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1 Reduction of proteinuria with angiotensin receptor blockers Jan Galle ARTICLE SUMMARY Renal pathophysiology is elicited by activation of angiotensin II type 1 (AT 1 ) receptors at all stages of renovascular disease. Angiotensin receptor blockers (ARBs) that specifically block the AT 1 receptor offer the potential to prevent or delay progression to end-stage renal disease independently of reductions in blood pressure. Proteinuria an early and sensitive marker for progressive renal dysfunction is reduced by ARB use in patients with type 2 diabetic nephropathy and microalbuminuria or macroalbuminuria. Retrospective analysis of data available from early trials has confirmed this finding, and has shown that albuminuria reduction is associated with lessening of cardiovascular risk. The ARB telmisartan is equivalent to enalapril in preventing glomerular filtration rate decline, and equivalent to valsartan in reducing proteinuria. Telmisartan is more effective than conventional therapy in lowering the risk of transition to overt nephropathy in hypertensive and normotensive oten patients. An additive effect has been seen in smaller studies when telmisartan has been added to lisinopril therapy, and high-dose telmisartan reduces albuminuria better than low-dose telmisartan. Similar data were obtained with other ARBs such as candesartan, losartan, an, valsartan, or irbesartan. These data support the proposition that blockade of the renin angiotensin system in beyond that required for maximum blood pressure reduction provides optimum renal protection. KEYWORDS angiotensin receptor blockers, diabetes, proteinuria, renal disease, renin angiotensin system blockade J Galle is Head of the Department of Nephrology and Dialysis at the Klinikum Lüdenscheid, and a Fellow of the Deutsche Gesellschaft für Kardiologie, Herz, und Kreislaufforschung and the Deutsche Herzstiftung, Lüdenscheid, Germany. Correspondence Direktor der Klinik für Nephrologie, Klinikum Lüdenscheid, Paulmannshöher Strasse 14, D Lüdenscheid, Germany Received 23 November 2006 Accepted 2 January doi: /ncpcardio0806 INTRODUCTION Proteinuria is an early and sensitive marker for progressive renal dysfunction. 1 In the early stages of kidney disease, very small amounts of protein are detectable in the urine (microalbuminuria). As the disease progresses to clinical or overt nephropathy, larger quantities of urinary protein can be measured (macroalbuminuria). Hemodynamic injury to the vascular endothelium and glomerulus can be induced by both systemic and glomerular hypertension, which is promoted by an activated renin angiotensin system (RAS). Angiotensin II, the primary agent of this system, is centrally involved in all stages of renal pathophysiology. 2 Angiotensin-II-receptor blockers (ARBs) are primarily prescribed as antihypertensive drugs, and several guidelines recommend these agents as first-line therapy for patients with arterial hyper- tension. 3 5 The benefits of ARBs extend, however, beyond lowering of blood pressure. Their use to selectively inhibit the angiotensin II type 1 (AT 1 ) ORREpr receptor can protect against the progression of kidney disease. This article addresses the central role of angiotensin II in the risk, development and progression of cardiovascular and renovascular disease and considers the potential of RAS blockade for preventing target-organ damage in patients with diabetic nephropathy. It also summarizes the findings from several trials, addressing the efficacy of ARB therapy (specifically with telmisartan) in comparison with that for an angiotensin-converting-enzyme (ACE) inhibition with enalapril, another ARB (valsartan), and conventional treatment in patients with and without hypertension. This information was first presented at a meeting sponsored by Boehringer Ingelheim and held in Lisbon on 28 and 29 April, The meeting, which addressed a range of topics related to RAS blockade, was endorsed by the European Society of Hypertension and the International Society of Nephrology. The meeting was called A new dawn in cardiovascular protection: total cardiovascular risk: rigorous treatment of risk factors. MAY 2007 VOL 4 SUPPLEMENT 2 NATURE CLINICAL PRACTICE CARDIOVASCULAR MEDICINE 1

2 Glomerular pressure injury Oxidative stress Proteinuria Nuclear factor-κb activation Hyperfiltration Glomerular capillary hypertension Chronic kidney disease Angiotensin II Reduction in nephron mass Extracellular matrix Adhesion molecules Chemotactic factors Macrophage infiltration TGF-β PAI-1 Figure 1 The central role of angiotensin II in the pathophysiology y of renal disease. Permission obtained from Lippincott, Williams & Wilkins Brewster UC and Perazella MA (2004) Am J Med 116: Abbreviations: PAI-1, plasminogen activator inhibitor 1; TGF-β, transforming growth factor β. ANGIOTENSIN NSIN II IN RENOVASCULAR AND CARDIOVASCULAR DISEASE Renal disease and coronary artery disease both develop through a general progression of pathophysiological physiological events, beginning with cardiovascular risk factors and culminating with end-organ disease. 6 Risk factors such as high blood pressure, raised concentrations of cholesterol, diabetes mellitus, litus, and insulin resis- tance elicit pathological changes in the heart and vasculature. ure. Changes include atherosclerosis, left ventricular hypertrophy, coronary vascular obstruction, and myocardial ischemia. Patients can go on to experience myocardial infarction and arrhythmia, rhy which can lead to sudden death. In patients who survive, ventricular wall remodeling eventually occurs, leading to increased muscle mass and cardiac dilatation, ultimately resulting in congestive heart failure. In renovascular disease, the same cardiovascular risk factors elicit pathological changes, such as endothelial dysfunction and microalbuminuria. These changes can lead to increased risk of coronary heart disease and nephrotic syndrome, reduced glomerular filtration rate (GFR), and nephrosclerosis. Eventually, endorgan damage occurs in the form of chronic kidney disease stage V. Angiotensin II is centrally involved in targetorgan damage at every stage of cardiovascular and renal pathophysiologies. Figure 1 illustrates the roles of angiotensin II in renal Cell proliferation Collagen deposition Apoptosis Glomerular sclerosis Tubulointerstitial fibrosis disease. 2 The major biological actions of angiotensin II in the kidney are mediated by two functionally distinct receptors, AT 1 and AT 2. 2 Activation of AT 1 receptors is responsible for the pathophysiological effects of angiotensin II, whereas activation of AT 2 receptors plays a part in opposing these pathophysiological effects. 7 AT 1 receptors are abundant in the efferent arterioles of each nephron of the kidney. Receptor activation by angiotensin II induces vasoconstriction, which raises glomerular capillary pressure and increases glomerular filtration, and leads to proteinuria. In addition to renal vasoconstriction induced by angiotensin II, direct profibrotic and proinflammatory matory actions of angiotensin II and aldosterone can promote kidney damage, seen as, for example, activation of plasminogen n activator inhibitor 1 or transforming growth factor β (Figure 1). 2 BLOCKING THE RAS TO PREVENT TARGET-ORGAN DAMAGE Potential of ARBs versus ACE inhibitors Angiotensin II is a central mediator of hemodynamic and nonhemodynamic processes of renal injury. Use of antihypertensive agents that block the RAS will, therefore, cause vasodilatation of the efferent arterioles in addition to lowering blood pressure. These actions should reduce intraglomerular pressure, thereby lessening proteinuria and providing renoprotective effects in patients with nephropathy. Although ACE inhibitors and ARBs both target the RAS, they do so in different ways. This difference might affect their potential benefits in end-organ protection. ACE inhibitors reduce blood pressure by blocking the conversion of angiotensin I to angiotensin II, as well as by preventing the breakdown of bradykinin and other vasoactive peptides. Other enzymatic pathways can, however, also lead to the generation of angiotensin II. Over time, therefore, these pathways might compensate for the effect of ACE inhibition, leading to a gradual return of angiotensin II to baseline levels. This phenomenon is known as angiotensin II escape. 8,9 By contrast, ARBs specifically block the AT 1 receptor, thereby effectively inhibiting the pathophysiological effects of angiotensin II. This action offers the potential for additional benefit beyond blood pressure reduction, including reduced proteinuria and the progression to end-stage renal disease (ESRD) in patients with type 2 diabetes and nephropathy. P 2 NATURE CLINICAL PRACTICE CARDIOVASCULAR MEDICINE GALLE MAY 2007 VOL 4 SUPPLEMENT 2

3 Table 1 Summary of important trials investigating the renoprotective effects of angiotensin-receptor blockers. Study Duration Drug Primary endpoint Systolic/diastolic blood pressure (mmhg) Patients with type 2 diabetes and microalbuminuria IRMA II 26 (n = 590) MARVAL 27 (n = 332) 2 years Irbesartan 150 mg, irbesartan 300 mg or placebo 24 weeks Valsartan mg or amlodipine 5 10 mg Patients with type 2 diabetes and macroproteinuria or reduced GFR RENAAL 16 (n = 1,513) IDNT 21 (n = 1,715) 3.4 years Losartan mg or placebo 2.6 years Irbesartan 300 mg, amlodipine 10 mg, or placebo Clinical trials assessing reductions in proteinuria and progression to ESRD ACE inhibitors and ARBs have been chosen for study in numerous clinical trials. 10 ACE inhibitors have been investigated in patients with type 1 or type 2 diabetes Overall, studies of these drugs in type 2 diabetes have provided no convincing cing evidence of efficacy beyond blood pressure control. 15 ARBs have been shown to reduce the inci- dence of hard endpoints (i.e. relate directly to renal function), such as doubling of baseline serum creatinine concentration or developelopment of ESRD. The Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study 16,17 included 1,513 patients with type 2 diabetes and nephropathy. The risk of developing these two hard endpoints was reduced by 25% and 28%, respectively, when compared with placebo. 16 Reduced progression of renal disease was seen in all three tertiles of baseline serum creatinine concentration. 17 In the Irbesartan Diabetic Nephropathy Trial (IDNT), 18 a total of 1,715 hypertensive patients with type 2 diabetes and urinary protein excretion of at least 900 mg/day were randomly assigned 300 mg irbesartan, 10 mg amlodipine, or placebo daily for a mean duration of 2.6 years. The risk of the primary composite endpoint (doubling of serum creatinine, development of ESRD, or death) was reduced in the ARB-treated patients by 20% compared with placebo (P P = 0.02) and by 23% compared with amlodipine group (P P = 0.006). In both RENAAL and IDNT, the superiority rity of ARB therapy was evident despite very similar changes in blood pressure in the comparator groups. As early as 2002, the results from these and other trials (Table 1) motivated the American Diabetes Association to recommend that use of ARBs should be standard in the treatment of diabetic nephropathy in patients with type 2 diabetes. 19 Evidence that has become available since that guideline was published has strengthened the case, and the Association s position has been reiterated. 20 For example, a post hoc subanalysis of the IDNT trial provided strong evidence of the blood-pressure-independent effects of irbesartan compared with amlodipine. 21 Figure 2 shows the relative risk of a renal endpoint in relation to systolic blood pressure and treatment (irbesartan, amlodipine, or placebo). In each treatment group, falls in systolic blood pressure during follow-up were associated with an reduced risk of reaching a renal endpoint. However, in all quartiles of systolic blood pressure, ARB-treated patients experienced improved renal outcomes compared with patients receiving amlodipine or placebo. The relative risk of a renal endpoint in patients taking amlodipine was similar to that in placebo-treated patients. Placebo was, however, Proteinuria (% change from baseline) Microalbuminuria 10/ 7; 12/ 7; 9/ 7 24%; 38%; 2% Microalbuminuria 11/ 7; 12/ 7 44%; 8% Death, doubling of creatinine, or need for dialysis or renal transplantation Death, doubling of creatinine, or need for dialysis or renal transplantation 12/ 8; 11/ 8 35%; 18% 20/ 10; 18/ 10; 14/ 7 33%; 6%; 10% Abbreviations: GFR, glomerular filtration rate; IDNT, Irbesartan Diabetic Nephropathy Trial; IRMA II, IRbesartan in patients with type 2 diabetes and MicroalbuminuriA; MARVAL, MicroAlbuminuria Reduction with VALsartan; RENAAL, Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan. MAY 2007 VOL 4 SUPPLEMENT 2 GALLE NATURE CLINICAL PRACTICE CARDIOVASCULAR MEDICINE 3

4 Relative risk of renal endpoint Amiodipine Placebo Irbesartan Treatment < >149 Quartile of mean SBP (mmhg) Figure 2 The close relationship between systolic blood od pressure and the risk of renal endpoint in the Irbesartan Diabetic Nephropathy Trial subanalysis. Permission obtained from the American Society of Nephrology Pohl MA et al. (2005) J Am Soc Nephrol 16: Abbreviation: SBP, systolic blood pressure. d on administered d on a background of standard antihypertensive therapy with drugs other than calcium-channel blockers or RAS inhibitors. As well as hard endpoints, ARBs have been extensively investigated in relation to so- called soft endpoints, especially proteinuria. Although this disorder does not directly cause death or disability, it is a key marker of various underlying pathophysiologies physiologies and is linked to decline in renal function, 22 systemic endothelial dysfunction, 23 target-organ damage, 24 and cardiovascular mortality. 25 ARBs have effectively reduced urinary protein concentrations in patients with type 2 diabetic nephropathy, independently of blood pressure lowering. These drugs act either by reducing microalbuminuria in early-stage kidney disease or macroalbuminuria in later-stage disease when GFR is already reduced (Table 1). 16,21,26,27 Overall, reductions in proteinuria seen with ARB treatment have been reported as greater than those with placebo or the calcium-channel blocker amlodipine, despite similar blood pressure reductions in the ARB and calcium-channel blocker groups. Albuminuria can be employed in risk stratification and treatment assessment. In a post hoc analysis of the LIFE study, decreased microalbuminuria after ARB treatment translated into a reduction in cardiovascular events in hypertensive patients without overt renal disease. 28 The primary analysis of the LIFE study 29 demonstrated that, in 9,193 patients with hypertension and left ventricular hypertrophy, the risk of the primary composite endpoint over 4 years (death, myocardial infarction, or stroke) was significantly lower among patients receiving the ARB losartan than among those taking the β- blocker atenolol, despite similar blood pressure reductions in both groups (23.8 versus 27.9 incidences per 1,000 patient-years, P = 0.021). In the post hoc analysis, the incidence of the primary composite endpoint was assessed in 8,206 patients according to four levels of baseline and in-treatment values of urinary albumin-to-creatinine ratio ( 0.5, , , and >3.0 mg/ mmol). 30 Albuminuria concentrations during therapy were closely associated ated with the risk of developing the primary composite endpoint. When urinary ry albumin-to-creatinine ratio decreased ed during treatment, with values moving from the lowest to the highest stratum, the risk for a cardiovascular endpoint increased by three- fold to fourfold. This observation, which was independent of blood-pressure-lowering effects, strongly suggests that treatment-induced reductions in albuminuria lead to decreased cardiovascular ar risk. The distribution of patients across the urinary albumin-to-creatinine ratio strata changed during the study: at baseline, the ratio for 43% of patients was less than 1 mg/mmol, but at 4 years the equivalent value was seen in 53%. OF Response to treatment was marked by movement of patients ratio values into a stratum that was associated with reduced cardiovascular risk. Monitoring of albuminuria could, therefore, be an important part of the management of hypertensive patients with albuminuria. Intensification of antihypertensive treatment might be considered to reduce urinary protein in patients with ratios in the highest-risk strata. The importance of minimizing the progression of albuminuria in patients with type 2 diabetes poses the question of whether ARBs should be considered for all such patients, whether they have hypertension or not. Only one major study has thus far assessed an ARB in this role: The INcipieNt to OVert Angiotensin II receptor blocker, Telmisartan, Investigation On type II diabetic Nephropathy (INNOVATION) study. 31 The results of this study have not yet been published. Choice of intervention for RAS blockade Although ARBs and ACE inhibitors are now established as the therapies of choice for 4 NATURE CLINICAL PRACTICE CARDIOVASCULAR MEDICINE GALLE MAY 2007 VOL 4 SUPPLEMENT 2

5 patients with diabetic nephropathy, much research remains to be done. A key question is whether one of these drug classes should be the preferred over the other. Only one study, the Diabetics Exposed to Telmisartan And enalapril (DETAIL) study, has so far attempted to address this issue. 32 DETAIL was a 5-year, prospective, multicenter, randomized, double-blind study done in 250 patients with type 2 diabetes and mild to moderate hypertension (seated diastolic/systolic blood pressure during therapy 95/180 mmhg), a urinary albumin excretion rate higher than 10 μg/min and lower than 1,000 μg/min, and normal or only mildly impaired GFR [Author: Correct?] ( 70 ml/min/1.73 m 2 ). Telmisartan has the longest plasma half-life and highest volume of distribution of all agents in the ARB class. 30 In patients with type 2 diabetes at the earliest stage of renal disease this drug can improve renal endothelial function. n. 33 Enalapril had previously been shown in a 6-year study to significantly reduce the decline e of renal function in patients with type 2 diabetes and microalbuminuria. 34 Eligible patients received forced titration with either mg telmiswith optional dose reduction to 40 mg or 10 mg, respectively. The primary endpoint was change in GFR, artan or mg enalapril, measured by the iohexol method, after 5 years of treatment. tment. The two treatments produced similar reductions in blood pressure. The GFR at 5 years was reduced to a similar degree by telmisartan or enalapril therapy (Figure 3), and the rate of decline reduced progressively during the study. 31 The typical annual rate of GFR decline in untreated diabetics with proteinuria i is ml/min/1.73 m By year 3 of the DETAIL study, the annual decline in GFR had stabilized to approximately 2 ml/min/1.73 m 2, which is similar to the agerelated decline expected in healthy individuals. 36 Interestingly, the mortality in DETAIL was unexpectedly low given the link between renal and cardiovascular disease. Only six patients died in each treatment group, which represented about 5% of the study population. By contrast, the expected mortality rate in older patients with type 2 diabetes of more than 5 years duration [Author: Correct?] is around 35% in those with microalbuminuria and 50% in those with macroalbuminuria. 37 The GFR-preserving effect provided by telmisartan in the DETAIL study may be Change in glomerular filtration rate (ml/min/1.73 m 2 ) compared with that of other ARBs in studies of renal disease progression, on, although the popu- lations and treatment durations differ between studies. 38 In DETAIL, the mean yearly decline in measured ed GFR was 3.7 ml/min/1.73 m 2 after 5 years of treatment with mg telmis- artan. 32 In RENAAL, the yearly decline in estimated GFR was 4.4 ml/min/1.73 m 2 after 3.4 years of treatment with 100 mg losartan. 16 In the IRbesartan in patients with type 2 diabetes and MicroalbuminuriA (IRMA 2) study, 21 the corresponding value was 5.7 ml/ min/1.73 m 2 after 2 years of treatment with 300 mg irbesartan, 21 and in IDNT it was 5.5 ml/min/1.73 m 2 after 2.6 years of treatment with the same dose. 26 A comparison of the antiproteinuric effects of different ARBs has been investigated in only one large study, a trial to investigate the efficacy of telmisartan versus VALsartan in hypertensive type-2 DIabetic patients with overt nephropathy (VIVALDI). 39 This study was a prospective, 1- year, multicenter, randomized, double-blind, parallel-group trial of patients with type 2 diabetes, hypertension (seated systolic/diastolic blood pressure >130/>80 mmhg), macroalbuminuria ( 900 mg/day) and serum creatinine μmol/l in women and μmol/l in men. Patients were randomized to receive 80 mg ARTICLE Enalapril Telmisartan Time (years) Number of patients at risk (total number [number carried forward]) Enalapril Telmisartan 103 (0) 86 (0) 110 (22) 99 (23) 113 (23) 102 (21) 113 (40) 102 (31) 113 (39) 103 (41) Figure 3 Changes from baseline in glomerular filtration rate with telmisartan versus enalapril in the DETAIL study. Permission obtained from Cambridge Medical Publications Makino H et al.. (2005) JInt Med Res 33: CTED MAY 2007 VOL 4 SUPPLEMENT 2 GALLE NATURE CLINICAL PRACTICE CARDIOVASCULAR MEDICINE 5

6 telmisartan or 160 mg valsartan once daily, with add-on therapy as required to achieve blood pressure control (<130/80 mmhg). The primary analysis was a noninferiority test of the 24 h urinary protein excretion rate. Since valsartan is an established, renoprotective therapy, 27 these data confirm that telmisartan is an attractive option in these patients. A sister trial to VIVALDI, A trial to compare telmisartan 40 mg titrated to 80 mg versus losartan 100 mg in hypertensive type-2 DiabEtic patients with Overt nephropathy (AMADEO), is currently ongoing and will provide further valuable information on the relative renoprotective effects of ARBs. 39 A prespecified meta-analysis based on the pooled data of the AMADEO ADEO and VIVALDI trials will also be performed. Maximizing blockade to increase efficacy Increasing evidence shows that the doses of ARBs and ACE inhibitors that provide maximum blood-pressure-lowering effects might not provide maximum renoprotective effects. Highh-dose ACE inhibitor dose ARB therapy (not high-dose therapy, as this is unlikely to be well tolerated) or combined ARBs and ACE inhibitor therapy have been en investigated in several trials. In an open-label, randomized study of 78 hyperten- sive patients with chronic, nondiabetic, ic, biopsy- proven nephropathies, reductions in proteinuria were compared for patients receiving 80 mg telmisartan once daily and patients taking 80 mg twice daily over 25 months. 40 Significant decreases were e reported in proteinuria in both treatment groups (P P <0.01), but urinary protein concentrations were reduced significantly more among patients receiving double-dose telmisartan (P <0.01). Reduction of proteinuria to lower than 0.3 g/day was achieved in 40% of patients treated with the double dose compared with 15% taking the once-daily regimen. In addition, in patients taking 80 mg twice daily, serum creatinine values remained stable. ACE inhibitors and ARBs act on different stages of the RAS cascade. An attractive alternative to high-dose ARB therapy, therefore, is combination therapy. 41 A meta-analysis included 21 studies of combination ACE inhibitor and ARB therapy in 654 patients with proteinuric renal disease. 42 The addition of an ARB to ACE inhibitor therapy resulted in reductions of proteinuria in patients with or without diabetes (210 mg/day and 582 mg/ day, respectively). In one trial, 192 patients received lisinopril or telmisartan for 6 months, after which half received add-on telmisartan or lisinopril. All patients who received combination therapy derived additional benefit, amounting to around 30% further reductions in albuminuria. 43 CONCLUSIONS Angiotensin II represents an important therapeutic target for effective reduction of blood pressure and for protection from progressive renal damage in susceptible patients. Specific blockade of the AT 1 receptor by ARBs inhibits the pathophysiological effects of angiotensin II. The renoprotective effects of ARBs are convincing, with data consistently showing effective reductions in proteinuria that are independent of effects on hypertension in patients with type 2 diabetic nephropathy. Furthermore, reductions in proteinuria correlate with reduced cardiovas- cular risk. In comparative studies of telmisartan and other blood-pressure-lowering therapies or placebo, renoprotection, reduced proteinuria and decline e in GFR to levels similar to expected age-related decline have been reported. Further reductions in proteinuria can be achieved by increasing the dose or by combining treatment with an ACE inhibitor. ARBs can, therefore, play an important part in reducing the progression of renal disease and can be expected to play an increasing role in treatment of patients with either established nephropathy or with known risk factors, such as diabetes or hypertension. OF KEY POINTS [AUTHOR: PLEASE CHECK THE EXPANDED KEY POINTS.] Injury to the vascular endothelium and glomerulus can be promoted by an activated renin angiotensin system and, therefore, inhibition of this system provides renoprotection RAS inhibition reduces proteinuria, which is a key factor in the progression of renal disease Blood pressure control is essential to prevent progression to end-stage renal disease, but because the mechanisms of angiotensin receptor blockers and angiotensin-convertingenzyme inhibitors differ, the effectiveness of the latter might decline over time Combination therapy with angiotensin receptor blockers and angiotensin-converting-enzyme inhibitors seems to produce additional bloodpressure-lowering effects to monotherapy 6 NATURE CLINICAL PRACTICE CARDIOVASCULAR MEDICINE GALLE MAY 2007 VOL 4 SUPPLEMENT 2

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8 Acknowledgments PAREXEL MMS provided writing assistance, comprising preparation of a draft from slides and audio transcript, preparation of figures and obtaining copyright permissions, proofreading, and reference checking. Competing interests [Author: Please sign the competing interests form and add the appropriate information here.] evaluation, classification, and stratification. Am J Kidney Dis 39 (Suppl 1): S1 S Valmadrid CT et al. (2000) The risk of cardiovascular disease mortality associated with microalbuminuria and gross proteinuria in persons with older-onset diabetes mellitus. Arch Intern Med 160: Barnett AH (2005) Preventing renal complications in diabetic patients: the Diabetics Exposed to Telmisartan And enalapril (DETAIL) study. Acta Diabetol 42 (Suppl 1): S42 S49 39 Weber M (2003) The telmisartan Programme of Research to show Telmisartan End-organ protection (PROTECTION) programme. J Hypertens 21 (Suppl): S37 S46 40 Aranda P et al. (2005) Long-term renoprotective effects of standard versus high doses of telmisartan in hypertensive nondiabetic nephropathies. Am J Kidney Dis 46: Wolf G and Ritz E (2005) Combination therapy with ACE inhibitors and angiotensin II receptor blockers to halt progression of chronic renal disease: pathophysiology and indications. Kidney Int 67: MacKinnon M et al. (2006) Combination therapy with an angiotensin receptor blocker and an ACE inhibitor in proteinuric renal disease: a systematic review of the efficacy and safety data. Am J Kidney Dis 48: Sengul AM et al. (2006) Beneficial effect of lisinopril plus telmisartan in patients with type 2 diabetes, microalbuminuria and hypertension. Diabetes Res Clin Pract 71: NATURE CLINICAL PRACTICE CARDIOVASCULAR MEDICINE GALLE MAY 2007 VOL 4 SUPPLEMENT 2