Does the combination of a renin inhibitor with a statin have potential for improved inhibition of atherosclerosis?

The concept that pharmacological inhibition of the renin–angiotensin–aldosterone system (RAAS) can reduce atherosclerosis is now well established [1]. In addition to the considerable evidence that components of the RAAS stimulate lesion development, targeting different components of the system has been shown to both reduce lesion formation and to increase markers of plaque stability. For example, in atherosclerosis-prone mice, administration of angiotensin II (Ang II) over long periods promotes lesion formation, whereas angiotensin-converting enzyme (ACE) inhibition, angiotensin 1 receptor antagonism [2] or mineralocorticoid receptor antagonism [3] reduces lesion size. An increasing body of evidence suggests that both Ang II-induced stimulation of lesion formation and the antiatherosclerotic effects of treatment (ACE inhibition/AT1 receptor antagonism) are independent of blood pressure; indicating a direct atherosclerotic effect of Ang II on the cells of the vascular wall. However, the exact mechanisms through which blockade of the RAAS alters lesion formation remain unclear. A relatively novel approach to inhibiting the RAAS is through the development of direct renin inhibitors, such as aliskiren (the first drug in this class licensed for clinical use) which is available for treatment of essential hypertension [4]. Inhibiting renin has several potential advantages over targeting components (e.g. ACE; AT1 receptors; mineralocorticoid receptors) lower down in the RAAS cascade. For example, renin inhibition should avoid the increased angiotensin I concentrations produced by ACE inhibition; the generation of unwanted angiotensin breakdown products [such as Ang(1–7)]; accumulation of bradykinin due to reduced ACE-mediated degradation; and the potential for excessive AT2 receptor activation in the presence of AT1 antagonists. Recent investigations in murine (hypertensive ApoE−/− and ldlr−/−) models of atherosclerosis [5,6] support the potential of renin inhibition as a therapeutic option for reducing atherosclerosis. These studies demonstrated that aliskiren reduced lesion size and increased markers of plaque stability; effects that were not due to reduction of circulating cholesterol and not wholly explained by reductions in blood pressure. In this issue, Kuhnast et al.[7] use the atherosclerotic APOE*3Leiden.CETP mouse model to extend this previous work by asking the logical question ‘does the combination of renin inhibition (with aliskiren) and HMGCoA reductase inhibition (atorvastatin) have any advantages over the use of atorvastatin alone?’. In this investigation, administration of aliskiren (15 mg/kg per day; subcutaneous infusion) reduced systolic blood pressure (by 19%; despite the APOE*3Leiden.CETP mice not exhibiting hypertension) but had no effect on plasma cholesterol. This contrasts with the effect of atorvastatin (3.6 mg/kg per day; in diet) which did not alter blood pressure but reduced total plasma cholesterol (by 24%). Both monotherapies reduced a number of measures of atherosclerotic lesion development (lesion area, lesion severity, macrophage incorporation, necrotic area) and increased measures of stability. In almost all cases the changes produced by atorvastatin were larger than those produced by aliskiren. The demonstration that aliskiren reduced blood pressure in this investigation was notable. Whilst previous use of this compound also reduced blood pressure in ldlr−/− and ApoE−/− mice [5,6], these animals were hypertensive, whereas the APOE*3Leiden.CETP mice used by Kuhnast et al.[7] were not (systolic blood pressure 103 ± 10 mmHg). Furthermore, Lu et al.[5] showed that doses of aliskiren that reduced systolic blood pressure in ldlr−/− mice had no effect in normotensive C57Bl6 controls. This opens the possibility that modulation of atherosclerosis in the APOE*3Leiden.CETP mice is a consequence of blood pressure reduction. The authors discount this mechanism, however, with the demonstration that the reductions in lesion size are independent of blood pressure. This indeed is consistent both with the recognition that atherosclerosis in the APOE*3Leiden.CETP is independent of elevated blood pressure and with the demonstration that the effects of aliskiren in the ldlr−/−and ApoE−/− mice are not attributable solely to reduced blood pressure [5,6]. Thus, in aliskiren it appears we have a compound which reduces lesion development, independent of its ability to reduce blood pressure, and without altering circulating cholesterol [5–7]. On the basis of these results, combination of aliskiren with the lipid-lowering statin certainly promises a combined effect that could improve on the performance of either drug alone. This approach would mirror the previous use of aliskirenin in combination with a statin (lovastatin) for the treatment of diabetes [8]. So do the antiatherosclerotic effects of these compounds combine to produce obvious benefit over monotherapy? On the evidence provided here, perhaps the most optimistic answer is ‘possibly’. Certainly there is no suggestion of any considerable additive or synergistic effect. For example, Kuhnast et al.[7] showed that, whilst aliskiren reduced lesion area by approximately 40% and atorvastatin by approximately 60%, the reduction obtained with the combined therapy (∼69%) was not significantly greater than atorvastatin alone. Furthermore, of the 15 parameters measured in the study there were five (systolic blood pressure; plaque stabilization; lesion number; T-cell accumulation; plasma E-selectin) for which there was a suggestion that the combination therapy produced a better outcome than atorvastatin monotherapy. However, in most of these any difference between atorvastatin and aliskirin + atorvastatin was small and not statistically significant. Only in measurement of lesion number was there a reduction (∼17%) with combination therapy that was not present with atorvastatin alone. On the basis of these results it would be hard to argue that a clinical trial using this combination is an attractive proposition. Investigations in mice are inevitably limited by the small quantities of material available for analysis. Kuhnast et al.[7] addressed the possibility that renin inhibition altered circulating inflammatory markers (levels of E-selectin, monocyte chemotactic protein-1, fibrinogen were unchanged). Whilst this approach was justified it, unfortunately, prevented the authors from investigating the impact of their treatment on the RAAS. Such investigations would be important in determining the appropriateness of the dose of aliskiren selected. The importance of dose in particular animal models has been highlighted elsewhere [5,9]. Lu et al.[5], demonstrating antihypertensive effects of aliskiren at 25 and 50 mg/kg per day but not at a lower dose (2.5 mg/kg per day), commented on the fact that aliskiren was less effective on murine renin than on the enzyme in humans (but more effective than in rats). It is not clear how Kuhnast et al.[7] chose the dose they used, nor how effectively it targeted the RAAS: the extent of renin inhibition cannot be ascertained since no relevant measurements were made. Furthermore, it has been suggested that the reduction in Ang II concentrations following renin inhibition prevents negative feedback, leading to increased release of renin from juxtaglomerular cells. This was addressed by Nussberger et al.[6] who, intriguingly, showed that plasma renin concentrations were higher (∼3-fold) after AT1A receptor antagonism than after renin inhibition. Whether renin inhibition produced a significant increase in plasma renin concentrations could not be determined in the work of Kuhnast et al.[7]. Finally, it would have been interesting to know whether co-administration with atorvastatin increased the concentration of aliskiren in the blood, as has been suggested elsewhere [10]. In conclusion, the study reported by Kuhnast et al.[7] is an important comparison of the antiatherosclerotic effects of a renin inhibitor (aliskiren) with the current gold standard treatment (HMGCoA reductase inhibition). This part of the study largely confirms the previous reports that aliskiren reduces lesion formation (although less dramatically than the atorvastatin) and increases plaque stability, with the advantage of using a murine model that is clearly not dependent on elevated blood pressure and is, arguably, a better representation of the human disease than the ApoE−/− or ldlr−/− mice [11]. Despite the suggestion that changes in lesion size and stability are the result of a reduction in the number of T cells and macrophages (but not of monocytes) in the vessel wall the mechanism responsible for the antiatherosclerotic action of aliskiren remains unclear. Furthermore, in spite of the encouraging effects of aliskiren on lesion size and stability, the modest benefits observed in combination with atorvastatin suggest that dual therapy with these agents (at least at these doses) is likely to be of minimal additional benefit in treatment of the disease in humans. Acknowledgements Conflicts of interest There are no conflicts of interest.