Section I: RAS manipulation E. Reducing risk in diabetes and the cardiometabolic syndrome ATP III criteria identify metabolic syndrome as a pervasive problem Content points: The Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III) highlights the importance of treating patients with the metabolic syndrome to prevent cardiovascular disease.20 ATP III defines the metabolic syndrome as > 3 of the following abnormalities:20 – Waist circumference >35 inches in women and >40 inches in men – Serum triglyceride level > 150 mg/dL – HDL-C < 50 mg/dL in women and <40 mg/dL in men; – Blood pressure > 130/85 mm Hg – Fasting serum glucose level > 110 mg/dL About 47 millions US adults have the metabolic syndrome based on the 2000 census.39 Estimates of prevalence of the metabolic syndrome in the US are high based on Third National Health and Nutrition Examination Survey (1988-1994) data:40 – The age-adjusted prevalence is 24%. – The prevalence increases from 6.7% among 20- to 29-year-olds to 43% among 60- to 69-year-olds. – Mexican Americans have the highest age-adjusted prevalence: 32%. – African Americans, the overall prevalence is 22%, but women have a 57% higher prevalence than men.

HOPE: Reduction in new-onset diabetes Content points: More details have been made available regarding prevention of diabetes with ACE inhibitors in high-risk patients in the HOPE study.40 As shown, the curves for cumulative risk for development of diabetes diverged after approximately 1 year. At study end, 102 (3.6%) in the ramipril group developed diabetes compared with 155 (5.4%) in the placebo group. The relative risk for developing diabetes among patients taking ramipril versus placebo was 0.66 (95% CI, 0.51 to 0.85, P < 0.001), representing a 34% risk reduction. Benefit was observed in all subgroups studied, demonstrating the broad range of patients at risk of diabetes who might benefit from an ACE inhibitor. These findings were not a primary or secondary outcome of the HOPE study and should be interpreted with caution. The HOPE study investigators are therefore embarking on a large prospective trial (Diabetes Reduction Assessment with Ramipril and rosiglitizone Medication [DREAM]) among individuals with impaired glucose tolerance to evaluate prospectively whether ramipril prevents diabetes.40

Potential mechanisms for reduction in new-onset diabetes with ACEI Content points: ACE inhibition may prevent the onset of diabetes through a wide range of potential mechanisms affecting both pancreatic ß-cells and directly affecting insulin.40 Mechanisms by which ACE inhibitors may slow or reverse the decline in ß-cell function include the following: – Reduce aldosterone secretion and renal potassium wasting, which could preserve ß-cell responsiveness – Increase islet blood flow and pancreatic ß-cell perfusion by reducing Ang II-mediated vasoconstriction in the pancreas Mechanisms by which ACE inhibitors may affect insulin include the following: – Reduce insulin-mediated glucose disposal (by a bradykinin-mediated increase in NO production), which decreases the need for pancreatic insulin secretion – Reduce insulin resistance at the liver and fat cells, which would reduce hepatic glucose production and lower free fatty acid levels.

CV risk reduction with ACEIs in type 2 diabetes: ABCD, CAPPP, and FACET Content points: A meta-analysis assessed the impact of ACE inhibitors vs other agents on cardiovascular outcomes in patients with diabetes. The meta-analysis included the Appropriate Blood Pressure Control in Diabetes (ABCD) trial, the Captopril Prevention Project (CAPPP), and the Fosinopril Amlodipine Cardiovascular Events Trial (FACET).41 The meta-analysis showed a significant benefit of ACE inhibitors in reducing acute MI, cardiovascular events, and mortality over comparative therapies. The risk reductions included acute MI, 63% (P < 0.001); cardiovascular events, 51% (P < 0.001); and all-cause mortality, 62% (P = 0.01). There was a 24% reduction in stroke, but it was not statistically significant. The data suggest that in addition to blood pressure reduction, other mechanisms, possibly including modulation of fibrinolysis, may be important in determining therapeutic effects. The findings suggest that the manner in which blood pressure is lowered is important.41

Evidence-based effects of antihypertensive agents in diabetic patients Content points: The most commonly prescribed antihypertensive agents available in the United States are presented in this slide. At the doses available for clinical use, most antihypertensive agents will produce a reduction in systolic or diastolic blood pressure of 5% to 10% with mild or moderate hypertension.42 Overall, there is strong evidence that pharmacologic therapy of hypertension in patients with diabetes is effective in producing substantial decreases in cardiovascular and microvascular outcomes and progression of nephropathy. These studies used different drug classes including ACE inhibitors, ARBs, diuretics, and ß-blockers as the initial therapy. The level of evidence ranges from clear evidence from well-conducted, randomized clinical trials (level A) to supportive evidence from poorly controlled clinical trials (level C).43 ACE inhibitors reduce coronary events, progression of renal disease, and stroke risk in patients with diabetes, based on level A evidence. ß-Blockers similarly reduce coronary events, renal disease progression, and stroke in diabetic patients. However, there are concerns about their effect on hypoglycemia, particularly regarding use of nonselective ß-blockers in patients taking insulin. Although it is unknown if this effect is clinically significant, it is probably prudent to avoid these agents in patients taking insulin. In other patients with diabetes, especially with a recent MI, the well-established benefits of ß-blockers outweigh potential risks.43 ARBs blunt the progression of renal disease, but data are limited on their impact on cardiovascular events. Low-dose thiazide diuretics reduce cardiovascular events in diabetic subjects. Use classes of drugs for which there is no long-term data on efficacy in improving outcomes when there is intolerance to other classes or specific indications for their use, or when additional drugs are required to achieve the blood pressure target.43

ADA: BP goals and treatment indictations for hypertensive diabetic patients Content points: This slide summarizes blood pressure goals and treatment guidelines from the 2002 Clinical Practice Guidelines issued by the American Diabetes Association.43 All patients with diabetes should have blood pressure measured at the time of diagnosis or initial office evaluation and at each scheduled visit. Because of the high cardiovascular risk associated with blood pressure >130/80 mm Hg, a target blood pressure goal of <130/80 mm Hg is considered the goal of treatment, if it can be safely achieved. In patients with blood pressure ranging from 130-139/80-89 mm Hg, behavioral therapy should be tried for up to three months, then drug therapy should be added. In patients with blood pressure >140/>90 mmHg, behavioral therapy and drug therapy should be started at the same time. Lifestyle modifications to lower blood pressure include the following: – Weight reduction can reduce blood pressure ~1 mm Hg for each kg of weight loss. – Sodium restriction (from a daily intake of 4600 mg to 2300 mg daily) produces reductions of ~5/~2-3 mm Hg in studies of patients with essential hypertension. – Physical activity of moderate intensity, such as 30-45 minutes of brisk walking most days of the week, has been shown to lower blood pressure. – Smoking cessation and moderation of alcohol intake are recommended.

ADA: Pharmacologic treatment of high BP in patients with diabetes— BP goal <130/80 mm Hg Content points: This slide summarizes the American Diabetes Association current guidelines for drug treatment of high blood pressure.43 Many studies demonstrate the benefits of ACE inhibitors on multiple adverse outcomes in patients with diabetes, including both macrovascular and microvascular complications, in patients with either mild or more severe hypertension and in both type 1 and type 2 diabetes. The established practice of choosing an ACE inhibitor as the first-line agent in most patients with diabetes is reasonable. Intial drug therapy, however, may be with ACE inhibitors, ARBs, ß-blockers or diuretics. Additional drugs may be chosen from these classes or another drug class. In hypertensive patients with microalbuminuria or clinical albuminuria, an ACE inhibitor or ARB should be strongly considered. If one class is not tolerated the other can be selected. In patients over age 55 years, with hypertension or without hypertension, but with another cardiovascular risk factor (history of cardiovascular disease, dyslipidemia, micoalbuminuria, smoking) an ACE inhibitor (if not contraindicated) should be considered to reduce the risk of cardiovascular events.43 This evidence is based on the HOPE study and the MICRO-HOPE substudy in patients with diabetes using ramipril 10 mg.15,28 It is very clear that many people will require three or more drugs to achieve the recommended target. Treatment decisions should be individualized based on the clinical characteristics of the patient, including comorbidities as well as tolerability, personal preferences, and cost. Achieving the blood pressure target with a regimen that does not produce burdensome side effects and is at reasonable cost to the patient is important.43

Majority of high-risk diabetic patients are not receiving optimal therapy Content points: Jones et al conducted a registry study of concomitant risk factors and current treatment in 1370 patients with type 2 diabetes at diabetes clinics in the north of England. They excluded patients who were dipstick positive for proteinuria. Their objective was to determine how many of the patients were high risk, as defined in the HOPE and MICRO-HOPE studies, and whether these patients were receiving an ACE inhibitor.44 They found that 1075/1370 patients (78%) met the MICRO-HOPE inclusion criteria: type 2 diabetes plus >1 risk factor (smoking, previous cardiovascular disease, hypertension, hypercholesterolemia, microalbuminuria). Although they were therefore candidates for ACE inhibitor treatment, only 311 (29%) were receiving an ACE inhibitor.45 Based on the results of the MICRO-HOPE study, the investigators calculated that adding ramipril to the treatment regimen of the 764 patients (71%) who were not receiving ACE inhibition would prevent 26 cardiovascular deaths and 63 major nonfatal cardiovascular events over the next 4.5 years.