People with raised blood pressure (hypertension), who are at increased risk of cardiovascular or renal disease because of excess weight, are particularly likely to benefit from a new class of blood-pressure lowering treatment called direct renin inhibitors (DRIs), experts said this week.
The first drug in the class, aliskiren (Tekturna/Rasilez) is now available in the US and Europe for treatment of high blood pressure. Like angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), aliskiren targets the renin-angiotensin system (RAS) implicated in hypertension and achieves equivalent or slightly superior reductions in blood pressure. The RAS-targeting approach has been shown to offer protection against heart and renal disease with the older drug classes but experts believe the new DRI class, which impacts on renin rather than angiotensin, could offer additional advantages.
“We know the RAS is directly implicated in aggravating proteinuria and renal damage,” reminded Michel Azizi, Professor of Vascular Medicine at Hospital Georges Pompidou, Paris, France. Renin is also found in the eye and plays a key role in the pathogenesis of diabetic retinopathy. Whilst blocking the RAS with ACEIs and ARBs has proven highly effective in reducing the incidence of cardiovascular and renal events in large clinical trials, their impact is ultimately limited, he pointed out. “ACE inhibition to block the conversion of angiotensin I to angiotensin II is not the rate-limiting step in suppressing activity of the RAS. Any reduction in activity of the RAS is compensated for by a reactive increase in renin via a physiological feedback-loop and is evident from an increase in plasma renin levels. The rate-limiting step is therefore to inhibit renin and prevent it binding to angiotensinogen.” Renin is the substrate for angiotensinogen in generating angiotensin 1. This is converted by an enzyme to angiotensin II – the substance that constricts blood vessels and raises blood pressure. ACEIs and ARBs are designed to prevent angiotensin II exerting its effects. However, renin can act independently of the catalytic activity converting angiotensin I in the circulation, via renin receptors in tissues.
Visceral fat cells express rennin
Peter Sever, Professor of Clinical Pharmacology and Therapeutics at Imperial College London, UK, said: “It is in the tissues – the kidney, eye, heart, blood vessels and brain – that renin activation is intimately related with pathological consequences.” Whilst any patient with elevated blood pressure will benefit from DRI therapies, he says: “Probably their greatest potential is in obesity where the RAS is believed to play a key role in the development of cardiovascular disease associated with abdominal fat. Visceral fat cells produce numerous substances that are toxic to the vasculature and among these, renin and other components of the RAS are excessively expressed.” Patients with Type 2 diabetes, who are prone to obesity and also cardiovascular, renal and eye damage, are also candidates for DRI therapy as an early component of blood pressure-lowering treatment, he added.
Alan Gradman, Professor of Medicine at Temple University, Philadelphia, and Chief of Cardiovascular Diseases at Western Pennsylvania Hospital, said “As monotherapy, aliskiren, which has a 40-hour half-life, has proved equivalent or superior to other blood pressure-lowering agents in providing 24-hour blood pressure control with placebo-like tolerability at doses of 150 to 300mg once-daily”. The ASPIRE HIGHER clinical trial program is now investigating the drug’s ability to reduce surrogate markers of damage to the heart, kidneys and other organs and will measure clinical endpoints including deaths, heart attacks, strokes and markers of renal failure in patients with diabetes, left ventricular hypertrophy and heart failure.
The AVOID trial in diabetes has already demonstrated aliskiren reduces proteinuria, a surrogate marker of toxic damage to the nephron resulting ultimately in end-stage renal disease that affects over 100,000 people each year. “The data on proteinuria are very compelling and together with its good tolerability profile, aliskiren appears to offer a great advantage,” he remarked. The ARB valsartan has already been shown to reduce proteinuria and consequent renal damage. Adding aliskiren to valsartan showed an additional 20 per cent reduction in proteinuria. Aliskiren and an ARB attack the RAS on two fronts so increase the magnitude of the effect seen with valsartan alone; together they appear to provide the most comprehensive suppression of this important marker, he suggested. “The ALTITUDE study is a logical extension of AVOID and will look at the safety and efficacy of a combination of aliskiren and valsartan in reducing clinical renal and cardiovascular endpoints.” Results are expected in 2011 or 2012.
A large 18,000-patient trial involving obese subjects with metabolic syndrome who are at risk of cardiovascular disease is also being planned for the future. It will demonstrate whether or not aliskiren treatment influences subsequent disease development in obese people by looking at clinical endpoints.
Aliskiren has been developed and is marketed by the Swiss pharmaceutical company Novartis. The company’s Global Head of Cardiovascular and Metabolic Drug Development, Dr Ameet Nathwani, said this week he believes DRIs have advantages independent of their blood-pressure-lowering abilities. In future, if clinical trials support the hypothesis, this could lead to their use in treating obese and other patients with cardiovascular or renal risk factors even if their blood pressure levels are normal or only mildly-elevated. One patient group of interest is people shown to have signs of “early vascular aging (EVA)” who are at increased risk of stroke and heart disease, he suggested. These patients can be identified by simple tests that GPs could employ, using pulse-wave velocity or the augmentation index of myocardial contractility. Arterial stiffness can alter the normal systolic and diastolic blood pressure ratio putting blood vessels under abnormal pressure.
Drugs that lower blood pressure in this population have to be shown to have no other adverse metabolic effects such as effects on lipids that could impact on atherogenesis, he stressed. “They also have to be well tolerated because asymptomatic patients are reluctant to take drugs on a long term basis if they cause side effects.” Drugs that lower blood pressure are only protective if patients with risk factors continue to take them, explained Professor Sever. Studies have shown that up to half of patients prescribed blood pressure-lowering treatments stop taking them within a year. A chief reason for this is because of side effects. So far, recommended prescribed doses of DRIs appear to have no adverse effects so it is hoped that patients will adhere to them long enough to derive their benefits, he noted.
Written by – Olwen Glynn Owen
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