Blockade of the renin angiotensin system for the primary prevention of diabetic nephropathy

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1 Review Blockade of the rei agiotesi system for the primary prevetio of diabetic ephropathy Practice Poits Merli C Thomas* & Robert MacGiley The prevetio of chroic kidey disease is a primary goal for diabetes maagemet. Lowerig blood pressure ca reduce the icidece of microalbumiuria i Type 1 or Type 2 diabetes, especially i patiets with hypertesio. Blockade of the rei agiotesi system (RAS) is a effective strategy to reduce blood pressure i diabetic patiets, but o more so tha other atihypertesive strategies. RAS blockers have a more favorable side-effects profile compared to other atihypertesive agets, meaig that geerally patiets are more likely to take them. Ay idepedet effect of RAS blockade for the primary prevetio of diabetic ephropathy, beyod blood-pressure cotrol, remais to be clearly established. New combiatio strategies usig rei ihibitors or aldosteroe atagoists, to achieve a more complete RAS blockade, have the potetial to improve real outcomes i patiets with diabetes. Summary There is clear evidece for the pathogeic role of the rei agiotesi system (RAS) i the progressio of diabetic kidey. Treatmet with either a a giotesi-covertig ezyme ihibitor or agiotesi receptor blocker have bee show to reduce proteiuria ad preserve real fuctio i patiets with diabetes ad chroic kidey disease. While such data provide a strog ratioale for early ad sustaied blockade of the RAS for the primary prevetio of kidey disease, cliical trial evidece to support this goal is limited ad icosistet. By cotrast, data from observatioal ad cliical trials clearly demostrate the primacy of blood-pressure cotrol i the developmet of diabetic kidey disease, especially i hypertesive patiets. Whether RAS blockade offers additioal beefits for primary prevetio, over-ad-above blood-pressure cotrol, remais cotetious. At best, ay idepedet effects o primary prevetio are modest, ad certaily ot the paacea evisaged by may practitioers. However, the better tolerability, efficacy ad side-effects profile of RAS blockers, ad other actios o retiopathy ad cardiovascular disease, meas that most patiets with diabetes curretly receive RAS blockers as first lie atihypertesive agets. The future developmet of more effective escape-proof regimes curretly offers the best way forward to realize the hope that RAS blockade will ultimately prevet diabetic kidey disease i the cliic as effectively as it does i aimal models. Geelog Cliical School, Deaki Uiversity Medical School, Waur Pods, Geelog, VIC Australia *Author for correspodece: Baker IDI Heart & Diabetes Istitute, PO Box 6492, Melboure, VIC 8008, Australia; Tel.: ; Fax: ; mthomas@bakeridi.edu.au /DMT Future Medicie Ltd Diabetes Maage. (2012) 2(1), part of ISSN

2 review Thomas & MacGiley Treatmet with either a agiotesi-covertig ezyme (ACE) ihibitor or a agiotesi receptor blocker (ARB) have bee show uequivocally to reduce proteiuria ad preserve real fuctio i patiets with diabetes ad chroic kidey disease (CKD) [1 3]. Such fidigs have led to widespread recommedatios for agets that block the rei agiotesi system (RAS) to be cosidered as the first-lie treatmet for the maagemet of diabetic CKD. However, eve i patiets receivig RAS blockers, the aticipated morbidity ad mortality observed i those with CKD, far exceeds that observed i patiets without CKD [4]. Cosequetly, itervetios that reduce the icidece of CKD are fudametally more importat for the maagemet of diabetes. It is curretly aticipated that betwee 25 ad 40% of patiets with Type 1 diabetes develop diabetic kidey disease. Twety to forty percet of patiets with Type 2 diabetes also develop kidey disease [5,6], mostly withi 10 years of diagosis [7]. With this icidece ad give that over 300 millio idividuals have diabetes worldwide [8], the prevetio of diabetic kidey disease r epresets a overwhelmig cliical priority. There is clear evidece for the pathogeic role of the RAS i the developmet of diabetic kidey [9]. For example, geetic overactivity of the RAS is associated with icreased icidece ad severity of kidey disease i aimal models of experimetal diabetes [10,11]. The icidece of microalbumiuria is also icreased i patiets with diabetes who are homozygous for the D allele of the ACE gee [12]. Such data provide a strog ratioale for early ad sustaied blockade of the RAS for the primary prevetio of kidey disease i all patiets with diabetes. However, cliical trial evidece to support this goal is limited ad icosistet. Furthermore, its iterpretatio has bee made more difficult because RAS blockers also lower blood pressure (BP), a key pathogeic factor that i its ow right, sigificatly cotributes to the developmet of microalbumiuria i diabetic patiets (Figure 1). Ideed, it has bee argued that the better, more sustaied ad less variable effects of RAS blockade o BP may partly explai the so-called idepedet beefits with respect to the primary prevetio of kidey disease. This review specifically explores the utility of RAS blockade for the primary prevetio of icidet microalbumiuria, ad the opportuities for creatig a more complete blockade, ad with it, potetially a more effective reoprotectio. 56 Diabetes Maage. (2012) 2(1) Blood-pressure cotrol for the prevetio of diabetic kidey disease The cotrol of BP represets a key target for the prevetio of diabetic kidey disease [13,14], as well as other microvascular complicatios [15]. Although hypertesio ca be a result of real dysfuctio, i may cases, hypertesio may precede the oset of CKD, suggestig that it is also a key etiological factor [16,17]. Real damage i hypertesive aimal models of diabetes is more proouced tha i ormotesive models [18,19]. For example, studies i the diabetic spotaeously hypertesive rat show that BP reductio, regardless of its modality, is associated with sigificat reoprotectio [20]. Yet surprisigly, studies examiig the utility of BP lowerig i patiets with diabetes have revealed oly variable effects for the primary prevetio of CKD, possibly reflectig variability i the kid of patiets recruited i these trials, ad i particular, their comorbidities icludig hypertesio. I patiets with Type 1 diabetes from the Microalbumiuria, Cardiovascular ad Real Outcomes-Heart Outcomes Prevetio Evaluatio (micro-hope) study, treatmet with the ACE ihibitor, ramipril (10 mg/day) effectively lowered the BP ad sigificatly reduced the icidece of microalbumiuria whe compared with placebo [21]. However, amog patiets with Type 1 diabetes i the EURODIAB Cotrolled Trial of Lisiopril i Isuli-Depedet Diabetes study who were ormoalbumiuric at baselie, o sigificat reductio i the icidece of microalbumiuria were observed i patiets usig the ACE ihibitor, lisiopril (10 20 mg), despite a small but sigificat reductio i diastolic BP [22]. Similarly, i a post-hoc aalysis of the Diabetic Retiopathy Cadesarta Trial (DIRECT), the ARB, cadesarta (16 mg/day), did ot reduce ew oset microalbumiuria i patiets with Type 1 diabetes, although the rate of chage of albumiuria was modestly lower [23]. Whe compared with studies i Type 1 diabetes, there is much better evidece that BP reductio reduces the icidece of micro a lbumiuria i patiets with Type 2 diabetes [13,14]. There have bee a umber of primary-prevetio studies i patiets with Type 2 diabetes usig a variety of atihypertesive agets icludig ACE ihibitors, ARBs, calcium chael blockers (CCBs), α-blockers, ad β-blockers, usually give i combiatio [13,14]. For example, i the UKPDS study of patiets with Type 2 diabetes,

3 Blockade of the rei agiotesi system for the primary prevetio of diabetic ephropathy a reductio of BP from 154 to 144 mmhg was associated with a 30% reductio i microalbumiuria [15]. I the large Actio i Diabetes ad Vascular Disease: Preterax ad Diamicro MR Cotrolled Evaluatio treatmet with the ACE ihibitor, peridopril ad idapamide (4 ad 1.25 mg daily) lowered the systolic BP by approximately 7 mmhg ad reduced ew-oset microalbumiuria by 26% whe compared with covetioal atihypertesive treatmet [24]. There was o BP threshold below which real beefit was lost. New-oset macroalbumiuria was also modestly reduced i the large Actio to Cotrol Cardiovascular Risk i Diabetes Blood Pressure (ACCORD BP) trial by aggressively targetig lower systolic BP levels ( 120 mmhg), but icidet microalbumiuria was ot p reveted (Figure 2) [25]. Each of these studies was coducted i hetero g eeous populatios, with a sigificat proportio of patiets with established or icidet hypertesio of variable etiology. Cosequetly, i patiets with Type 2 diabetes the use of blood-pressure lowerig i the absece of a elevated BP remais cotroversial. I the UKPDS study, o threshold for the impact of elevated BP was able to be determied for ay outcome [15]. This coclusio has also bee iferred from meta-aalysis data, which foud that the efficacy of BP reductio appears to be idepedet to the baselie BP [14]. Ideed, it has bee argued that there is o such thig as a ormotesive diabetic [26]. However, studies that have tried to examie the utility of atihypertesive agets i ormotesive subjects, comparig their reoprotective actios agaist placebo, have bee largely disappoitig. For example, i ormotesive patiets with Type 2 diabetes from the micro-hope study, the ACE ihibitor, ramipril (10 mg/day) did ot reduce the icidece of ew-oset microalbumiuria [21]. Similarly, i Type 2 diabetic patiets erolled i the DIRECT study the ARB, cadesarta (16 mg/day) failed to reduce the developmet of microalbumiuria, despite lower BP levels i the cadesarta-treated group [23]. Better blood-pressure lowerig by blockig the RAS There is o doubt that drugs that block the RAS are effective atihypertesive agets. Whe used as mootherapy, RAS blockers ca achieve reduced BP levels similar to that achieved by other atihypertesive itervetios. However, RAS blockade Review? Primary prevetio of CKD Blood-pressure lowerig Figure 1. Blood-pressure depedet ad idepedet actios of rei agiotesi system blockade o the primary prevetio of kidey disease i patiets with diabetes. CKD: Chroic kidey disease. i some aspects of BP cotrol, there are data to suggest that RAS blockers may be differet to other blood-pressure lowerig strategies, eve for the same achieved reductio i mea BP levels observed at cliic visits. For example, some have argued that the beefits of RAS blockade observed i the (micro-hope) study may simply reflect the better 24 h ad ight time cotrol of BP achieved with ramipril (10 mg/day) [27]. Aother differece betwee BP lowerig strategies may be their effects o BP variability, beyod similar lowerig mea blood-pressure levels. For example, it is kow that visit-tovisit variability i BP are idepedetly associated with the risk of diabetic ephropathy, over ad above mea BP cotrol [28]. Ideed i the DCCT study, visit-to-visit variability i BP explaied as much of the variability i icidet ephropathy as differeces i mea BP [28]. Despite lowerig the BP, mootherapy with RAS blockers may paradoxically icrease visit-to-visit variability whe compared with other atihypertesive classes [29]. I theory this may offset reoprotective gais i other areas achieved through RAS blockade ad potetially cotribute to the icosistet fidigs observed i cliical trials usig mootherapy or few other agets. By cotrast there is also some suggestio that atihypertesive combiatios that cotai RAS blockers result i the least BP variability [30]. Potetially this may explai why reo protective advatages have bee largely reported i studies of hypertesive patiets whe RAS blockade is oe of usually three or four differet a tihypertesive agets. The other key advatage of RAS blockade is its tolerability ad compliace [31]. Although ACE ihibitors may iduce a troublesome cough i some idividuals, compliace with ACE ihibitors is better tha with CCBs or diuretics, 57

4 review Thomas & MacGiley Patiets at study ed poit (%) * Macroalbumiuria Microalbumiuria Normoalbumiuria Stadard Itesive 20 0 Figure 2. Uriary albumi excretio status at ed poit i the Actio to Cotrol Cardiovascular Risk i Diabetes Blood Pressure trial comparig aggressively targetig lower systolic blood-pressure levels (<120 mmhg) to stadard therapy (<140 mmhg). *Versus stadard therapy (p = 0.009). Data take from [25]. which are sigficiatly limited by edema ad uriary frequecy, respectively. β-blockers have importat cardioprotective actios i patiets with diabetes, idepedet to blood-pressure lowerig, but are also hampered by effects o lethargy, sleep disturbace ad effects o glucose cotrol. ARBs appear to be, o average, the most tolerated of all atihypertesive agets. Take together, these effects mea that patiets prescribed RAS blockers are geerally more likely to be takig them [31], which ultimately traslates ito better BP cotrol o a i tetio to treat basis. Beyod blood-pressure lowerig: a ratioale for blockig the RAS Activatio of the itra-real RAS ad the subsequet geeratio of agiotesi II (Ag II) appear to be amog the most importat iitiators of real ijury i diabetic kidey disease [9]. Activatio of the itrareal RAS promotes systemic hypertesio ad promotes activatio of the sympathetic ervous system ad sesitivity to the effects of oradrealie i the kidey [32]. Ag II-mediated real hypertrophy also cotributes to icreased proximal salt reabsorptio [33]. The key role of the RAS i promotig systemic hypertesio associated with diabetes is illustrated by studies showig that ew-oset hypertesio i patiets with Type 2 diabetes 58 Diabetes Maage. (2012) 2(1) may be preveted by blockade of the RAS [34]. Amog the earliest chages i the diabetic kidey are a icrease i efferet arteriolar toe leadig to a icrease i itracapillary pressure ad a loss of autoregulatio [35]. Early work by Zatz ad colleagues showed that a reductio i itraglomerular hydraulic pressure slowed the developmet of kidey disease i streptozotoci-treated diabetic aimals, effectively likig hemodyamic chages i the glomerulus ad progressive diabetic ephropathy [35]. Oe of the most importat mediators of this altered hemodyamic respose is the RAS. Blockade of the RAS selectively reduces efferet arteriolar toe, thereby reducig glomerular capillary pressure ad hemodyamic stress o the glomerulus [36]. This actio has bee used to explai why, at least i experimetal diabetes, RAS blockade appears to be more efficacious i prevetig real ijury whe compared with similar BP reductio. However, the real actios of Ag II i diabetes are ot limited to hemodyamic effects. Cosiderable experimetal evidece exists for a direct role of the RAS i kidey ijury. Ag II is also a importat stimulus for iflammatio, oxidative stress ad fibrogeesis i the kidey. For example, Ag II triggerig the expressio ad release of the profibrogeic regulator, TGF-β1 ad coective tissue growth factor

5 Blockade of the rei agiotesi system for the primary prevetio of diabetic ephropathy i the kidey [37]. The primacy of the RAS i diabetes-associated pathology is elegatly illustrated by studies i rat mesagial cells, i which glucose-iduced TGF-β1 secretio is completely abrogated by AT1 receptor blockade [38]. Additioally, Ag II iflueces a rage of other kow pathogeic mediators i the diabetic kidey, such as protei kiase C ad the iflammatory regulator, uclear trascriptio factor, NF-κB ad the accumulatio of advaced glycatio ed-products. By cotrast, ihibitio of the RAS i experimetal diabetes is associated with reduced real cytokie expressio, ihibitio of protei kiase C ad reduced advaced glycatio ed-product accumulatio. Ag II may also directly act to ihibit matrix metalloprotease activity, leadig to augmeted matrix accumulatio [38]. This reduced matrix degradatio i diabetic kidey disease may be restored by blockade of the RAS, implyig a key role for Ag II i m odulatig matrix turover i diabetes [39]. The formatio of reactive oxyge species (ROS), as a result of oxidative stress, is also recogized as a key compoet i the developmet of diabetic kidey disease. ROS are directly cytotoxic ad upregulate iflammatio ad fibrosis. The expressio ad activity of NADPH oxidase represets the major source of ROS i the diabetic kidey. NADPH oxidase is directly activated by Ag II, followig activatio of the AT1 receptor [40]. This pro-oxidat actio may also cotribute to the real cosequeces of activatio of the AT1 receptor, ad therei the beefits arisig from its blockade i the settig of diabetic kidey disease. BP-idepedet reoprotective effects of RAS blockade From the above physiological ratioale, early blockade of the RAS i patiets with diabetes would seem both logical ad ecessary for the prevetio of progressive kidey disease. Such observatios have directly led to studies that aimed to specifically explore the utility of RAS blockade beyod blood-pressure lowerig i patiets with diabetes. However, these studies have largely failed to demostrate a clear ad idepedet efficacy for the primary prevetio of microalbumiuria. I oe study of 200 ormotesive patiets with ormoalbumiuria, treatmet with the ACE ihibitor, peridopril (2 mg/day), for 4 years, saw a reductio i the developmet of microalbumiuria, despite Review havig a eutral effect o mea systolic BP [41]. Agaist this, the Rei Agiotesi System Study treated 285 ormotesive patiets with Type 1 diabetes ad ormoalbumiuria with either the ACE ihibitor, ealapril (20 mg/day), the ARB losarta (100 mg/day) or placebo ad followed them for 5 years. Iterestigly, more, ot less patiets treated with the ARB, losarta, progressed to microalbumiuria, tha was the case i patiets radomized to receive placebo treatmet (17 vs 4%; log rak p = 0.02). Patiets radomized to receive the ACE ihibitor, ealapril, also showed o advatage over placebo (6 vs 4%; p = ot sigificat). Chages i the fractio of glomerular volume occupied by mesagium, a histological marker of diabetic kidey disease quatified o real biopsy material, were also o differet betwee treatmet ad placebo groups [42]. A umber of studies have also explored the hypothesis that ihibitio of the RAS i patiets with Type 2 diabetes has additioal beefits o kidey disease, beyod blood-pressure lowerig. However, like those i Type 1 diabetes, these data are mixed ad variable. The UKPDS demostrated that tight bloodpressure cotrol, whether achieved by a ACE ihibitor or by β-blockers, was associated with a 29% reductio i the risk of microalbumiuria (p < 0.009) but the study was ot powered to detect betwee-drug differeces [43]. I the FACET fosiipril (20 mg/day) ad amlodipie (10 mg/day) were compared i patiets with hypertesio ad Type 2 diabetes, showig o idepedet protective actio of ACE ihibitio. Similarly, i the Type 2 diabetes arms of the EURODIAB Cotrolled Trial of Lisiopril i Isuli-Depedet Diabetes, Micro-HOPE ad DIRECT studies, o reoprotective advatages of RAS blockade were observed, despite lower achieved BPs. Put together with observatioal fidigs i a meta-aalysis, Casas et al cotroversially cocluded that ACE or ARBs provided o reoprotective effect beyod BP cotrol [44]. This study has bee widely criticized because of methodological flaws ad, i particular the iclusio of post hoc real data from the ALLHAT study, which because of its size, domiated the outcomes aalysis. Noetheless, its coclusios were cosistet with the theavailable data, ad subsequet aalyses have ot overtured these cotroversial fidigs. While subsequet cliical studies have observed positive effects from RAS blockade, 59

6 review Thomas & MacGiley may of these studies deliberately icluded hypertesive patiets. For example, the Bergamo Nephrologic Diabetes Complicatios Trial i hypertesive patiets with Type 2 diabetes did fid that the risk of developig microalbumiuria was reduced by half followig the use of the ACE ihibitor, tradolapril (2 mg/day), but ot by the calcium chael atagoist, verapamil (240 mg/ day), despite equivalet BP reductio. Agai, the itervetio was particularly effective i patiets with the highest BPs, which determied the majority of its overall effect i this trial. Similarly, i the recetly published Radomized Olmesarta ad Diabetes Microalbumiuria Prevetio study, the ARB, olmesarta (40 mg/ day) reduced the developmet of microalbumiuria by 15% i mildly hypertesive patiets with Type 2 diabetes, beyod that observed i the placebo arm [45]. However, blood-pressure levels were slightly lower i the olmesarta-treated group tha i the placebo-treated group (126 vs 129 mmhg), so the questio as to whether RAS blockade has truly blood-pressure idepedet actios o the developmet of diabetic real disease effectively remais uaswered. I additio, treatmet with olmesarta was associated with a paradoxical icrease i cardiovascular deaths, specifically i patiets with established cardiovascular disease, leadig to the suggestio that this stratagem, although reoprotective, may have sigificat drawbacks. Olmesarta (10 40 mg/day) also was associated with icreased cardiac deaths i the Olmesarta Reducig Icidece of Ed stage real disease i diabetic Nephropathy Trial [46], suggestig this may ot have bee a chace fidig. However, give the morbidity ad excess mortality associated with CKD, it is likely that the reoprotective efficacy of this itervetio will become more the i mportat feature i the log ru. Coclusio Data from observatioal ad cliical trials demostrate the importace of BP i the developmet of diabetic kidey disease. Blood-pressure cotrol will reduce the icidece of kidey disease i patiets with diabetes, especially i hypertesive patiets. This appears to be the case o matter how it is achieved. Cosequetly, most guidelies curretly recommed the aggressive maagemet of hypertesio i diabetic idividuals without kidey disease, with or without RAS blockade [1]. Whether RAS blockade offers additioal beefits for primary prevetio 60 Diabetes Maage. (2012) 2(1) over-ad-above blood-pressure cotrol, remais cotetious. At best, ay idepedet effects o primary prevetio achieved by RAS blockers beyod blood-pressure lowerig are modest, ad certaily ot the p aacea evisaged by may practitioers. Some of the failure of trials of RAS blockade to cosistetly demostrate prevetio of microalbumiuria may relate to the variable doses, timig ad efficacy of agets used i trials. Certaily, some studies have used isufficietly low doses of ACE ihibitor or ARBs to achieve effective RAS blockade ad reoprotectio. This may be importat as the reoprotective effects of RAS blockade i diabetic patiets with CKD appears to be dose depedet, over ad above blood-pressure lowerig [3]. However, such a hypothesis has ot bee formally tested i diabetic patiets without CKD. Aother cotributig factor to the apparet lack of additioal efficacy of RAS blockade may also be statistical power. Idividually, almost all trials that have bee udertake are uderpowered (too small with too few evets) to evaluate icidet microalbumiuria. Moreover, the largest studies are geerally post-hoc aalyses, which whe combied with small uderpowered trials i meta-aalyses may lead to distorted coclusios. I effect, this meas that there is o defiitive evidece, oe way or the other. This does ot mea RAS blockade has o role. O the cotrary, give the better tolerability, efficacy ad side-effects profile of RAS blockers over other atihypertesive agets [31], as well as added beeficial effects o retio pathy [23] ad cardiovascular disease [47], most patiets with diabetes without CKD curretly receive RAS blockers as first-lie atihypertesive agets. Ideed, most patiets will iitially or ultimately eed combiatio atihypertesive therapy to cotrol their BP, i which case RAS blockade will almost always be utilized i routie cliical practice. This is ot icorrect. However, the reaso for doig so must be more tha ay direct actios for the primary p revetio of microalbumiuria. Future perspective: a better blockade of the RAS Over the ext decade may more ACE ihibitors ad ARBs will come off patet. This will mea the costs of such therapy will fall ad more geeric compouds will become available. As such the cost:beefit ratio of these agets will

7 Blockade of the rei agiotesi system for the primary prevetio of diabetic ephropathy further improve. There appears to be o advatage or eed for ay ew agets of this class, thus, the future of RAS blockade must be to build a smarter, more sustaied blockade i c ombiatio with other agets. The RAS is a homeostatic regulator that relies o feedback regulatio to achieve ad sustai the delicate balace required for vascular fuctio. However, this feedback regulatio is itrisically atagoistic to the therapeutic goal of blockig the RAS (Figure 3). For example, the suppressio of plasma Ag II ad aldosteroe cocetratios by ACE ihibitors is i practice rather weak, variable ad usustaied [48 50]. I fact, up to half the patiets treated with ACE ihibitors there will be a paradoxical overshoot i aldosteroe cocetratios 12 moths after treatmet commeces [51,52]. This escape pheomeo also occurs with ARBs possibly due to activatio of the AT2 receptor [53]. Ideed equal rates of elevated aldosteroe levels are observed amog subjects o ACE ihibitors, ARBs, or a combiatio of both [53], which may explai the lack of additive effect observed i some cliical studies. I order to achieve the best reoprotective outcomes usig RAS blockade there has bee a recet focus o a way to circumvet the escape ad achieve sustaied reductios i Ag II [54,55]. Oe approach has bee to block the feedback iductio of rei, usig orally active selective rei ihibitors, such as aliskire, SPP635, SPP676 ad SPP1148. These agets specifically ihibit the ezymatic cleavage of agiotesioge to Ag I, ad iduce a dose depedet ad sustaied decrease i Ag II tissue ad plasma levels [56]. Selective rei ihibitio is able to achieve blood-pressure lowerig comparable (but o better tha) ARBs ad ACE ihibitors i hyper tesive idividuals [56]. Cosequetly, most studies have looked at the potetial for combiatio of ACE ihibitios or ARBs with rei ihibitors, where feedback rei overactivity potetially atteuates their utility as mootherapies. Certaily, better blood-pressure cotrol ca be achieved with combiatio therapy [57]. I additio, although ot a primary prevetio study, the AVOID trial treated 599 hypertesive patiets with Type 2 diabetes ad ephropathy with the rei ihibitor, aliskire (150 mg daily titrated to 300 mg daily) after 3 moths or placebo added to the ARB, losarta (100 mg/day) for over 6 moths. I this study, there was a sigificat fall i proteiuria ( 20%) ad a reduced icidece of Review real impairmet i patiets receivig aliskire [58]. Similar additive atiproteiuric effects have bee reported whe aliskire has bee used i combiatio with the ARB, irbesarta [59]. As yet this strategy has ot bee tested i the primary prevetio of ephropathy, although a ratioale is quite clear ad will almost certaily be studied post hoc. Whether the feedback iductio of prorei that occurs followig ihibitio of its ezymatic activity is able to idepedetly iduce sigalig pathways via the prorei receptor curretly remais to be established, although some researchers have variously reported real dysfuctio, iflammatio ad oxidative stress iduced by prorei i experimetal models. At the same time, blockade of prorei sigalig may be v asculoprotective i experimetal diabetes. Aother strategy to re-emerge as a potetial therapeutic cadidate may be to combie RAS blockers with agets that prevet aldosteroe bidig to mieralocorticoid receptors, such as spiroolactoe ad eplereoe. Some (but ot all) studies suggest this combiatio may have additioal reoprotective actios i patiets with established ephropathy [60]. However, it is uclear whether the beefits of combiatio therapy are specifically ehaced i patiets with aldosteroe escape, or simply because of better blood-pressure cotrol with ehaced diuresis. There may also be uforesee problems with combiatio therapy, with oe study reportig higher levels of Ag II ad a icreased icidece Agiotesioge + + Rei Aliskeri Agiotesi I Toi ACE Chymase CAGE Agiotesi II ACE ihibitors ARBs AT2 receptor AT1 receptor Figure 3. Feedback regulatio of the rei agiotesi system. Activatio of homeostatic feedback pathways (dashed lie) meas that effective blockade of the rei agiotesi system ad suppressio of aldosteroe sythesis ca be escaped. ARB: Agiotesi receptor blocker. 61

8 review Thomas & MacGiley of escape i patiets receivig spiroolactoe i combiatio with covetioal RAS blockade [61]. Hyperkalemia is also a major adverse effect, particularly i patiets with comorbid cardiac disease or kidey disease who rely o aldosteroe for potassium balace. Give these risks ad the lack of iterest of cliical trials usig older drugs such as aldosteroe, it is ulikely that such dual or triple blockade has much of a future, except as a bechmark for rei ihibitio. Papers of special ote have bee highlighted as: of iterest 2 3 Strippoli GF, Craig M, Deeks JJ, Schea FP, Craig JC. Effects of agiotesi covertig ezyme ihibitors ad agiotesi II receptor atagoists o mortality ad real outcomes i diabetic ephropathy: systematic review. BMJ 329(7470), 828 (2004). Kuz R, Friedrich C, Wolbers M, Ma JF. Meta-aalysis: effect of mootherapy ad combiatio therapy with ihibitors of the rei agiotesi system o proteiuria i real disease. A. Iter. Med. 148(1), (2008). Blacklock CL, Hirst JA, Taylor KS, Steves RJ, Roberts NW, Farmer AJ. Evidece for a dose effect of rei agiotesi system ihibitio o progressio of microalbumiuria i Type 2 diabetes: a meta-aalysis. Diabet. Med. 28(10), (2011). 4 Karalliedde J, Viberti, G. Microalbumiuria ad cardiovascular risk. Am. J. Hypertes. 17, (2004). 5 Ismail N, Becker B, Strzelczyk P, Ritz E. Real disease ad hypertesio i oisuli-depedet diabetes mellitus. Kidey It. 55(1), 1 28 (1999) Parvig HH, Hommel E, Mathiese E et al. Prevalece of microalbumiuria, arterial hypertesio, retiopathy ad europathy i patiets with isuli depedet diabetes. Br. Med. J. (Cli. Res. Ed.) 296(6616), (1988). Schmitz A, Vaeth M, Mogese CE. Systolic blood pressure relates to the rate of progressio of albumiuria i NIDDM. Diabetologia 37(12), (1994). Daaei GFM, Lu Y, Sigh GM et al.; Global Burde of Metabolic Risk Factors of Chroic Diseases Collaboratig Group (Blood Glucose). Natioal, regioal, ad global treds i fastig plasma glucose ad diabetes The authors have o relevat affiliatios or fiacial ivolvemet with ay orgaizatio or etity with a fiacial iterest i or fiacial coflict with the subject matter or materials discussed i the mauscript. This icludes employmet, cosultacies, hooraria, stock owership or optios, expert t e stimoy, grats or patets received or pedig, or royalties. No writig assistace was utilized i the productio of this mauscript. prevalece sice 1980: systematic aalysis of health examiatio surveys ad epidemiological studies with 370 coutryyears ad 2.7 millio participats. Lacet 378(9785), (2011). Refereces 1 Fiacial & competig iterests disclosure Cooper ME. Iteractio of metabolic ad haemodyamic factors i mediatig experimetal diabetic ephropathy. Diabetologia 44(11), (2001). Kelly DJ, Cox AJ, Tolcos M, Cooper ME, Wilkiso-Berka JL, Gilbert RE. Atteuatio of tubular apoptosis by blockade of the rei agiotesi system i diabetic Re2 rats. 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Care 23(Suppl. 2), S35 S39 (2000). 22 Radomized placebo-cotrolled trial of lisiopril i ormotesive patiets with isulidepedet diabetes ad ormoalbumiuria or microalbumiuria. The EUCLID study group. Lacet 349(9068), (1997). 23 Bilous R, Chaturvedi N, Sjølie AK et al. Effect of cadesarta o microalbumiuria ad albumi excretio rate i diabetes: three radomized trials. A. Iter. Med. 151, (2009). 24 Patel A, MacMaho S, Chalmers J et al.: ADVANCE Collaborative Group. Effects of a fixed combiatio of peridopril ad idapamide o macrovascular ad microvascular outcomes i patiets with Type 2 diabetes mellitus (the ADVANCE trial): a radomized cotrolled trial. Lacet 370, (2007).

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Cardiol. 37(7), (2001). 49 Staesse J, Lije P, Fagard R, Verschuere LJ, Amery A. Rise i plasma cocetratio of aldosteroe durig log-term agiotesi II suppressio. J. Edocriol. 91(3), (1981). 50 Lee AF, MacFadye RJ, Struthers AD. Neurohormoal reactivatio i heart failure patiets o chroic ACE ihibitor therapy: a logitudial study. Eur. J. Heart Fail. 1(4), (1999). 51 Bomback AS, Klemmer PJ. The icidece ad implicatios of aldosteroe breakthrough. Nat. Cli. Pract. Nephrol. 3(9), (2007). 52 Schjoedt KJ, Aderse S, Rossig P, Tarow L, Parvig HH. Aldosteroe escape durig blockade of the rei-agiotesialdosteroe system i diabetic ephropathy is associated with ehaced declie i glomerular filtratio rate. Diabetologia 47(11), (2004). 53 Horita Y, Taura K, Taguchi T, Furusu A, Koho S. Aldosteroe breakthrough durig therapy with agiotesi-covertig ezyme ihibitors ad agiotesi II receptor blockers i proteiuric patiets with immuoglobuli A ephropathy. Nephrology (Carlto). 11(5), (2006). 54 Pitt B. 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Suppl. (86), S64 S70 (2003) Svesso P, de Faire U, Sleight P, Yusuf S, Ostergre J. Comparative effects of ramipril o ambulatory ad office blood pressures: a HOPE Substudy. Hypertesio 38(6), E28 E32 (2001). Kilpatrick ES, Rigby AS, Atki SL. The role of blood pressure variability i the developmet of ephropathy i Type 1 diabetes. Diabetes Care 33(11), (2010). Key paper suggestig that risk exteds beyod mea cotrol. Webb AJFU, Mehta Z, Rothwell PM. Effects of atihypertesive-drug class o iteridividual variatio i blood pressure ad risk of stroke: a systematic review ad meta-aalysis. Lacet 375(9718), (2010). Parati GSH, Bilo G, Macia G. Evaluatig 24h atihypertesive efficacy by the smoothess idex: a meta-aalysis of a ambulatory blood pressure moitorig database. J. Hypertes. 28(11), (2010). 31 Kroish IM, Woodward M, Sergie Z, Ogedegbe G, Falzo L, Ma DM. Meta-aalysis: impact of drug class o adherece to atihypertesives. 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Most recet trial of rei agiotesi system blockade for primary prevetio of ephropathy. 63

10 review Thomas & MacGiley Nussberger J, Wuerzer G, Jese C, Bruer HR. Agiotesi II suppressio i humas by the orally active rei ihibitor Aliskire (SPP100): compariso with ealapril. Hypertesio 39(1), E1 E8 (2002). Drummod W, Sireko YM, Ramos E, Baek I, Keefe DL. Aliskire as add-o therapy i the treatmet of hypertesive diabetic patiets iadequately cotrolled with valsarta/hct combiatio: a placebocotrolled study. Am. J. Cardiovasc. Drugs. 11(5), (2011) Type 2 diabetes, hypertesio, ad albumiuria. Diabet. Care 32(10), (2009). Persso F, Lewis JB, Lewis EJ, Rossig P, Holleberg NK, Parvig HH. Impact of baselie real fuctio o the efficacy ad safety of aliskire added to losarta i patiets with Type 2 diabetes ad ephropathy. Diabet. Care 33(11), (2010). 60 Sato A HK, Naruse M, Saruta T. Effectiveess of aldosteroe blockade i patiets with diabetic ephropathy. Hypertesio 41, (2003). Trial of aliskeri as a add o i the treatmet of ephropathy. 61 va de Wal RMPH, Lok DJ, Boomsma F et al. Determiats of icreased agiotesi II levels i severe chroic heart failure patiets despite ACE ihibitio. It. J. Cardiol. 106(3), (2006). Persso F, Rossig P, Reihard H et al. Real effects of aliskire compared with ad i combiatio with irbesarta i patiets with Diabetes Maage. (2012) 2(1)