Sankyo's angiotensin II receptor blocker (ARB) olmesartan medoxomil demonstrates antiinflammatory activity in hypertensive patients.
SummaryEarlier this year data was reported that Sankyo's angiotensin II receptor blocker (ARB) olmesartan medoxomil may offer improved anti-hypertensive activity when compared to other therapeutic agents within this highly competitive $31 billion market. More recently clinical data has appeared that shows olmesartan to have additional anti- inflammatory activity in hypertensive patients with vascular inflammation. This may confer additional therapeutic benefit since inflammation is an etiological compo
Earlier this year data was reported that Sankyo's angiotensin II receptor blocker (ARB) olmesartan medoxomil may offer improved anti-hypertensive activity when compared to other therapeutic agents within this highly competitive $31 billion market. More recently clinical data has appeared that shows olmesartan to have additional anti- inflammatory activity in hypertensive patients with vascular inflammation. This may confer additional therapeutic benefit since inflammation is an etiological component of atherosclerosis and both vascular inflammation/atherosclerosis and hypertension are risk factors for cardiovascular events. Furthermore this recent study reports benefits of dual treatment with olmesartan and a second Sankyo product, the anti-dyslipidemic pravastatin raising possibilities of single pill treatments.
DailyUpdates 22nd September, 2004: An estimate based on IMS sales figures indicates that the antihypertensive market was valued at $31 billion in 2003 reflecting a 13% rise since the previous year. Genericization has seen the continued demise in cash terms of the four major antihypertensive classes - ACE inhibitors, calcium channel blockers (CCBs), beta blockers and diuretics - while in prescription terms beta blockers and diuretics actually increased. This has meant that the net growth in the value of the hypertension market over the last five years has been attributable almost entirely to the ongoing rise of the angiotensin II receptor blocker (ARB) class. Analysts predict that the strong growth of the ARB Diovan (valsartan) will make it the leading global antihypertensive by 2007 with estimated sales of $3.3 billion, displacing the CCB Norvasc (amlodipine) from its long-standing position.
Due to the financial incentive in developing a drug that can demonstrate an advance in antihypertensive efficacy over existing products, and the continued growth in the worldwide prevalence of hypertension, the antihypertensive market continues to attract a high level of R&D investment from the huge number of pharmaceutical companies that are represented in this market. Since approaches to treating hypertension are well-understood, and because pharmacological targets for antihypertensives are diverse there is considerable scope for this R&D activity.
It is no longer possible to select a gold standard drug class in the treatment of hypertension. Once the mantle for diuretics and beta blockers, ACE inhibitors and CCBs have gradually staked their claim within the antihypertensives market. Ongoing large-scale clinical trials with ARBs are now resulting in a shift in physician preference from ACE inhibitors to ARBs. ARBs have an improved side effect profile compared to earlier therapeutic classes. The EUTOPIA investigators have recently reported a further advantage of the ARB, olmesartan.
The need to address risk factors beyond hypertension, in particular raised lipids, has led to a demand for combination therapies that can treat more than one risk factor at a time (click here for an evaluation of cross-risk factor treatment). Antihypertensive combinations, both with and without a statin, are likely to be common in the future. Likewise the development of cardiovascular agents that target more than one risk factor would also be of benefit. Hypertension and atherogenic dyslipidemia are both major cardiovascular risk factors and in their paper published in the August edition of the journal Circulation, Fliser et al report that the ARB, olmesartan reduces vascular inflammation a key etiological component of atherosclerosis.
Inflammation is now accepted as a central feature of atherosclerosis. Foam cells are macrophages that have migrated as monocytes from the circulation into the subendothelial layer of the intima. In addition to the presence of foam cells, T cells feature prominently in plaques. Macrophages, foam cells and T cells all promote local inflammation and neointimal growth through the expression of cytokines and growth factors, especially in the context of hypercholesterolemia. This active inflammatory process promotes the formation of unstable "vulnerable" atherosclerotic plaque.
In their recent prospective double-blind multi center placebo-controlled study Fliser et al evaluated the anti-inflammatory effect of olmesartan medoxomil in patients with essential hypertension and signs of vascular microinflammation.
After 6 weeks treatment with olmesartan systolic and diastolic blood pressures dropped from 158 and 100mm hg to 140 and 86mm hg respectively. In addition this study demonstrates the novel finding that olmesartan also reduces serum levels of the inflammatory markers, C-reactive protein, TNF-alpha, IL-6 and MCP-1 compared to baseline, while measures of dyslipidemia were unchanged. Blood pressure partially dropped in placebo patients however with the exception of a transient reduction in plasma IL-6 levels an anti-inflammatory effect was not observed suggesting that anti-inflammatory effects of olmesartan were unrelated to its hypotensive activity. After 6 weeks, pravastatin was added to both treatment arms and at week 12 a drop in cholesterol and LDL cholesterol levels was observed in patients whether or not olmesartan was coadministered. In the presence of both agents, the anti-inflammatory effect observed at week 6 was still present. The previously reported anti-inflammatory effects of pravastatin were not observed in this trial but this may reflect the study size.
Olmesartan medoxomil, developed by Sankyo was approved for marketing in the by the FDA in 2002 where it is sold by laboratories. Data published earlier in the year showed that at the usual recommended starting doses, approximately twice as many patients treated with olmesartan achieved goal blood pressure of less than 140/90 mm Hg compared to losartan or valsartan suggesting that olmesartan will provide increasingly strong competition for leading ARBs. Fliser et al's clinical study suggests that olmesartan has an additional impact on microvascular inflammation allowing it to simultaneously target two cardiovascular risk-factors placing further pressure on other ARBs. Sankyo's portfolio of cardiovascular drugs also includes pravastatin (click here for an evaluation of anti-dyslipidemics), and the additional effect that pravastatin has on dyslipidemia when administered in combination with olmesartan suggests that the two agents used concomitantly represent an effective combination treatment for patients with hypertension and dyslipidemia and may represent underlie a successful future single pill combination product.
Source: Antiinflammatory effects of angiotensin II subtype 1 receptor blockade in hypertensive patients with microinflammation. Circulation. 2004 Aug 31;110(9):1103-7. Epub 2004 Aug 16.
This article is highlighted in the September 22nd edition of DailyUpdates-Cardiovascular Disease, LeadDiscovery's unique bulletin of breaking journal articles and press releases for the drug discovery community. To access the article and to view today's bulletin click here