Angiotensin II-Receptor Blockers: Clinical Relevance and Therapeutic Role

Jo E. Rodgers and J. Herbert Patterson

Disclosures

Am J Health Syst Pharm. 2001;58(8) 

In This Article

Role of the RAS in Disease

Background Over the past two decades, longitudinal observational studies have repeatedly highlighted the importance of hypertension as a risk factor in the development of cardiovascular and cerebrovascular disease, including coronary heart disease, heart failure, and stroke.[25] Many clinical studies have shown that ARBs lower blood pressure as effectively as other antihypertensive agents, including -blockers, calcium-channel blockers, and ACE inhibitors.[26,27,28,29,30] Typically, four to six weeks of therapy are required to achieve the full therapeutic effects.

ARBs: Antihypertensive efficacy. Some data suggest that ARBs have varying abilities to lower blood pressure.[31,32,33] However, a meta-analysis of 43 randomized clinical trials (in 11,281 patients) comparing ARBs with placebo, drugs in other antihypertensive classes, and other ARBs found comparable blood pressure reductions for all ARBs; response rates were 48-55%.[34] While dosage adjustment resulted in slightly greater blood pressure reductions and response rates, the addition of hydrochlorothiazide had a substantially greater effect. Overall, the meta-analysis demonstrated a nearly flat dose- response curve for ARBs and a substantial additive effect with combined ARB-hydrochlorothiazide therapy.

ACE inhibitors: Long-term outcomes. ARBs have not been studied in any randomized controlled trials assessing long-term outcomes in patients with hypertension. ACE inhibitors have not been compared with placebo in this clinical setting but were associated with similar or less total cardiovascular events than thiazides and -blockers in the Captopril Prevention Project (CAPPP) (10,985 hypertensive patients) and atenolol in the United Kingdom Prospective Diabetes Study (UKPDS) (1,148 hypertensive patients with type 2 diabetes mellitus).[35,36] In two other trials in patients with hypertension and diabetes, ACE inhibitors were associated with significantly fewer cardiovascular events than were dihydropyridine calcium-channel blockers.[37,38] In the Fosinopril versus Amlodipine Cardiovascular Events Randomized Trial (FACET), 380 patients with type 2 diabetes mellitus and hypertension were given fosinopril or amlodipine for 3.5 years.[37] Other antihypertensive agents were added as needed to achieve blood pressure control. There was no significant difference in blood pressure, lipid levels, or glycemic control between the two groups; however, there was a 51% lower risk of the combined endpoint of MI, stroke, and angina requiring hospitalization in the ACE inhibitor-treated group. Similarly, in a subgroup analysis of 470 hypertensive patients, enalapril was associated with a ninefold lower risk of MI than the calcium-channel blocker nisoldipine.[38] This difference was not seen in a trial that involved patients with only hypertension (no diabetes) and all calcium antagonist types.[39]

Despite these discrepancies, the Heart Outcomes Prevention Evaluation (HOPE) trial provided compelling results in a somewhat similar study population.[40] The HOPE trial was designed to assess the effect of ramipril in patients at high risk for cardiovascular events. This study enrolled 9297 patients 55 years of age or older (mean age, 66 years) who had evidence of vascular disease or diabetes plus one other cardiovascular risk factor. Potential cardiovascular risk factors allowed were hypertension, increased total cholesterol levels, low high-density-lipoprotein cholesterol levels, cigarette smoking, and documented microalbuminuria. Patients were excluded if they were known to have heart failure or a left ventricular ejection fraction (LVEF) of <40%. The trial had a placebo-controlled, 2 x 2 factorial design and evaluated both ramipril 10 mg/day and vitamin E 400 IU daily. The primary study endpoint was a composite of MI, stroke, and death from cardiovascular causes. Compared with placebo, ramipril significantly reduced the risk of the composite endpoint (relative risk [RR] = 0.78, p < 0.001). Ramipril also significantly reduced all-cause mortality (RR = 0.84, p < 0.005), cardiovascular mortality (RR = 0.74, p < 0.001), MI (RR = 0.80, p < 0.001), and stroke (RR = 0.68, p < 0.001). Revascularization procedures, cardiac arrest, heart failure, and complications related to diabetes were also significantly reduced with ramipril. Noncardiovascular mortality rates were not different between the two treatment groups.

Long-term trials with findings similar to those of the HOPE trial have not been conducted with ARBs. Several large trials assessing morbidity and mortality in hypertensive patients receiving ARBs are ongoing (Table 3).

ARBs: Dosage and administration. The dose-response curve for ARBs is relatively flat. Therefore, adding another agent may be necessary to achieve adequate blood pressure control in some patients. Patients requiring reductions in blood pressure beyond those obtained with ARB monotherapy may benefit from the addition of hydrochlorothiazide. This has an additive effect, producing greater reductions in blood pressure than with either agent alone.[5,6,7,8,9,10] Furthermore, blood pressure lowering may be greater with the addition of a low-dose diuretic than with upward adjustment of the ARB dosage.[41] Several studies have demonstrated safety and efficacy of an ARB plus a diuretic, a calcium-channel blocker, or a -blocker.[42,43,44] Theoretically, combination therapy, with its smaller drug doses, may have a superior adverse- effect profile. Several ARBs are available in fixed-combination formulations that allow for once-daily administration, including a combination of losartan 50 mg, hydrochlorothiazide 12.5 mg, losartan 100 mg, and hydrochlorothiazide 25 mg (Hyzaar); a combination of irbesartan and low-dose hydrochlorothiazide in daily doses of 150/12.5 mg and 300/12.5 mg (Avalide); and a combination of valsartan with low-dose hydrochlorothiazide in daily doses of 80/12.5 mg and 160/12.5 mg (Diovan HCT).

Background. Angiotensin II can induce hypertrophy of the vascular smooth muscle and myocardium. These effects are thought to cause structural alterations in the affected organ systems and may be very important in the pathogenesis of chronic hypertensive cardiovascular diseases. Angiotensin II is involved in atherosclerosis and in the remodeling and repair of the myocardium after an MI. Increased angiotensin II levels have been implicated as an important contributor to the neurohormonal activation that is deleterious in heart failure.[45,46]

Left ventricular remodeling occurs after an ischemic, toxic, or inflammatory event that results in cell death (e.g., an MI) or during hemodynamic overload of the myocardium (e.g., aortic stenosis). Remodeling may occur despite the initial response of hypertrophy of viable myocytes, which helps maintain stroke volume and cardiac output.[47,48,49] If the myocytic hypertrophy cannot support stroke volume or wall tension, the left ventricle begins to dilate, eventually leading to left ventricular failure.[50] These changes (ventricular remodeling) are initially adaptive, helping to preserve cardiac performance and maintain left ventricular pressure and stroke volume. If, however, the remodeling process continues, it may lead to further dilation and hypertrophy, declining systolic and diastolic function, and clinically overt heart failure.[50,51]

Benefits of RAS inhibition. Blocking the RAS not only decreases myocytic hypertrophy independent of blood pressure lowering but also has cardioprotective and cardioreparative properties that affect the development of pathological fibrosis, which affects coronary artery circulation, myocardial stiffness, and arrhythmogenesis. Furthermore, blocking the RAS might affect ischemic events through several possible mechanisms, including reduced coronary wall thickness, endothelial protection, improved coronary reserve, decreased coronary microvascular decompression via reversal of ventricular interstitial fibrosis and myocytic hypertrophy, and reduced platelet aggregation.[52]

Hypertensive patients with left ventricular hypertrophy have a significantly increased risk of mortality.[53] Several meta-analyses have assessed antihypertensive therapy and reduction of left ventricular hypertrophy.[54,55] These studies suggest that ACE inhibitors are superior to other antihypertensives in reducing hypertrophy, independent of antihypertensive efficacy. Another meta-analysis suggested that both ACE inhibitors and long-acting calcium-channel blockers are superior to other agents in left ventricular hypertrophy.[56] More complete data are necessary before any firm conclusions can be drawn.

ARBs versus ACE inhibitors. ACE inhibitors are considered the cornerstone of therapy in heart failure patients. The beneficial hemodynamic and neurohormonal effects of ACE inhibitors in patients with heart failure include reduced systemic vascular resistance, increased cardiac output, and decreased levels of serum norepinephrine, aldosterone, and arginine vasopressin.[57] Furthermore, multiple studies have found a reduction in mortality and an improvement in functional capacity in patients with heart failure of any severity treated with ACE inhibitors.[58,59,60] However, morbidity and mortality from this condition remain quite high. ACE inhibitors do not completely block the effects of angiogtensin II and are actually associated with an increase in circulating angiotensin II in heart failure patients.[16] Furthermore, ACE inhibitor therapy is often limited by the adverse effects related to bradykinin production.

Limited data suggest that ARBs have physiological effects that may benefit heart failure patients. ARBs decrease both preload and afterload, which in turn decreases ventricular wall stress.[61] Thus, ARBs may restore the balance between myocardial oxygen supply and demand. In animals and humans, ARBs have decreased mean arterial pressure, systemic vascular resistance, and coronary vascular resistance without a reflex increase in heart rate.[61,62,63] They decrease concentrations of circulating norepinephrine and inhibit aldosterone formation.[61,63] Two animal studies found that losartan reduces left ventricular hypertrophy.[64,65]

Dickstein et al.[66] compared losartan with enalapril in patients with moderate to severe heart failure after eight weeks of therapy. Losartan and enalapril produced similar improvement in neurohormonal status and exercise capacity. In the Losartan Pilot Exercise Study, losartan potassium 25-50 mg/day was compared with enalapril maleate 20 mg/day for 12 weeks.[67] There was no difference between treatment groups in LVEF, dyspnea-fatigue index, distance covered in a six-minute walking test, or treadmill exercise-test duration. A similar study compared the effects of irbesartan and lisinopril in 134 patients with an LVEF of 40% who had been stabilized with an ACE inhibitor. After discontinuation of the ACE inhibitor, the patients were randomized to treatments with irbesartan (adjusted to 150 mg/day) or lisinopril (adjusted to 20 mg/day) for three months. Both therapies yielded similar improvements in exercise tolerance, LVEF, and cardiothoracic ratio.[68] In each of these studies, losartan was safe and well tolerated.

The ELITE study was the first long-term study (48 weeks) to prospectively compare an ARB (losartan) with an ACE inhibitor (captopril) in elderly patients with heart failure.[13] The study enrolled patients 65 years of age or older with an LVEF of 40% who had not previously received ACE inhibitors. Although no differences in the primary endpoint (effect on renal function) emerged, the investigators reported that the risk of death and hospital admission for heart failure was 32% lower with losartan than with captopril (p = 0.075). The decrease in risk was primarily attributable to a decrease in all-cause mortality (and in sudden death) in the losartan group versus the captopril group (4.8% versus 8.7%, respectively; RR = 46%, p = 0.035). In view of the suggestion that ARBs may have a greater benefit in heart failure patients than ACE inhibitors, an effort to clarify the effect of losartan on mortality was undertaken in the ELITE II trial.

ELITE II involved more than 3000 patients with evidence of heart failure. Patients were enrolled if they were 60 years old, had New York Heart Association (NYHA) class II- IV heart failure, and had an LVEF of 40%.[69] They had never received an ACE inhibitor or an ARB or had received such therapy for less than seven days in the three months prior to study entry.[68] The patients were allowed to receive standard heart failure therapy, including digoxin and diuretics, and were stratified for -blocker use. The study subjects were randomized to either losartan (n = 1574) or captopril (n = 1578) and were followed for a mean of 1.5 years (until 510 deaths occurred). Targeted dosages of captopril hydrochloride (50 mg three times daily) and losartan potassium (50 mg daily) were therapeutic goals. The primary end-point was all-cause mortality, and the secondary endpoint was the frequency of sudden death or cardiac arrest with resuscitation. Other endpoints included the combined endpoint of all-cause mortality, all-cause hospitalization, safety, and tolerability.

There was no significant difference in all-cause mortality between the losartan group (280 deaths) and the captopril group (250 deaths) (RR = 1.13, 95% confidence interval [CI] = 0.95-1.35, p = 0.16). Unlike the ELITE study, ELITE II found more deaths in the losartan group than in the captopril group. There was no significant difference in the number of sudden deaths or cardiac arrests with resuscitation between the losartan group (142 events) and the captopril group (115 events) (RR = 1.24, 95% CI = 0.94- 1.59, p = 0.08). The two groups did not differ significantly with respect to the combined endpoint of all-cause mortality and hospitalization (RR = 1.07, 95% CI = 0.96-1.18, p = 0.21). There was a significantly higher frequency of patient withdrawal related to adverse events in the captopril group (20.8% versus 12.2%, p = 0.002). The difference was due to a higher rate of cough.

ELITE II did not confirm the hypothesis that losartan is superior to captopril in improving survival in patients with heart failure due to systolic dysfunction. ELITE II did confirm that losartan is significantly better tolerated than captopril. The investigators concluded that ACE inhibitors should remain the standard of therapy. ARBs remain an alternative in patients who are intolerant of ACE inhibitor therapy.

The Study of Patients Intolerant of Converting Enzyme Inhibitors (SPICE) evaluated the tolerability of the ARB candesartan in heart failure patients (LVEF, <35%) considered intolerant of ACE inhibitor therapy.[70] ACE inhibitor intolerance was attributed to cough (67%), hypotension (15%), or renal dysfunction (11%). Patients were randomized in a 2:1 ratio to receive candesartan (n = 179) or placebo (n = 91). The targeted candesartan dosage was 16 mg/day. A majority (148, or 83%) of the candesartan recipients tolerated the drug and finished the 12-week study. There was a 4.1% higher discontinuation rate with candesartan than placebo; the difference was not significant. Of the 31 patients who discontinued candesartan (17%), 21 had an adverse event, including hypotension (5 patients) and renal insufficiency (7 patients). The rate of drug discontinuation because of renal insufficiency was similar between the two groups (4% in the candesartan group and 3% in the placebo group). ACE inhibitor-specific reasons (cough, angioedema, hyperkalemia, taste disturbance) accounted for the ACE inhibitor intolerance in 75% of the patients, general vasodilator reasons (symptomatic hypotension and renal failure) were responsible in 15%, and both were responsible in 10%. The authors reported that candesartan had higher tolerability when ACE inhibitors had been stopped for a reason believed to be specific to ACE inhibitors (predominately cough); however, no specific results were reported. The frequency of death and morbidity (worsening heart failure, MI, all-cause hospitalization, and hospitalization for heart failure) was not significantly different between the candesartan and placebo groups. The study was limited by a lack of objective documentation of previous intolerance to ACE inhibitors. The investigators concluded that candesartan was well tolerated despite previous ACE inhibitor intolerance. However, the effect of candesartan on major clinical endpoints, including death, remains to be determined. Several trials of ARBs in heart failure are ongoing that include death as an endpoint (Table 3).

Combination ARB and ACE inhibitor therapy. The combination of ACE inhibitors and ARBs offers the theoretical advantage of blocking the actions of angiotensin II while increasing bradykinin levels. However, with combination therapy, ACE inhibition could lead to less angiotensin II production and thus less stimulation of angiotensin II types 1 and 2 receptors. Stimulation of type 1 receptors is deleterious, while stimulation of type 2 receptors may be beneficial. Thus, combination therapy may result in less angiotensin II formation and stimulation of the type 2 receptor, leading to less effective therapy. Furthermore, combination therapy is unlikely to have a more tolerable adverse- effect profile than ACE inhibitors alone. A study in rats with spontaneous hypertension suggested that an ARB plus an ACE inhibitor was more effective than an ACE inhibitor alone in improving systemic and coronary hemodynamics.[71] Another study in transgenic rats with renin-dependent hypertension found that combination therapy had an additive effect.[72]

A few clinical studies in healthy subjects and post-MI and heart failure patients assessed the safety and antihypertensive efficacy of the combination of an ACE inhibitor and an ARB. The combination produced an additive reduction in mean blood pressure and an additive effect on the increase in plasma renin activity compared with either an ACE inhibitor or an ARB alone in 12 healthy subjects who were mildly sodium depleted.[73,74] Di Pasquale et al.[75] conducted a 10-day study in 44 post-MI patients and found that combination therapy was safe in this group. Another study assessed 119 patients with chronic symptomatic heart failure over six weeks and found that combination therapy resulted in greater reductions in serum aldosterone than an ACE inhibitor alone and was well tolerated.[76] Hamroff et al.[77] assessed 43 patients with chronic symptomatic heart failure receiving maximally recommended or tolerated ACE inhibitor therapy and reported that combination therapy was safe and resulted in additional vasodilation. Similarly, Baruch et al.[78] reported that adding valsartan to long-term ACE inhibitor therapy in heart failure patients led to a sustained decrease in systolic and diastolic blood pressure and pulmonary capillary wedge pressure after four weeks of therapy.

Several clinical trials have assessed ARB-ACE inhibitor combinations for the management of heart failure symptoms.[79,80,81] Most of these studies were limited by short follow-up times of three to six months. Combination therapy resulted in a greater increase in LVEF and a greater reduction in end-systolic volume and in end-diastolic volume at rest and during peak exercise than did placebo.[79] The combination has also produced a greater increase in LVEF and treadmill exercise time than an ACE inhibitor alone.[80] In patients with severe heart failure, the combination reduced NYHA functional class and increased maximum exercise capacity.[81]

In the Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) pilot study, 768 patients with NYHA class II-IV heart failure, an LVEF of <40%, and a six-minute walking distance of <500 m were randomized to therapy with candesartan (4, 8, or 16 mg) (n = 327), enalapril (20 mg) (n = 109), or the combination of candesartan (4 or 8 mg) and enalapril (20 mg) (n = 332).[82] This study assessed exercise tolerance, ventricular function, quality of life, neurohormone levels, and tolerability after 43 weeks of therapy. The primary endpoint was six-minute walking distance. The study was not designed to assess effects on morbidity and mortality; however, it was terminated early because of an increased number of heart failure-related hospitalizations and deaths in the candesartan and candesartan plus enalapril groups compared with the enalapril group.

Overall, there were no differences among the three groups in NYHA functional class, six-minute walking distance, or quality of life. The rate of clinical events, including death and hospitalization, did not differ significantly among the groups; however, death and any heart failure-related hospitalization were significantly less frequent in the combination group than in the enalapril group (p = 0.037). There was also a significant difference among the three groups in the frequency of hospitalization alone (p = 0.048). There was a non-significant increase in LVEF and a significantly smaller increase in end-diastolic and end-systolic volumes (p < 0.01) and in blood pressure (p < 0.05) with combination therapy than with either drug alone. The combination therapy significantly decreased the level of aldosterone at 17 weeks (p < 0.05) and the level of brain natriuretic peptide at 43 weeks (p < 0.01).

RESOLVD was not a full-scale clinical trial with sufficient power to detect changes in relevant clinical endpoints. Nineteen weeks after the start of therapy, patients were further randomized to metoprolol or placebo, yielding six treatment groups for assessment. Finally, multiple variables were analyzed. Because of these limitations, it is difficult to draw conclusions from this trial. Most patients in the combination group continued therapy for almost one year.

The Valsartan Heart Failure Trial (Val-HeFT), a large, double-blind, multicenter trial, enrolled 5010 patients with NYHA functional class II (62%) or III (36%) heart failure.[83] While this trial was not considered an assessment of an ACE inhibitor-ARB combination, 93% of the patients were taking an ACE inhibitor at baseline. Also, approximately 35% were receiving -blockers at baseline. The patients were randomized to placebo or valsartan 40 mg twice daily, adjusted upward to a target of 160 mg twice daily. The average dosage achieved was 254 mg/day. The primary endpoints were all-cause mortality and combined all-cause mortality and morbidity. After approximately two years of follow-up, valsartan had no effect on all-cause mortality (p = 0.80). However, all-cause morbidity plus mortality was reduced by 13.3% (28.8% in the valsartan group versus 32.1% in the placebo group) (RR = 0.87, 95% CI = 0.79-0.96, p = 0.009). The reduction in this combined endpoint was primarily related to a 27.5% reduction in hospitalizations for heart failure. Additional beneficial effects were seen with several secondary end-points, including NYHA functional class, LVEF, and signs and symptoms of heart failure. An attenuation in the beneficial effects of valsartan was seen both in patients taking ACE inhibitors and in patients taking -blockers. A negative outcome among those taking -blockers and valsartan occurred only in those also taking an ACE inhibitor. The study confirmed that ACE inhibitor-intolerant patients with heart failure should be taking an ARB. Caution is warranted when adding an ARB if the patient is already taking both an ACE inhibitor and a -blocker.

ACE inhibitors have also been found to reduce mortality in patients with heart failure of any severity, including asymptomatic left ventricular dysfunction.60 In several trials, ACE inhibitors have been found to reduce mortality in post-MI patients with an LVEF of <40%.[84,85] Ongoing studies are assessing the role of ACE inhibitors in patients with coronary artery and peripheral atherosclerotic disease. The role of ARBs in the treatment of these cardiovascular diseases has not yet been defined.

Background. Angiotensin II constricts afferent and efferent arterioles and directly affects sodium and bicarbonate excretion. Furthermore, angiotensin II controls mesangial cell function, norepinephrine release from sympathetic nerves, and renin release from juxtaglomerular cells.[86] The main factors controlling renal hemodynamics are systemic blood pressure and afferent and efferent arteriolar resistance. Prostaglandins and angiotensin II are the main determinants of renal arteriolar resistance. Prostaglandins are potent dilators of afferent and efferent arterioles. Angiotensin II is a potent constrictor of the efferent arteriole and a relatively weak constrictor of the afferent arteriole.[87]

Blocking the RAS has several advantages for renal function. Inhibiting the RAS dilates arteries and decreases systemic blood pressure. In the kidneys, decreased efferent arteriolar resistance lowers intraglomerular pressure, resulting in a decrease in the albumin excretion rate, which helps to slow progression of chronic renal failure.[87,88] Inhibiting the RAS with ARBs achieves results similar to those with ACE inhibitors in healthy subjects, including a reduction in filtration fraction and an increase in urinary sodium excretion.[18,89] Both agents are associated with adverse effects in extreme volume depletion.[90]

ACE inhibitors: Renal protective effects. Hypertension, which contributes to increased intraglomerular pressure, is an independent risk factor for renal failure, particularly when accompanied by hyperglycemia. Management of hypertension is the cornerstone of prevention and treatment of diabetic renal disease.[91,92] Clinical trials in hypertensive diabetics have clearly demonstrated that the decline in the glomerular filtration rate can be slowed and proteinuria decreased with adequate management of hypertension.[93,94]

Inhibition of angiotensin II with ACE inhibitors or ARBs could arrest the sequence of events leading to end-stage renal disease by decreasing efferent arteriolar resistance and by blocking the arteriolar hypertrophic effects of angiotensin II. Interruption of the RAS with ACE inhibitors has proven beneficial for hypertensive and normotensive patients with diabetes.[95,96] In insulin-dependent patients with proteinuric diabetic nephropathy, captopril unequivocally retarded the progression of renal insufficiency, as measured by both the change in creatinine clearance and the requirement for dialysis or renal transplantation.[95]

Captopril also prevented the progression of microalbuminuria to proteinuria in patients with type 1 diabetes mellitus.[96] ACE inhibitors have been shown to reduce either microal-buminuria or proteinuria or to prevent their appearance in patients with type 2 diabetes mellitus, although the results to date have not been as convincing for type 1 diabetes mellitus.[97,98,99] A meta-analysis of studies of ACE inhibitors and other antihypertensive drugs in patients with type 1 and type 2 diabetes mellitus found a reduction in proteinuria with ACE inhibitor therapy independent of blood pressure reduction, treatment duration, type of diabetes, or stage of nephropathy.[100] A reduction in proteinuria seen with other antihypertensive agents was explained by reductions in blood pressure.

An assessment of some of the conditions that could influence the antiproteinuric effects of ACE inhibitors found a dose- and time-related response, as well as a strong dependence on dietary sodium restriction.[101] The response to ACE inhibitors was not dependent on initial proteinuria, blood pressure, or glomerular filtration rate. Therefore, ACE inhibitors have been advocated by the American Diabetes Association and the National Kidney Foundation for most diabetic patients with microalbuminuria, proteinuria, or hypertension.[102,103]

ARBs: Renal protective effects. Most of the clinical studies evaluating the renal protective effects of ARBs have been performed in animal models of hypertension, diabetes, and renal impairment. In several rat models, ACE inhibitors and ARBs were found to protect against cardiovascular end-organ damage independent of the effect on blood pressure.[104,105] In rats with experimentally induced diabetes, ARBs reduced blood pressure and glomerular injury.[106,107] ARBs prevented renal damage in several other rat models of renal injury.[108,109,110,111]

A few studies examining the renal protective effects of ARBs in humans have been published. In a four-month study in 13 patients with hypertension and renal disease, losartan 50 or 100 mg/day produced favorable systemic and renal hemodynamic changes, including a decrease in mean arterial pressure, an increase in effective renal plasma flow (ERPF), and a dose-dependent decrease in urinary protein excretion.[112] The effects of losartan and enalapril were studied in 11 patients with nondiabetic proteinuria and hypertension.[113] The protocol consisted of seven one-month study periods in which the patients consecutively received placebo, 50 mg of losartan, 100 mg of losartan, placebo, 10 mg of enalapril, 20 mg of enalapril, and placebo once daily. Proteinuria, blood pressure, and renal function were measured at the end of each study period. Proteinuria and blood pressure decreased with both doses of losartan and enalapril, whereas ERPF increased and the glomerular filtration rate remained stable. The decrease in urinary protein excretion was similar for both drugs. In two small studies, losartan and candesartan also reduced urinary protein excretion in patients with essential hypertension and patients with mild hypertension and type 2 diabetes mellitus.[114,115] The role of ARBs is being investigated in several studies assessing renal effects and microalbuminuria in patients with and without diabetes. Long-term studies evaluating the renal protective effects of ARBs in diabetic nephropathy are ongoing (Table 3).

Insulin sensitivity. Both positive and neutral effects of ACE inhibitors and ARBs on insulin sensitivity in diabetes have been reported. Captopril and enalapril had no effect on insulin sensitivity in normotensive patients with type 2 diabetes mellitus, while trandolapril had no effect in hypertensive patients with type 2 diabetes mellitus.[116,117] Two other studies found neither captopril nor enalapril to have any effect in patients with essential hypertension.[118,119] Lisinopril improved insulin sensitivity, while losartan had no effect in nondiabetic hypertensive patients.[120] In hypertensive rats, both quinapril and losartan improved insulin sensitivity, but quinapril was more effective.[121] While these study results are inconsistent, there is some suggestion that if ACE inhibitors prove to be distinguishable from ARBs in terms of disease-related outcomes, the reason may be the selective effects of ACE inhibitors on insulin resistance and insulin-mediated vascular function. Additional studies are needed.

Renal dysfunction. Agents that inhibit the RAS have paradoxical effects on renal function. They cause renal vasodilation, prevent reductions in glomerular filtration in hypertension, reduce proteinuria, and reduce morbidity and mortality in diabetic nephropathy. On the other hand, in states of low fixed renal blood flow (e.g., bilateral renal artery stenosis, severe congestive heart failure, and severe sodium and volume depletion), ACE inhibitors may worsen renal function and may even precipitate acute renal failure. In these states, renal function is often referred to as angiotensin dependent. Both ACE inhibitors and ARBs should be used cautiously in patients with renal dysfunction, especially those whose renal function may depend on the RAS (e.g., patients with severe heart failure). Potassium levels should be closely monitored. These agents should be avoided in patients with bilateral renal artery stenosis and unilateral renal artery stenosis with a single kidney.[5,6,7,8,9,10]

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