Rationale for Double Renin-Angiotensin-Aldosterone System Blockade

The clinical benefits of both angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) extend beyond blood pressure reduction to encompass tissue-protective effects in target organs, such as the heart, vasculature, and kidneys, that underlie the reductions in cardiovascular mortality and morbidity seen in large outcome trials. However, these effects are achieved by different mechanisms. ACE inhibitors reduce circulating and tissue angiotensin II levels and potentiate the beneficial effects of bradykinin, including generation of nitric oxide (NO). By contrast, the protective effects of ARBs are owing to the blockade of the angiotensin II type 1 (AT1) receptors and possibly also to the stimulation of angiotensin II type 2 (AT2) receptors, again resulting in NO release. In addition, some ARBs, such as telmisartan, are selective activators of peroxisome proliferator–activated receptor-γ (PPAR-γ), thereby increasing insulin sensitivity. In contrast to other PPAR-γ ligands, such as the thiazolidinediones, activation of this receptor by telmisartan does not result in weight gain. The complementary mechanisms of action of ACE inhibitors and ARBs create a rationale for combination therapy in high-risk patients. The benefits of this approach with telmisartan are being investigated in clinical trials, such as the Ongoing Telmisartan Alone in Combination with Ramipril Global Endpoint Trial (ONTARGET).