Combination ACE inhibitors and angiotensin II receptor blockers for hypertension

OBJECTIVE: To review data concerning combined angiotensin-converting enzyme (ACE) inhibitor and angiotensin II receptor blocker (ARB) therapy for hypertension. DATA SOURCES: MEDLINE (1966-April 2003), IPA (1970-April 2003), and EMBASE (1974-April 2003) with search terms of ACE inhibitor, angiotensin receptor blocker, essential hypertension, and combination therapy. DATA SYNTHESIS: ACE inhibitors provide incomplete blockade of the renin-angiotensin system, sometimes leading to loss of blood pressure control. Addition of ARBs may in theory further reduce blood pressure. Studies of combined ACE inhibitor and ARB therapy for managing hypertension were evaluated. CONCLUSIONS: While studies have shown statistically significant blood pressure reductions with ACE/ARB combination therapy, clinical significance is lacking. Further trials are needed before routine use of the combination can be recommended.     

Renoprotective effects of adding angiotensin II receptor blocker to maximal recommended doses of ACE inhibitor in diabetic nephropathy: a randomized double-blind crossover trial

OBJECTIVE: We evaluated the renoprotective effects as reflected by short-term changes in albuminuria of dual blockade of the renin-angiotensin system (RAS) by adding an angiotensin II receptor blocker (ARB) to treatment with maximal recommended doses of an ACE inhibitor (ACEI) in patients with type 2 diabetes and nephropathy. RESEARCH DESIGN AND METHODS: A total of 20 patients (17 men and 3 women) with type 2 diabetes along with hypertension and nephropathy were enrolled in this double-blind, randomized, two-period, crossover trial of 8 weeks of treatment with the ARB candesartan 16 mg daily and placebo added in random order to existing treatment with lisinopril/enalapril 40 mg daily or captopril 150 mg daily. At the end of each treatment period, we evaluated albuminuria in three 24-h urinary collections by turbidimetry, 24-h ambulatory blood pressure (ABP) using the Takeda-TM2420, and glomerular filtration rate (GFR) by the (51)Cr-EDTA plasma-clearance technique. RESULTS: During monoblockade of the RAS by ACEI treatment, albuminuria was 706 (349-1,219) mg/24 h [geometric mean (IQR)]; 24-h ABP was 138 +/- 3/72 +/- 2 mmHg (mean +/- SE); and GFR was 77 +/- 6 ml x min(-1) x 1.73 m(-2) (mean +/- SE). During dual blockade of the RAS by addition of candesartan 16 mg daily, there was a mean (95% CI) reduction in albuminuria of 28 (17-38) compared with ACEI alone (P < 0.001). There was a modest reduction in systolic/diastolic 24-h ABP of 3/2 mmHg (-2 to 8 systolic, -2 to 5 diastolic; NS). Changes in albuminuria did not correlate to changes in ABP. Addition of candesartan 16 mg daily induced a small, insignificant decrease in GFR of 4 (-1 to 9) ml x min(-1) x 1.73 m(-2). CONCLUSIONS: Dual blockade of the RAS provides superior short-term renoprotection independent of systemic blood pressure changes in comparison with maximally recommended doses of ACEI in patients with type 2 diabetes as well as nephropathy.     

The renal protective effects of angiotensin II receptor blockers in type 2 diabetes mellitus

OBJECTIVE: To review the renal protective effects of angiotensin II receptor blockers (ARBs) in patients with type 2 diabetes mellitus. DATA SOURCES: A MEDLINE search (1966-March 2004) was completed using irbesartan, candesartan, losartan, valsartan, eprosartan, olmesartan, telmisartan, renal protection, nephropathy, albuminuria, and type 2 diabetes mellitus as key words. STUDY SELECTION AND DATA EXTRACTION: All identified English-language articles were reviewed. References of the identified sources were used to identify additional articles. Articles representative of the subject matter of our review were included. DATA SYNTHESIS: ARBs have extensive data showing their renal protective benefits in hypertensive type 2 diabetic patients with microalbuminuria or proteinuria. The benefits are over and above that of blood pressure reduction alone and extend to normotensive diabetic patients as well. Maximizing the ARB dose before adding additional therapies or another renal-protecting agent (angiotensin-converting enzyme [ACE] inhibitor or non-dihydropyridine calcium-channel blocker) may be superior to adding another class of antihypertensive, even if similar blood pressures can be achieved. CONCLUSIONS: ARBs are an important therapy for hypertensive type 2 diabetic patients and can benefit normotensive diabetic patients as well. ARB dosage optimization or the addition of a second renoprotective agent (ACE inhibitor or non-dihydropyridine calcium-channel blocker) may be important for optimal renoprotection, although further research is clearly needed in this area.     

Effects of renin-angiotensin system inhibition on end-organ protection: can we do better?

BACKGROUND: The renin-angiotensin system (RAS) is a major regulator of blood pressure (BP) and vascular response to injury. There is increasing evidence that RAS inhibition may provide end-organ protection independent of BP lowering. Two drug classes directly target angiotensin II through complementary mechanisms. Angiotensin-converting enzyme (ACE) inhibitors block the conversion of angiotensin I to the active peptide angiotensin II and increase the availability of bradykinin. Angiotensin receptor blockers (ARBs) selectively antagonize angiotensin II at AT 1 receptors and may also increase activation of the AT 2 receptor and modulate the effects of angiotensin II breakdown products. OBJECTIVES: This paper presents an overview of clinical data supporting the use of RAS inhibitors (ACE inhibitors and ARBs) as monotherapy or combination therapy based on the known role of the RAS in BP regulation and the vascular response to injury, and considers the implications of the data for future treatment. METHODS: Relevant experimental and clinical studies were identified by searching MEDLINE (1969-June 30, 2007) using the primary search terms renin-angiotensin system, angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, and dual RAS blockade. Trials included in the review were large (>200 patients), prospective, randomized controlled studies evaluating the effect of RAS inhibition on end-organ protection in various high-risk populations. RESULTS: Eleven clinical trials each were identified that evaluated the effect of ACE-inhibitor and ARB monotherapy on end-organ protection. Five trials were identified that evaluated the effects of combination therapy with an ACE inhibitor and an ARB compared with treatment with either agent alone in different patient populations using different end points. In hypertensive patients with type 2 diabetes and microalbuminuria, combination ACE-inhibitor/ARB therapy resulted in better BP control than either agent alone (mean difference, 11.2 mm Hg systolic [P = 0.002], 5.9 mm Hg diastolic [P = 0.003]), as well as greater reductions in microalbuminuria (mean difference in albumin:creatinine ratio, 34%; P = 0.04). Compared with monotherapy, dual RAS inhibition reduced the occurrence of a doubling of the serum creatinine concentration or end-stage renal disease by 60% to 62% in patients with nondiabetic renal disease (P = 0.018 vs ACE inhibitor alone; P = 0.016 vs ARB alone). A recently published study reported a nonsignificant benefit for combination therapy over monotherapy only in a subset of hypertensive patients with high levels of microalbuminuria at baseline (58.1% vs 43.4% reduction, respectively). In patients with heart failure and left ventricular ejection fraction 相似文献   

Gene polymorphisms of renin-angiotensin system in patients with kidney diseases

Blockade of the renin-angiotensin system (RAS), such as angiotensin-converting enzyme inhibitor and/or angiotensin receptor blocker, has been well appreciated as a renoprotective treatment in proteinuric glomerular diseases. However, not all patients with glomerular diseases respond well to this therapy. Single nucleotide polymorphisms (SNPs) in angiotensin-converting enzyme (ACE) and angiotensinogen may be involved in the inter-individual difference in the responsiveness to the renoprotective efficacy of the RAS blockade. This review focuses on the interface between genomics and therapeutics in the renin-angiotensin system in IgA nephropathy, the most prevalent form of primary glomerulonephritis and one of the major causes of end-stage renal disease in the world.     

The role of renin inhibition in treating the hypertensive patient with diabetes: a summary of preclinical and clinical evidence

Comorbid hypertension and diabetes is common and associated with substantially greater cardiovascular and renal risk relative to hypertension alone. Tissue renin-angiotensin system (RAS) overactivity is a hallmark of diabetes and contributes to target organ damage. Treatment guidelines recommend angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) for reducing cardiorenal risk in patients with hypertension plus diabetes. However, these agents only partially prevent cardiovascular and renal morbidity/mortality. Further attempts to improve clinical outcomes have focused on the use of an ACE inhibitor plus an ARB, but this combination has not demonstrated a favorable risk-benefit profile. Direct renin inhibitors provide a more comprehensive blockade of the RAS compared with ACE inhibitors or ARBs, and may be of particular benefit in counteracting tissue RAS overactivity. In this article, the role of the RAS in diabetic hypertension and the preclinical and clinical effects of direct renin inhibitor therapy on target organs are reviewed.     

Who is tested for diabetic kidney disease and who initiates treatment? The Translating Research Into Action For Diabetes (TRIAD) Study

OBJECTIVE: We examined factors associated with screening for albuminuria and initiation of ACE inhibitor or angiotensin receptor blocker (ARB) treatment in diabetic patients. RESEARCH DESIGN AND METHODS: We conducted surveys and medical record reviews for 5,378 patients participating in a study of diabetes care in managed care at baseline (2000-2001) and follow-up (2002-2003). Factors associated with testing for albuminuria were examined in cross-sectional analysis at baseline. Factors associated with initiating ACE inhibitor/ARB therapy were determined prospectively. RESULTS: At baseline, 52% of patients not receiving ACE inhibitor/ARB therapy and without known diabetic kidney disease (DKD) were screened for albuminuria. Patients > or =65 years of age, those with higher HbA(1c), those with cardiovascular disease (CVD), and those without hyperlipidemia were less likely to be screened. Of the patients with positive screening tests, 47% began ACE inhibitor/ARB therapy. Initiation of therapy was associated with positive screening test results, BMI > or =25 kg/m(2), treatment with insulin or oral antidiabetic agents, peripheral neuropathy, systolic blood pressure > or =140 mmHg, and CVD. Of the patients receiving ACE inhibitor/ARB therapy or with known DKD, 63% were tested for albuminuria. CONCLUSIONS: Screening for albuminuria was inadequate, especially in older patients or those with competing medical concerns. The value of screening could be increased if more patients with positive screening tests initiated ACE inhibitor/ARB therapy. The efficiency of screening could be improved by limiting screening to diabetic patients not receiving ACE inhibitor/ARB therapy and without known DKD.     

Combined therapy with an angiotensin II receptor blocker and an angiotensin-converting enzyme inhibitor in heart failure

OBJECTIVE: To evaluate the safety, tolerability, and efficacy of chronic combination therapy with an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II receptor blocker (ARB) in the management of heart failure. DATA SOURCES: Clinical literature was accessed through MEDLINE (January 1966-June 2000). Key search terms included angiotensin-converting enzyme inhibitor; losartan; combined modality therapy; drug effects; heart failure, congestive; and receptors, angiotensin. DATA SYNTHESIS: Heart failure is widely prevalent and continues to be associated with high morbidity and mortality, even with currently recommended care. At the moderate doses studied for patients with mild heart failure in brief trials, combined ACE inhibitor and ARB therapy was well tolerated and had an additive effect in reducing blood pressure and relieving symptoms of heart failure. CONCLUSIONS: An ARB combined with an ACE inhibitor may benefit heart failure patients who are receiving all other recommended therapies. Further trials are needed to evaluate long-term safety effectiveness, quality of life, and survival before the combination can be recommended for routine use.     

Slowing the progression of renal disease in diabetic patients

OBJECTIVE: To review recent clinical trials that evaluate the most appropriate therapeutic options for delaying the progression of nephropathy in type 2 diabetic patients. DATA SOURCES: Primary and review articles were retrieved through a MEDLINE search (January 1990-January 2000). STUDY SELECTION AND DATA EXTRACTION: All studies related to attenuating the progression of nephropathy in diabetic patients were evaluated and included in this review. DATA SYNTHESIS: Clinical trials with angiotensin-converting enzyme inhibitors (ACEI) have consistently demonstrated a decrease in the progression of renal disease in diabetic patients. The angiotensin-2 receptor blocker (ARB) losartan has been shown to reduce microalbuminuria to the same extent as the ACEI enalapril. The nondihydropyridine calcium-channel blockers (NCCBs) verapamil and diltiazem have also been shown to decrease urinary albumin excretion. Clinical literature suggests that if monotherapy with an ACEI or ARB does not provide an adequate response, an NCCB should be added to the regimen. CONCLUSIONS: ACEIs should be considered first-line therapy for diabetic patients with nephropathy. ARBs should be considered as an alternative for patients who are unable to tolerate an ACE inhibitor due to adverse effects. If blood pressure goals are not achieved with an ACEI or ARB, then the addition of an NCCB should be considered.     

Dual blockade of the renin-angiotensin system in diabetic nephropathy: a randomized double-blind crossover study.

OBJECTIVE: Many patients with diabetic nephropathy (DN) have levels of albuminuria > 1 g/day and blood pressure >135/85 mmHg, despite antihypertensive combination therapy, including recommended doses of ACE inhibitors, e.g., lisinopril/enalapril at 20 mg daily. We tested the concept that such patients might benefit from dual blockade of the renin-angiotensin system (RAS). RESEARCH DESIGN AND METHODS: We performed a randomized double-blind crossover study of 2 months treatment with candesartan cilexetil 8 mg once daily and placebo in addition to previous antihypertensive treatment. We included 18 type 2 diabetic patients with DN fulfilling the above-mentioned criteria. All received recommended doses of ACE inhibitor and, in addition, 15 patients received diuretics, 11 received a calcium channel antagonist, and 3 received a beta-blocker. At the end of each treatment period, we measured the glomerular filtration rate (GFR), 24-h blood pressure, albuminuria, and IgGuria. RESULTS: The addition of candesartan to usual antihypertensive therapy induced a mean (95% CI) reduction in albuminuria of 25% (2-58), P = 0.036 (geometric mean [95% CI] from 1,764 mg/24 h [1,225-2,540] to 1,334 mg/24 h [890-1,998]). It also produced a mean reduction of 35% (9-53) in the fractional clearance of albumin (P = 0.016), a reduction of 32% (1-54) in fractional clearance of IgG (P = 0.046), a reduction in 24-h systolic blood pressure of 10 mmHg (2-18) (P = 0.019) (mean +/- +/- SE) from 148 +/- 3 to 138 +/- 5 mmHg, and a mean reduction in GFR of 5 ml. min(-1). 1.73 m(-2) (0.1-9) (P = 0.045). CONCLUSIONS: Dual blockade of the RAS reduces albuminuria and blood pressure in type 2 diabetic patients with DN responding insufficiently to previous antihypertensive therapy, including ACE inhibitors in recommended doses.     

Does renin‐angiotensin system blockade have a role in preventing diabetic retinopathy? A clinical review

Diabetes management has increasingly focused on the prevention of macrovascular disease, in particular for type 2 diabetes. Diabetic retinopathy, one of the main microvascular complications of diabetes, is also an important public health problem. Much of the care invested in retinopathy relates to treatment rather than prevention of disease. Tight glycaemic and blood pressure control helps to reduce the risk of retinopathy, but this is not easy to achieve in practice and additional treatments are needed for both primary and secondary prevention of retinopathy. A renin-angiotensin system (RAS) has been identified in the eye and found to be upregulated in retinopathy. This has led to specific interest in the role of RAS blockade in retinopathy prevention. The recent DIRECT programme assessed use of the angiotensin receptor blocker (ARB) candesartan in type 1 and type 2 diabetes. Although the primary trial end-points were not met, there was a clear trend to less severe retinopathy with RAS blockade. A smaller trial, RASS, reported reduced retinopathy progression in type 1 diabetes from RAS blockade with both the ARB losartan and the angiotensin converting enzyme (ACE) inhibitor enalapril. The clinical implications of these new data are discussed.     

Beneficial effects of adding spironolactone to recommended antihypertensive treatment in diabetic nephropathy: a randomized, double-masked, cross-over study

OBJECTIVE: The objective of this study was to evaluate the safety and short-term effect of adding spironolactone to conventional antihypertensive treatment including diuretics and maximally recommended doses of an ACE inhibitor or an angiotensin II receptor blocker (ARB) on albuminuria and blood pressure in type 2 diabetic patients with nephropathy. RESEARCH DESIGN AND METHODS: Twenty-one type 2 diabetic patients with nephropathy were enrolled in a randomized, double-masked, cross-over study. Patients were treated in random order with spironolactone 25 mg once daily and matched placebo for 8 weeks, respectively, in addition to ongoing antihypertensive treatment including diuretics and maximally recommended doses of an ACE inhibitor and/or an ARB. At the end of each treatment period, albuminuria, 24-h ambulatory blood pressure (ABP), and glomerular filtration rate (GFR) were determined. RESULTS: During the addition of placebo, values were as follows: albuminuria (geometric mean [range]) 1,566 [655-7,762] mg/24 h, ABP (mean +/- SE) 138 +/- 3/71 +/- 1 mmHg, and GFR (mean +/- SE) 74 +/- 6 ml/min per 1.73 m2. During the addition of spironolactone, albuminuria was reduced by 33% (95% CI 25-41) (P < 0.001), fractional clearance of albumin by 40% (24-53) (P < 0.001), and 24-h ABP by 6 mmHg (2-10) for systolic and 4 mmHg (2-6) for diastolic (P < 0.001 for both). The change in albuminuria did not correlate with the change in systolic 24-h ABP (r = 0.19, P = 0.42) or diastolic 24-h ABP (r = 0.01, P = 0.96). Spironolactone treatment induced an insignificant reversible reduction in GFR of 3 ml/min per 1.73 m2 (-0.3 to 6) (P = 0.08). One patient was excluded from the study due to hyperkalemia. Otherwise treatment was well tolerated. CONCLUSIONS: Our study suggests that spironolactone safely adds to the reno- and cardiovascular protective benefits of treatment with maximally recommended doses of ACE inhibitor and ARB by reducing albuminuria and blood pressure in type 2 diabetic patients with nephropathy.     

Tissue gene expression of renin-angiotensin system in human type 2 diabetic nephropathy

OBJECTIVE: Recent studies have proved that blockade of the renin-angiotensin system (RAS) retards the progression of diabetic nephropathy, whereas hyporeninemia is known as a typical state in diabetic subjects. The purpose of this study is to determine whether expression levels of RAS differ between nondiabetic and diabetic renal tissues with accurate quantitative method. RESEARCH DESIGN AND METHODS: Subjects were 66 nondiabetic and 8 diabetic patients with biopsy-proven renal diseases. The eight diabetic subjects suffered from type 2 diabetes with overt proteinuria. Renal histology revealed typical diffuse or nodular lesions with linear IgG deposit on immunofluorescent staining and thickened basement membrane on electronic microscopy. Total RNA from a small part of the renal cortical biopsy specimens was reverse-transcribed, and the resultant cDNA was amplified for new major components of RAS (i.e., renin, renin receptor, angiotensinogen, ACE, ACE2, angiotensin II type 1 receptor, and angiotensin II type 2 receptor) and measured. RESULTS: Among these components, a significant upregulation was observed in the ACE gene in diabetic renal tissue. CONCLUSIONS: The results suggest that renal tissue RAS might be activated in the respect that ACE gene expression is upregulated in spite of a tendency to low renin expression in type 2 diabetic nephropathy.     

Combination renin-angiotensin system blockade and angiotensin-converting enzyme 2 in experimental myocardial infarction: implications for future therapeutic directions

The RAS (renin-angiotensin system) is activated after MI (myocardial infarction), and RAS blockade with ACEis [ACE (angiotensin-converting enzyme) inhibitors] or ARBs (angiotensin receptor blockers) slows but does not completely prevent progression to heart failure. Cardiac ACE is increased after MI and leads to the formation of the vasoconstrictor AngII (angiotensin II). The enzyme ACE2 is also activated after MI and degrades AngII to generate the vasodilator Ang-(1-7) [angiotensin-(1-7)]. Overexpression of ACE2 offers cardioprotective effects in experimental MI, but there is conflicting evidence as to whether the benefits of ACEis and ARBs are mediated through increasing ACE2 after MI. In the present study, we assessed the effect of an ACEi and ARB, alone and in combination, on cardiac ACE2?in a rat MI model. MI rats received vehicle, ACEi (ramipril; 1?mg/kg of body weight), ARB (valsartan; 10?mg/kg of body weight) or combination (ramipril at 1?mg/kg of body weight and valsartan at 10?mg/kg of body weight) orally for 28?days. Sham-operated rats were also studied and received vehicle alone. MI increased LV (left ventricular) mass (P<0.0001), impaired cardiac contractility (P<0.05) and activated cardiac ACE2 with increased gene (P<0.05) and protein expression (viable myocardium, P<0.05; border zone, P<0.001; infarct, P<0.05). Ramipril and valsartan improved remodelling (P<0.05), with no additional effect of dual therapy. Although ramipril inhibited ACE, and valsartan blocked the angiotensin receptor, neither treatment alone nor in combination augmented cardiac ACE2 expression. These results suggest that the cardioprotective effects of ramipril and valsartan are not mediated through up-regulation of cardiac ACE2. Strategies that do augment ACE2 after MI may be a useful addition to standard RAS blockade after MI.     

Sustained 24-hour blockade of the renin-angiotensin system: a high dose of a long-acting blocker is as effective as a lower dose combined with an angiotensin-converting enzyme inhibitor

Whether a higher dose of a long-acting angiotensin II receptor blocker (ARB) can provide as much blockade of the renin-angiotensin system over a 24-hour period as the combination of an angiotensin-converting enzyme inhibitor and a lower dose of ARB has not been formally demonstrated so far. In this randomized double-blind study we investigated renin-angiotensin system blockade obtained with 3 doses of olmesartan medoxomil (20, 40, and 80 mg every day) in 30 normal subjects and compared it with that obtained with lisinopril alone (20 mg every day) or combined with olmesartan medoxomil (20 or 40 mg). Each subject received 2 dose regimens for 1 week according to a crossover design with a 1-week washout period between doses. The primary endpoint was the degree of blockade of the systolic blood pressure response to angiotensin I 24 hours after the last dose after 1 week of administration. At trough, the systolic blood pressure response to exogenous angiotensin I was 58% +/- 19% with 20 mg lisinopril (mean +/- SD), 58% +/- 11% with 20 mg olmesartan medoxomil, 62% +/- 16% with 40 mg olmesartan medoxomil, and 76% +/- 12% with the highest dose of olmesartan medoxomil (80 mg) (P = .016 versus 20 mg lisinopril and P = .0015 versus 20 mg olmesartan medoxomil). With the combinations, blockade was 80% +/- 22% with 20 mg lisinopril plus 20 mg olmesartan medoxomil and 83% +/- 9% with 20 mg lisinopril plus 40 mg olmesartan medoxomil (P = .3 versus 80 mg olmesartan medoxomil alone). These data demonstrate that a higher dose of the long-acting ARB olmesartan medoxomil can produce an almost complete 24-hour blockade of the blood pressure response to exogenous angiotensin in normal subjects. Hence, a higher dose of a long-acting ARB is as effective as a lower dose of the same compound combined with an angiotensin-converting enzyme inhibitor in terms of blockade of the vascular effects of angiotensin.     

The benefits of angiotensin II receptor blockers in patients with renal insufficiency or failure

Hypertension occurs frequently in patients with renal disease and contributes to the development of end-stage renal disease. Because the renin angiotensin system (RAS) influences hypertension and renal disease, angiotensin-converting enzyme (ACE) inhibitors have been used successfully to treat and reduce renal consequences of hypertension. This review assesses how angiotensin II (A-II) influences renal disease and explores the effectiveness of losartan, a selective A-II receptor blocker, in patients with renal disease. Clinical trials have demonstrated that losartan is a safe and effective treatment for hypertension in renally impaired patients and produces renal hemodynamic effects akin to those seen with ACE inhibitors. However, losartan demonstrates a greater uricosuric effect than ACE inhibitors and does not produce cough, a significant side effect frequently associated with ACE inhibitors. Further studies will determine whether combination therapy with an ACE inhibitor and A-II receptor blocker will provide additional RAS blockade and synergistic benefits in patients with renal disease.     

Angiotensin-converting enzyme gene polymorphism: is there a link to nephropathy in patients with type 1 diabetes?

OBJECTIVE: To evaluate the association between the angiotensin-converting enzyme (ACE) gene polymorphism and diabetic nephropathy in patients with type 1 diabetes. DATA SOURCES: Citations were selected using the MEDLINE database. Only those citations involving human subjects and available in English were selected. Key search words included angiotensin-converting enzyme (ACE), polymorphism, nephropathy, and type 1 diabetes. STUDY SELECTION: Selection criteria consisted of all MEDLINE-referenced clinical trials, review articles, and editorial comments assessing the potential link between the ACE gene polymorphism and diabetic nephropathy in insulin-dependent diabetes mellitus published between January 1990 and February 1998. DATA SYNTHESIS: Because diabetic nephropathy is a serious complication of type 1 diabetes, focus has been placed on the early identification of and intervention with patients genetically susceptible to this complication. Because the ACE gene polymorphism has an effect on plasma ACE concentration variations among individuals, it has been investigated as a potential genetic marker for diabetic nephropathy. The best studies to date are reviewed in order to assess the utility of the ACE polymorphisms as a genetic marker of diabetic nephropathy in patients with type 1 diabetes, and to determine what implications this holds for drug treatment. CONCLUSIONS: Although the ACE gene polymorphism's potential link to diabetic nephropathy in patients with type 1 diabetes has been debated, the most definitive studies show that an association exists. Large epidemiologic studies must now be conducted to determine the implications this polymorphism holds for the best treatment strategies in the care of these patients.     

Manipulating the angiotensin system--new approaches to the treatment of solid tumours

Angiotensin II (Ang II), a main effector peptide in the renin-angiotensin system (RAS), plays a fundamental role as a vasoconstrictor in controlling cardiovascular function and renal homeostasis. Ang II also acts as a growth promoter or angiogenic factor via type 1 angiotensin II receptors (AT1Rs) in certain tumour cell lines. Recent studies have shown the activation of the local RAS in various tumour tissues, including the abundant generation of Ang II by angiotensin-converting enzyme (ACE) and the upregulation of AT1R expression. Thus, considerable attention has been paid to the role of the RAS in cancer and its blockade as a new approach to the treatment of cancer. There is increasing evidence that the Ang II-AT1R system is involved in tumour growth, angiogenesis and metastasis in experimental models, suggesting the therapeutic potential of an ACE inhibitor and AT1R blocker, both of which have been used as antihypertensive drugs. In addition, specific Ang II-degrading enzymes are expressed in tumours and play a regulatory role in cell proliferation and invasion. This review focuses on the role of the Ang II-AT1R system in solid tumours, particularly in the progression of gynaecological cancer, and presents the clinical potential of manipulating the angiotensin system as a novel and promising strategy for cancer treatment.     

What is the role of direct renin inhibitors in the treatment of the hypertensive diabetic patient?

The renin-angiotensin system (RAS) is the most important mechanism leading to cardiovascular and renal damage in diabetic patients. Studies conducted until now have unequivocally demonstrated that antihypertensive treatment with RAS blockers (angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers) improve the prognosis of patients with diabetes, by reducing rates of cardiovascular events and preventing or delaying the progression of diabetic nephropathy. However, despite the benefits of such treatment, cardio-renal events are still very frequent in diabetics. Several strategies for reducing this cardiovascular and renal risk have been proposed, but among them, a more complete blockade of the RAS seems the most attractive. Direct renin inhibitors are RAS blockers with some particularities, such as their ability to reduce plasma renin activity or the possibility to modulate tissue and intracellular RAS, which could represent a theoretical advantage when treating diabetic patients. In experimental and clinical studies conducted until now, aliskiren is able to reduce blood pressure in diabetics, alone or in combination with ACE inhibitors or angiotensin-receptor blockers. Moreover, aliskiren reduces markers of cardiac and renal disease, such as left ventricular hypertrophy or post-infarction ventricular remodeling, as well as proteinuria in diabetics already treated with other RAS blockers. The translation of these promising results to the clinical arena is currently being investigated in the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE), where more than 8600 diabetic patients with chronic kidney disease and at high-risk of cardio-renal events are treated with aliskiren or placebo added to the current treatment consisting of another RAS blocker. If positive, aliskiren will be the treatment of choice in the prevention of cardiorenal disease in diabetics.     

Recent changes in the landscape of combination RAS blockade

The renin–angiotensin system (RAS) is a prime target for cardiovascular drug therapy. Inhibition of the RAS lowers blood pressure and confers protection against cardiovascular and renal events. These latter benefits cannot be entirely attributed to blood pressure lowering. Angiotensin-converting enzyme (ACE)-inhibitors and angiotensin receptor blockers (ARBs) have been studied extensively and, while there is irrefutable evidence that these agents mitigate the risk for cardiovascular and renal events, their protection is incomplete. In outcomes studies that have employed ACE-inhibitors or ARBs there has been a relatively high residual event rate in the treatment arm and this has been ascribed, by some, to the fact that neither ACE-inhibitors nor ARBs completely repress RAS. For this reason, combined RAS blockade with an ACE-inhibitor and ARB has emerged as a therapeutic option. In hypertension, combined RAS blockade elicits only a marginal incremental drop in blood pressure and it does not further lower the risk for cardiovascular events. In chronic heart failure and proteinuric renal disease, combining these agents in carefully selected patients is associated with a reduction in clinical events. Irrespective of the setting, dual RAS blockade is associated with an increase in the risk for adverse events, primarily hyperkalemia and worsening renal function. The emergence of the direct renin inhibitor, aliskiren, has afforded clinicians a new strategy for RAS blockade. Renin system blockade with aliskiren plus another RAS agent is the subject of ongoing large-scale clinical trials and early studies suggest promise for this strategy. Currently, combined RAS blockade with an ACE-inhibitor and an ARB should not be routinely employed for hypertension; however, the combination of an ACE-inhibitor or ARB with aliskiren might be considered in some patients given the more formidable blood pressure-lowering profile of this regimen. In carefully selected patients with heart failure or kidney disease, combination therapy with two RAS inhibitors should be considered.