DUAL RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM INHIBITION: TOO MUCH OF A GOOD THING?
A.H. Jan Danser, Erasmus MC, Rotterdam, The Netherlands
The beneficial effects of ACE inhibitors (ACEi) and AT1 receptor blockers (ARBs) are due to blockade of tissue Ang II. Such blockade is often incomplete, due to activation of feedback mechanisms within the RAS (‘Ang II escape’). Tissue angiotensin generation depends on the uptake of circulating renin, and renin inhibitors (RI) may already bind to renin before it reaches tissue sites, thereby effectively inducing RAS blockade. Indeed, the rise in renin (indicating the degree of RAS blockade) has been suggested to be larger during RI than during other RAS blockers, and tissue Ang II remained better suppressed. Yet, recently the ALTITUDE study was halted because the addition of a RI to an ACEi/ARB in diabetic patients with nephropathy did not yield additional benefit, and resulted in increased side effects, including hypotension and end-stage renal disease. These findings mimic earlier studies in high-risk patients with established cardiovascular disease or diabetes treated with an ACEi+ARB (ONTARGET trial) and in rodents treated with an ACEi+ARB on top of a low-salt diet. The latter study revealed that dual RAS blockade induced hypotension and renal failure, accompanied by massive rises in renin, depleting angiotensinogen. These deleterious effects were prevented by a high-salt diet. Clearly, we now need a full understanding of why dual blockade might be harmful and whether this applies to some or all patients. Second, we need to establish whether the three types of RAS blockers, when given separately, are identical. This talk will summarize the current status with regard to these topics.