Aliskiren: the first renin inhibitor for clinical treatment

Key Points The first evidence of the existence of renin was presented by Tigerstedt over 100 years ago. However, the importance of renin and the renin–angiotensin system (RAS) in the pathogenesis of cardiovascular disease was only fully realized in the 1970s. Although the preferred target in the RAS was renin, at the top of the cascade, it was another 20 years before the first inhibitors of renin were available for clinical research. The discovery and development of aliskiren (Tekturna) led to it becoming the first orally active renin inhibitor to be approved for clinical use. It was granted approval for the treatment of hypertension by the US Food and Drug Administration and the European Medicines Agency in 2007. Aliskiren has shown efficacy as a monotherapy. Owing to its long duration of action, aliskiren has been shown to reduce daytime and night-time blood pressure (BP), and its effects last up to 4 weeks after therapy is stopped. Combining aliskiren with other antihypertensive drugs, such as low-and high-dose angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), calcium-channel blockers and diuretics, results in a greater therapeutic efficacy, without adverse drug interactions being observed. Aliskiren has been shown to be safe and efficacious in various patient populations including the elderly, different racial groups, diabetic patients, obese patients and patients with reduced renal and hepatic function. Aliskiren shows potential for end-organ protection on top of standard therapy with ACE inhibitors and ARBs in patients with diabetic kidney disease and in patients with heart failure. When aliskiren is added to standard therapy there is a further positive therapeutic effect on surrogate markers of kidney and heart disease. Renin inhibition opens up new therapeutic potential for more complete blockade of the RAS and further decreases in cardiovascular morbidity and mortality. The renin–angiotensin system, which is a key regulator of blood pressure, has been successfully targeted by several classes of drugs for the treatment of cardiovascular disease. However, renin — the protease at the top of the cascade — although highly attractive as a target, has also proved to be challenging. Here, we describe how these challenges were tackled in the discovery and development of aliskiren, the first renin inhibitor to be approved for clinical use. The first evidence of the existence of renin was presented over 100 years ago. H