Drug Topics - January 14, 2008 - (Page 36) 36 DRUG TOPICS JANUARY 14, 2008 www.drugtopics.com CONTINUING EDUCATION proteinuria was inversely related with a decrease in GFR. Reducing proteinuria also decreased the risk of doubling of creatinine levels and development of ESRD. The incidence of cough was higher in the ramipril group than placebo; otherwise side effects were comparable between both groups. The REIN-2 trial confirmed that patients receiving more intensive blood pressure lowering (130/80 mmHg) by adding a dihydropyridine calcium channel blocker did not provide any additional benefit compared with conventional blood pressure control (134/82 mmHg) in chronic non-diabetic kidney disease. The MICRO-HOPE substudy of the HOPE trial revealed that adding ramipril to patients at high risk for cardiovascular events is beneficial. Ramipril at doses up to 10mg/d decreased the risk of progression from microalbuminuria to overt nephropathy by 24% and reduced the incidence of cardiovascular outcomes. There was a relative risk reduction of 25% in the ramipril group in primary outcomes (MI, stroke, or cardiovascular death). This shows that reducing urinary albumin excretion decreases the risk for cardiovascular events. The ramipril group experienced a higher incidence of dry cough, dizziness, or hypotension than placebo. giotensin II causes vasoconstriction and stimulates the release of aldosterone when AT1 is activated. In Type 2 diabetes ARBs are more effective than other antihypertensive agents in slowing progression of kidney disease with overt nephropathy due to Type 2 diabetes per NKF K/DOQI. The clinical data that support the use of ARBs in the presence of proteinuria with hypertension involve Type 2 diabetes. Three trials that will be discussed are The Reduction of Endpoints in NIDDM with Angiotensin II Antagonist Losartan (RENAAL), The Irbesartan Diabetic Nephropathy Trial (IDNT), and IRbesartan MicroAlbuminuria in hypertensive patients with Type 2 diabetes (IRMA 2). A summary of these trials can be found in Table 3. The RENAAL study looked at losartan (50-100mg/day) in comparison with placebo. Both groups were taking conventional antihypertensive therapy (thiazide diuretics, calcium channel blockers, beta-blockers, alpha blockers, centrally acting agonists). The subjects included in this study had Type 2 diabetes, hypertension, and nephropathy. After treatment for a mean of 3.4 years, losartan reduced proteinuria by 35% over conventional therapy and significantly reduced doubling of serum creatinine and incidence of end-stage renal disease. Adverse effects resulting in discontinuation of the medication were similar between both groups. The most common adverse effects were hyperkalemia and doubling of serum creatinine. The IDNT trial looked at the effects of irbesartan, amlodipine, and placebo (conventional antihypertensive therapy – diuretics, beta-blockers, alpha blockers, and centrally acting agents) on the rate of progression of diabetic nephropathy. All subjects included had Type 2 diabetes, hypertension, and proteinuria (urinary protein excretion of ≥ 900mg/24hrs). The irbesartan group reduced the rate progression of diabetic Angiotensin II receptor blockers (ARBs) ARBs play a significant role comparable to ACEIs. Like ACEI, ARBs are considered first-line agents for hypertension with diabetic or non-diabetic kidney disease. They contain the same compelling indications as ACEIs, which were discussed above. These agents benefit blood pressure, kidney function, and proteinuria by binding to the AT1 and AT2 receptor. They have a 1000-fold higher affinity for the AT1 receptor. ARBs bind to the AT1 receptor blocking the RAAS and preventing the production and effect of angiotensin II. As mentioned earlier, anTable 2 Clinical trials of ACEIs in diabetic/nondiabetic kidney disease Trials Effect of AngiotensinConverting-Enzyme Inhibition On Diabetic Nephropathy trial Regimens Captopril 25 mg t.i.d., placebo Renal end point Primary: Doubling of the baseline serum creatinine concentration Secondary: Degree of proteinuria; Reduction in death, dialysis, and transplantation Rate of GFR decline Results 48% risk reduction for captopril compared with placebo 30% decrease by captopril vs. placebo 50% reduction by captopril compared with placebo 0.53 ml/min ramipril 0.88 ml/min placebo 18% reduction with ramipril; 40% reduction with placebo Relative risk reduction of 25% with ramipril compared with placebo Decreased the risk of progression from microalbuminuria to overt nephropathy by 24% compared with placebo REIN Ramipril 5 mg, placebo Risk of doubling of serum creatinine level or progressing to ESRD MICRO-HOPE Ramipril 10 mg, placebo Primary: MI, stroke, or cardiovascular death Secondary: Progression from microalbuminuria to overt nephropathy http://www.drugtopics.com
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