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Routine blood pressure lowering with the fixed combination of perindopril and indapamide in 11,140 patients with type 2 diabetes was very well tolerated and produced substantial benefits in reducing all-cause and cardiovascular mortality, the primary combined outcome of macro- or microvascular events, total coronary events, and total renal events, as reported previously. We present here a wealth of evidence, most of it previously published either in journal articles or in recent abstract form, that the relative risk reductions conferred by the combination of perindopril and indapamide are broadly consistent across subgroups defined by a wide range of baseline characteristics, including blood pressure at entry, age from below 65 to above 75 years, total cardiovascular risk defined according to the European guidelines, stage of chronic disease, and cognitive function. Furthermore, we report that the absolute risk reductions are significantly greater in those with increased cardiovascular risk, with more advanced nephropathy and in older subjects. We confirm that the effects of blood pressure lowering with perindopril-indapamide and of intensive glucose control with the gliclazide modified release (MR)-based regimen are independent and produce substantial additional benefits when combined. We also discuss these results in the context of other major trials and demonstrate how they extend the evidence on the benefits of blood pressure lowering in patients with diabetes. Finally, we present evidence that the results of The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE trial) are broadly generalizable to patients with type 2 diabetes in community practice, and that if the joint benefits from routine blood pressure lowering with perindopril-indapamide and more intensive control with the gliclazide-MR-based regimen were applied worldwide, close to 2 million lives would be saved over the next 5 years.
Routine blood pressure lowering with the fixed combination of perindopril and indapamide in 11,140 patients with type 2 diabetes was very well tolerated and produced substantial benefits in reducing all-cause and cardiovascular mortality, the primary combined outcome of macro- or microvascular events, total coronary events, and total renal events, as reported previously. We present here a wealth of evidence, most of it previously published either in journal articles or in recent abstract form, that the relative risk reductions conferred by the combination of perindopril and indapamide are broadly consistent across subgroups defined by a wide range of baseline characteristics, including blood pressure at entry, age from below 65 to above 75 years, total cardiovascular risk defined according to the European guidelines, stage of chronic disease, and cognitive function. Furthermore, we report that the absolute risk reductions are significantly greater in those with increased cardiovascular risk, with more advanced nephropathy and in older subjects. We confirm that the effects of blood pressure lowering with perindopril-indapamide and of intensive glucose control with the gliclazide modified release (MR)-based regimen are independent and produce substantial additional benefits when combined. We also discuss these results in the context of other major trials and demonstrate how they extend the evidence on the benefits of blood pressure lowering in patients with diabetes. Finally, we present evidence that the results of The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE trial) are broadly generalizable to patients with type 2 diabetes in community practice, and that if the joint benefits from routine blood pressure lowering with perindopril-indapamide and more intensive control with the gliclazide-MR-based regimen were applied worldwide, close to 2 million lives would be saved over the next 5 years.
Chronic activation of the renin-angiotensin-aldosterone system (RAAS) plays a key role in the development of hypertension, and cardiac and renal diseases. RAAS inhibitors, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), improve cardiovascular and renal outcomes. However, studies have shown that residual morbidity and mortality remains high, despite current optimal treatment. More comprehensive control of the RAAS might provide additional reductions in morbidity and mortality. Direct renin inhibitors offer the potential for enhanced RAAS control as they target the system at the point of activation, thereby reducing plasma renin activity (PRA); by contrast, ARBs and ACE inhibitors increase PRA. Elevated PRA is independently associated with cardiovascular morbidity and mortality. A single-pill combination of the direct renin inhibitor, aliskiren, and the ARB, valsartan, at once-daily doses of 150/160 mg and 300/320 mg, has recently been approved by the US FDA for the treatment of hypertension in patients not adequately controlled on aliskiren or ARB monotherapy, and as initial therapy in patients likely to need multiple drugs to achieve their blood pressure goals. This article examines the efficacy, safety and tolerability of aliskiren/valsartan combination therapy, and considers the evidence for the potential organ-protection benefits of this treatment.
Monotherapy with most antihypertensive agents reduces systolic BP by about 10 mmHg ('Rule of 10'). Thus, the majority of hypertensive patients require combination therapy to achieve BP goals. In this review, we provide a brief overview of the renin-angiotensin-aldosterone system (RAAS) and discuss the rationale, clinical evidence, and shortcomings related to the use of angiotensin-converting enzyme (ACE) inhibitors in combination with angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]). We summarize the rationale and clinical evidence supporting the use of the direct renin inhibitor (DRI) aliskiren, particularly in combination with other antihypertensive classes, including in high-risk patients with diabetes mellitus and with or without diabetic nephropathy. DRIs may be useful in combination with ACE inhibitors or ARBs as they provide a more complete blockade of the RAAS, effectively suppressing residual angiotensin II production and the counter-regulatory increase in plasma renin activity observed in patients receiving monotherapy with ACE inhibitors or ARBs.
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