Medical Management of Diabetes and Heart Disease - part 10 potx

Nonpharmacological Risk Reduction 269 9. Improved quality of life and self-esteem, and reduced psychological stress. The primary side effect of acute exercise is hypoglycemia. Patients require specific guidelines either to increase carbohydrate consumption or to decrease medication based on the intensity of exercise and relationship of the planned exercise to the timing of the next meal. For those attempting to lose weight, medication adjustment is chosen over adding extra calories. For some, exercise after a meal without medication adjustment is preferred. Postexercise, late-onset hypoglycemia (PEL) occurs several hours following an exercise session and is a significant concern for those treated with insulin or insulin secretagogues. Post- exercise late-onset hypoglycemia can be the result of acutely increased insulin mobilization and sensitivity, increased glucose utilization, replenishment of gly- cogen stores, and defective counterregulatory mechanisms. Patients need to learn how to prevent PEL by remembering to supplement carbohydrates during the postexercise phase, to reduce the dose of insulin that peaks during the postexer- cise phase, and to monitor blood glucose frequently. The American Diabetes Association recommends a graded exercise test for patients at high risk for underlying cardiovascular disease based on the following criteria (16): age Ͼ35 years; type 2 diabetes of Ͼ10 years duration; type 1 diabe- tes of Ͼ15 years duration; presence of any additional risk factor for coronary artery disease; presence of microvascular disease (including microalbuminuria); peripheral vascular disease; and autonomic neuropathy. Rhythmic exercises with the use of the lower extremities, such as walking or cycling, are safely recommended. Patients with established cardiovascular dis- ease usually require supervision in a monitored cardiac rehabilitation program. Unfortunately, little is known about how to increase or maintain participation in exercise programs. Relapse is common and all health care providers play a role in supporting patients in their efforts at exercise. V. QUALITY OF LIFE AND OBSTACLES TO CARE The delivery of diabetes care and education has undergone a paradigm shift from giving advice and blaming the patient for failure to providing patients with the choice of aggressive, individualized treatment and an education plan tailored to their needs. This shift has melded health care providers and patients as partners in managing a devastating disease. The demands for daily self-management of diabetes are so formidable that each component of the diabetes education curricu- lum includes discussion of the psychosocial needs of the patient. The embar- rassment of hypoglycemia and resultant fear, the social aspects of eating and dealing with well-meaning family members who comment on food choices, the 270 Peragallo-Dittko sense of failure associated with elevated blood glucose readings despite a sincere effort, and the frustrations of needing medication when self-image associates pill taking with the sick role are a few examples of the psychosocial complexities. Effective diabetes education begins with listening to the patient and his percep- tion of life with diabetes. Health care professionals can identify with patients who cannot manage to follow every single diabetes management recommendation because we cannot follow them either. Regardless of type of management, such as fee-for-service or managed care, chart reviews suggest that only about 50% of patients are asked to have their HbA1c measured even once a year, despite a recommendation for screening every 6 months. An even smaller proportion of patients are being screened on an annual basis for such complications as hyperlipidemia, retinopa- thy, proteinuria, or foot pathology. The compelling evidence that tight control of blood glucose, blood pressure, and lipids provides measurable improvement in outcomes warrants new initiatives. For both patients and health professionals, the opportunities and challenges are abundant. REFERENCES 1. Bantle JP, Swanson JE, Thomas W, Laine DC. Metabolic effects of dietary sucrose in type II diabetic subjects. Diabetes Care 1993;16:1301–1305. 2. Peterson DB, Lambert J, Gerring S, Darling P, Carter RD, Jelfs R, Mann JI. Sucrose in the diet of diabetic patients—just another carbohydrate? Diabetologia 1986;29: 216–220. 3. Brownell KD, Wadden TA. Etiology and treatment of obesity: understanding a seri- ous, prevalent, and refractory disorder. J Consult Clin Psychol 1992;60:505–517. 4. Foreyt JP. Issues in the assessment and treatment of obesity. J Consult Clin Psychol 1987;55:677–684. 5. Wing RR, Blair EH, Bononi P, Marcus MD, Watanabe R, Bergman RN. Caloric restriction per se is a significant factor in improvements in glycemic control and insulin sensitivity during weight loss in obese NIDDM patients. Diabetes Care 1994; 17:30–36. 6. Kelley DE, Wing R, Buonocore C. Sturis J, Polonsky K, Fitzsimmons M. Relative effects of calorie restriction and weight loss in non-insulin-dependent diabetes melli- tus. J Clin Endocrinol Metab 1993;77:1287–1293. 7. Wing RR, Koeske R, Epstein LH, Nowak MP, Gooding W, Becker D. Long-term effects of modest weight loss in type II diabetic patients. Arch Intern Med 1987; 147:1749–1753. 8. Watts NB, Spanheimer RG, DiGirolamo M, Gebhart SS, Musey VC, Siddiq YK, Phillips LS. Prediction of glucose response to weight loss in patients with non- insulin-dependent diabetes mellitus. Arch Intern Med 1990;150:803–806. 9. Franz MJ, Horton ES Sr, Bantle JP, Beebe CA, Brunzell JD, Coulston AM, Henry Nonpharmacological Risk Reduction 271 RR, Hoogwerf BJ, Stacpook PW. Nutrition principles for the management of diabe- tes and related complications: a technical review. Diabetes Care 1994;17:490–518. 10. Rubin RR, Peyrot M, Saudek, CD. The effect of a diabetes education program incor- porating coping skills training on emotional well-being and diabetes self-efficacy. Diabetes Educ 1993;19:210–214. 11. Bastyr III EJ, Stuart CA, Brodows RG, Schwartz S, Graf CJ, Zagar A, Robertson KE. Therapy focused on lowering postprandial glucose, not fasting glucose, may be superior for lowering HbA1c. Diabetes Care 2000;23:1236–1241. 12. Haire-Joshu D, Glasgow RE, Tibbs, TL. Smoking and diabetes. Diabetes Care 1999; 22:1887–1898. 13. Eriksson KF, Lindgarde F. Prevention of type II diabetes mellitus by diet and physi- cal exercise. The 6 year Malmo Feasibility Study. Diabetologia 1991;34:891–898. 14. Schneider SH, Khachadurian AK, Amorosa LF, Clemow L, Ruderman NB. Ten- year experience with an exercise-based outpatient lifestyle modification program in the treatment of diabetes mellitus. Diabetes Care 1992;15(suppl 4):1800–1810. 15. Vanninen E, Uusitupa M, Siitonen O, Laitinen J, Lansimies E. Habitual physical activity, aerobic capacity, and metabolic control in patients with newly diagnosed type II diabetes mellitus: effect of a 1-year diet and exercise intervention. Diabeto- logia 1992;35:340–346. 16. American Diabetes Association. Diabetes mellitus and exercise. Diabetes Care 2000; 23:S50–S54. 17. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 2001; 285:2486–2497. 18. American Diabetes Association. Management of dyslipidemia in adults with diabe- tes. Diabetes Care 2001;24:S58–S61. 19. Franz MJ, Kulkarni K, Daly AS, Gillespie SJ. In: Funnell MM, Hunt C, Kulkarni K, Rubin RR, Yarborough PC, eds. A Core Curriculum for Diabetes Education, 3rd ed. Chicago: American Association of Diabetes Educators, 1998:211. 16 Future Directions: Elucidation of Mechanisms as Targets for Therapy David J. Schneider and Burton E. Sobel University of Vermont, Burlington, Vermont Optimal treatment of patients with diabetes requires an understanding of the mechanisms underlying the disease. Treatment must be designed not only to con- trol hyperglycemia but also to prevent or retard complications that result from diverse processes underlying the development of diabetes. This chapter will focus on the therapeutic promise of elucidation of such processes and their cardiovascu- lar consequences. All diabetic subjects exhibit hyperglycemia. Yet hyperglycemia is only the tip of an iceberg of abnormalities in carbohydrate, lipid, and protein metabolism. Although insulin deficiency is the hallmark of type 1 diabetes, 90% of diabetic subjects suffer from type 2 diabetes, a disorder of dysinsulinemia. For decades before its onset, insulin resistance and compensatory increases in the concentra- tion of insulin and its precursors in blood are present, particularly postprandially. Impaired glucose tolerance occurs eventually as compensatory mechanisms fail. Early treatment may delay the onset of frank diabetes and prevent or retard the development of cardiovascular complications. Diabetes per se, independent of coexistent cardiovascular risk factors, ac- celerates the progression of cardiovascular disease. In addition, diabetes acts synergistically with other determinants of cardiac risk such as hypertension and hyperlipidemia. The specific pathways involved must be identified to optimize prevention of the resultant cardiovascular sequelae. 273 274 Schneider and Sobel I. TREATMENT OF THE HORMONAL AND METABOLIC ABNORMALITIES OF DIABETES Control of hyperglycemia retards progression of microvascular disease in both type 1 and type 2 diabetes. Accordingly, stringent glycemic control is imperative. Yet glycemic control exerts only a modest impact in retarding progression of macrovascular disease. Clearly other steps are needed. The recently initiated BARI 2D trial has been designed to provide informa- tion useful in this regard. Patients are being assigned randomly to stringent and comparable glycemic control with regimens that are either insulin-sensitizing (fo- cusing on glitazones and metformin) or inulin-providing (focusing on insulin and sulfonylureas) regimens. Thus, the potential value of reduction of insulin resis- tance is being assessed. The effects of the two approaches on activation of coagu- lation, platelets, and fibrinolysis will be clarified as well. Because patients with type 2 diabetes are insulin-resistant, provision of exogenous insulin may be the most successful means for providing an adequate supply of substrate for energy in injured cells. By contrast, provision of additional insulin may have potentially deleterious effects such as promoting thrombosis. The provision of insulin may increase the potential for thrombin generation, in- creased reactivity of platelets, and decrease the fibrinolytic response. In combina- tion, these effects may exacerbate thrombosis, predispose to reocclusion of in- farct-related vessels, and delay resolution of thrombotic occlusion. Accordingly, treatment with insulin in the setting of acute myocardial infarction may entail risk. In addition, induction of hypoglycemic episodes may be particularly delete- rious in association with myocardial ischemia. Thus, further study is needed to determine the nature of optimal metabolic control and the method by which it can best be achieved. Nevertheless, results in the DIGAMI study demonstrated that stringent gly- cemic control at the time of occurrence of acute myocardial infarction reduces the incidence of subsequent cardiac events. The improved outcome is consistent with previously demonstrated beneficial effects of infusion of glucose, insulin, and potassium in nondiabetic subjects who sustain an acute myocardial infarction. II. ATHEROGENESIS IN DIABETES The traditional concept that atherogenesis is an orderly process of progressive luminal encroachment leading ultimately to occlusion has been refined. Both plaque evolution and occlusion of vessels often reflect precipitous and often re- peated rupture of vulnerable atherosclerotic plaques. Thus, rupture of vulnerable plaques is the most common proximate cause of acute coronary syndromes. Such plaques are characterized by a high lipid content, a thin, relatively acellular cap, a paucity of vascular smooth muscle cells, and inflammatory cells, particularly Future Directions 275 macrophages, in the shoulder regions. The substrate for plaque rupture is a lipid- laden, often necrotic core with an overlying acellular fibrous cap. Initiators of rupture can be intrinsic to the plaque, such as activation of matrix metallopro- teinases by macrophages in the shoulder region, or extrinsic, such as high shear forces exerted by nonlaminar flow of blood. Diabetes accelerates evolution of vulnerable plaques. How it does so is being explored vigorously so that novel and effective prophylactic and therapeutic targets can be identified. Diabetic subjects (regardless of symptoms) should be treated to lower LDL cholesterol below 100 mg/dL to reduce the evolution of vulnerable plaques. Be- cause diabetes is associated with increased small dense LDL and oxidized LDL, each atherogenic treatment should be designed to reduce their concentrations. Paradoxically, migration of smooth muscle cells into the neointima may protect against plaque vulnerability. Thus, increased cellularity of the cap region appears to reduce the risk of plaque rupture. Cell surface proteolysis mediated by plasminogen activators (urokinase type and tissue type) is critical in migration. Accordingly, the balance between plasminogen activators and their primary in- hibitor, plasminogen activator inhibitor type-1 (PAI-1), is likely to be one deter- minant of neointimal cellularity. Patients with diabetes have increased concentra- tions of PAI-1 in blood and in vessel walls. Modulation of expression of these proteins is likely to become a target for treatment. Inflammation, reflected by markers in blood such as C-reactive protein, is increased in subjects predisposed to plaque rupture. Diabetes appears to intensify inflammation and the deleterious effects of inflammation. Elucidation of interac- tions between diabetes and inflammation should lead to novel treatment strategies to prevent or retard coronary atherogenesis sequelae such as acute coronary syn- dromes precipitated by plaque rupture. The prevalence of hypertension in diabetic subjects is high. This condition increases external mechanical forces on vulnerable plaques and promotes plaque rupture or erosion. Altered flow attributable to atherosclerotic plaque contributes. The association between hypertension and plaque rupture underlies the need for aggressive control of blood pressure (to a target of less than 130/85). Even more aggressive control may be beneficial in reducing the incidence of cardiac events. Therapy with ACE inhibitors and/or angiotensin-1 receptor blockers may be par- ticularly useful because of its nephroprotective effects. In addition, it may nor- malize deranged fibrinolysis attributable to angiotensin-dependent synthesis of PAI-1. III. ATHEROGENESIS IN THE PREDIABETIC STATE The 15% incidence of cardiac death in the first 10 years after the diagnosis of diabetes emphasizes the profound acceleration of progression of atherosclerosis that occurs long before diabetes becomes overt. The prediabetic state provides 276 Schneider and Sobel particularly fertile ground for germination of vulnerable plaques. Thus, a focus on treatment in the prediabetic state is likely to be important in preventing cardio- vascular events later in ultimately diabetic subjects. One example is women with the polycystic ovary syndrome. These subjects are insulin-resistant and often have postprandial hyperglycemia. They are also often hypertensive. They are at in- creased risk for coronary artery disease. Accordingly, therapy designed to amelio- rate insulin resistance is under intense investigation. IV. THROMBOSIS COMPLICATING PLAQUE RUPTURE Diabetes increases the risk of thrombosis complicating plaque rupture. Accord- ingly, diabetic compared with nondiabetic subjects are more likely to be the vic- tims of acute coronary syndromes including myocardial infarction and unstable angina and of sudden cardiac death secondary to thrombosis in response to plaque rupture. Exaggerated thrombosis can predispose to recurrent events and to accel- erated progression of atherosclerosis. Accordingly, mechanisms of prothrombosis must be delineated and their therapeutic implications exploited. Diabetes exerts complex and diverse effects leading to activation of coagu- lation. Thrombin generation and activity are increased, platelets are primed, and the fibrinolytic response is impaired because of increased expression of PAI-1. The causes are attributable to both hormonal and metabolic abnormalities char- acteristic of diabetes. Accordingly, optimal treatment of diabetes that achieves metabolic control and normalizes the hormonal abnormalities should attenuate the prothrombotic state. In the BARI 1 study, percutaneous coronary intervention in patients with diabetes was found to be followed by increased cardiac mortality over 5 years. One mechanism contributing to the negative outcome may have been the exagger- ated thrombotic response to vessel injury. Results in subsequent studies have shown that treatment with powerful antiplatelet agents (glycoprotein IIb-IIIa in- hibitors) reduces the incidence of complications after coronary intervention and in patients with acute coronary syndromes. Beneficial effects are particularly pro- nounced in diabetic subjects. A reduction in mortality 6 months after coronary intervention is evident in diabetic subjects treated with abciximab during the procedure. Treatment with tiroliban of patients with acute coronary syndromes reduces markedly their risk of complications over the next 30 days. V. CARDIOMYOPATHY AND DIABETES Induction of cardiomyopathic changes in hearts of animals rendered insulin defi- cient is a well-recognized phenomenon. Accordingly, the term ‘‘diabetic cardio- Future Directions 277 myopathy’’ has been extant for decades. Implicated derangements include im- paired function of the sarcoplasmic reticulum, an organelle responsible for the uptake and release of intracellular calcium and, therefore, pivotal in modulating cardiac contractility. However, cardiomyopathy changes may not be related ex- clusively to metabolic derangements typical of insulin deficiency. They occur also in hearts of patients with type 2 diabetes whose hyperglycemia is well con- trolled. Abnormalities in myocardial ultrasonic backscatter are seen in diabetic sub- jects even when ventricular systolic and diastolic function are normal. Such changes have been attributed to intramyocardial edema, alterations in the nature and deposition of collagen, and accumulation of advanced glycation products. Patients with diabetes who sustain acute myocardial infarction exhibit greater impairment in ventricular function and more severe congestive heart fail- ure normalized for infarct size than do nondiabetic subjects. Factors implicated in causing such derangements include limitation of energy supply attributable to insulin resistance in the myocardium and diminished availability of intracellular glucose and its metabolites for oxidative phosphorylation, impaired calcium cy- cling associated with abnormalities in the sarcoplasmic reticulum calcium- sensitive ATPase, and contributions of advanced glycation end products to cross- linking structural proteins and augmenting myocardial stiffness. Elucidation of specific mechanisms responsible for cardiomyopathic changes associated with diabetes should enhance prevention and treatment of ventricular functional impairment under basal conditions and in response to myo- cardial insults. VI. SUMMARY A worldwide epidemic of diabetes is in progress. In the United States alone, over 16 million subjects have the disease. Many more are insulin-resistant. The progression of cardiovascular disease is accelerated by diabetes itself and by its interactions with other determinants of cardiac risk. Further elucidation of mecha- nisms responsible will undoubtedly lead to improved treatment designed to di- minish the progression of cardiovascular disease that is all too prominent in dia- betes. SUGGESTED READING 1. Bucala R, Makita Z, Zoschinsky T, Cerami A, Vlassara H. Lipid advanced glyco- sylation: pathway for lipid oxidation in vivo. Proc Natl Acad Sci USA 1993; 90: 6434–6438. 278 Schneider and Sobel 2. Carmeliet P, Moons L, Lijnen R, et al. Inhibitory role of plasminogen activator inhibitor-1 in arterial wound healing and neointimal formation. A gene targeting and gene transfer study in mice. Circulation 1997; 96:3180–3191. 3. Davies MJ, Woolf N, Katz DR. The role of endothelial denudation injury, plaque fissuring and thrombosis in the progression of human atherosclerosis. Atheroscler Rev 1991; 23:105–113. 4. Davies MJ, Richardson PD, Woolf N, Kratz DR, Mann J. Risk of thrombosis in human atherosclerotic plaques: Role of extracellular lipid, macrophage, and smooth muscle content. Br Heart J 1993; 69:377–381. 5. Ehrmann DA, Schneider DJ, Sobel BE, Cavaghan MK, Imperial J, Rosenfield RL, Polonsky KS. Troglitazone improves defects in insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis in women with polycystic ovary syndrome. J Clin Endocrinol Metab 1997; 82:2108–2116. 6. Fontbonne A, Tchobroutsky G, Eschwege E, Richard JL, Claude JR, Rosselin GE. Coronary heart disease mortality risk: Plasma insulin level is a more sensitive marker than hypertension or abnormal glucose tolerance in overweight males. The Paris prospective study. Int J Obes 1988; 12:557–565. 7. Haffner SM, Lehto S, Ronnemaa T, et al.: Mortality from coronary heart disease in subjects with type 2 diabetes and in non-diabetic subjects with and without prior myocardial infarction. N Engl J Med 1998; 339:229–234. 8. Jaffe AS, Spadaro JJ, Schechtman K, Roberts R, Geltman EM, Sobel E. Increased congestive heart failure after myocardial infarction of modest extent in patients with diabetes mellitus. Am Heart J 1984; 108:31–37. 9. Kabbani SS, Watkins MW, Ashikaga T, Terrien EF, Holoch PA., Sobel BE, Schnei- der DJ. Platelet reactivity characterized prospectively: A determinant of outcome 90 days after percutaneous coronary intervention. Circulation 2001; 104:181–186. 10. Kruszynska Y, Yu JG, Sobel BE, Olefsky JM. Effects of troglitazone on blood con- centrations of plasminogen activator inhibitor 1 in patients with type 2 diabetes mel- litus and in lean and obese normal subjects. Diabetes 2000; 49:633–639. 11. LeWinter MM. Diabetic cardiomyopathy: An overview. Coron Artery Dis 1996; 7: 95–98. 12. Malmberg K, Norhammar A, Wedel II, Ryden L. Glucometabolic state at admission: Important risk market of mortality in conventionally treated patients with diabetes mellitus and acute myocardial infarction. Long-term results from the Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction Study. Circulation 1999; 99:2626–2632. 13. Perez JE, McGill JB, Santiago JV, Schechtman KB, Waggoner AD, Miller JG, Sobel BE. Abnormal myocardial acoustic properties in diabetic patients and their correla- tion with the severity of disease. J Am Coll Cardiol 1992; 19:1154–1162. 14. Schneider DJ, Sobel BE. Synergistic augmentation of expression of plasminogen activator inhibitor type-1 induced by insulin, very-low-density lipoproteins, and fatty acids. Coron Artery Dis 1996; 7:813–817. 15. Sobel BE. The potential influence of insulin and plasminogen activator inhibitor type-1 on formulation of vulnerable atherosclerotic plaques associated with type 2 diabetes. Proc Assoc Am Physicians 1999; 111:313–318. 16. Sobel BE. Acceleration of restenosis by diabetes: Pathogenetic implications. Circu- lation 2001; 103:1165–1187. [...]... rate and hyperinsulinemia precede the development of type II diabetes in the offspring of diabetic parents Ann Intern Med 1990; 113:909–915 About the Editors BURTON E SOBEL is Amidon Professor and Chair of the Department of Medicine and Professor of Biochemistry at the University of Vermont College of Medicine and Physician-in-Chief, Fletcher Allen Health Care, Burlington, Vermont The editor of Medical. .. Research Group The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus N Engl J Med 1993; 329:977–986 19 The BARI Investigators Influence of diabetes on 5-year mortality and morbidity in a randomized trial comparing CABG and PTCA in patients with multivessel disease The Bypass Angioplasty Revascularization Investigation... editor of Medical Management of Heart Disease (Marcel Dekker, Inc.) and the author or coauthor of over 820 publications, he has lectured at universities and conferences throughout the world He is a member of the Royal Society of Medicine, the American Heart Association, and the American College of Cardiology He received the A.B degree (1958) from Cornell University, Ithaca, New York, and the M.D degree... (1962) magna cum laude from Harvard Medical School, Boston, Massachusetts DAVID J SCHNEIDER is Associate Professor of Medicine and Director of the Vascular Biology Unit at the University of Vermont College of Medicine, Burlington, Vermont He is the author or coauthor of more than 50 publications and a Fellow of the American Heart Association and the American College of Cardiology Dr Schneider obtained... treatment, 95 102 Dyspnea, CHF, 218 DCCT, 10 11, 16–17, 109 , 179–181 Deadly quartet, 36, 38 Diabetes, gestational, 10 11, 140 metabolic aspects, 1–3 complications, 3–4 pathogenesis, 178 treatment, future, 273–277 type 1 (see Type 1 diabetes) type 2 (see Type 2 diabetes) Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI), 6, 192 Diabetes Control and Complications Trial (DCCT), 10 11,... Group, 192 Apo A-1, 124 Apo B, 86 Apo C-II, 88 Apo C-III, 88 Apo E, 88, 89 Apolipoprotein, 86 characteristics, 87 Apolipoprotein A-1 (apo A-1), 124 Apolipoprotein B (apo B), 86 281 282 Apolipoprotein C-11 (apo C-II), 88 Apolipoprotein C-III (apo C-III), 88 Apolipoprotein E (apo E), 88, 89 Appropriate Blood Pressure Control in Diabetes (ABCD), 72 Appropriate Blood Pressure Control in Diabetes Part 2 with... factor-alpha (TNFalpha), 5, 24, 138, 141 Type 1 diabetes, 10 11 cardiovascular disease, 11–19 coronary heart dieases, mortality, 13 fasting lipid metabolism abnormalities, 94 hypertriglyceridemia, 90–91 insulin therapy, 17 LDL, 92 291 [Type 1 diabetes] macrovascular disease, hypothesis, 17 postprandial lipid metabolism abnormalities, 89 prevalence, 65 VLDL, 92 Type 2 diabetes, 10 cardiovascular disease, ... (FPA), 108 109 Finland, metabolic syndrome, 20 Fluvastatin, 99 Fosinopril, 73 Fosinopril Amlodipine Cardiovascular Events Randomized Trial (FACET), 73 FPA, 108 109 Free fatty acids (FFA), 24, 119–120, 138 Frequently sampled intravenous glucose tolerance test (FSIVGTT), 46, 142 FSIVGTT, 46, 142 Furosemide, CHF, 220 285 Gemfibrozil, 99 100 PAI-1, 112 Genetics, hypertension, 67 Gestational diabetes, 10 11,... arterial thrombotic events, 106 Coagulation factor Va, 107 Coagulation factor Xa, 107 Coagulation system, type 2 diabetes, 108 109 Colesevalem, 101 Colestipol, 101 283 Congestive heart failure (CHF), 66, 166, 211–227 diet, 219 dyspnea, 218 hypertension, 218, 226 low ejection fraction heart failure, pharmacological therapy, 219– 224 management, 218–227 mechanisms underlying, 217–218 normal ejection fraction,... proteins, 88–89 Intra-abdominal tissue, CT, 48 MRI, 48 sonography, 48 Intravascular ultrasound (IVUS), CAD, 165 287 IRAS, 51 IRS, 24, 39–40, 137 IRS-1, 5 IRS-2, 5 IVUS, CAD, 165 JNC-VI, 75–76, 191 Joint National Committee on Prevention, Detection and Treatment of High Blood Pressure, Sixth Report, 75–76, 191 Kidney-pancreas transplantation, 14 LACI, 107 LADA, 15 Latent autoimmune diabetes in adults (LADA), . Professor of Biochemistry at the University of Vermont College of Medicine and Physician-in-Chief, Fletcher Allen Health Care, Burlington, Ver- mont. The editor of Medical Management of Heart Disease. providers and patients as partners in managing a devastating disease. The demands for daily self -management of diabetes are so formidable that each component of the diabetes education curricu- lum. development of type II diabetes in the offspring of diabetic parents. Ann Intern Med 1990; 113:909–915. About the Editors BURTON E. SOBEL is Amidon Professor and Chair of the Department of Medicine and