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A “touch of sugar” can be fatal
Editorial
A “touch of sugar” can be fatal Charles M. Clark, Jr, MD, and R. Clark Perry, DO Indianapolis, Ind
See related article on page 919. In this issue of the Journal, Brand et al1 report (see page 919) the effects of peripheral artery disease and glucose intolerance on subsequent cardiovascular events, defined as the development of coronary disease, heart failure, or stroke. They observe that the presence of carotid or femoral bruits alone is associated with increased cardiovascular events of 1.5 and 2.4 times, respectively, in men and 1.5 and 1.8 times in women. Absent pedal pulses yields event rates of 4.4 times in men and 3.9 in women. Additionally, these rates are roughly doubled when glucose intolerance is also present. This study expands previous Framingham data in demonstrating the significant cardiovascular morbidity and mortality rates associated with abnormal glucose metabolism.2 When combined with other epidemiologic studies, the data suggest that for any given cardiovascular risk factor, or combination thereof, diabetes increases the risk of cardiovascular deaths or events by 2- to 4-fold.2-4 The atherosclerotic events associated with diabetes have become significant public health issues. Three separate epidemiologic studies have shown major cardiac event rates of approximately 5% per year in persons with type 2 diabetes.5-7 Despite affecting 3% of the US population,8 type 2 diabetes accounts for 17% of all deaths in this country,9 65% of which are caused by cardiovascular events.9 In 1986, an estimated 342,000 persons died with diabetes. As points of reference, recent US statistics estimate 45,000 deaths will occur this year secondary to breast cancer as well as prostate cancer10 and acquired immunodeficiency syndrome.11 The article by Brand et al defines glucose intolerance as a casual glucose ≥140 mg/dL (7.8 mmol/L) or treatment with hypoglycemia agents. We currently define diabetes as a fasting glucose >125 mg/dL (7
From Regenstrief Institute for Health Care, Richard Roudebush Veterans Affairs Medical Center, Indiana University Medical School, Dept. of Internal Medicine, Division of Endocrinology and Metabolism. Reprint requests: Charles M. Clark, Jr, MD, Indiana University Medical Center, Regenstrief Health Center, 1001 W 10th Street, 5th Floor, Indianapolis, IN 46202. Am Heart J 1998;136:762-4. 0002-8703/98/$5.00 + 0 4/1/91933
mmol/L) or a 2-hour postprandial glucose of ≥200 mg/dL (11.1 mmol/L).12 Thus the population reported consists of a combination of what we now define as glucose intolerance and type 2 diabetes. To determine at what level the concentration of glucose becomes associated with increased risk for cardiovascular disease, we must look to other studies. Several studies demonstrate that cardiovascular risk begins at glucose levels below that which currently define diabetes. In an analysis of 20-year follow-up data from the Whitehall, Paris Prospective and the Helsinki Policemen studies of nondiabetic men, those in the upper 20% of postprandial glucose levels, and those in the upper 2.5% of fasting glucose levels had significant increases in all-cause mortality rates.13 Further, those in the upper 2.5% of fasting and postprandial glucose levels had increased mortality rates attributed to cardiovascular events. Because diabetes is defined by glucose levels associated with microvascular disease, these data suggest that the risk for macrovascular disease may begin at a lower glucose concentration than for microvascular disease. This may help explain why nearly 25% of patients have established cardiovascular disease at the time of diagnosis of diabetes.14 Given that, is it fair to ask whether hyperglycemia, per se, is responsible for the increase in vascular disease or one of the other features commonly seen in type 2 diabetes: insulin resistance, obesity, hypertension, and hyperlipidemia? Whereas there are no definitive answers to this question, the preponderance of evidence is that the hyperglycemic state, per se, contributes directly to cardiovascular disease. There is solid epidemiologic evidence relating the HbA1c values to the incidence of cardiovascular events and deaths.5,15,16 Additionally, the hyperglycemic state is associated with platelet and coagulation abnormalities that are readily reversible when glucose levels are normalized.17 Presently, we do not know if reversal of hyperglycemia will decrease subsequent cardiovascular events; nor do we know when that treatment needs to begin. There are no controlled clinical trials addressing macrovascular disease as did the Diabetes Control and Complications Trial (DCCT) for microvascular complications.18 The United Kingdom Prospective Diabetes
American Heart Journal Volume 136, Number 5
Study (UKPDS) group may have some answers to these questions this September when their data are reported after following 5000 newly diagnosed diabetic patients for nearly 20 years.19 As to when to treat, the Diabetes Prevention Program (DPP) should be able to address that issue. This prevention trial will follow 4000 persons at risk for diabetes for 7 years randomized into 3 groups: control, diet and exercise, and metformin, with the primary end point of progression to diabetes and secondary cardiovascular end points. The clinician, however, is faced with the problem of what to do today with the patient in his or her office. Certainly, given the complex nature of cardiovascular disease in diabetes, we must aggressively treat lipids20 and hypertension and provide aspirin unless contraindicated.21 Angiotensin-converting enzyme inhibitors should be the first-line drug in hypertension and should also be used in patients with microalbuminuria, even in the absence of hypertension.22 To address treatment issues of hyperglycemia, we need to look at the relative risks and benefits of intensively treating diabetes. For type 1 diabetes, benefits of improved glucose control on microvascular disease are so overwhelming that there should be no further debate. For every 10% reduction in HbA1c there is a corresponding 40% reduction in microvascular complications.23 These results should apply to type 2 diabetes as well because the pathophysiology of these complications is the same in both types of diabetes.24 The difference between the two types of diabetes is the theoretical risk that increasing insulin concentrations, either endogenously or exogenously, would increase cardiovascular events.25 The problem with that construct is that there are no diabetes trials supporting it, and there are two trials that directly contradict it. The Japanese type 2 trial with intensive insulin therapy demonstrated reductions in microvascular complications similar to the DCCT and reductions in macrovascular events, albeit not significant given the low rate among the Japanese.26 The second study was the DIGAMI trial in which type 2 diabetics with acute myocardial infarction were randomized to receive either intensive insulin therapy or standard care.27 The intensive insulin program consisted of intravenous insulin in the Coronary Care Unit followed by subcutaneous multidose insulin therapy in the outpatient setting. At 1 year, the intensively treated group had a >25% decreased death rate, and this benefit continued after 3 years.28
Clark and Perry 763
As discussed above, diabetes is a significant risk factor for the development of cardiovascular disease and its associated morbidity and mortality rates as demonstrated once again by Dr Brand and colleagues. We conclude that both type 1 and type 2 patients will have significant benefit from the reduction of HbA1c in terms of microvascular disease and possibly cardiovascular disease as well. The goal should be constant for both types of diabetes: HbA1c of 7% or less.24 Even though various treatment regimens (eg, sulfonureas, metformin, acarbose, troglitazone, and insulin) may have individual theoretical advantages or disadvantages, the most important issue is likely to be glucose control. Because type 2 diabetes is characterized by progressive beta-cell failure, most patients with type 2 diabetes will progress from diet therapy only to a single agent to combination therapy and eventually to insulin either alone or in combination with an oral agent. The important premise to remember is to advance the treatment strategy as the disease progresses so that the glycemic goal is maintained. Glucose levels of ≥110 mg/dL are no longer considered “normal.”12 We find it fascinating that cardiologists have debated for years the small but significant benefits of one thrombolytic agent over another in regards to improving survival. On the other hand, how many cardiologists have taken the DIGAMI results seriously and implemented the practice of improving glycemic control given the potentially enormous effects on decreasing morbidity and mortality rates in diabetic patients? It is time to take diabetes seriously!
References 1. Brand FN, Kannel WB, Evans J, Larson MG, Wolf PA. Glucose intolerance, physical signs of peripheral artery disease and risk of cardiovascular events. Am Heart J 1998;136:919-27. 2. Wilson PWF, Kannel WB. Epidemiology of hyperglycemia and atherosclerosis. In: Ruderman N, Williamson J, Brownlee M, editors. Hyperglycemia, diabetes, and vascular disease. New York, NY: Oxford University Press; 1992. p 21-9. 3. Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and 12-year cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 1993;16:434-44. 4. Colwell JA. Clinical trials of antiplatelet agents in diabetes mellitus: rationale and results. Semin Thromb Hemost 1991;17:439-44. 5. Kuusisto J, Mykkanen L, Pyorala K, Laakso M. NIDDM and its metabolic control predict coronary heart disease in elderly subjects. Diabetes 1994;43:960-7. 6. ETDRS Investigators. Aspirin effects on mortality and morbidity in patients with diabetes mellitus: Early Treatment Diabetic Retinopathy Study report 14. JAMA 1992;268:1292-300. 7. Janka HU. Five-year incidence of major macrovascular complications in diabetes mellitus. Horm Metab Res Suppl 1985;15:15-9.
American Heart Journal November 1998
764 Clark and Perry
8. Kenny SJ, Aubert RE, Geiss LS. Prevalence and incidence of non-insulindependent diabetes. In: Harris MI, Cowie CC, Stern MP, Boyko EJ, Reiber GE, Bennett PH, editors. Diabetes in America. 2nd ed. Washington, DC: US Government Printing Office; 1995. p 47-68. 9. Geiss LS, Herman WH, Smith PJ. Mortality in non-insulin-dependent diabetes. In: Harris MI, Cowie CC, Stern MP, Boyko EJ, Reiber GE, Bennett PH, editors. Diabetes in America. 2nd Ed. Washington, DC: US Government Printing Office; 1995. p 233-57. 10. Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics 1998. CA Cancer J Clin 1998;48:6-29. 11. The Centers for Disease Control and Prevention. Update: trends in AIDS incidence, deaths, and prevalence: United States, 1996. JAMA 1997;277:874-5. 12. The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 1998;21(suppl 1): S5-19. 13. Balkau B, Shipley M, Jarrett RJ, et al. High blood glucose concentration is a risk factor for mortality in middle-aged nondiabetic men. Diabetes Care 1998;21:360-7. 14. United Kingdom Prospective Diabetes Study Group. UK Prospective Diabetes Study 6: complications in newly diagnosed type 2 diabetic patients and their association with different clinical and biochemical risk factors. Diabetes Res 1990;13:1-13. 15. Gall M-A, Borch-Johnsen K, Hougaard P, Nielsen FS, Parving H-H. Albuminuria and poor glycemic control predict mortality in NIDDM. Diabetes 1995;44:1303-9. 16. Klein R. Hyperglycemia and microvascular and macrovascular disease in diabetes. Diabetes Care 1995;18:258-68. 17. Sugimoto H, Franks DJ, Lecavalieer L, Chiasson JL, Hamet P. Therapeutic modulation of growth-promoting activity in platelets from diabetics. Diabetes 1987;36:1137-45. 18. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and
19.
20. 21. 22. 23.
24.
25. 26.
27.
28.
progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977-86. United Kingdom Prospective Diabetes Study Group. UK Prospective Diabetes Study (UKPDS). VIII. Study design, progress and performance. Diabetologia 1991;34:877-90. American Diabetes Association. Management of dyslipidemia in adults with diabetes. Diabetes Care 1998;21 (suppl 1):S36-9. Colwell JA. Aspirin therapy in diabetes. Diabetes 1997;20:1767-71. American Diabetes Association. Diabetic nephropathy. Diabetes Care 1998;21 (suppl 1):S50-3. The Diabetes Control and Complications Trial Research Group. The relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the diabetes control and complications trial. Diabetes 1995;44:968-83. American Diabetes Association. Standards of medical care for patients with diabetes mellitus. Diabetes Care 1998;21 (suppl 1): S23-31. Sobel BE. Potentiation of vasculopathy by insulin: implications from an NHLBI clinical alert. Circulation 1996;93:1613-5. Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Prac 1995; 28:103-17. Malmberg K, Ryden L, Efendic S, et al. Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): effects on mortality at 1 year. J Am Coll Cardiol 1995; 26:57-65. Malmberg K. Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction) Study Group. BMJ 1997;314:1512-5.
AVAILABILITY OF JOURNAL BACK ISSUES As a service to our subscribers, copies of back issues of the American Heart Journal for the preceding 5 years are maintained and are available for purchase from Mosby until inventory is depleted, at a cost of $13.00 per issue. The following quantity discounts are available: 25% off on quantities of 12 to 23, and one third off on quantities of 24 or more. Please write to Mosby, Inc., Subscription Services, 11830 Westline Industrial Drive, St. Louis, MO 63146-3318, or call (800)453-4351 or (314)4534351 for information on availability of particular issues. If unavailable from the publisher, photocopies of complete issues may be purchased from UMI, 300 N. Zeeb Rd., Ann Arbor, MI 48106, (313)761-4700.
A “touch of sugar” can be fatal Charles M. Clark, Jr, MD, and R. Clark Perry, DO Indianapolis, Ind
See related article on page 919. In this issue of the Journal, Brand et al1 report (see page 919) the effects of peripheral artery disease and glucose intolerance on subsequent cardiovascular events, defined as the development of coronary disease, heart failure, or stroke. They observe that the presence of carotid or femoral bruits alone is associated with increased cardiovascular events of 1.5 and 2.4 times, respectively, in men and 1.5 and 1.8 times in women. Absent pedal pulses yields event rates of 4.4 times in men and 3.9 in women. Additionally, these rates are roughly doubled when glucose intolerance is also present. This study expands previous Framingham data in demonstrating the significant cardiovascular morbidity and mortality rates associated with abnormal glucose metabolism.2 When combined with other epidemiologic studies, the data suggest that for any given cardiovascular risk factor, or combination thereof, diabetes increases the risk of cardiovascular deaths or events by 2- to 4-fold.2-4 The atherosclerotic events associated with diabetes have become significant public health issues. Three separate epidemiologic studies have shown major cardiac event rates of approximately 5% per year in persons with type 2 diabetes.5-7 Despite affecting 3% of the US population,8 type 2 diabetes accounts for 17% of all deaths in this country,9 65% of which are caused by cardiovascular events.9 In 1986, an estimated 342,000 persons died with diabetes. As points of reference, recent US statistics estimate 45,000 deaths will occur this year secondary to breast cancer as well as prostate cancer10 and acquired immunodeficiency syndrome.11 The article by Brand et al defines glucose intolerance as a casual glucose ≥140 mg/dL (7.8 mmol/L) or treatment with hypoglycemia agents. We currently define diabetes as a fasting glucose >125 mg/dL (7
From Regenstrief Institute for Health Care, Richard Roudebush Veterans Affairs Medical Center, Indiana University Medical School, Dept. of Internal Medicine, Division of Endocrinology and Metabolism. Reprint requests: Charles M. Clark, Jr, MD, Indiana University Medical Center, Regenstrief Health Center, 1001 W 10th Street, 5th Floor, Indianapolis, IN 46202. Am Heart J 1998;136:762-4. 0002-8703/98/$5.00 + 0 4/1/91933
mmol/L) or a 2-hour postprandial glucose of ≥200 mg/dL (11.1 mmol/L).12 Thus the population reported consists of a combination of what we now define as glucose intolerance and type 2 diabetes. To determine at what level the concentration of glucose becomes associated with increased risk for cardiovascular disease, we must look to other studies. Several studies demonstrate that cardiovascular risk begins at glucose levels below that which currently define diabetes. In an analysis of 20-year follow-up data from the Whitehall, Paris Prospective and the Helsinki Policemen studies of nondiabetic men, those in the upper 20% of postprandial glucose levels, and those in the upper 2.5% of fasting glucose levels had significant increases in all-cause mortality rates.13 Further, those in the upper 2.5% of fasting and postprandial glucose levels had increased mortality rates attributed to cardiovascular events. Because diabetes is defined by glucose levels associated with microvascular disease, these data suggest that the risk for macrovascular disease may begin at a lower glucose concentration than for microvascular disease. This may help explain why nearly 25% of patients have established cardiovascular disease at the time of diagnosis of diabetes.14 Given that, is it fair to ask whether hyperglycemia, per se, is responsible for the increase in vascular disease or one of the other features commonly seen in type 2 diabetes: insulin resistance, obesity, hypertension, and hyperlipidemia? Whereas there are no definitive answers to this question, the preponderance of evidence is that the hyperglycemic state, per se, contributes directly to cardiovascular disease. There is solid epidemiologic evidence relating the HbA1c values to the incidence of cardiovascular events and deaths.5,15,16 Additionally, the hyperglycemic state is associated with platelet and coagulation abnormalities that are readily reversible when glucose levels are normalized.17 Presently, we do not know if reversal of hyperglycemia will decrease subsequent cardiovascular events; nor do we know when that treatment needs to begin. There are no controlled clinical trials addressing macrovascular disease as did the Diabetes Control and Complications Trial (DCCT) for microvascular complications.18 The United Kingdom Prospective Diabetes
American Heart Journal Volume 136, Number 5
Study (UKPDS) group may have some answers to these questions this September when their data are reported after following 5000 newly diagnosed diabetic patients for nearly 20 years.19 As to when to treat, the Diabetes Prevention Program (DPP) should be able to address that issue. This prevention trial will follow 4000 persons at risk for diabetes for 7 years randomized into 3 groups: control, diet and exercise, and metformin, with the primary end point of progression to diabetes and secondary cardiovascular end points. The clinician, however, is faced with the problem of what to do today with the patient in his or her office. Certainly, given the complex nature of cardiovascular disease in diabetes, we must aggressively treat lipids20 and hypertension and provide aspirin unless contraindicated.21 Angiotensin-converting enzyme inhibitors should be the first-line drug in hypertension and should also be used in patients with microalbuminuria, even in the absence of hypertension.22 To address treatment issues of hyperglycemia, we need to look at the relative risks and benefits of intensively treating diabetes. For type 1 diabetes, benefits of improved glucose control on microvascular disease are so overwhelming that there should be no further debate. For every 10% reduction in HbA1c there is a corresponding 40% reduction in microvascular complications.23 These results should apply to type 2 diabetes as well because the pathophysiology of these complications is the same in both types of diabetes.24 The difference between the two types of diabetes is the theoretical risk that increasing insulin concentrations, either endogenously or exogenously, would increase cardiovascular events.25 The problem with that construct is that there are no diabetes trials supporting it, and there are two trials that directly contradict it. The Japanese type 2 trial with intensive insulin therapy demonstrated reductions in microvascular complications similar to the DCCT and reductions in macrovascular events, albeit not significant given the low rate among the Japanese.26 The second study was the DIGAMI trial in which type 2 diabetics with acute myocardial infarction were randomized to receive either intensive insulin therapy or standard care.27 The intensive insulin program consisted of intravenous insulin in the Coronary Care Unit followed by subcutaneous multidose insulin therapy in the outpatient setting. At 1 year, the intensively treated group had a >25% decreased death rate, and this benefit continued after 3 years.28
Clark and Perry 763
As discussed above, diabetes is a significant risk factor for the development of cardiovascular disease and its associated morbidity and mortality rates as demonstrated once again by Dr Brand and colleagues. We conclude that both type 1 and type 2 patients will have significant benefit from the reduction of HbA1c in terms of microvascular disease and possibly cardiovascular disease as well. The goal should be constant for both types of diabetes: HbA1c of 7% or less.24 Even though various treatment regimens (eg, sulfonureas, metformin, acarbose, troglitazone, and insulin) may have individual theoretical advantages or disadvantages, the most important issue is likely to be glucose control. Because type 2 diabetes is characterized by progressive beta-cell failure, most patients with type 2 diabetes will progress from diet therapy only to a single agent to combination therapy and eventually to insulin either alone or in combination with an oral agent. The important premise to remember is to advance the treatment strategy as the disease progresses so that the glycemic goal is maintained. Glucose levels of ≥110 mg/dL are no longer considered “normal.”12 We find it fascinating that cardiologists have debated for years the small but significant benefits of one thrombolytic agent over another in regards to improving survival. On the other hand, how many cardiologists have taken the DIGAMI results seriously and implemented the practice of improving glycemic control given the potentially enormous effects on decreasing morbidity and mortality rates in diabetic patients? It is time to take diabetes seriously!
References 1. Brand FN, Kannel WB, Evans J, Larson MG, Wolf PA. Glucose intolerance, physical signs of peripheral artery disease and risk of cardiovascular events. Am Heart J 1998;136:919-27. 2. Wilson PWF, Kannel WB. Epidemiology of hyperglycemia and atherosclerosis. In: Ruderman N, Williamson J, Brownlee M, editors. Hyperglycemia, diabetes, and vascular disease. New York, NY: Oxford University Press; 1992. p 21-9. 3. Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and 12-year cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 1993;16:434-44. 4. Colwell JA. Clinical trials of antiplatelet agents in diabetes mellitus: rationale and results. Semin Thromb Hemost 1991;17:439-44. 5. Kuusisto J, Mykkanen L, Pyorala K, Laakso M. NIDDM and its metabolic control predict coronary heart disease in elderly subjects. Diabetes 1994;43:960-7. 6. ETDRS Investigators. Aspirin effects on mortality and morbidity in patients with diabetes mellitus: Early Treatment Diabetic Retinopathy Study report 14. JAMA 1992;268:1292-300. 7. Janka HU. Five-year incidence of major macrovascular complications in diabetes mellitus. Horm Metab Res Suppl 1985;15:15-9.
American Heart Journal November 1998
764 Clark and Perry
8. Kenny SJ, Aubert RE, Geiss LS. Prevalence and incidence of non-insulindependent diabetes. In: Harris MI, Cowie CC, Stern MP, Boyko EJ, Reiber GE, Bennett PH, editors. Diabetes in America. 2nd ed. Washington, DC: US Government Printing Office; 1995. p 47-68. 9. Geiss LS, Herman WH, Smith PJ. Mortality in non-insulin-dependent diabetes. In: Harris MI, Cowie CC, Stern MP, Boyko EJ, Reiber GE, Bennett PH, editors. Diabetes in America. 2nd Ed. Washington, DC: US Government Printing Office; 1995. p 233-57. 10. Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics 1998. CA Cancer J Clin 1998;48:6-29. 11. The Centers for Disease Control and Prevention. Update: trends in AIDS incidence, deaths, and prevalence: United States, 1996. JAMA 1997;277:874-5. 12. The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 1998;21(suppl 1): S5-19. 13. Balkau B, Shipley M, Jarrett RJ, et al. High blood glucose concentration is a risk factor for mortality in middle-aged nondiabetic men. Diabetes Care 1998;21:360-7. 14. United Kingdom Prospective Diabetes Study Group. UK Prospective Diabetes Study 6: complications in newly diagnosed type 2 diabetic patients and their association with different clinical and biochemical risk factors. Diabetes Res 1990;13:1-13. 15. Gall M-A, Borch-Johnsen K, Hougaard P, Nielsen FS, Parving H-H. Albuminuria and poor glycemic control predict mortality in NIDDM. Diabetes 1995;44:1303-9. 16. Klein R. Hyperglycemia and microvascular and macrovascular disease in diabetes. Diabetes Care 1995;18:258-68. 17. Sugimoto H, Franks DJ, Lecavalieer L, Chiasson JL, Hamet P. Therapeutic modulation of growth-promoting activity in platelets from diabetics. Diabetes 1987;36:1137-45. 18. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and
19.
20. 21. 22. 23.
24.
25. 26.
27.
28.
progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977-86. United Kingdom Prospective Diabetes Study Group. UK Prospective Diabetes Study (UKPDS). VIII. Study design, progress and performance. Diabetologia 1991;34:877-90. American Diabetes Association. Management of dyslipidemia in adults with diabetes. Diabetes Care 1998;21 (suppl 1):S36-9. Colwell JA. Aspirin therapy in diabetes. Diabetes 1997;20:1767-71. American Diabetes Association. Diabetic nephropathy. Diabetes Care 1998;21 (suppl 1):S50-3. The Diabetes Control and Complications Trial Research Group. The relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the diabetes control and complications trial. Diabetes 1995;44:968-83. American Diabetes Association. Standards of medical care for patients with diabetes mellitus. Diabetes Care 1998;21 (suppl 1): S23-31. Sobel BE. Potentiation of vasculopathy by insulin: implications from an NHLBI clinical alert. Circulation 1996;93:1613-5. Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Prac 1995; 28:103-17. Malmberg K, Ryden L, Efendic S, et al. Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): effects on mortality at 1 year. J Am Coll Cardiol 1995; 26:57-65. Malmberg K. Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction) Study Group. BMJ 1997;314:1512-5.
AVAILABILITY OF JOURNAL BACK ISSUES As a service to our subscribers, copies of back issues of the American Heart Journal for the preceding 5 years are maintained and are available for purchase from Mosby until inventory is depleted, at a cost of $13.00 per issue. The following quantity discounts are available: 25% off on quantities of 12 to 23, and one third off on quantities of 24 or more. Please write to Mosby, Inc., Subscription Services, 11830 Westline Industrial Drive, St. Louis, MO 63146-3318, or call (800)453-4351 or (314)4534351 for information on availability of particular issues. If unavailable from the publisher, photocopies of complete issues may be purchased from UMI, 300 N. Zeeb Rd., Ann Arbor, MI 48106, (313)761-4700.