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Circulation. 2005;111:3078-3086
Published online before print June 6, 2005, doi: 10.1161/CIRCULATIONAHA.104.517839
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(Circulation. 2005;111:3078-3086.)
© 2005 American Heart Association, Inc.

Epidemiology

Admission Glucose and Mortality in Elderly Patients Hospitalized With Acute Myocardial Infarction

Implications for Patients With and Without Recognized Diabetes

Mikhail Kosiborod, MD; Saif S. Rathore, MPH; Silvio E. Inzucchi, MD; Frederick A. Masoudi, MD; Yongfei Wang, MS; Edward P. Havranek, MD; Harlan M. Krumholz, MD, SM

From the Section of Cardiovascular Medicine (M.K., S.S.R., Y.W., H.M.K.), Section of Endocrinology (S.E.I.), and the Robert Wood Johnson Clinical Scholars Program (M.K., H.M.K.), Department of Internal Medicine, and the Section of Health Policy and Administration, Department of Epidemiology and Public Health (H.M.K.), Yale University School of Medicine; Center for Outcomes Research and Evaluation, Yale–New Haven Health (H.M.K.), New Haven, Conn; and Division of Cardiology, Department of Medicine (F.A.M., E.P.H.), Denver Health Medical Center, Denver, Colo.

Correspondence to Dr Harlan M. Krumholz, Yale University School of Medicine, 333 Cedar St, PO Box 208088, New Haven, CT 06520-8088. E-mail harlan.krumholz{at}yale.edu

Received October 29, 2004; revision received February 9, 2005; accepted March 2, 2005.


*    Abstract
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Background— The relationship between admission glucose levels and outcomes in older diabetic and nondiabetic patients with acute myocardial infarction is not well defined.

Methods and Results— We evaluated a national sample of elderly patients (n=141 680) hospitalized with acute myocardial infarction from 1994 to 1996. Admission glucose was analyzed as a categorical (≤110, >110 to 140, >140 to 170, >170 to 240, >240 mg/dL) and continuous variable for its association with mortality in patients with and without recognized diabetes. A substantial proportion of hyperglycemic patients (eg, 26% of those with glucose >240 mg/dL) did not have recognized diabetes. Fewer hyperglycemic patients without known diabetes received insulin during hospitalization than diabetics with similar glucose levels (eg, glucose >240 mg/dL, 22% versus 73%; P<0.001). Higher glucose levels were associated with greater risk of 30-day mortality in patients without known diabetes (for glucose range from ≤110 to >240 mg/dL, 10% to 39%) compared with diabetics (range, 16% to 24%; P for interaction <0.001). After multivariable adjustment, higher glucose levels continued to be associated with a graded increase in 30-day mortality in patients without known diabetes (referent, glucose ≤110 mg/dL; range from glucose >110 to 140 mg/dL: hazard ratio [HR], 1.17; 95% CI, 1.11 to 1.24; to glucose >240 mg/dL: HR, 1.87; 95% CI, 1.75 to 2.00). In contrast, among diabetic patients, greater mortality risk was observed only in those with glucose >240 mg/dL (HR, 1.32; 95% CI, 1.17 to 1.50 versus glucose ≤110 mg/dL; P for interaction <0.001). One-year mortality results were similar.

Conclusions— Elevated glucose is common, rarely treated, and associated with increased mortality risk in elderly acute myocardial infarction patients, particularly those without recognized diabetes.


Key Words: diabetes mellitus • elderly • glucose • mortality • myocardial infarction


*    Introduction
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Prior studies have suggested that an elevated admission glucose level is common in patients with acute myocardial infarction (AMI) and is a risk factor for increased mortality and in-hospital complications.1–20 On the basis of these reports and similar findings in patients with critical illness,21 the association between glucose levels and adverse outcomes has been a focus of growing attention from expert groups and professional societies.22,23 However, although recommendations are being developed for strict glucose management in all hospitalized patients,22,23 glucose measurement is not included in AMI risk indexes,24–27 and current AMI guidelines do not suggest specific therapeutic targets for glucose control.28–30

This relative lack of guidance concerning the risk stratification and management of AMI patients with elevated glucose may reflect the fact that many aspects of the relationship between glucose levels and mortality in AMI patients have not been adequately defined. First, because of limited sample sizes, previous studies could not evaluate the nature of the association between glucose and mortality across the full spectrum of glucose values.1–5,7–20 Second, although glucose is commonly elevated in hospitalized AMI patients both with and without known diabetes,6,8,9 it is unclear whether hyperglycemia portends a different prognosis based on patients’ diabetes status. Most prior studies did not directly compare the effect of glucose on outcomes in patients with and without recognized diabetes,1,4,5,7,9–11,14,15,17,20 and the few that did produced conflicting results.2,3,8,12,13,18,19 Although some studies have suggested that hyperglycemia-associated risk is greater in patients with AMI who do not have antecedent diabetes than in those with diabetes,2,12,13 others showed that this risk is similar across patient groups.3,8,18,19 Third, most previous investigations did not evaluate the association between glucose and increased mortality in the context of contemporary AMI management1,5,6,8–10,14,16 and did not fully account for differences in severity of AMI or comorbid conditions that are more prevalent in patients with hyperglycemia.1,3,7–13,15,16,20 Finally, despite the fact that the elderly represent a growing majority of AMI patients31 and have a high prevalence of unrecognized and established diabetes,32 few data are available concerning the risks associated with hyperglycemia in this patient population.

These gaps in knowledge limit practical application of glucose levels in risk stratification and management of patients with AMI and underscore the need for a large, contemporary analysis of glucose values and outcomes in hospitalized AMI patients with and without known diabetes. Accordingly, we analyzed data from the Cooperative Cardiovascular Project (CCP), a nationally representative, community-based sample of elderly patients hospitalized with AMI from 1994 to 1996. The large size of the patient sample and the focus on the elderly provided an ideal opportunity to address the current knowledge gaps.


*    Methods
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Cooperative Cardiovascular Project
The development and background for the CCP are described in detail elsewhere.33 In brief, the CCP was a national program developed by the Centers for Medicare and Medicaid Services to improve the quality of care for Medicare beneficiaries hospitalized with AMI. The cohort included 234 769 fee-for-service beneficiaries discharged from acute care nongovernmental hospitals in the United States with a primary discharge diagnosis of AMI (International Classification of Diseases, ninth revision, clinical modification [ICD-9-CM] code 410) between January 1994 and February 1996, excluding AMI readmissions (ICD-9-CM code 410.x2).34 Detailed clinical data were subsequently abstracted from medical records by trained medical record reviewers. The reliability of this abstraction process has previously been reported.35

To ensure examination of a representative cohort of older patients admitted with AMI, we excluded patients <65 years of age, those without a clinically confirmed diagnosis of AMI, and those with extreme admission glucose values (<70 or >600 mg/dL). For patients who appeared more than once in the sample, only the first admission record was included, thereby excluding readmission records. We excluded patients whose records could not be linked to the American Hospital Association data or the 1990 US Census and those who were hospitalized outside the 50 states and the District of Columbia. Patients who were transferred from another facility were excluded because the details of their initial presentation and management could not be ascertained. We also excluded patients who were discharged after the study period, had unknown mortality status, and had unknown admission glucose. Finally, patients with a terminal illness (defined as documented life expectancy <6 months) were excluded, because their treatment might not have been directed primarily at improving survival. In total, 93 089 patients met ≥1 of the above exclusion criteria, leaving a final study cohort of 141 680 patients.

Admission Glucose and Diabetes Status
Admission glucose was categorized into the following groups: ≤110, >110 to 140, >140 to 170, >170 to 240, and >240 mg/dL, similar to previously published cut points.21 Admission glucose was also analyzed as a continuous variable in increments of 10 mg/dL.

Patients were classified as having recognized diabetes if their medical records contained documentation of a previous history of diabetes, diagnosis of diabetes on admission, or the use of an oral antihyperglycemic agent or insulin at the time of hospital admission.

Additional Variables
Hospital characteristics were obtained by linking data for each patient’s treating hospital with the 1994 American Hospital Association Annual Survey of Hospitals.36 The attending physician, defined as "the clinician who is primarily and largely responsible for the care of the patients from the beginning of the hospital episode,"37 was identified for each patient by his or her Unique Physician Identification Number in the Medicare Part A claims.38 Attending physician specialty was then obtained by linking the identification number with the American Medical Association physician Masterfile.39

Outcomes
The outcomes were 30-day and 1-year all-cause mortality from the day of admission, as ascertained from the Medicare Enrollment Database.40

Statistical Analysis
Baseline demographic and clinical characteristics were compared across the 5 glucose groups by use of Pearson’s {chi}2 test for categorical variables and the F test for continuous variables. Insulin administration during hospitalization was compared within subgroups of patients with and without recognized diabetes through the use of Pearson’s {chi}2 test.

The unadjusted association between groups of admission glucose and mortality at 30 days and 1 year was tested with Pearson’s {chi}2 test. Multivariable Cox proportional-hazards regression models assessed whether the association between admission glucose levels and mortality over 30 days and 1 year was independent of other patient and provider characteristics. Variables clinically considered or previously demonstrated to be prognostically important33 and those identified in bivariate analyses as predictors of 30-day and 1-year mortality were entered into the models. Covariates included sociodemographic factors (age, gender, race, median income, nursing home residence); medical history (prior heart failure, hypertension, diabetes, cerebrovascular disease, peripheral vascular disease, smoking, chronic obstructive pulmonary disease, dementia, immobility, urinary incontinence); admission characteristics, including time to presentation, vital signs (heart rate, systolic blood pressure), Killip class, left ventricular ejection fraction, presence of anterior AMI, presence of ST-segment elevation, Q waves, left bundle-branch block or atrial fibrillation on the ECG; cardiac arrest on admission; laboratory values on admission (creatinine, white blood cell count, hematocrit); peak creatine kinase; and medications on admission (aspirin, ß-blockers, calcium channel blockers, nitrates, diuretics, bronchodilators). Models also adjusted for hospital characteristics (mean AMI volume, location, level of cardiac care facilities, nonprofit/for-profit status, teaching status), attending physician specialty, and clustering of patients by hospital.

To assess whether glucose-associated mortality risks differed in patients with and without known diabetes, the Mantel-Haenzel test for heterogeneity was used to compare crude mortality at 30 days and 1 year. Multivariable models assessing the association between admission glucose and 30-day and 1-year mortality were then repeated, including admission glucose-diabetes interaction terms to assess whether glucose-associated mortality risks differed between patients with and without known diabetes. Analyses were also repeated, modeling glucose as a continuous variable to assess 30-day and 1-year mortality associated with successive 10-point glucose increments in patients with and without recognized diabetes.

Analyses were conducted with SAS 8.02 (SAS Institute Inc) and Stata version 8.0 (Stata Corp). Use of the CCP database was approved by the Yale University School of Medicine Human Investigation Committee.

Role of the Funding Source
The sponsors of this work played a key role in the collection of data and approved the work submitted for publication. They did not have a role in the study design, analysis, and interpretation of data or in the writing of the manuscript.


*    Results
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The median admission glucose was 150 mg/dL (interquartile range, 120 to 210 mg/dL; Figure 1), and 30.4% of patients had documented diabetes. Compared with patients who had lower admission glucose, greater proportions of those with higher glucose were female; had a history of documented diabetes, hypertension, prior AMI, and heart failure; and presented with anterior AMI, higher Killip class, higher peak creatine kinase, higher creatinine, and lower left ventricular ejection fraction (Table 1Down). A substantial proportion of patients with elevated glucose did not have previously recognized diabetes (eg, 58% in the group with glucose >170 to 240 mg/dL, 26% in the group with glucose >240 mg/dL). A lower proportion of patients without recognized diabetes received insulin during hospitalization compared with diabetics, even when hyperglycemia was severe (Table 2).



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  		Figure 1. Distribution of admission glucose values in patient sample.


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  		TABLE 1. Patient Characteristics*


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  		TABLE 1. Continued


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  		TABLE 2. Insulin Administration Rates During Hospitalization in Patients With and Without Recognized Diabetes*

Higher admission glucose levels were associated with successively higher crude 30-day and 1-year mortality (Figure 2). Glucose-associated mortality risks differed between patients with and without known diabetes. Although higher admission glucose levels were associated with a steep, graded increase in 30-day and 1-year mortality in patients without known diabetes (for glucose range from ≤110 to >240 mg/dL: 10% to 39% for 30-day mortality, 22% to 55% for 1-year mortality), this relationship was not present in patients with established diabetes (for glucose range from ≤110 to >240 mg/dL: 16% to 24% for 30-day mortality, 35% to 41% for 1-year mortality; Figure 3A and 3B). Overall, higher glucose levels were associated with a significantly greater increase in the risk of 30-day and 1-year mortality in patients who did not have recognized diabetes than in diabetics (P for interaction <0.001).



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  		Figure 2. Relationship between admission glucose values and crude 30-day and 1-year mortality in all patients (30-day mortality for glucose ≤110 mg/dL, 11.0%; glucose >110 to 140 mg/dL, 13.4%; glucose >140 to 170 mg/dL, 17.7%; glucose >170 to 240 mg/dL, 22.4%; glucose >240 mg/dL, 27.8%; 1-year mortality for glucose ≤110 mg/dL, 22.8%; glucose >110 to 140 mg/dL, 25.4%; glucose >140 to 170 mg/dL, 30.4%; glucose >170 to 240 mg/dL, 37.5%; glucose >240 mg/dL, 44.6%).



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  		Figure 3. A, Relationship between admission glucose values and crude 30-day mortality in patients with and without recognized diabetes (patients with diabetes: for glucose ≤110 mg/dL, 16.2%; glucose >110 to 140 mg/dL, 14.3%; glucose >140 to 170 mg/dL, 15.7%; glucose >170 to 240 mg/dL, 17.6%; glucose >240 mg/dL, 23.8%; patients without recognized diabetes: for glucose ≤110 mg/dL, 10.5%; glucose >110 to 140 mg/dL, 13.3%; glucose >140 to 170 mg/dL, 18.1%; glucose >170 to 240 mg/dL, 25.9%; glucose >240 mg/dL, 39.2%). B, Relationship between admission glucose values and crude 1-year mortality in patients with and without recognized diabetes (patients with diabetes: for glucose ≤110 mg/dL, 34.5%; glucose >110 to 140 mg/dL, 31.7%; glucose >140 to 170 mg/dL, 31.3%; glucose >170 to 240 mg/dL, 34.3%; glucose >240 mg/dL, 41.0%; patients without recognized diabetes: glucose ≤110 mg/dL, 21.7%; glucose >110 to 140 mg/dL, 24.7%; glucose >140 to 170 mg/dL, 30.3%; glucose >170 to 240 mg/dL, 39.8%; glucose >240 mg/dL, 55.1%).

After multivariable adjustment, patients with higher admission glucose levels remained at increased risk of both 30-day and 1-year mortality compared with patients whose admission glucose was ≤110 mg/dL. Higher glucose levels were associated with a greater increase in relative risk of 30-day and 1-year mortality in patients without recognized diabetes compared with diabetics (P for interaction <0.001). In patients without established diabetes, there was a graded increase in the risk of death over 30 days as admission glucose became progressively elevated. In contrast, among patients with diabetes, a glucose-associated mortality risk over 30 days was seen only among those with severe hyperglycemia. Results were similar for 1-year mortality (Table 3).


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  		TABLE 3. Effect of Admission Glucose on Mortality After Multivariable Adjustment

Differences in glucose-associated mortality risks between patients with and without known diabetes persisted when analyses were repeated with admission glucose modeled as a continuous variable (in 10-mg/dL increments). Although in the normal glucose range patients without a history of diabetes had a lower risk-adjusted 30-day mortality than patients with diabetes, their risk increased more steeply at higher glucose levels, surpassing the risk of patients with diabetes at {approx}140 mg/dL (Figure 4A, P for interaction <0.001). The results were similar for 1-year mortality, with the risk in nondiabetic patients surpassing that of the diabetic group at a blood glucose level of {approx}170 mg/dL (Figure 4B, P for interaction <0.001).



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  		Figure 4. Direct comparison of risk-adjusted 30-day mortality (A) and 1-year mortality (B) in patients with and without recognized diabetes across range of glucose values.


*    Discussion
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Our large, nationally representative study of elderly patients hospitalized with AMI indicates that the nature of the relationship between admission glucose and mortality is different in patients with and without recognized diabetes. Elevated glucose is common, infrequently treated, and associated with a steep, linear mortality increase in patients without recognized diabetes. In contrast, elevated glucose levels are not associated with an increased relative risk of mortality in patients with diabetes, except at severe levels of hyperglycemia. Surprisingly, elevated admission glucose confers at least as high or a higher risk of 30-day and 1-year mortality in patients without known diabetes as in those with diabetes.

Our study substantially expands the current understanding of the relationship between admission glucose values and adverse outcomes in patients with AMI. First, we directly compared the nature of the relationship between elevated glucose and mortality in patients with and without known diabetes across the full spectrum of glucose values. Thus, the results of our study could be used as practical guides for risk assessment, as well as for future clinical trials of tight glycemic control in AMI patients with and without recognized diabetes. Second, we established the prognostic value of elevated glucose in elderly patients hospitalized with AMI. Given the high prevalence of known and unrecognized diabetes in this understudied group of patients,32 appropriate risk stratification and intervention based on admission glucose values may be of substantial benefit. Finally, by demonstrating differences in the way insulin therapy was administered in patients with and without known diabetes, our study offers insight into a possible mechanism of higher mortality in AMI patients without recognized diabetes.

Our findings highlight an important potential opportunity to improve care and outcomes for hyperglycemic AMI patients without known diabetes. Experience in other patient populations41 indicates that tight glycemic control with insulin therapy during hospitalization may be at least as important for these patients as in diabetics.42 A recent large randomized clinical trial of glucose-insulin-potassium infusion in patients with AMI showed no benefit of this therapy,43 in contrast to previous smaller studies.44–47 In that trial, however, there was no requirement for stringent blood glucose control. It is possible that therapies based on specific blood glucose target zones will improve outcomes in hyperglycemic AMI patients without previously known diabetes, as was previously demonstrated in critically ill patients41 and in diabetic patients with AMI.42 Large-scale randomized clinical trials are needed to definitively establish the utility of target-driven aggressive glucose control in this patient group. Our results suggest that these trials should use a target glucose of ≤110 mg/dL and are in agreement with the recent statements by the American Diabetes Association and American College of Endocrinology on in-hospital glucose management.22,23

Whether hyperglycemia is a mediator or marker of adverse outcomes remains unclear. In any patient, diabetic or not, elevated glucose during AMI could in part reflect the severity of illness resulting from a high catecholamine state and increased circulating concentrations of other factors, such as cortisol. Other concurrent illnesses like bacterial infections and sepsis would have further deleterious effects on carbohydrate metabolism and glucose levels. Although we controlled the results for multiple demographic and clinical factors, including the severity of AMI, a possibility of residual confounding by these unmeasured factors cannot be entirely excluded. However, physiological and clinical data suggest that hyperglycemia may have a detrimental effect on ischemic myocardium. Higher glucose levels in patients with AMI have been associated with higher free fatty acid concentrations, insulin resistance, and impaired myocardial glucose use, thus increasing the consumption of oxygen and potentially worsening ischemia.48,49 Furthermore, clinical studies have also demonstrated that tight glycemic control with insulin can markedly lower mortality in critically ill patients, including those with AMI.41,42,50,51 The mechanism behind this beneficial effect of insulin may be its impact on inhibiting lypolysis, reducing free fatty acid concentrations and improving myocardial glucose use,49 as well as its antithrombotic,52,53 anti-inflammatory, and vasodilatory properties.54

Even though we could not definitively establish the exact mechanism for the interaction between glucose, adverse outcomes, and diabetes status, a possible explanation is that some hyperglycemic AMI patients without a history of diabetes (particularly those with glucose >240 mg/dL) are true diabetics who have been neither diagnosed nor adequately managed and thus may represent a higher-risk cohort. A few small reports have suggested that between 25% and 70% of these patients may in fact have undiagnosed diabetes.16,55,56 In addition, our data demonstrate that hyperglycemic patients without recognized diabetes were treated with insulin much less frequently than those with established diabetes. Given reported toxic effects of elevated glucose on ischemic myocardium48,49 and potential benefits of stringent glucose control in patients with AMI,42,49,52–54 this therapeutic difference may have partially accounted for the disparity in outcomes. Alternative explanations for the interaction between glucose and diabetes status also exist. It is likely that a substantial proportion of hyperglycemic patients without a history of diabetes had at least an underlying insulin resistance, which may have conferred higher risk of mortality, as suggested by others.57 Finally, it is also possible that a greater degree of stress was required for a nondiabetic patient to achieve the same hyperglycemic state as a diabetic counterpart. Previous studies have demonstrated that nondiabetic AMI patients with hyperglycemia have substantially elevated catecholamine levels,10 which could induce endothelial dysfunction and thrombosis and impair myocardial metabolism.49,58 However, we have controlled for multiple clinical indicators of disease severity in our multivariable model. Thus, greater severity of illness among patients without recognized diabetes is an unlikely explanation for our findings.

Our study has certain limitations. Given its retrospective nature, a possibility of residual confounding by unmeasured factors cannot be eliminated. However, the effect of glucose on outcomes persisted after extensive adjustment for AMI severity and burden of comorbidities. Our analysis was limited to admission glucose values. Therefore, we could not determine how many patients with elevated glucose on admission had persistent hyperglycemia during hospitalization, and we could not assess the effectiveness of in-hospital insulin therapy or its relation to outcomes. It is possible that some AMI patients without recognized diabetes were not treated with insulin because their hyperglycemia did not persist. Because glycosylated hemoglobin levels were not collected and the follow-up information was limited, we do not know how many of those patients without recognized diabetes were diagnosed with diabetes after discharge. Finally, because our study was limited to patients ≥65 years of age, the results may not apply to younger patients with AMI.

In conclusion, elevated glucose is common, rarely treated, and associated with a much greater increase in the risk of death among AMI patients without antecedent history of diabetes compared with diabetics. Aggressive glycemic control during hospitalization and appropriately stringent follow-up, diabetes screening, and risk factor modification may represent opportunities to improve care in this group of patients.


*    Acknowledgments
 
Dr Kosiborod is supported by the Robert Wood Johnson Foundation Clinical Scholars Program; Saif Rathore is supported by NIH/National Institute of General Medical Sciences Medical Scientist Training Grant GM07205; and Dr Masoudi is supported by NIH Research Career Award K08-AG01011.

Disclosure

The analyses on which this publication is based were performed under contract 500-02-C0-01, Utilization and Quality Control Peer Review Organization for the State of Colorado, sponsored by the Centers for Medicare and Medicaid Services (CMS, formerly the Health Care Financing Administration), Department of Health and Human Services. The content of the publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. The authors assume full responsibility for the accuracy and completeness of the ideas presented. This article is a direct result of the Health Care Quality Improvement Program initiated by CMS, which has encouraged identification of quality improvement projects from analysis of patterns of care, and therefore required no special funding on the part of this contractor. Ideas and contributions to the authors concerning experiences in engaging with issues presented are welcomed.


*    Footnotes
 
Guest Editor for this article is Gregory L. Burke, MD, MSc.


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