Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association.

Abstract

HomeCirculationVol. 100, No. 10Diabetes and Cardiovascular Disease Free AccessOtherPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessOtherPDF/EPUBDiabetes and Cardiovascular Disease A Statement for Healthcare Professionals From the American Heart Association Scott M. Grundy, Ivor J. Benjamin, Gregory L. Burke, Alan Chait, Robert H. Eckel, Barbara V. Howard, William Mitch, Sidney C. SmithJr and James R. Sowers Scott M. GrundyScott M. Grundy Search for more papers by this author , Ivor J. BenjaminIvor J. Benjamin Search for more papers by this author , Gregory L. BurkeGregory L. Burke Search for more papers by this author , Alan ChaitAlan Chait Search for more papers by this author , Robert H. EckelRobert H. Eckel Search for more papers by this author , Barbara V. HowardBarbara V. Howard Search for more papers by this author , William MitchWilliam Mitch Search for more papers by this author , Sidney C. SmithJrSidney C. SmithJr Search for more papers by this author and James R. SowersJames R. Sowers Search for more papers by this author Originally published7 Sep 1999https://doi.org/10.1161/01.CIR.100.10.1134Circulation. 1999;100:1134–1146is corrected byCorrectionThis statement examines the cardiovascular complications of diabetes mellitus and considers opportunities for their prevention. These complications include coronary heart disease (CHD), stroke, peripheral arterial disease, nephropathy, retinopathy, and possibly neuropathy and cardiomyopathy. Because of the aging of the population and an increasing prevalence of obesity and sedentary life habits in the United States, the prevalence of diabetes is increasing. Thus, diabetes must take its place alongside the other major risk factors as important causes of cardiovascular disease (CVD). In fact, from the point of view of cardiovascular medicine, it may be appropriate to say, “diabetes is a cardiovascular disease.”Clinical Presentations of Diabetes MellitusThe most prevalent form of diabetes mellitus is type 2 diabetes. This disorder typically makes its appearance later in life. The underlying metabolic causes of type 2 diabetes are the combination of impairment in insulin-mediated glucose disposal (insulin resistance) and defective secretion of insulin by pancreatic β-cells. Insulin resistance develops from obesity and physical inactivity, acting on a substrate of genetic susceptibility.12 Insulin secretion declines with advancing age,34 and this decline may be accelerated by genetic factors.56 Insulin resistance typically precedes the onset of type 2 diabetes and is commonly accompanied by other cardiovascular risk factors: dyslipidemia, hypertension, and prothrombotic factors.78 The common clustering of these risk factors in a single individual has been called the metabolic syndrome. Many patients with the metabolic syndrome manifest impaired fasting glucose (IFG)9 even when they do not have overt diabetes mellitus.10 The metabolic syndrome commonly precedes the development of type 2 diabetes by many years11 ; of great importance, the risk factors that constitute this syndrome contribute independently to CVD risk.Recently, new criteria have been accepted for the diagnosis of diabetes.9 The upper threshold of fasting plasma glucose for the diagnosis of diabetes has been lowered from ≥140 mg/dL to ≥126 mg/dL. The upper threshold for normoglycemia likewise has been reduced from <115 to <110 mg/dL. A fasting plasma glucose of 110 to 125 mg/dL is now designated IGF. These changes removed the need for oral glucose tolerance testing for diagnosis of diabetes; a diagnosis rests entirely on confirmed elevations of fasting plasma glucose. Furthermore, the terms insulin-dependent diabetes mellitus and non–insulin-dependent diabetes mellitus have been replaced by type 1 diabetes and type 2 diabetes, respectively.The other form of diabetes mellitus is type 1 diabetes, which follows immunologic destruction of pancreatic β-cells.12 Type 1 diabetes usually begins early in life and is often called juvenile diabetes. This form of diabetes frequently produces microvascular complications, nephropathy, and retinopathy,12 but it also predisposes to CHD.13 Because type 2 diabetes occurs much more commonly than type 1 diabetes, the present statement will emphasize type 2 diabetes. Nonetheless, type 1 diabetes will be integrated into the overall strategy of cardiovascular risk reduction.Scope of the ProblemAt least 10.3 million Americans carry a diagnosis of diabetes mellitus.14 Another 5.4 million are estimated to have undiagnosed diabetes.14 Approximately 90% of patients with diabetes have the type 2 variety.14 The onset of type 2 diabetes usually precedes clinical diagnosis by several years.14 An increasing prevalence of type 2 diabetes cannot be divorced from the rising prevalence of obesity and physical inactivity in our society. An estimated 97 million adults in the United States are overweight or obese.15 Furthermore, ≈75% of adult Americans have minimal physical activity or daily exercise.16 Both excess body fat and physical inactivity predispose to type 2 diabetes. Several ethnic groups are particularly susceptible to type 2 diabetes: Hispanics, blacks, Native Americans, and Asians (especially South Asians).17181920 The growing ethnic diversity, including these groups, contributes to the increasing prevalence of type 2 diabetes in the United States.Diabetes as a Major Risk FactorA large body of epidemiological and pathological data documents that diabetes is an independent risk factor for CVD in both men and women.212223 Women with diabetes seem to lose most of their inherent protection against developing CVD.2124 CVDs are listed as the cause of death in ≈65% of persons with diabetes.25 Diabetes acts as an independent risk factor for several forms of CVD. To make matters worse, when patients with diabetes develop clinical CVD, they sustain a worse prognosis for survival than do CVD patients without diabetes.262728 These considerations have convinced the Scientific Advisory and Coordinating Committee of the American Heart Association (AHA) that diabetes mellitus deserves to be designated a major risk factor for CVD. This formal designation commits the AHA to a greater emphasis on diabetes as a risk factor in its scientific and educational programs. This statement provides the scientific rationale for the decision to classify diabetes as a major risk factor for CVD.Diabetes and Specific CVDAtherosclerotic CHDBoth type 1 diabetes and type 2 diabetes are independent risk factors for CHD.212223 Moreover, myocardial ischemia due to coronary atherosclerosis commonly occurs without symptoms in patients with diabetes.29 As a result, multivessel atherosclerosis often is present before ischemic symptoms occur and before treatment is instituted. A delayed recognition of various forms of CHD undoubtedly worsens the prognosis for survival for many diabetic patients.Diabetic CardiomyopathyOne reason for the poor prognosis in patients with both diabetes and ischemic heart disease seems to be an enhanced myocardial dysfunction leading to accelerated heart failure (diabetic cardiomyopathy).3031323334353637 Thus, patients with diabetes are unusually prone to congestive heart failure. Several factors probably underlie diabetic cardiomyopathy: severe coronary atherosclerosis, prolonged hypertension, chronic hyperglycemia, microvascular disease, glycosylation of myocardial proteins, and autonomic neuropathy. Improved glycemic control, better control of hypertension, and prevention of atherosclerosis with cholesterol-lowering therapy may prevent or mitigate diabetic cardiomyopathy. An early clinical trial38 suggested that sulfonyl ureas used for control of hyperglycemia are cardiotoxic and may exacerbate diabetic cardiomyopathy. This side effect, however, was not confirmed in a recent large clinical trial.39StrokeMortality from stroke is increased almost 3-fold when patients with diabetes are matched to those without diabetes.40 The most common site of cerebrovascular disease in patients with diabetes is occlusion of small paramedial penetrating arteries.41 Diabetes also increases the likelihood of severe carotid atherosclerosis.4243 Patients with diabetes, moreover, are likely to suffer irreversible brain damage with carotid emboli that otherwise would produce only transient ischemic attacks in persons without diabetes. Approximately 13% of patients with diabetes >65 years old have had a stroke.44Renal DiseaseRenal disease is a common and often severe complication of diabetes.45 Approximately 35% of patients with type 1 diabetes of 18 years’ duration will have signs of diabetic renal involvement.46 Up to 35% of new patients beginning dialysis therapy have type 2 diabetes.47 End-stage renal disease (ESRD) appears to be especially common among Hispanics, blacks, and Native Americans with diabetes.4849505152 For patients with diabetes who are on renal dialysis, mortality rates probably exceed 20% per year.47 When diabetes is present, CVD is the leading cause of death among patients with ESRD.535455Covariate Risk FactorsProspective studies22232425262728293031323334353637383940 indicate that all of the major cardiovascular risk factors—cigarette smoking, hypertension, and high serum cholesterol—continue to act as independent contributors to CVD in patients with diabetes. As already mentioned, clustering of metabolic risk factors, called the metabolic syndrome, occurs commonly in type 2 diabetes.56 The onset of hyperglycemia in patients with the metabolic syndrome appears to accelerate atherogenesis, possibly by enhanced formation of glycosylated proteins and advanced glycation products5758 and/or by increasing endothelial dysfunction.59 These direct consequences of hyperglycemia probably contribute to the microvascular disease underlying nephropathy and retinopathy, and they may promote macrovascular disease as well.Predisposing Risk FactorsSeveral predisposing factors simultaneously affect the development of CVD and diabetes mellitus. Among these concomitant factors are obesity, physical inactivity, heredity, sex, and advancing age. The mechanisms whereby they predispose to chronic diseases are complex and often overlapping. To some extent, these predisposing factors exacerbate the major risk factors: dyslipidemia, hypertension, and glucose tolerance; and they may cause CVD and diabetes mellitus through other pathways as well. To a large extent, both CVD and diabetes must be prevented through control of the predisposing risk factors. Modification of life habits is at the heart of the public health strategy for prevention of CVD and diabetes mellitus. High priorities are the prevention (or treatment) of obesity and promotion of physical activity. Drug therapy nonetheless may be required to control the metabolic risk factors, particularly when they arise from genetic aberration and aging. Effective drugs are currently available for treatment of hypertension and dyslipidemia. Hypoglycemic agents also are available for treatment of type 2 diabetes, but new pharmacological strategies are under investigation for more effective treatment and prevention.Insulin Resistance and the Metabolic SyndromeMost patients with type 2 diabetes have insulin resistance. Indeed, insulin resistance seems to predispose to both CVD and diabetes.60 Research suggests that insulin resistance is a multisystem disorder that induces multiple metabolic alterations. Factors that contribute to insulin resistance are genetics,61 obesity,62 physical inactivity,63 and advancing age.64 Patients with insulin resistance often have abdominal obesity.65 Metabolic risk factors that occur commonly in patients with insulin resistance are atherogenic dyslipidemia, hypertension, glucose intolerance, and a prothrombotic state.60 Each of these risk factors can be reviewed briefly.Atherogenic DyslipidemiaAtherogenic dyslipidemia is characterized by 3 lipoprotein abnormalities: elevated very-low-density lipoproteins (VLDL), small LDL particles, and low high-density-lipoprotein (HDL) cholesterol (the lipid triad). The lipid triad occurs frequently in patients with premature CHD and appears to be an atherogenic lipoprotein phenotype independent of elevated LDL cholesterol.66676869 Most patients with atherogenic dyslipidemia are insulin resistant.697071 Atherogenic dyslipidemia in diabetic patients often is called diabetic dyslipidemia. Many patients with atherogenic dyslipidemia also have an elevated serum total apolipoprotein B.72 Growing evidence suggests that all of the components of the lipid triad are independently atherogenic. Together they represent a set of lipoprotein abnormalities besides elevated LDL cholesterol that promote atherosclerosis.HypertensionHypertension is a well-established major risk factor for CVD.22 It increases risk for both CHD and stroke and contributes to diabetic nephropathy.73 Several investigators7475 report a positive association between insulin resistance and hypertension; this finding suggests that elevated blood pressure deserves to be listed among the components of the metabolic syndrome. Hypertension nonetheless is a multifactorial disorder, and the mechanistic connections between insulin resistance and hypertension are largely conjectural; even so, evidence for a causal link is growing.76 When hypertension coexists with overt diabetes, which it commonly does, the risk for CVD, including nephropathy, is doubly increased.Elevated Plasma GlucoseFor several years after onset of insulin resistance, fasting and postprandial glucose levels typically are normal. During this period, pancreatic β-cells are able to increase insulin secretion in response to insulin resistance and thereby maintain normal plasma glucose levels. In some people, however, insulin secretion declines with aging, and elevated glucose concentrations appear. The first abnormality in plasma glucose in patients with insulin resistance is IFG (or impaired glucose tolerance).9 The presence of IFG usually accompanies long-standing insulin resistance. It is currently estimated that 13.4 million adults, 7.0% of the US population, have IFG.14 Many prospective studies7778 show that IFG (or impaired glucose tolerance) is a risk factor for CVD; the degree of independence as a risk factor, however, is uncertain, because IGF commonly coexists with other components of the metabolic syndrome.11 A patient with IFG nonetheless must be considered at risk for both CVD and type 2 diabetes. As already indicated, once categorical hyperglycemia develops, it counts as an independent risk factor for CVD.22Prothrombotic StateA newly recognized component of the metabolic syndrome is a prothrombotic state.76 Patients with insulin resistance frequently manifest several alterations in coagulation mechanisms that predispose them to arterial thrombosis. These alterations include increased fibrinogen levels,79 increased plasminogen activator inhibitor-1,80 and various platelet abnormalities.81LDL Cholesterol and Atherogenesis in Diabetic PatientsAn elevated concentration of serum LDL cholesterol is a major risk factor for CHD.82 In fact, some elevation of LDL cholesterol appears to be necessary for the initiation and progression of atherosclerosis. In populations having very low LDL cholesterol levels, clinical CHD is relatively rare, even when other risk factors—hypertension, cigarette smoking, and diabetes—are common.83 In contrast, severe elevations in LDL cholesterol can produce full-blown atherosclerosis and premature CHD in the complete absence of other risk factors.84The view has been expressed that most patients with diabetes do not have an elevated serum LDL cholesterol; if not, a high LDL serum cholesterol would not be a common risk factor in patients with diabetes. It is true that most patients who have diabetes do not have marked elevations of LDL cholesterol, but these patients nonetheless carry high enough levels to support the development of atherosclerosis.85 A role for LDL in hyperglycemic patients became apparent in recent clinical trials, eg, the Scandinavian Simvastatin Survival Study (4S),8687 the Cholesterol and Recurrent Events (CARE) trial,8889 and the Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID).90 In all of these trials, aggressive LDL-lowering therapy reduced recurrent CHD events in patients with diabetes.Cigarette SmokingCigarette smoking is a leading risk factor for CVD. Patients with diabetes who are smokers are doubly at risk. Unfortunately, many patients continue to smoke despite having diabetes; for these patients, the benefits that can be derived from modifying other risk factors are mitigated.Diabetic NephropathyDiabetic nephropathy can be divided into 4 phases: microalbuminuria, macroalbuminuria, the nephrotic syndrome, and chronic renal failure.45 Microalbuminuria (urine albumin 30 to 300 mg/d or <300 mg/g creatinine) is the first clinical sign of diabetic damage to the kidney.9192 Not only is microalbuminuria a harbinger of progressive kidney damage, but its presence also reflects a higher risk for CVD.92939495 Macroalbuminuria (urine albumin >300 mg/d or >300 mg/g creatinine) usually denotes significant diabetic nephropathy and will be followed by a decline in glomerular filtration rate (GFR). The majority of patients with diabetes who have macroalbuminuria also have hypertension9697 ; in these patients, control of hypertension slows the decline in GFR.9899100 Some patients with diabetes develop the nephrotic syndrome (urine protein >3 g/d); diabetic dyslipidemia in such patients often is compounded by nephrotic dyslipidemia, most notably by higher cholesterol levels. The nephrotic syndrome usually heralds progressive renal insufficiency; thereafter, ESRD ensues and dialysis and/or transplantation become necessary to sustain life.Risk Assessment in the Diabetic PatientRisk assessment must take into account the major risk factors (cigarette smoking, elevated blood pressure, abnormal serum lipids and lipoproteins, and hyperglycemia) and predisposing risk factors (excess body weight and abdominal obesity, physical inactivity, and family history of CVD). Identification of risk factors is a major first step for developing a plan for risk reduction in persons with diabetes. Specific steps in the evaluation of the major risk factors in such persons are presented in Table 1. These steps include a thorough medical history, careful physical examination, and appropriate laboratory measurements. Specialized testing may be particularly useful, eg, 24-hour monitoring of ambulatory blood pressure by automated techniques. Lipoprotein analysis should draw a clear distinction between elevated LDL cholesterol concentrations and atherogenic dyslipidemia (or diabetic dyslipidemia) as manifested by elevated triglycerides and small LDL and low HDL cholesterol levels. Even borderline-high-risk LDL cholesterol levels (130 to 159 mg/dL) are of concern in patients with diabetes and call for aggressive intervention. The quality of glycemic control can best be assessed by periodic measurement of hemoglobin A1c. Furthermore, because hyperglycemia per se confers increased risk for CVD, the presence of other risk factors—smoking, hypertension, even borderline-high-risk LDL cholesterol, and atherogenic dyslipidemia—signifies enhanced risk and signals the need for more aggressive intervention on all risk factors.Risk assessment in the diabetic patient is not complete until predisposing risk factors—obesity, physical inactivity, and family history of premature CVD—have been evaluated (Table 2). Identification of predisposing risk factors will provide insight into the causation of the major risk factors. The finding of abdominal obesity, as evidenced by an increased waist circumference, usually indicates the presence of insulin resistance. A careful assessment of the status of the predisposing risk factor sets the stage for therapeutic modification of life habits. A genetic basis for risk, as revealed by a positive family history of CVD or diabetes, may point to the need for pharmacological control of risk factors. Moreover, a positive family history often uncovers family members who also need risk-factor intervention.Clinical EvaluationDetection of Clinical and Subclinical CVDProspective studies101 document an increased likelihood of sudden cardiac death and unrecognized myocardial infarctions in patients with diabetes. Moreover, acute ischemic syndromes, peripheral arterial disease, and advanced CVD complications occur more commonly in patients with diabetes than in those without.101 Because the typical cardiac symptoms often are masked in patients with diabetes, the diagnosis of myocardial infarction commonly is missed or delayed. Effective strategies for earlier detection of clinical CVD could reduce morbidity and mortality in patients with diabetes. In addition, detection of subclinical atherosclerosis and early clinical manifestation of CVD could lead to more effective primary prevention in some patients with diabetes.Table 3 outlines a general approach to the detection of clinical and subclinical CVD in the hyperglycemic patient. Stress testing for myocardial ischemia and dysfunction should be performed in accord with general American College of Cardiology (ACC)/AHA guidelines102 ; Table 3 lists further special considerations for exercise testing in patients with diabetes. Noninvasive evaluation of cardiac function in hyperglycemic patients suspected of having myocardial dysfunction may be a useful guide to cardiovascular management in some of these patients. Many patients with diabetes suffer from an autonomic dysfunction that impairs quality of life and predisposes to life-threatening cardiovascular complications. Finally, the finding of subclinical CVD signals the need for institution of more aggressive preventive measures.Evaluation of Renal StatusChronic renal failure is a major clinical outcome in patients with diabetes. It is more likely to develop in type 1 diabetes than in type 2 diabetes. However, the high prevalence of type 2 diabetes makes it a major cause of ESRD. The renal status of patients with diabetes therefore must be appropriately monitored so that effective intervention can be introduced early in the course of renal disease. Table 4 outlines the steps in evaluation. Testing for urine albumin and protein is the first step. Microalbuminuria is indicative of early diabetic nephropathy. In patients with type 1 diabetes, it is a harbinger of ongoing renal damage; in type 2 diabetes, it signifies enhanced risk for CVD. Macroalbuminuria and/or nephrotic-range proteinuria predicts a decline in renal function. Patients with macroalbuminuria should be referred to a nephrologist who can rule out another kidney disease and who can help to plan a strategy for preventing progression to ESRD. This strategy should include aggressive management of hypertension to blood pressure levels of <130/85 mm Hg. Although the serum creatinine is not a sensitive indicator of the degree of loss of GFR, a rising serum creatinine plotted as changes in the reciprocal of serum creatinine versus time provides a means of determining the rate of decline in renal function. Direct measurement of GFR is the most reliable estimate of the amount of residual kidney function but is more expensive and technically demanding.Cardiovascular Clinical ManagementMedical (Noninvasive) Management of Diabetic Patients With Clinical CVDCompelling evidence, including data from recent clinical trials, demonstrates that comprehensive medical intervention in patients with established atherosclerotic CVD has thefollowing benefits: it extends overall survival; improves quality of life; decreases the need for intervention procedures, such as angioplasty and coronary artery bypass graft surgery; and reduces the incidence of subsequent myocardial infarction.103 In many patients with CHD, aggressive risk reduction with medical therapy will delay or eliminate the need for revascularization procedures. Treatment of risk factors in patients with established CHD or other clinical atherosclerotic disease has been called secondary prevention. Although the number of patients with diabetes included in clinical trials has been limited, the available results suggest that these patients respond to secondary prevention interventions at least as well as those without diabetes.8687888990 Consequently, the general guidelines for noninvasive, medical management in secondary prevention can be applied when patients with diabetes have clinical atherosclerotic CVD. Table 5 summarizes the AHA/ACC guide103 to comprehensive risk reduction in patients with clinical coronary and other vascular disease, as modified for CVD patients with diabetes.A few general comments can be made about application of these guidelines to patients with diabetes. Because cigarette smoking remains a powerful risk factor in patients with diabetes, a major effort must be made to overcome the smoking habit. The AHA has recently published practical guidelines for assisting patients in smoking cessation.104 For lipid management, the primary goal of therapy is to reduce LDL-cholesterol levels to ≤100 mg/dL.103 This goal should be achieved by addition of drug therapy (when necessary) to maximal dietary therapy. Statins are first-line therapy to achieve an LDL cholesterol of ≤100 mg/dL. When triglycerides remain >200 mg/dL in patients receiving statin therapy, consideration should be given to adding a fibrate to achieve the secondary goal of lipid management, ie, a triglyceride <200 mg/dL. Although nicotinic acid effectively lowers triglycerides and raises HDL levels in patients with type 2 diabetes, its tendency to worsen hyperglycemia causes it to be relatively contraindicated. The goal of blood pressure control is to reduce blood pressure to <135/85 mm Hg in hypertensive patients105 ; this goal often will require antihypertensive drug therapy.Treatment of hyperglycemia is stepwise and typically dependent on duration of disease. To prevent microangiopathy, neuropathy, and perhaps macrovascular disease, a prudent therapeutic goal is to reduce the glycohemoglobin to ≤1% above the upper limit of normal.39106 Weight loss and increased exercise are first-line therapy for reducing hyperglycemia. If hyperglycemia persists, a sulfonylurea or metformin can be used next. The recent UK Prospective Diabetes Study39 revealed the safety and efficacy of sulfonylureas in control of hyperglycemia in diabetic patients. Metformin also proved efficacious, although an apparent increase in death rates on the combination of metformin and sulfonylureas calls for more study on the safety of this combination.107Another promising group of agents for treatment of type 2 diabetes includes the thiazolidenediones. These agents lower glucose levels by reducing insulin resistance. The first drug in this class to be approved for clinical use was troglitazone. This agent is approved for use in combination with insulin therapy to improve glycemic control. Unfortunately, troglitazone produces rare but severe liver toxicity108109110 ; the possibility of this adverse reaction requires close monitoring of patients. Nonetheless, despite its potential hepatotoxicity, troglitazone is currently being widely used to treat hyperglycemia. New drugs of the same class, rosiglitazone and pioglitazone, may have less potential hepatotoxicity. A different type of drug available for glucose control is acarbose; this agent partially blocks glucose absorption. In patients who fail to achieve glucose control and near-normal hemoglobin A1c levels by changes in life habits and oral hypoglycemic agents, insulin should be initiated.Other risk-reduction strategies in patients with diabetes deserve attention equal to that given glucose control. Patients with type 2 diabetes should increase physical activity and eliminate excess body weight; both may be facilitated with the help of professional guidance. Antiplatelet agents have become almost routine in patients with atherosclerotic CVD, and their use can be extended to patients with diabetes who have established atherosclerotic disease. β-Blockers reduce cardiovascular mortality after myocardial infarction. They may be particularly effective in patients with diabetes, who are at risk for symptomatic ischemic episodes secondary to increased sympathetic activity.111 β-Blockers are often mentioned as being contraindicated for patients with diabetes because of their blocking of hypoglycemic symptoms in the presence of a hypoglycemic regimen. Clinicians should be aware of this potential danger, although this side effect need not preclude use of β-blockers when CHD patients have diabetes. Angiotensin-converting enzyme (ACE) inhibitors are widely prescribed in the post–myocardial infarction period to favorably influence myocardial remodeling and fibrosis, and they should be continued indefinitely in all patients with reduced left ventricular ejection fraction or symptoms of heart failure. Unfortunately, limited data are available on use of estrogen replacement therapy in postmenopausal women with diabetes; a recent clinical trial calls into question its putative benefit in postmenopausal, nondiabetic women with established CHD.112Management of Diabetic NephropathyMore than one strategy has been shown to slow the progression of nephropathy in patients with diabetes. A general approach is outlined in Table 6. Specific interventions include control of hyperglycemia, treatment of hypertension (particularly by use of ACE inhibitors), sodium restriction, and dietary protein restriction. Treatment of hypertensi