Sen Selcuk, Ufuktepe Baran, Özünal Zeynep Günes, Üresin Yagiz
Department of Medical Pharmacology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
EXCLI J. 2014 Sep 24;13:1111-9. eCollection 2014.
The coexistence of hypertension and diabetes increases the incidence of cardiovascular events and long-term morbidity and mortality. Blood pressure should be controlled with the most appropriate drugs as well as tight blood glucose control in patients with diabetes and hypertension. RAAS (Renin Angiotensin Aldosterone System) blockers have an important role in the treatment of these patients, in this sense, ACEi and ARB remained the major treatment option in hypertension guidelines. The most recent RAAS blocker to be approved by the FDA was aliskiren in 2007, a renin inhibitor. Studies showed that aliskiren is as effective as other antihypertensive drugs and has a safety profile similar to placebo. The potent renin inhibitor aliskiren directly inhibits the RAAS system at its rate limiting step and differently from other RAAS blockers; it decreases plasma renin activity (PRA). Although the relationship of increased PRA levels and cardiovascular risk has been shown, it is unclear if the PRA decrease provided by aliskiren has an impact on clinical outcomes and cardiovascular endpoints. On the other hand, large trials like ASPIRE, AVANT-GARDE, ALTITUDE, ASTRONAUT, which investigated the combination of aliskiren with other RAAS blockers, failed to show the expected outcomes or resulted with an increased incidence of adverse effects, which raised more questions. As a result of the ALTITUDE trial, combination of aliskiren with an ACEi or ARB is not recommended in patients with hypertension and diabetes, or at least moderate renal dysfunction. Trials designed to prove aliskiren's efficacy in new indications like diabetes, may face similar problems related to dual RAAS blockade because in the majority of cases, the optimal treatment is achieved with an ACEi or ARB. In this conjuncture, the increase in adverse events seen with aliskiren might be related to dual RAAS blockade rather than aliskiren directly. For instance, it is unclear whether the adverse event incidence would be the same, less, or higher if ALTITUDE was designed to investigate ACEi and ARB combination without aliskiren. In fact, every new molecular entity and mechanism of action faces the same barriers. For the time being, differentiating points like PRA lowering effects as an add-on therapy to calcium channel blockers or hydrochlorothiazide, and the populations that might have additional benefit, should be carefully investigated.
高血压与糖尿病并存会增加心血管事件的发生率以及长期发病率和死亡率。对于糖尿病合并高血压患者，应使用最合适的药物控制血压，并严格控制血糖。肾素血管紧张素醛固酮系统（RAAS）阻滞剂在这些患者的治疗中发挥着重要作用，从这个意义上说，ACEI（血管紧张素转换酶抑制剂）和ARB（血管紧张素Ⅱ受体拮抗剂）仍是高血压指南中的主要治疗选择。2007年被美国食品药品监督管理局（FDA）批准的最新RAAS阻滞剂是阿利吉仑，一种肾素抑制剂。研究表明，阿利吉仑与其他抗高血压药物效果相当，且安全性与安慰剂相似。强效肾素抑制剂阿利吉仑在限速步骤直接抑制RAAS系统，与其他RAAS阻滞剂不同；它可降低血浆肾素活性（PRA）。虽然已表明PRA水平升高与心血管风险有关，但尚不清楚阿利吉仑降低PRA是否会对临床结局和心血管终点产生影响。另一方面，像ASPIRE、AVANT - GARDE、ALTITUDE、ASTRONAUT等研究阿利吉仑与其他RAAS阻滞剂联合使用的大型试验，未能显示出预期结果，或导致不良反应发生率增加，这引发了更多问题。ALTITUDE试验的结果表明，不建议在高血压合并糖尿病患者或至少有中度肾功能不全的患者中使用阿利吉仑与ACEI或ARB联合治疗。旨在证明阿利吉仑在糖尿病等新适应症中疗效的试验，可能会面临与双重RAAS阻断相关的类似问题，因为在大多数情况下，使用ACEI或ARB可实现最佳治疗。在这种情况下，阿利吉仑导致的不良事件增加可能与双重RAAS阻断有关，而非阿利吉仑本身直接导致。例如，如果ALTITUDE试验设计为研究不使用阿利吉仑的ACEI和ARB联合治疗，不良事件发生率是否会相同、更低或更高尚不清楚。事实上，每个新的分子实体和作用机制都面临同样的障碍。目前，应仔细研究诸如作为钙通道阻滞剂或氢氯噻嗪附加治疗时降低PRA的效果以及可能有额外益处的人群等差异点。
