FOREWORD
Insulin as a Cardiovascular Therapeutic: Improving Glycemic Control in Patients With Coronary Artery Disease
Carl J. Pepine, MD, MACC*
Division of Cardiovascular Medicine, University of Florida College of Medicine, Gainesville, Florida
Manuscript received April 3, 2008;
accepted April 28, 2008.
* Reprint requests and correspondence: Dr. Carl J. Pepine, University of Florida College of Medicine, Division of Cardiovascular Medicine, 1600 SW Archer Road, Box 100277, Gainesville, Florida 32610-0277 (Email: Carl.Pepine{at}medicine.ufl.edu).
Established in 1994, the Vascular Biology Working Group (VBWG) is organized under the auspices of the University of Florida College of Medicine. Through regional, national, and international meetings, publications, and other educational activities, the VBWG encourages the review, exchange, and assimilation of research data. VBWG activities gather together experts from diverse specialties to provide a comprehensive, multidisciplinary perspective on emerging cardiovascular issues. The present supplement is a collection of articles on the cardiovascular implications of endogenous and exogenous insulin.
A high prevalence of hyperglycemia among acute myocardial infarction (AMI) patients without known diabetes mellitus was recognized as early as 1931 (1), and more recently, the enormous magnitude and consequences of this finding have been noted (2–6). These data indicate that up to one-half of hospitalized AMI patients have elevated blood sugars (2) and that this finding is associated with increased risk for adverse outcomes among those with or without prior documented diabetes. In 1 recent study of 141,680 AMI patients, one-half of the patients had a glucose level on admission  150 mg/dl (3). In pooled data from 11 trials in acute coronary syndrome (ACS) patients, diabetes was associated with excess in-hospital, 30-day, and 1-year mortality rates (4). In other studies, the risk increase was even greater when diabetes was accompanied by hyperglycemia than it was for patients with diabetes and normal admission glucose levels (2). Importantly, patients with admission hyperglycemia but without known diabetes had an almost 4-fold increase in risk of in-hospital death compared with patients without diabetes and with normal admission glucose levels. Thus, it is clear that hyperglycemia among ACS patients is a very common and important clinical problem deserving closer attention (5).
These findings assume even greater implications in light of the relentless rise in obesity and associated cardiometabolic syndrome occurring in the U.S. and worldwide (6). Accordingly, this supplement was developed to gather perspectives and to share new data on this important clinical problem. We have assembled subject matter experts from cardiovascular medicine and endocrinology to provide overviews of selected aspects of the issue of ACS and hyperglycemia, with its implications and management.
The supplement begins with Dr. Heinrich Schelbert (7) reviewing functional disturbances of the coronary circulation that are associated with insulin resistance. Using radiotracer-based techniques to make noninvasive assessments of coronary artery reactivity in response to various stressors, his studies have led to significant advances in this area. He makes the point that the high mortality rate associated with insulin resistance states is, at it least in part, related to functional, rather than structural, disturbances of the vasculature. These primarily involve endothelium, leading to impairment of antiatherosclerotic properties, which then promote the development of atherosclerosis.
In the next article, Drs. Antonio Ceriello, Stuart W. Zarich, and Roberto Testa (8) discuss clinical studies highlighting novel strategies for glycemic control in hospitalized patients. They clarify some of the confusion associated with intravenous infusion by glucose-insulin-potassium cocktails used in early studies versus newer strategies to maintain tight glycemic control as early as possible in ACS with insulin infusion. They conclude that among patients in critical care units, intensive glucose control in-hospital reduces all-cause mortality and cardiovascular risk, and clearly lowers the risk of renal disease.
Then, Dr. Paresh Dandona and colleagues (9) summarize the anti-inflammatory and antioxidant actions of insulin. Not only does insulin induce endothelial nitric oxide release and suppress several important inflammatory mediators, it also induces platelet synthesis and inhibits platelet aggregation. They outline the rationale for use of insulin in ACS.
Next, Dr. Edward S. Horton (10) provides a very concise overview of the current state of management of diabetes for cardiovascular specialists. He discusses the use of long- and short-acting insulins, either separately or in pre-mixed preparations, in an approach to target euglycemia that should be driven by regular monitoring of glycemic control. He provides an excellent update on the mechanisms of action and characteristics of oral antihyperglycemic agents and injectable peptide hormones used to treat type 2 diabetes.
Drs. Cooper-DeHoff, Pacanowski, and I (11) deal with the metabolic effects of commonly prescribed cardiovascular medications and suggest strategies for tailoring treatment regimens to minimize adverse cardiometabolic impact. We conclude that identification of patients at risk for hyperglycemia should be part of cardiovascular therapeutics, with the plan to avoid drugs that cause or aggravate hyperglycemia whenever possible.
Finally, Drs. Orasanu and Plutzky (12) put their collection of papers into perspective relative to the inter-relationships between macrovascular and microvascular disease in diabetes. This is truly a critical overview of this difficult topic.
In summary, hyperglycemia in the setting of ACS carries enormous consequences, and a heightened awareness of patients at risk should lead to earlier recognition and improved management that will reduce the risks for adverse outcomes.
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Footnotes
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Dr. Pepine has received grant/research support from or has consultant agreements with AstraZeneca, Boehringer-Ingelheim, CV Therapeutics, Pfizer, Sanofi-Aventis, Schering-Plough, Daiichi-Sankyo/Lilly, and Merck.
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References
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1. Cruikshank N. Coronary thrombosis and myocardial infarction with glycosuria BMJ 1931;1:618-619.[Free Full Text]2. Capes SE, Hunt D, Malmberg K, Gerstein HC. Stress hyperglycaemia and increased risk of death after myocardial infarction in patients with and without diabetes: a systematic overview Lancet 2000;355:773-778.[CrossRef][Web of Science][Medline] 3. Kosiborod M, Rathore SS, Inzucchi SE, et al. Admission glucose and mortality in elderly patients hospitalized with acute myocardial infarction: implications for patients with and without recognize diabetes Circulation 2005;111:3078-3086.[Abstract/Free Full Text] 4. Donahoe SM, Stewart GC, McCabe CH, et al. Diabetes and mortality following acute coronary syndromes JAMA 2007;298:765-775.[Abstract/Free Full Text] 5. Deedwania P, Kosiborod M, Barrett E, et al. Hyperglycemia and acute coronary syndrome: a scientific statement from the American Heart Association Diabetes Committee of the Council on Nutrition, Physical Activity, and Metabolism Circulation 2008;117:1610-1619.[Abstract/Free Full Text] 6. Fox CS, Coady S, Sorlie PD, et al. Increasing cardiovascular disease burden due to diabetes mellitus. The Framingham Heart Study. Circulation 2007;115:1544-1550.[Abstract/Free Full Text] 7. Schelbert HR. Coronary circulatory function abnormalities in insulin resistance: insights from positron emission tomography J Am Coll Cardiol 2009;53(Suppl S):S3-S8.[Abstract/Free Full Text] 8. Ceriello A, Zarich SW, Testa R. Lowering glucose to prevent adverse cardiovascular outcomes in a critical care setting J Am Coll Cardiol 2009;53(Suppl S):S9-S13.[Abstract/Free Full Text] 9. Dandona P, Chaudhuri A, Ghanim H, Mohanty P. Insulin as an anti-inflammatory and antiatherosclerotic modulator J Am Coll Cardiol 2009;53(Suppl S):S14-S20.[Abstract/Free Full Text] 10. Horton ES. Defining the role of basal and prandial insulin for optimal glycemic control J Am Coll Cardiol 2009;53(Suppl S):S21-S27.[Abstract/Free Full Text] 11. Cooper-DeHoff RM, Pacanowski MA, Pepine CJ. Cardiovascular therapies and associated glucose homeostasis: implications across the dysglycemia continuum J Am Coll Cardiol 2009;53(Suppl S):S28-S34.[Abstract/Free Full Text] 12. Orasanu G, Plutzky J. The continuum of diabetic vascular disease: from macro to micro J Am Coll Cardiol 2009;53(Suppl S):S35-S42.[Abstract/Free Full Text]
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