Current Hypertension Reviews - Volume 5, Issue 3, 2009

In this “Hot Topic” issue of Current Hypertension Reports we focus on the role of blood pressure control in diabetes and novel aspects of the renin angiotensin system. This issue includes current experimental and clinical evidence and covers important “burning” issues such as, 1. what is the optimal blood pressure target in diabetes and hypertension, 2. is there superiority of inhibitors of the renin angiotensin system (RAS) over other antihypertensive agents, 3. does combination therapy have additional benefits in terms of vascular protection and 4. which novel therapeutic options are on the horizon for better treatment and prevention of vascular complications in diabetes and hypertension? There is overwhelming evidence for an increased cardiovascular risk in the setting of concomitant hypertension and diabetes. Therefore, excellent blood pressure control is particularly important in patients who also suffer from diabetes or insulin resistance. The article by R. MacIsaac et al. addresses the question as to which blood pressure target should be aimed for. Various United States and European guidelines including the American Diabetes Association (ADA) recommendations suggest BP targets < 130/80 mm Hg for patients with diabetes. There is new evidence that further blood pressure (BP) reduction may confer superior cardiovascular benefits as shown in the recently published ADVANCE study. The ADVANCE study showed that BP reduction with perindopril and indapamide in patients usually not considered hypertensive resulted in further significant cardiovascular and renal benefits. However, the ADVANCE study did not include a comparator combination group and can therefore not answer the question as to which combination medications may be superior in preventing cardiovascular (CV) events. However, as already suggested in previous studies such as in HOPE, EUROPA, LIFE and UKPDS, the results of the ADVANCE study support current BP lowering guidelines which recommend a target BP of < 130/80 mm Hg in patients with type 2 diabetes. The ongoing BP lowering arm of the ACCORD trial will also help to substantiate the evidence supporting a continuous relationship between BP levels and the development of diabetes related vascular complications. In that trial, a group of patients with systolic blood pressures of less than 120 mm Hg is being compared to a less intensively treated group where the aim is a systolic blood pressure of less than 140 mm Hg.

This review focuses on trials that have examined the relationship between blood pressure (BP) lowering strategies and cardiovascular and renal outcomes in subjects with type 2 diabetes. In particular, we highlight the results of the recently completed BP-arm of the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation) study. Active therapy with perindopril and indapamide compared with placebo significantly reduced blood pressure (134.7/74.8 vs 140.4/77.0 mmHg) and the primary endpoint of the trial, a composite of major macrovascular and microvascular events. Active therapy also reduced the secondary end points of cardiovascular death and development of renal events. Importantly, the study shows that in a group of patients with BP levels within the range that would not usually be classified as hypertensive, further reductions in BP resulted in clinically significant cardiovascular and renal benefits. It supports the combination of perindopril and indapamide as an effective BP lowering strategy in type 2 diabetes. However, as other BP lowering strategies were not compared, the BP-lowering arm of the ADVANCE study does not answer the question as to what is the best medication or combination of medications that should be employed to reduce BP levels in type 2 diabetes.

Cardiovascular diseases (CVDs) are the major causes of morbidity and mortality in persons with diabetes, and many factors, including hypertension, contribute to this high prevalence of macrovascular complications. Hypertension is approximately twice as frequent in subjects with diabetes compared with non-diabetic patients. Furthermore, up to 75Y% of CVD in diabetes may be attributable to hypertension, leading to recommendations for more aggressive treatment (i.e. reducing blood pressure to < 130/80 mmHg) in persons with coexistent diabetes and hypertension. Macroangiopathy in diabetes is manifested by accelerated atherosclerosis which affects heart, brain and peripheral arteries. The pathogenesis of this accelerated atherosclerosis is multifactorial and includes a very complex interaction. Several data suggest a key role for renin-angiotensin system (RAS) activation in the pathophysiology of macrovascular complications in diabetic hypertensive subjects. Consequently, RAS blockade exerts potent antiatherosclerotic effects, which are mediated by their antihypertensive, anti-inflammatory, antiproliferative, and oxidative stress lowering properties. Inhibitors of the system, ie, angiotensin converting enzyme inhibitors and angiotensin receptor blockers, are now first line treatment to prevent CVD in patients with diabetes and hypertension. In addition, recent clinical trials have suggested that RAS blockade may protect against the development of de-novo diabetes in at-risk patients. Finally, the recent identification of new components of the RAS should provide fertile territory to not only examine new targets linked to the RAS but potentially to design more rational treatments for the prevention of CVD in patients with diabetes and hypertension.

The ONTARGET trial programme tested the effects of the angiotensin AT1 receptor blocker (ARB), telmisartan, alone or in combination with the angiotensin converting enzyme (ACE) inhibitor, ramipril, in more than 25.000 patients at high cardiovascular risk including diabetes on a combined endpoint consisting of cardiovascular death, non-fatal stroke or myocardial infarction and hospitalisation for congestive heart failure. Patient selection and study procedures followed the previous HOPE trial. In the parallel TRANSCEND study, nearly 6.000 patients, all intolerant to ACE inhibition, were subjected to telmisartan or placebo. In ONTARGET, telmisartan proved to be non-inferior to ramipril with respect to the combined primary endpoint and all secondary endpoints, and was better tolerated than ramipril. Combination treatment (dual RAS blockade) was not superior to ramipril (and telmisartan-) treatment but associated with more side effects. In TRANSCEND, telmisartan was not superior to placebo when applying the above combined primary endpoint but was significantly better with respect to the predefined main secondary endpoint corresponding to HOPE, i.e. excluding hospitalization for congestive heart failure. Telmisartan thus proved to be the first and so far the only representative of the ARB class that can be used as an alternative to the “gold standard” ACE-inhibitor, ramipril, in patients at high cardiovascular risk with or without hypertension.

Type 2 Diabetes Mellitus (T2DM) and hypertension (HTN) both increase cardiovascular disease (CVD) morbidity and mortality, and impose a tremendous burden on worldwide heath care systems in recent years. The mechanisms underlying the frequent coexistence of T2DM and HTN, two main components of the Cardiometabolic Syndrome (CMS), remain to be fully uncovered. Interestingly, both conditions are linked by chronic inflammatory processes and insulin resistance that are instigated by enhanced activation of the Renin Angiotensin Aldosterone System (RAAS). Inappropriate activation of the RAAS and insulin resistance with compensatory hyperinsulinemia trigger numerous pathophysiological pathways that ultimately result in endothelial dysfunction, inflammation, proliferation, and remodeling in cardiovascular and renal tissue. Blockade of RAAS has proven beneficial in the management of T2DM and HTN as well as associated CVD and chronic kidney diseases. This review focuses on current knowledge about the role of RAAS and insulin resistance and accompanying inflammation and oxidative stress in the pathophysiology that links DM and HTN.

The renin angiotensin system (RAS) is a key homeostatic regulator that relies on feedback regulation to achieve and sustain the delicate balance required for healthy physiological function. A number of negative feedback loops exist within the RAS that counterbalance the effects of conventional RAS blockade. Indeed, instead of reducing levels of Ang II and aldosterone, exaggerated feedback responses lead to a paradoxical elevation in many patients treated with RAS blockers. This ‘escape’ has been used to explain a number of clinically-relevant phenomena including progressive left ventricular hypertrophy, deteriorating cardiac and renal function in the face of full-dose RAS blockade. Escape has been thought to be mediated by reactive increases in renin activity and Ang I, which is then converted to Ang II, via non- ACE pathways (or by ACE when inhibitors are cleared). The reduced expression and activity of the angiotensinase Angiotensin Converting Enzyme 2 (ACE2) following RAS blockade may have a role. Bystander activation of the uninhibited AT2 receptor during long-term angiotensin receptor blockade (ARB) can also increase aldosterone synthesis. Feed forward or positive feedback loops also exist within the RAS, which exaggerate the effects of signaling and contribute to progressive hypertension and vascular damage. For example, Ang II acts to increase the expression of angiotensinogen in the kidney and the liver. The strong association between adverse outcomes and activation of feedback pathways provide a strong rationale for specifically targeting feedback as part of any vasculo-protective strategy.

The renin-angiotensin system (RAS) is a major physiological regulator of body fluid volume, electrolyte balance, and arterial blood pressure. The octapeptide, angiotensin (Ang) II, is the main effector of the RAS and overactivity of Ang II is a major contributor to pathological changes in cardiovascular disease; exemplified by the vasoprotective effects observed with RAS inhibition that extend beyond blood pressure reduction. However, an emerging concept of the RAS is the unique roles of shorter peptide fragments other than Ang II, such as Ang (1-7), Ang III and Ang IV. These peptides were initially thought to be inactive breakdown products of Ang II; however, they are now recognized as active components of the RAS, often with their own unique biological profile. This review will focus on the cardiovascular functions of these and other newly-discovered Ang peptides. The effects of these peptides will be discussed in the context of their actions at a number of non-AT1 receptors and the likely interplay with RAS inhibition.

Discovery of (pro)renin receptor uncovered a novel function of renin/prorenin as the receptor ligands in addition to enzyme and its precursor. Binding of renin and prorenin to the (pro)renin receptor activate two major signaling pathways: the locally generatedangiotensin II-dependent pathway as a result of the enzymatic activation of renin/prorenin, and the angiotensin II-independent (pro)renin receptor mediated intracellular pathway, involving hypertrophic, hyperplasic, and profibrotic signals. A specific blocker of the receptor was discovered through identification of amino acid sequence of prorenin pro-segment which binds to the receptor and leads to non-proteolytic alteration of prorenin to its active form. A peptide which contains this sequence was found to block the binding of prorenin to its receptor. Its continuous infusion in animal models of diabetes and low-renin hypertension significantly inhibited the development and progression of nephropathy, but (pro)renin receptor blockade was not effective on the clipped kidney of 2K1C rats or rat models of high-renin hypertension. Since renin is still active without a (pro)renin receptor, (pro)renin receptor blockade provides a maximum benefit under low-renin conditions. Thus, (pro)renin receptor blockade can be a effective therapeutic approach for chronic kidney disease with low renin levels in the plasma.

Diabetic retinopathy affects a significant proportion of people with diabetes. Epidemiological studies suggest that hypertension is related to diabetic retinopathy, and major clinical trials has provided clear evidence that controlling blood pressure in diabetic patients with hypertension reduces the incidence and progression of retinopathy and visual loss. The United Kingdom Prospective Diabetes Study (UKPDS) showed that a 10 mmHg reduction in systolic blood pressure is associated with a 10% reduction in the risk of retinopathy. However, the UKPDS suggest that adequate blood pressure control must be maintained over time for sustained benefits on retinopathy and other microvascular complications. Recent trials suggest that there is a limit to retinopathy risk reduction achievable through lowering blood pressure to near normal levels. Newer trials also provide initial evidence that specific inhibition of the renin angiotensin system (RAS), particularly with angiotensin II-receptor blockers (ARB), may have an additional protective effect against retinopathy. Early detection of retinopathy through comprehensive dilated eye examinations by eye care providers, controlling modifiable risk factors (glucose, blood pressure and lipids) and appropriate referral for treatment are the cornerstones in management of diabetic retinopathy in the community.

Blockade of angiotensin II (Ang II) has potential therapeutic benefit for ocular diseases including diabetic retinopathy and retinopathy of prematurity. Perhaps the most studied is diabetic retinopathy where angiotensin converting enzyme inhibition and angiotensin type 1 receptor blockade (AT1-RB) is beneficial. The importance of Ang II has recently been highlighted with DIRECT (DIabetic REtinopathy Candesartan Trial) reporting that the AT1-RB, candesartan, reduced the incidence of retinopathy in type 1 diabetic patients and enhanced regression in type 2 diabetic patients. Prorenin may also be a causative factor in diabetic retinopathy in humans, with early studies reporting that prorenin is elevated in both plasma and vitreous. Recently, interest in prorenin has re-emerged with the identification of a prorenin receptor [(P)RR] which binds both renin and prorenin and induces signal transduction pathways that are independent of Ang II. Studies by one group have reported that a particular (P)RR inhibitor provides protective effects in experimental retinopathy of prematurity and uveitis. However, controversy exists about the effectiveness of this (P)RR inhibitor with other groups failing to find organ protection. This review discusses these findings and evaluates whether prorenin and the (P)RR may be relevant for certain ocular diseases and a possible target for therapeutic intervention.