Does the rennin inhibitor aliskiren offer promising novel opportunities in the treatment of cardiovascular diseases?
Authors:
K. Horký
Authors‘ workplace:
II. interní klinika kardiologie a angiologie 1. lékařské fakulty UK a VFN Praha, přednosta prof. MUDr. Aleš Linhart, DrSc.
Published in:
Vnitř Lék 2007; 53(4): 364-370
Category:
Reviews
Overview
The renin-angiotensin-aldosterone system (RAAS) plays an important part in the pathogenesis of arterial hypertension and the complications it causes in organs (the heart, the circulatory system, the brain, the kidneys), heart failure and kidney diseases. Materials that block the most upstream point of the RAAS cascade (ACE inhibitors – ACEI, AT1-receptor (AT1R) blockers, aldosterone receptor blockers) have greatly expanded our options in the treatment and primary and secondary prevention of cardiovascular and renal diseases. ACEI and AT1R blockers interrupt the normal feedback provided by the release of renin into the circulatory system from the kidneys. After they are applied the reactive increase in active circulating renin leads to increased creation of angiotensin I and angiotensin II and the subsequent return of aldosterone secretions to pre-treatment values (”escape” phenomenon). The possible negative effect of these intermediary products of an incomplete blockade of RAAS on organ complications lead to an effort to develop a material that could block the renin-angiotensin cascade at its first stage – i.e. a renin blocker. The first efforts with renin antibodies or peptide analogues of renin prosegments failed to satisify the basic requirements for long term medication – effectiveness when used orally. In recent years the first non-peptidic, oral renin ihibitor providing sustained effects has been developed, aliskiren fumarate. Aliskiren reduces BP depending on the dose (50–300 mg/day) in monotherapy or in combination with hydrochlorothiazide. Aliskiren lowers plasma renin activity (PRA) and neutralises the activation of the RAAS triggered by hydrochlorothiazide. Ambulatory BP monitoring has shown that taking the medicine once a day has a 24-hour effect and its continued residence in the kidneys suggests renoprotective effects. The compound is in the third stage of clinical tests as a monotherapy or in combination for the treatment of hypertension. It has also been shown to have an influence on the regression of cardiac hypertrophy (Aliskiren in Left-Ventricular Hypertrophy trial – ALLAY), the treatment of heart failure (Aliskiren Observation of Heart Failure Treatment trial – ALOFT) and diabetic (Aliskiren in the Evaluation of Proteinuria in Diabetes trial – AVOID). In April 206, the FDA permitted the use of aliskiren in the USA for the treatment of high BP and it is currently undergoing testing in Europe. The renin inhibitor has minimal undesirable side effects, like AT1-receptor blockers. The slightly lower effectiveness of aliskiren than AT1-receptor blockers in reducing BP is caused by the fact that it does not block bradykinins. It is recommended as a monotherapy for clinical use or in combination with other antihypertensive medicines for conditions with high levels of PRA including its rise after diuretics, ACEI and AT1-receptor blockers. Aliskiren could therefore be used primarily with young patients, Caucasians, persons with ACEI intolerance, and also in diseases where angiotensin II is involved in the pathogenesis and the secondary prevention of cardiovascular disease. It is also safe for persons with concurrent renal problems, because it is mainly removed by the liver without great interference with other materials. Like ACEI, the renin inhibitor has a vasodilatory effect which could potentially improve the elasticity of arteries. The medicine has the same limitations and contraindications as ACEI and AT1R blockers, such as pregnancy and bilateral renal artery stenosis. A definitive assessment of the benefit of this new class of medicines and its broad application in the treatment of cardiovascular and other diseases will require demonstration of its long term effect on morbidity and mortality, as well as comparison with other RAAS blockers in long clinical studies, which represent research programmes lasting another 7 to 8 years.
Key words:
renin inhibitors – antihypertensive effect – organoprotective effects – results of preliminary studies – status in the treatment of hypertension
Sources
1. Azizi M, Ménard J. Combined blockade of the renin-angiotensin systém with angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists. Circulation 2004; 109: 2492-2499.
2. Pfeffer MA, McMurray JJ, Velazquez EJ et al. Valsartan, captopril or both in myocardial infarction complicated by heart failure, left ventricular dysfunction or both. N Engl J Med 2003; 349: 1893-1906.
3. Lewis EJ, Hunsincker LG, Bain RP et al. The effect of angiotensin-converting inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 1993; 329: 1456-1462.
4. Brenner BM, Cooper ME, deZeeuw et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345: 861-869.
5. Yusuf S, Sleight P, Pogue J et al. Effects of an angiotensin-converting enzyme inhibitor ramipril on cardiovascular events in high-risk patients. The Heart Outcomes Prevent Evaluation Study Investigators. N Engl J Med 2000; 342: 145-143.
6. Stanton A, Jensen C, Nussberger J et al. Blood pressure lowering in essential hypertension with an oral renin inhibitor, aliskiren. Hypertension 2003; 42: 1137-1143.
7. O´Brien E, Barton J, Nussberger J et al. Aliskiren reduces blood pressure and suppresses plasma renin activity in combination with a thiazide diuretic, an angiotensin-converting enzyme inhibitor, or an angiotensin receptor blocker. Hypertension 2007; 49: 276-284.
8. Michel JB, Guettier C, Philippe M et al. Active immunization against renin in normotensive marmosets. Proc Natl Acad Sci USA 1987:;84: 4346-4350.
9. Bolis G, Fung AKL, Greer J et al. Renin inhibitors: dipeptide analogues of angiotensinogen incorporating transition-state, nonpeptidic replacements at the scissible bond. J Med Chem 1987; 30: 1729-1737.
10. MacFayden RJ, Jones CR, Doig JK et al. Responses to an orally active renin inhibitor, remkiren (RO-42-5892), after controlled salt depletion in humans. J Cardiovasc Pharmacol 1995; 25: 347-353.
11. Ménard J, Boger RS, Mayse DM et al. Dose-dependent effects of the renin inhibitor zankiren-HCl after a single orgal dose in mildly sodium-depleted normotensive subjects. Circulation 1995; P1: 330-338.
12. Azizi M. Renin inhibition. Curr Opin Nephrol Hypertens 2006; 15: 505-510.
13. Ganten D, Wagner J, Zeh K et al. Species specificity of renin kinetics in transgenic rats harboring the human renin and angiotensinogen genes. Proc Natl Acad Sci USA1992; 898: 7806-7810.
14. Vinson GP, Saridogan E, Puddefoot JR et al. Tissue renin-angiotensin systems and reproduction. Human Reprod 1997; 12: 651-662.
15. Richter WF, Whitby BR, Chou RC. Distribution of remikiren, a potent orally active inhibitor of human renin in laboratory animals. Xenobiotica 1996; 26: 243-254.
16. Zhang Q, Kohara K, Qui HY et al. Comparative effects of three sites of renin-angiotensin blockade on the regression of left ventricular hypertrophy in sponaneously hypertensive rats. Am J Ther 1997; 4: 199-202.
17. Kiowski W, Beermann J, Rickenbacher P et al. Angiotensinogenic versus nonangiotensinogenic hemodynamic effects of converting enzyme inhibition in patients with chronic heart failure. Assessment by acute renin and converting enzyme inhibition. Circulation 1994; 90: 2748.2756.
18. Stanton A. Potential of renin inhibition in cardiovascular disease. J Renin Angiotensin Aldosterone System (JRAAS) 2003; 4: 6-10.
19. Vaidyanathan S, Valencia J, Kemp C et al. Lack of pharmacokinetc interactions of aliskiren, a novel direct renin inhibitor for the treatment of hypertension, with the antihypertensives amlodipine, valsartan, hydrochlorothiazide (HCTZ) and ramipril in healthy volunteers. Int J Clin Pract 2006; 60: 1343-2356.
20. Villamil A, Chrysant S, Calhoun D et al. The novel renin inhibitor aliskiren provides effective blood pressure control in patients with hypertension when used alone or in combination with hydrochlorothiazide. J Clin Hypertens 2006; 8: Suppl A: A100.
21. Staessen JA, Li V, Richart T. Oral renin inhibitors. Lancet 2006; 368: 1449-1456.
22. Gradman AH, Schmieder RE, Lins RT et al. Aliskiren, a novel orally active renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients. Circulation 2005; 111: 1012-1018.
23. Dolan E, Stanton A, Thijs L et al. Superiority of ambulatory over clinic blood pressure measurement in predicting mortality. The Dublin Outcome Study. Hypertension 2005; 46: 156-161.
24. Van Paassen P, de Zeeuw D, Navis G et al. Renal and systemic effects of continued treatment with renin inhibitor remikiren in hypertensive patients with normal and impaired renal function. Nephrol Dial Transplant 2000; 15: 637-643.
Labels
Diabetology Endocrinology Internal medicineArticle was published in
Internal Medicine
![Issue 4](https://www.prolekare.cz/media/cache/resolve/journal_issue/media/image_pdf/db285e0fb61b468632e2ac4263975460.jpeg)
2007 Issue 4
Most read in this issue
- Lipoprotein (a)
- How corticoids, growth hormone and oestrogens influence lipids and atherosclerosis
- Side effects of pharmacotherapy on lipid levels
- Can reduction in resting heart rate be beneficial for patients?