25%, p = 0.09) did not reach statistical significance (Fig. 2).
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Figure 2 Non-diagnostic ST-segment elevation during acute myocardial infarction. Males (55 patients) compared with overall study population (88 patients) subdivided by infarct size. White bars = control; black bars = sulfonylureas. CPK = creatinine phosphokinase.
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Discussion
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This is the first pilot study suggesting that sulfonylurea drugs may attenuate ST-segment elevation during an AMI. These medications are known to block the cardiac KATP channels. Cardiac KATP channels are located in the cytoplasmic and mitochondrial membrane (2–8,10). Glipizide and glyburide have greater affinity for the cytoplasmic cardiac KATP channels than glimepiride and the first-generation sulfonylureas (3,11).
The function of the cardiac cytoplasmic KATP channel under physiologic conditions is unclear; however, its function during ischemia is partially known. These KATP channels are normally closed in non-hypoxic heart tissue. It is only during ischemia, when ATP falls and ADP rises (ATP not being regenerated from ADP through oxidative phosphorylation), that these channels open. Activation of KATP channels mediates an efflux and extracellular accumulation of potassium (K+) with resultant hyperpolarization of the cell and shortening of the action potential. This shortening of the action potential is thought to predispose to lethal arrhythmias by promoting re-entry during ischemia (2–8).
An experimental study demonstrated that the opening of KATP channels plays an important role in the development of ECG ST-segment elevation during myocardial injury (6). This study showed that ST-segment elevation during acute myocardial injury in animals could be blunted by glyburide (KATP channel blocker), but potentiated by pinacidil (KATP channel opener) in non-ischemic tissue. By reducing the ischemia-related accumulation of K+ in the extracellular space, treatment with sulfonylureas may lead to less hyperpolarization of the resting membrane potential within the ischemic area and thus less ST-segment elevation on the surface ECG (5–7).
We found that diabetic patients with AMI who were taking sulfonylureas were less likely to meet the standard ECG criteria for administration of thrombolytic therapy (Fig. 1, Table 2). Those patients on sulfonylurea drugs had a reduced magnitude of ST-segment elevation during AMI as compared with diabetics not on sulfonylureas (Table 2). For CPK levels between 500 and 1,000 mg/dl, the difference was statistically significant. In patients with CPK >1,000 mg/dl, there was a trend toward a greater number of non-diagnostic ST-segment elevation in the sulfonylurea group, though this did not reach statistical significance. It is possible that the greater the extent of myocardial injury, the less the attenuation of the ST-segment elevation caused by sulfonylurea drugs, owing to the overwhelming number of cardiac KATP channels that open.
There was no difference in the frequency of non-diagnostic ST-segment elevation in patients with peak CPK levels <500 mg/dl. The control group with CPK levels <500 mg/dl was the only subgroup to have a small trend towards more non-diagnostic ST-segment elevation, particularly in the female population. However, these smaller CPK levels are more characteristic of non–Q-wave AMI, which generally presents with no ST-segment changes because the small area of tissue involved is not reflected on the epicardial surface. We believe this could explain the limited impact of sulfonylureas in the subgroup with peak CPK levels <500 mg/dl.
Interestingly, the control group had a greater percentage of AMI with CPK >500 mg/dl as compared with the sulfonylurea group (59% vs. 37%, p = 0.05). The nature of this finding is unclear, though we could only speculate that this could have been the result of a higher thrombolytic use in the control group with a subsequent rapid washout of cardiac enzymes. Sulfonylureas are not known to have a cardioprotective effect in AMI size. In fact, these medications have been implicated in the interference of ischemic preconditioning during acute ischemic events, resulting in a larger size of AMI (12–17).
Because of the difference in gender composition of the sulfonylurea and control groups, we cannot exclude the possibility that the results were due to the female preponderance in the study group. The significant difference in mean ST-segment elevation between groups in the male population (Table 2) suggests that the attenuation of the ST-segment elevation could be truly due to the sulfonylurea drug rather than the gender differences between groups. Unfortunately, the rest of the male subgroup analysis did not provide us with any concrete reassurance that these findings were not attributable to gender difference. We must be cautious in drawing any conclusions from the male subgroup analysis because the number of patients was small.
Mortality was not an end point in this study. In the 1970s, an increase in cardiovascular mortality was attributed to tolbutamide (18). We found that patients taking sulfonylureas received less thrombolytic therapy when compared with diabetics treated with other hypoglycemic agents (Table 2). Recently, a non-randomized trial showed an increased mortality in diabetics treated with sulfonylureas after direct angioplasty for AMI (19). However, the United Kingdom Prospective Diabetes Study (UKPDS) trial (20) and a study by Brady et al. (21) noted that the second-generation sulfonylureas do not increase mortality during acute coronary events. Furthermore, sulfonylureas have also been demonstrated to have antiarrhythmic properties, decreasing lethal arrhythmias during acute coronary events by attenuating action potential shortening (re-entry mechanism) (9,22–25). Thus, we believe that these medications may not affect overall cardiovascular mortality when both effects are taken into consideration.
Our study is subject to the inherent limitations of a retrospective study. The sample size is too small to detect statistically significant differences in subgroup analysis. We cannot exclude the possibility that the attenuation of ST-segment elevation (non-diagnostic ST-segment elevation) in the sulfonylurea group was related to the preponderance of women. However, the significant difference in mean ST-segment elevation in the male population (Table 2) leads us to believe that the attenuation of the ST-segment elevation is a true drug-related effect. Another limitation to consider is the possibility of different sizes of myocardial infarctions between sulfonylurea and control groups, even with exactly the same CPK level, due to a rapid washout of enzymes in the patients receiving thrombolytic therapy. Unfortunately, there is no gold standard to assess the true size of an AMI.
Few reports consider initial ECG to be non-diagnostic in 45% of all patients shown to have an AMI (26). We present a pilot study, because sample size estimate was particularly difficult to calculate in diabetics owing to the lack of data of non-diagnostic ECG in this specific population during AMI. We are currently expanding the size of the study population to increase the power of our analysis. Our findings were based on patients taking either glyburide or glipizide. We may not find the same results in patients treated with glimepiride or first-generation sulfonylureas (low affinity for the KATP channel in the heart muscle). Large-scale evaluations will be necessary to confirm these preliminary findings and clarify these issues.
In summary, this is the first clinical study to suggest that attenuation of electrocardiographic ST-segment elevation during moderate-sized AMI occurs in diabetic patients treated with sulfonylurea drugs. Because such attenuation of ST-segment elevation may delay the diagnosis of AMI in this subgroup of patients, we believe that the criteria for thrombolysis or the use of another hypoglycemic agent should be reconsidered in this high-risk population, providing further research confirms our observation.
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Acknowledgments
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The authors are grateful to Alfredo Rojas, PhD, and Anila Medina, MD, for their help and advice in the statistical analysis of this study. We also want to thank Jody Collins and Honey Flynn for their full support in gathering all the information and data necessary for the preparation and publication of this article.
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