Inhibitors of the Renin–Angiotensin System: Proven Benefits, Unproven Safety

Drugs that affect the renin–angiotensin–aldosterone system are effective in several important diseases. Using them safely and effectively is a basic clinical skill for physicians who treat chronic disease in adults. Activation of the renin–angiotensin–aldosterone system occurs in essential and renal hypertension and predisposes patients to progressive chronic kidney disease. The main effector peptide of the renin–angiotensin system is angiotensin II, which has neural, renal, cardiovascular, and adrenal effects. Two classes of drugs affect angiotensin II: Inhibitors of angiotensin-converting enzyme (ACE) inhibit its formation, and angiotensin-receptor blockers (ARBs) affect its action on cells. Neither of these classes is 100% effective in achieving its biochemical goal (1). Therefore, which drug class is more effective and what the effect is when the 2 classes are used together are important questions for clinicians.

Angiotensin-converting enzyme inhibitors and ARBs are used for hypertension and in patients with kidney disease. Although both drug classes are highly effective in lowering blood pressure in patients with essential hypertension, their comparative antihypertensive effectiveness and their relative advantages and disadvantages are uncertain. Inhibition of the renin–angiotensin system reduces proteinuria—a risk factor for progression of chronic kidney disease—in part independently of its effect on blood pressure (2). However, whether ARBs are as effective antiproteinuric agents as ACE inhibitors, and whether the combination of both is preferable to either agent alone, is also uncertain.

Two articles in this issue (3, 4) attempt to answer these questions. Through systematic review and meta-analysis, they examine the antihypertensive and antiproteinuric effectiveness of ACE inhibitors and ARBs. Although both of these outcomes are surrogate markers for clinical outcomes, such as end-stage renal disease or heart failure, they also fulfill many of the criteria for reliably predicting adverse outcomes. Both reviews were methodologically strong. They used standardized protocols with predefined criteria; extracted data on study …