The disappointing news for manufacturers of anti-obesity treatments this week could mean doctors will increasingly look for drugs for obese patients that protect them against the adverse consequences of visceral fat such as the new class of direct renin inhibitors (DRI).

Speaking in London, Prof Peter Sever, Head of Clinical Pharmacology and Therapeutics at Imperial College London, UK, said obesity was probably the area of greatest potential for DRIs which lower blood pressure by blocking the action of the renin-angiotensin-system (RAS) at its key point – renin production. His comments came just as concerns about psychiatric side effects associated with Sanofi-Aventis’ Acomplia (rimonabant) were resurfacing in The Lancet, while the British Medical Journal weighed in with a meta-analysis that found three anti-obesity therapies recommended for long-term use – Acomplia, Roche’s Xenical (orlistat) and Abbott’s Meridia/Redictil (sibutramine) reduced weight by less than 5kg or 5% of total body weight.

The first and so far only DRI is Novartis’ award-winning agent aliskiren, marketed as Tekturna in the US where it has been available as mono or add-on therapy for hypertension since March and as Rasilez in Europe where it has been available since September. To date, worldwide sales have reached $20 million according to Novartis’ third-quarter results but the company says sales are increasing rapidly, particularly in the USA, where it is being approved for reimbursement in increasing numbers of formularies.

At doses of 150mg or 300mg once-daily, aliskiren has been shown to offer equivalent or small increased benefits in blood pressure control without adverse effects. At higher doses it can cause diarrhoea. Its good tolerability and long-half life giving 24-hour blood pressure control and therefore reduced susceptibility to early morning heart attacks makes it attractive say experts involved in clinical trials. However, its real advantage is perceived in its mechanism of action impinging on the RAS at source. Aliskiren has already been shown in the AVOID trial involving diabetes patients to reduce proteinuria to a greater extent than other means of targeting the RAS. This suggests it may offer advantages in protection against cardiovascular and renal damage for patients, such as obese people with metabolic syndrome or type 2 diabetes, who are at increased risk.

The RAS is believed to play a key role in the development of cardiovascular disease associated with abdominal fat, says Prof Sever. Renin is chief among numerous substances expressed by visceral fat cells that are toxic to blood vessels. 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.

Renin is the substrate for angiotensinogen in generating angiotensin 1 and can act independently of catalytic activity converting angiotensin 1, via renin receptors in tissues. “It is in the tissues – the kidney, eye, heart, blood vessels and brain – that renin activation is intimately related with pathological consequences,” he noted.

Novartis’ Global Head of Cardiovascular and Metabolic Drug Development, Dr Ameet Nathwani, believes DRIs have advantages beyond their blood-pressure-lowering abilities that could in future make them be considered as one of several options for treating obese and other patients with cardiovascular or renal risk factors despite normal or only mildly-elevated blood pressure levels. One patient group of interest is people shown to have signs of ‘early vascular aging (EVA)’ who are at increased risk of stroke, 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.

Drugs that lower blood pressure in this population have to be shown to have no other adverse metabolic effects that could impact on atherogenesis, he stressed. “They also have to be well tolerated because asymptomatic patients are more likely to take a multivitamin tablet long term than a statin or anti-hypertensive.” Novartis is looking at fixed dose combinations including a ‘poly-pill’ to aid compliance, he hinted, with a combination of aliskiren and a thiazide diuretic being one logical combination and aliskiren and a statin and an agent targeting precursors of diabetes, another. “The idea of combining agents that target lipids, insulin resistance and blood pressure in one pill is key for us” he remarked. [Novartis also markets Galvus (vildapgliptin) in some markets which has been mooted as a future strategy for pre-diabetes.]

Alan Gradman, Professor of Medicine at Temple University, Philadelphia, and Chief of Cardiovascular Diseases at Western Pennsylvania Hospital, said Novartis’ ASPIRE HIGHER clinical trial programme is now investigating aliskiren’s ability to reduce surrogate markers of end organ damage and clinical endpoints in patients with diabetes, left ventricular hypertrophy and heart failure including elderly subjects.

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 been shown to reduce renal damage. Adding aliskiren to valsartan showed an additional 20% 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 with mildly elevated blood pressure and dyslipidaemia profiles 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 but results will take years to become available.

Aliskiren was developed in collaboration with Swiss-based biopharmaceutical company Speedel, which has three next-generation DRIs in trials – two in Phase I and one in Phase IIa – though it is currently currently at loggerheads with Novartis over Tekturna royalties. By Olwen Glynn Owen