No of antihypertensive agents Trial Target BP mm Hg 1234

UKPDS ABCD MDRD HOT AASK IDNT

Fig. 4. Multiple antihypertensive agents are needed to achieve target blood pressure. BP, blood pressure; DBP, diastolic blood pressure; MAP, mean arterial pressure; SBP, systolic blood pressure. (Adapted from Bakris GL, Williams M, Dworkin L, et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. Am J Kidney Dis 2000;36(3):646-61; with permission.)

DBP <85

DBP <75

MAP <92

DBP <80

MAP <92

Fig. 4. Multiple antihypertensive agents are needed to achieve target blood pressure. BP, blood pressure; DBP, diastolic blood pressure; MAP, mean arterial pressure; SBP, systolic blood pressure. (Adapted from Bakris GL, Williams M, Dworkin L, et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. Am J Kidney Dis 2000;36(3):646-61; with permission.)

improves renal outcomes in patients with type 2 diabetes and nephropathy over and above the improvement attributable to blood pressure control alone. The renoprotective effect of losartan corresponded to an average delay of 2 years in the need for dialysis or kidney transplantation. The recent RENAAL study and the Irbesartan Type 2 Diabetic Nephropathy Trial found ARBs to offer the greatest benefit for slowing progression of renal disease in type 2 diabetic nephropathy. In contrast, however, the HOPE trial showed that ACE inhibitors, specifically ramipril, have the greatest evidence for prevention of CV outcomes in patients with renal insufficiency, regardless of diabetic status. CV outcomes were secondary endpoints in the RENAAL and IDNT trials, and with the exception of heart failure for losartan, no benefits on CV outcomes were statistically significant. Because evidence has shown that patients with elevated serum creatinine levels (>1.4 mg/dL) are just as likely to die from CV disease as to reach end-stage renal disease, it is unclear as to which should be the focus for treatment for clinicians. This question can only be answered by another large, long, randomized, controlled trial using a strictly evidence-based approach. Given the similarity of actions between the ARB and ACE inhibitors, it is likely there is considerable overlap of both benefits and side effects between the two, although ARB may have a lower incidence of cough and hyperkalemia. Trials comparing ARBs with ACE inhibitors are lacking, and more data are needed. Until that information is available, the selection of the appropriate antihy-pertensive agent should be tailored to the needs of the patient with careful consideration of both medical and economic factors. Regardless of the choice between an ACE inhibitor and an ARB, however, post hoc analysis of clinical trials and observational data clearly indicate that patients with chronic kidney disease, even if the disease is considered mild (ie, serum creatinine levels >1.4 mg/dL), are at significantly greater risk of CV morbidity and mortality than those with better kidney function. Currently, ARBs are the only evidence-based treatment strategy for patients with type 2 diabetes mellitus and proteinuria and are recommended as initial treatment of choice by the National Kidney Foundation [31].

The Losartan Intervention for Endpoint Reduction in Hypertension trial also demonstrated beneficial effects of ARBs in the prevention of stroke events. To conclude, pharmacologic therapy to block the renin-angiotensin system should be mandatory in patients with diabetic nephropathy (including patients with microalbuminuria).

Beta-blockers are recommended for patients with established CV disease, particularly in the presence of coronary artery disease or prior history of myocardial infarction. Findings from the Anti-hypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial suggest that alpha-blockers may have less benefit and could even be harmful when compared with diuretics, amlodi-pine, or lisinopril [32]. Individuals who have supine hypertension along with significant orthostasis can possibly be treated with short-acting antihyperten-sive agents such as captopril or oral clonidine at bedtime.

The reduction of elevated blood pressure to the target blood pressure should be the primary goal. This point is well demonstrated in the United

Kingdom Prospective Diabetes Study, which showed no difference in endpoints in patients in whom aggressive blood pressure control was achieved with either captopril or atenolol, whereas a significant difference was noted between the aggressively treated group and the control group. It may be appropriate to select a specific group of antihypertensives for initial treatment because of Specific comorbidities in an individual patient. Also, because most diabetic hypertensive patients require more than two antihypertensive agents, it is prudent to start therapy with at least two drugs, usually as a combination product, to achieve the target blood pressure promptly and to reduce the risk of CV events.

Hyperglycemia

A causal relationship between hyperglycemia and microvascular disease is well established. Studies have also documented that glycemic control delays or prevents the manifestations of microvascular disease. The relationship between hyperglycemia and macrovascular disease has been a subject of constant debate, however. The largest study addressing this issue, the UKPDS, was designed to show whether intensive control of glucose lowers the risk of complications compared with conventional treatment in newly diagnosed type 2 diabetics [33,34]. Approximately 2500 patients were enrolled in each group. During a mean follow-up of 10 years, with intensive therapy there was a 12% reduction in any diabetes-related endpoint and a significant reduction in the microvascular endpoints (25% reduction; P = 0.0099). A 16% reduction in myocardial infarction (P = 0.052) and nonsignificant reductions in diabetes-related and all-cause mortality were noted in the intensively treated group. Thus, although the value of tight glycemic control for prevention of microvascular disease is un-disputable, the UKPDS does not strongly suggest a similar benefit in controlling macrovascular disease.

A more recent epidemiologic study, the European Prospective Investigation of Cancer and Nutrition-Norfolk study, found a continuous relationship between all-cause mortality and glycosylated hemoglobin even for values in the nondiabetic range [35]. In this European study, 4662 men aged 45 to 79 years whose glycosylated hemoglobin had been measured at a baseline survey conducted between 1995 and 1997 were followed until December 1999. The main outcome measured was mortality from all causes, from CV disease, from ischemic heart disease, and from other causes. Men with known diabetes had increased mortality from all causes, CV disease, and ischemic disease (RRs, 2.2, 3.3, and 4.2, respectively; P < 0.001 independent of age and other risk factors) compared with men without known diabetes. The increased risk of death among men with diabetes was largely explained by the hemoglobin A1c (HbA1c) concentration. HbA1c was related to subsequent all-cause, CV, and ischemic heart disease mortality throughout the study population; the lowest rates were seen in those with HbA1c concentrations below 5%. An increase of 1% in HbA1c was associated with a 28% (P < 0.002) increase in risk of death independent of age, blood pressure, serum cholesterol, body mass index, and cigarette smoking. This effect remained (RR, 1.46; P = 0.05 adjusted for age and risk factors) after men with known diabetes, a HbA1c concentration greater than 7%, or a history of myocardial infarction or stroke were excluded. These data suggest that the 16% risk reduction in the incidence of myocardial infarction found in the UKPDS is a significant difference.

Postprandial hyperglycemia has recently been identified as a potential risk factor for CV disease (Fig. 5) [36]. The study was undertaken by the European Diabetes Epidemiology Study Group in 1997. Baseline data were collected on glucose concentrations at fasting and 2 hours after the 75-g oral glucose tolerance test from 13 prospective European cohort studies, which included 18,048 men and 7316 women aged 30 years or older. Mean follow-up was 7.3 years. The risk of death for the different diagnostic glucose categories was assessed. Within each fasting glucose classification, mortality increased with increasing 2-hour glucose levels. There was, however, no trend for increasing fasting glucose concentrations, for 2-hour glucose classifications of impaired glucose tolerance, or diabetes. This finding suggests that fasting glucose concentrations alone do not identify individuals at increased risk of death associated with hyperglycemia. There are, however, no universally accepted guidelines for therapy. The American College of Endocrinology recommends a 2-hour postprandial target glucose level of less than 140 mg/dL. To summarize, although it remains to be unequivocally proven that intensive glycemic control improves risk of CV outcomes, such control does significantly impact the incidence of microvascular

Fasting plasma glucose (mmol/L) ^

Fig. 5. Increased 2-hour glucose is associated with increased mortality. Adjusted for age, center, sex. (From European Diabetes Epidemiology (DECODE) Group. Is the current definition for diabetes relevant to mortality risk from all causes and cardiovascular and noncardiovascular diseases? Diabetes Care 2003;26(3):688-96; with permission.)

Fasting plasma glucose (mmol/L) ^

Fig. 5. Increased 2-hour glucose is associated with increased mortality. Adjusted for age, center, sex. (From European Diabetes Epidemiology (DECODE) Group. Is the current definition for diabetes relevant to mortality risk from all causes and cardiovascular and noncardiovascular diseases? Diabetes Care 2003;26(3):688-96; with permission.)

complications. Currently, the American Diabetes Association (ADA) recommends a glycosylated hemoglobin goal of 7%, whereas the American College of Endocrinology recommends a goal of less than 6.5%.

The choice of hypoglycemic therapy (as discussed in detail in another article in this issue) should be influenced by consideration of multiple factors including body mass index, renal function, comorbidities, financial issues, and patient preferences. In general, in the absence of contraindications, overweight individuals should initially be treated with metformin. The TZDs, an important therapeutic drug class, are effective in reducing blood sugar. Their hypoglycemic action is mediated by increasing muscle uptake of glucose, thereby decreasing insulin resistance. They also reduce hepatic glucose production. The primary action of these drugs is mediated through activation of the peroxisome proliferator-activated receptor-y receptor, a nuclear receptor with a regulatory role in differentiation of cells. This receptor is expressed in adipocytes, vascular tissue, and other cell types. These drugs improve endo-thelial function, reduce intra-abdominal adipose tissue, improve pancreatic beta-cell function, and exert anti-inflammatory actions that may contribute to antiatherosclerotic effects. Ongoing trials are evaluating the nonglycemic effects of these agents on CV outcomes. The prospective pioglitazone clinical trial (PROACTIVE) has randomly assigned more than 5000 patients with type 2 diabetes and documented CV disease to pioglitazone or placebo as add-on therapy to other hypoglycemic treatment. The Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD) study is using rosiglitazone in a similar design. Clinicians should consider using appropriate strategy based on individual patient characteristics and prevailing practices until results of these studies substantiate the benefit of the TZDs in reducing CV disease outcomes.

Increased thrombotic tendency

Many prothrombotic factors in the diabetic patient increase the risk for arterial thrombosis leading to myocardial infarction or strokes. These factors include platelet dysfunction (Box 1), increased fibrinogen levels, increased von Wille-brand's factor, increased factor VII, increased

Box 1. Platelet dysfunction in diabetes

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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