The renin angiotensin aldosterone system as a therapeutic target

Angiotensin-converting enzyme (ACE) inhibitors were initially developed in the late 1970s for treatment of hypertension. Their use has since been expanded to heart failure, postmyocardial infarction, and renal disease. ACE inhibitors, by

Table 2

Studies on prevention of type 2 diabetes with life style modifications

Variables

Finnish Diabetes Prevention Study [15]

Da Qing Impaired Glucose Tolerance and Diabetes Study [14]

Diabetes Prevention Program [16]

Mean age ± 1 SD Women (%) Mean BMI kg/m2 Study duration (yrs) White (%)

Other ethnic groups (%) Study groups

Adjusted reduction in incidence of type 2 diabetes (%)

control intervention (weight loss, diet, physical activity)

control diet exercise diet + exercise diet 31 exercise 46 diet + exercise 42

placebo metformin life style intervention (weight loss, diet, physical activity) metformin 31 life style intervention 58

blocking the conversion of angiotensin I to angiotensin II and by catalyzing the breakdown of bradykinin, exert numerous beneficial effects that maintain blood pressure and salt and water homeostasis. In addition, the vasodilating, antiinflammatory, plaque-stabilizing, antithrombotic, and antiproliferative properties of ACE inhibitors produce salutary effects. Numerous studies have demonstrated a significant benefit with use of ACE inhibition. The Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS), the Studies on Left Ventricular Dysfunction (SOLVD) treatment and prevention study, and the Vasodilator-Heart Failure Trial II (V-HeFT II) demonstrated significant overall mortality reduction in patients with congestive heart failure treated with enalapril. The Survival and Ventricular Enlargement trial (SAVE) and the International Study of Infarct Survival 4 (ISIS-4) study also revealed a survival benefit in postmyocardial infarction patients treated with captopril. In the Acute Infarction Ramipril Efficacy (AIRE) study, mortality was reduced in patients with recent myocardial infarction and overt congestive heart failure who were treated with ramipril. In addition, ramipril provided significant benefit in cardiovascular outcomes and mortality in patients with cardiovascular disease or diabetes and one other risk factor in the AIRE study. Lisinopril, trandolapril, and zofenopril improved survival in patients with acute myocardial infarction, recent myocardial infarction with left ventricular dysfunction, and acute myocardial infarction, respectively (Table 3) [23-32]. Angiotensin receptor blockers also have shown significant benefit in both cardiovascular and renal outcomes (Table 4) [33-45]. Losartan compared with atenolol in patients with hypertension and left ventricular hypertrophy showed reduction in composite cardiovascular mortality, myocardial infarction, and stroke in the Losartan Intervention for Endpoint (LIFE) study (relative risk [RR], 13%; P = 0.021) [33]; in the Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan (OPTI-MAAL) study, but losartan showed no difference in all-cause mortality compared with captopril in in subjects with acute myocardial infarction [38]. Also, no difference in mortality was noted with losartan compared with captoril in the ELITE II Losartan Heart Failure Survival Study of congestive heart failure [40]. The Reduction of End Points in Non-Insulin-Dependent Diabetes Melli-tus with the Angiotensin II Antagonist Losartan (RENAAL) study found a significant reduction of serum creatinine levels, end-stage renal disease, and death with losartan compared with placebo in patients with diabetic nephropathy (RR, 16%; P = 0.02) [37]. The Valsartan Heart Failure Trial (Val HeFT) compared valsartan with placebo for treatment of heart failure and revealed no difference in mortality but found a significant reduction in hospitalization [41]. When valsartan was added to captopril following acute myocardial infarction in the Valsartan in Acute Myocardial Infarction Trial (VALIANT) study, there was no difference in mortality or composite endpoints compared with either of the medications alone [39]. The Valsartan Antihypertensive Long-term use

Table 3

Summary of angiotensin-converting enzyme inhibitor clinical trials

Trial

ACE inhibitor

Patient group

Outcome

CONSENSUS (N = 253) SOLVD, treatment arm (N = 2569) V-HeFT II (N = 804)

SOLVD, prevention arm (N = 4228)

AIRE (N = 2006) ISIS-4 (N > 50,000) GISSI-3 (N = 19,394) TRACE (N = 1749) SMILE (N = 1556)

enalapril versus placebo enalapril versus placebo enalapril versus hydralazine isosorbide captopril versus placebo enalapril versus placebo ramipril versus placebo Captopril versus placebo lisinopril versus open control trandolapril versus placebo zofenopril versus placebo

recent MI with asymptomatic LVD asymptomatic LVD

recent MI with overt CHF acute MI acute MI

recent MI with LVD acute MI

# overall mortality

# overall mortality

# overall mortality

# overall mortality

# death and hospitalization from CHF

# overall mortality

# overall mortality

# overall mortality

# overall mortality

# overall mortality

Definitions: CHF, congestive heart failure; GISSI-3, Gruppo Italiano per lo Studio della Sopravvivvenza nell'Infarto Miocardica III; LVD, left ventricular dysfunction; MI, myocardial infarction; NYHA, New York Heart Association; SMILE, Survival of Myocardial Infarction Long-Term Evaluation trial; TRACE, Trandolapril Cardiac Evaluation trial. From Refs. [23-32].

Evaluation (VALUE) trial found no difference in composite endpoints of mortality and morbidity between valsartan and amlodipine [34]. Irbesartan was compared with amlodipine (in the IDNT study) [35] and with placebo (in the Irbesartan MicroAlbuminuria [IRMA] study) [36] in patients with diabetic nephropathy. [36], Irbesartan showed significant reduction of overt proteinuria, end-stage renal disease and doubling of serum creatinine. In the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) study, candesartan also showed reduction in composite endpoints of mortality and morbidity compared with placebo in heart failure patients with left ventricular dysfunction (Table 4) [42-45].

The rationale for considering RAAS inhibition in patients at risk of developing diabetes is based on the following concepts:

1. The role of activation of RAAS, the ensuing detrimental effects on cardiovascular and renal disease, and extensive evidence indicating that ACE inhibition favorably affects the heart, vasculature, and kidney, with improved patient outcomes

2. The deleterious effects of angiotensin II on vasculature and its role in endothelial dysfunction

3. The close relationship between insulin resistance (a precursor of diabetes and cardiovascular disease) and endothelial dysfunction

4. The pathways of insulin signaling and angio-tensin II in the vascular wall and the in-tracellular crosstalk between these signaling pathways that lends theoretical credence to the concept of diabetes prevention through RAAS blockade

5. Clinical evidence in secondary outcomes of prevention of new onset of diabetes from studies on RAAS inhibition

6. Clinical studies of ACE/angiotensin receptor blocker (ARB) inhibition and outcomes of markers of insulin resistance

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