Angiotensin Receptor Blockers in Diabetic Nephropathy: Renal andCardiovascular End Points
By Hans-Henrik Parving, Steen Andersen, Peter Jacobsen, Per K. Christensen,Kasper Rossing, Peter Hovind, Peter Rossing, and Lise Tarnow
he activity of the renin–angiotensin-aldosterone system (RAAS) is elevated both in the circulation and in the renalissue of diabetic and nondiabetic nephropathies. The increased RAAS activity plays an important role in theemodynamic and nonhemodynamic pathogenetic mechanisms involved in kidney disease. Previous studies haveemonstrated that albuminuria is not only a marker of glomerular lesions, but also a progression promoter, andnally a powerful predictor of the long-term beneficial effect of blood pressure-lowering therapy. Randomizedrossover and parallel blind studies in patients with diabetic nephropathy have demonstrated that angiotensin IIeceptor blockers (ARB) induce favorable changes in systemic blood pressure, renal hemodynamics, and protein-ria similar to those induced by angiotensin-converting enzyme (ACE) inhibition. Studies have revealed the optimalenoprotective dose for some ARBs; however, additional dose titration studies are urgently needed to obtain theaximum benefit of this valuable new class of compounds. The combination of ARB and ACE inhibition is well
olerated and even more effective than monotherapy in reducing systemic blood pressure and albuminuria iniabetic nephropathy. In addition, dual RAAS blockade is safe and well tolerated. Impaired autoregulation oflomerular filtration rate (GFR); demonstrated with some blood pressure-lowering agents implies disturbances inhe downstream transmission of the systemic blood pressure into the glomerulus, leading to capillary hypertensionr hypotension depending of the level of blood pressure. ARB does not interfere with GFR autoregulation inypertensive diabetic patients. In contrast to previous observational studies with ACE inhibition, long-termreatment with ARB has similar beneficial renoprotective effect on progression of diabetic kidney disease inypertensive diabetic patients with ACE II and DD genotypes. ARB can prevent/delay development of diabeticephropathy independently of its beneficial blood pressure-lowering effect in patients with type 2 diabetes andicroalbuminuria. Recently, two landmark studies led to the following conclusion: “Losartan and Irbesartan
onferred significant renal benefit in patients with type 2 diabetes and nephropathy. This protection is independentf the reduction in blood pressure it causes. The ARB is generally safe and well tolerated.” A recent metaanalysis
ndicates that ARBs reduce cardiovascular events mainly because of reduction in first hospitalization for conges-ive heart failure in hypertensive type 2 diabetic patients with albuminuria. The studies mentioned here suggest thatRB represents a beneficial treatment of hypertension and proteinuria in incipient and overt diabetic nephropathy.2004 Elsevier Inc. All rights reserved.
nnpmcitstsiarp
tD
DG
HROUGH DECADES, diabetic nephropathyhas been regarded as an irreversible and rap-
dly progressive disease with high morbidity andortality.1,2 The natural history of diabetic ne-
hropathy, that is, without antihypertensive treat-ent, is characterized by arterial blood pressure
levation, increasing albuminuria, and a relentlessecline in glomerular filtration rate (GFR) of, onverage, 10 to 12 mL/min/year.3,4 Diabetic ne-hropathy has become the leading cause (25-47%)f end-stage renal disease (ESRD) in Europe, thenited States, and Japan. Unfortunately, the pro-ortion of ESRD patients with diabetes is expectedo increase considerably because the number ofiabetic patients (mainly type 2) in the world isxpected to double within the next 15 years, andecause the individual diabetic patient lives longernd is therefore at greater risk of developing lateomplications, including diabetic nephropathy. Anarly onset of diabetes will furthermore add to theurden of diabetic nephropathy. The relative mor-ality from cardiovascular disease is nearly 40-fold
5
ncreased in type 1 patients with proteinuria and
eminars in Nephrology, Vol 24, No 2 (March), 2004: pp 147-15
inefold increased in type 2 patients with overtephropathy6 as compared with the backgroundopulation. In addition to the high cardiovascularortality, the incidence of nonfatal stroke, myo-
ardial infarction, and peripheral vascular diseases also enhanced and the prognosis is much worsehan in the nondiabetic population. The averageurvival time from onset of proteinuria was only 5o 7 years before the introduction of antihyperten-ive treatment in these patients.7 The prognosis hasmproved over the last decade mainly because ofggressive antihypertensive treatment.7-10 Duringecent years, even further improvement in therognosis and in the course of the disease and its
ssociated vascular complications have been ob-erved by the use of drugs blocking the reninngiotensin aldosterone system (RAAS).10-14
The objective of this review is to analyze thehort-term and long-term renoprotective effects ofpecific intervention in the renin–angiotensin sys-em by angiotensin II subtype 1 receptor blockadeARB) in diabetic patients with microalbuminuriand overt nephropathy. In addition, the impact ofAAS blockade using these new compounds onardiovascular events in type 2 patients with incip-ent and overt nephropathy are analyzed.
Originally, Remuzzi and Bertani15 describedhat albuminuria is not only a marker of underlyinglomerular damage, but also a risk factor/marker inelation to initiation and progression of diabeticnd nondiabetic kidney disease. Their concept haseen supported in several animal and human stud-es as recently reviewed by Rossing.16 Further-
ore, several studies in patients with and withoutiabetic kidney disease have demonstrated firsthat the severity of baseline proteinuria is an im-ortant predictor of the rate of loss of renal func-ion.17-20 Second, the reduction in proteinuria whenatients with nephropathy are being treated withntihypertensive treatments predicts the efficacy ofubsequent renoprotection—the greater the reduc-ion, the better the efficacy.20-24 Third, the residualroteinuria during treatment with antihypertensiverugs is proportional to the rate of loss in renal
unction in both diabetic and nondiabetic kidney t
isease.25,26 Consequently, de Jong et al.26 sug-ested that titration against albuminuria should bemajor goal in renoprotective therapy. Most recentata from the Reduction of End points in NIDDMith the Angiotensin II Antagonist Losartan
RENAAL) study has clearly demonstrated that theeduction of proteinuria over the entire study pe-iod accounts for approximately half of the treat-ent effect of losartan on the risk reduction for
nd-stage renal failure.13 If the primary compositend point of RENAAL was taken into consider-tion (doubling of serum creatinine, developmentf ESRD, or death), proteinuria explained nearly00% of the treatment effect of this ARB. On thisackground, it seems important to suggest thatroteinuria must be regarded as a valid surrogatend point in renal trials.
Short-term double-blind, randomized parallel orrossover studies carried out in type 1 and type 2iabetic patients with microalbuminuria or overtephropathy have demonstrated that ARBs andngiotensin-converting enzyme (ACE) inhibitionave similar beneficial effect on proteinuria, bloodressure, and renal hemodynamics (Fig 1).27-29
hese findings indicate that the reduction in albu-inuria and blood pressure during ACE inhibition
re primarily caused by interfering in the RAAS.urthermore, the initial time course of the reduc-
ion in arterial blood pressure and albuminuria areoncordant, which suggests that systemic and renalemodynamic mechanisms are of primary impor-ance in the reduction of albuminuria.30,31 In addi-
Fig 1. Relative changesin glomerular filtration rate(■ ), mean arterial bloodpressure (}), and albumin-uria (●) compared with pla-cebo in 16 type 1 diabeticpatients with diabetic ne-phropathy. Reprinted fromKidney International with per-mission.29 *P <0.05. Eachtreatment period lasted 2months.
ion, other studies have clearly documented that
pmbtpastuhiugtnmmeimbnsccadf
adnt(ewcmnttiCAmpw2
pIs1walastd
ddftsipcomobbu
bsb
AnscphAeaTiscAfd
ANGIOTENSIN BLOCKERS IN DIABETIC NEPHROPATHY 149
art of the reduction in proteinuria during treat-ent with ARBs is independent of the beneficial
lood pressure-lowering effect.11 Interestingly, pa-ients who respond favorably to one class of anti-roteinuric drugs (eg, ARBs) also respond favor-bly to other classes of antiproteinuric drugs,upporting a main role for individual patients fac-ors in responsiveness or resistance to antiprotein-ric intervention.32 Studies in animals and manave revealed that the following factors play a rolen the transglomerular passage of proteins: glomer-lar capillary size and charge selectivity, the trans-lomerular hydraulic pressure, nephrin concentra-ion in the filtration slit membrane, and podocyteumber and function.2 Studies in man have docu-ented that ARB is capable of reducing the abnor-al size selectivity in early diabetic kidney dis-
ase.33 Furthermore, blockade of the RAAS systemn man leads to a reduction in the estimated glo-erular capillary pressure.34 Animal and human
iopsy studies have documented that ARBs canormalize the content of nephrin in the filtrationlit membrane and finally that this compound isapable of reducing loss of podocytes.35,36 In con-lusion, ARBs reduce proteinuria by hemodynamicnd nonhemodynamic mechanisms. Proteinuria re-uction must be regarded as a surrogate end pointor renoprotection.
OPTIMAL DOSE OF ANGIOTENSIN RECEPTORBLOCKADES FOR RENOPROTECTION
Although drugs blocking the RAAS system haven important renoprotective effect, the optimalosing for renoprotection for such compounds hasot been evaluated in the past. Previously, inves-igators have chosen the dose of ACE inhibitorACEI) or ARB by measurement of maximal ben-ficial effect on blood pressure, usually in patientsith essential hypertension. Animal studies have
learly documented a discrepancy between the he-odynamic effect of these compounds and the
onhemodynamic benefits on various growth fac-ors and cytokines.37 Furthermore, as already men-ioned, ARB has a lot of beneficial effects that arendependent of the systemic blood pressure effect.onsequently, studies of dose-related efficacy ofCEI or ARB with dose titration based on theaximal antiproteinuric effect for optimal reno-
rotection are needed. In the irbesartan in patientsith type 2 diabetes and microalbuminuria (IRMA11
) study, increasing doses of irbesartan were ap- o
lied in 590 type 2 patients with microalbuminuria.rbesartan at a dosage of 300 mg once daily wasuperior in lowering albuminuria as compared with50 mg irbesartan daily. Blood pressure levelsere identical in the two arms. Furthermore, both
rms show a benefit compared with blood pressureowering to a similar level using compounds thatre not blocking the RAAS system. However, ithould be stressed that the study did not revealhe optimal dosing of irbesartan (eg, 600/900 mgaily); such studies are ongoing.In type 2 patients with overt nephropathy, a
ose-escalation study has revealed that the optimalose of another ARB, candesartan, is 16 mg dailyor renoprotection as reflected by short-term reduc-ion in albuminuria.38 The highest dose used in thattudy was 32 mg candesartan daily. Finally, wenvestigated 50 consecutive hypertensive type 1atients with diabetic nephropathy receiving in-reasing doses of 50, 100, and 150 mg losartannce daily in three periods, each lasting 2onths.39 This study revealed that the optimal dose
f losartan is 100 mg daily for renoprotection andlood pressure reduction in such patients. It shoulde stressed that this dose was actually the dosesed in the RENAAL study.In conclusion, renoprotective dose for ARBs is
eing evaluated; however, additional dose-titrationtudies are urgently needed to obtain the maximumenefit of this valuable new class of compounds.
RENOPROTECTION WITH DUALRENIN–ANGIOTENSIN SYSTEM BLOCKADE
The rationale for a combination therapy withRBs and ACEI is based on the assumption thatonclassic pathways of the RAAS produce a sub-tantial amount of angiotensin II. The chymaseonversion of angiotensin I to angiotensin II ap-ears to be activated in disorders such as the failingeart and kidney.40 Second, during long-termCEI treatment, the phenomenon of “CE-escape”
volves, that is, plasma levels of angiotensin II andldosterone returning to pretreatment levels.40
hird, the beneficial effect of ARB can be reducedf stimulation of the AT2 receptor contributes sub-tantially as recently suggested in animal studies,41
learly documenting that specific blockade of theT2 receptor has a beneficial effect on kidney
unction and structure. Finally, combining bothrug classes could simply provide a higher degree
f blockade of the classic RAAS pathway, and
ts
sebstmtut(ipoptmnatrltobccocdfsaptAoiwamtawsoith
db8ocsi4a7GcmnpdfiTrbwoetmeda2mrgetaeatcrsoopndbt
s
PARVING ET AL150
hereby the tissue activity of the system as demon-trated in animals studies.42
Originally, Mogensen and coworkers43 de-cribed that 16 mg candesartan once daily is asffective as 20 mg lisinopril once daily in reducinglood pressure and microalbuminuria in hyperten-ive patients with type 2 diabetes. Combinationreatment with both drugs in the same doses asentioned here was well tolerated and more effec-
ive in reducing blood pressure and microalbumin-ria. However, Agarwal44 reported that combina-ion therapy was not superior to ACE inhibition40 mg lisinopril) alone in decreasing proteinurian a small group of hypertensive proteinuric blackatients with advanced renal failure of differentrigin. Surprisingly, the study showed a loweredlasma renin activity and enhanced GFR duringreatment with 50 mg losartan daily on top of 40g lisinopril. Because many patients with diabetic
ephropathy have levels of albuminuria �1 g/daynd blood pressure �135/85 mm Hg, despite an-ihypertensive combination therapy, including theecommended dose of ACE inhibitors, eg, 20 mgisinopril/enalapril daily, we evaluated the concepthat such patients might benefit from dual blockadef the renin angiotensin system.45,46 In type 2 dia-etes, we performed a randomized, double-blind,rossover study of 2 months treatment with 8 mgandesartan cilexetil once daily or placebo on topf ACEI, diuretics, and in most cases a calciumhannel blocker.45 Our study revealed a 25% re-uction in albuminuria and a 35% reduction inractional clearance of albumin in addition to aignificant reduction in systemic blood pressure. In
similar group of albuminuric type 1 diabeticatients46 responding insufficiently to antihyper-ensive treatment with recommended doses ofCE inhibitors and diuretics, we tested the effectf dual RAAS blockade by performing a random-zed, double-blind, crossover study with 2 monthsith 300 mg irbesartan once daily or placebo
dded on top of previous antihypertensive treat-ent (three drugs, including ACEI). Irbesartan
reatment reduced albuminuria by 37% and causedreduction in blood pressure of 8/5 mm Hg,
hereas GFR remained unchanged. The study thusuggests that dual blockade of the RAAS couldffer additional renal and cardiovascular protectionn type 1 diabetic patients with diabetic nephropa-hy responding insufficiently to conventional anti-
ypertensive therapy, including recommended A
ose of ACEI and diuretics. In another double-lind, randomized, crossover trial,47 we evaluatedweeks treatment with placebo, 20 mg benazepril
nce daily, 80 mg valsartan once daily, and theombination of 20 mg benazepril and 80 mg val-artan daily. The study revealed that dual blockadenduced an additional reduction in albuminuria of3% compared with any type of monotherapy andreduction in systemic 24-hour blood pressure of
/7 mm Hg compared with both monotherapies.FR was reversibly reduced on dual blockade
ompared with monotherapy and placebo. Treat-ents were safe and well tolerated. However, until
ow, all studies in diabetic nephropathy have com-ared dual blockade of the RAAS with submaximaloses of monotherapy and, as a consequence, bene-cial effect could have been overestimated.43,45-47
herefore, we tested if the addition of the maximalecommended dose of ARB offers more completelockade of the RAAS in type 1 diabetic patientsith diabetic nephropathy receiving maximal rec-mmended dose of ACE inhibitors (eg, 40 mgnalapril once daily).48 We performed a crossoverrial with 8 weeks treatment with placebo or 300g irbesartan daily added on top of a maximal
nalapril dose (40 mg). Our study revealed thatual blockade of the RAAS induces a reduction inlbuminuria of 25% and a significant reduction in4-hour systolic and diastolic blood pressure of 8/4m Hg (Table 1). GFR and plasma potassium
emained unchanged during both treatment re-imes. Dual blockade was still safe and well tol-rated. Finally, we evaluated the same concept inype 2 diabetic patients with hypertension and di-betic nephropathy treated with 40 mg lisinopril/nalapril.49 During dual blockade of the RAAS byddition of 16 mg candesartan daily for 8 weeks,here was a mean reduction in albuminuria of 28%ompared with ACEI alone. There was a modesteduction in 24-hour systolic/diastolic blood pres-ure of 3/2 mm Hg. No significant change in GFRccurred. Long-term studies evaluating doublingf serum creatinine/development of ESRD/death inatients with diabetic nephropathy are urgentlyeeded. Data from nondiabetic kidney disease, asiscussed elsewhere, has demonstrated that duallockade induces an additional long-term renopro-ective effect as compared with monotherapy.50
In conclusion, dual blockade of the RAAS isuperior to the maximal recommended dose of
CE inhibitors with regard to lowering of protein-
unes
tGamgmsawlsisssgturdaroqihtrtr
adrtsipscitiscmCbw
wt
tataawfi
A2GP
ANGIOTENSIN BLOCKERS IN DIABETIC NEPHROPATHY 151
ria and blood pressure in diabetic patients withephropathy. Long-term trials are needed to furtherstablish the role of dual blockade of the RAASystem in renal and cardiovascular protection.
RENAL AUTOREGULATION AND ANGIOTENSINRECEPTOR BLOCKADE
Normal renal autoregulation enables the kidneyo maintain a fairly constant renal blood flow andFR as the mean blood pressure varies between 80
nd 160 mm Hg.51 This process can be linked toechanisms that are intrinsic to the kidney: a myo-
enic reflex in the afferent arteriole and tubuloglo-erular feedback. We have previously demon-
trated that autoregulation of GFR is impaired orbolished in type 1 and type 2 diabetic patientsith diabetic nephropathy.52,53 Impaired autoregu-
ation of GFR implies disturbances in the down-tream transmission of the systemic blood pressurento the glomerulus that lead to capillary hyperten-ion or hypotension, depending on the level ofystemic blood pressure. Treatment of hyperten-ion in patients with normal renal function does notenerally cause renal dysfunction; however, in pa-ients with hypertension and nephropathy, it is notncommon for serum creatinine concentration toise as blood pressure is lowered. Many physiciansecrease the dose of antihypertensive medications a result of this initial response to blood pressureeduction. Unfortunately, such an approach is notptimal for long-term renoprotection and conse-uently should be discouraged. The initial declinen renal function during blood pressure lowering isemodynamic in origin and not the result of struc-ural damage to the kidney. On the contrary, theeduction should be viewed as an indication thathe intraglomerular pressure has been successfully
Table 1. Dual Blockade of the Renin–AngiotensinPatients With Diabetic Nephropathy
* Geometric mean (95% confidence interval)Abbreviation: GFR, glomerular filtration rate.NOTE. Values represented are mean (standard error of
educed. t
The impact on renal autoregulation of differentntihypertensive drugs in animals has been eluci-ated, whereas information in humans is scanty, aseviewed by Palmer.51 Recently, we demonstratedhat the ARB candesartan can reduce blood pres-ure without adversely altering the preserved abil-ty to autoregulate GFR in hypertensive type 2atients without nephropathy.54 By contrast, inimilar patients treated with the dihydropyridinealcium antagonist isradipine, GFR autoregulations impaired in a sizable proportion of hypertensiveype 2 diabetic patients.55 In some patients, thempairment is so severe that a completely pres-ure–passive vasculature is present in which anyhange in the mean arterial blood pressure isatched by a proportional change in the GFR.onsequently, it is of major importance to keep thelood pressure well controlled within narrow limitshen using a calcium antagonist alone.In conclusion, ARB reduces blood pressure
ithout adversely affecting the renal autoregula-ion of GFR.
RENOPROTECTIVE EFFECT OF RAASBLOCKADE IN DIABETIC NEPHROPATHY:
INTERACTION WITH ANGIOTENSIN-CONVERTING ENZYME INSERTION/DELETION
GENOTYPE?
The beneficial short- and long-term renopro-ective effect of ACE inhibition is reduced inlbuminuric diabetic patients homozygous forhe deletion allele compared with the insertionllele of the ACE/ID gene polymorphism.56-59 Inn attempt to overcome this harmful interaction,e evaluated the short-term renoprotective ef-
ect in diabetic nephropathy of the ARB losartann patients homozygous for the insertion (II) or
60
With 300 mg Irbesartan Once Daily in 24 Type 1d With 40 mg Enalapril Once Daily
ashout, patients received 50 mg losartan dailyollowed by 100 mg daily in two treatment pe-iods, each lasting 2 months. Both doses of Lo-artan significantly lowered blood pressure, al-uminuria, and GFR. Losartan at a dosage of 100g was more effective than 50 mg in reducing
lbuminuria, 51% versus 33%, respectively. Noifferences in the impact of losartan between thensertion and the deletion groups were observed.onsequently, the data suggest that losartan of-
ers similar short-term renoprotective and bloodressure-lowering effects in albuminuric hyper-ensive type 1 patients with ACE II and DDenotypes. The study was continued for a meanollow-up period of 3 years61 with GFR, albu-inuria, and 24-hour blood pressure measure-ents carried out every 6 months (Fig 2). At
aseline, the previously mentioned variablesere similar in the two genotype groups, anduring the study, the rate of GFR decline was 2.9ersus 3.4 mL/min/year in II versus DD, respec-ively nonsignificant by difference. Albuminuriand blood pressure were significantly reduceduring the study with no differences noted be-ween genotypes. During follow up, albuminuriaas decreased by 75% in both genotype groups.
n conclusion, in contrast to previous observa-ional studies with ACE inhibitors, long-termreatment with ARB has similar beneficial reno-rotective effect on progression of diabetic ne-hropathy in patients with ACE II and DD ge-otypes. From a renoprotective treatment pointf view, this finding suggests equal benefit to allatients irrespective of the ACE/I/D genotype.
PREVENTION OF DIABETIC NEPHROPATHYWITH ANGIOTENSIN RECEPTOR BLOCKADE
Antihypertensive treatment has a renoprotectiveffect in hypertensive patients with type 2 diabetesnd microalbuminuria as reviewed by Parving.62
owever, there has been conflicting evidence re-arding the existence of a specific renoprotectiveffect, that is, a beneficial effect on kidney functioneyond the hypotensive effect, of agents such asCE inhibitors in patients with type 2 diabetes andicroalbuminuria.Therefore, we evaluated the renoprotective ef-
ect of an ARB irbesartan in hypertensive patientsith type 2 diabetes and microalbuminuria.11 A
otal of 590 hypertensive patients with type 2 dia-
etes and microalbuminuria were enrolled in this �
ultinational, randomized, double-blind, placebo-ontrolled study of irbesartan, at a dose of either 150g daily or 300 mg daily and followed for 2 years.The primary outcome was time to onset of dia-
etic nephropathy, defined by persistent albumin-ria in overnight specimens, with a urinary albu-in excretion rate greater than 200 �g/min and at
east 30% higher than the baseline level. The base-ine characteristics in the three groups were simi-ar. Ten patients in the 300-mg group (5.2%) and9 patients in the 150-mg group (9.7%) reached therimary end point, as compared with 30 patients inhe placebo group (14.9%) (hazard ratios, 0.3095% confidence interval [CI], 0.14-0.61; P
Fig 2. Impact of losartan (100 mg/day) on 24-hourean arterial blood pressure (MABP; A), albuminuria
or the two Irbesartan groups, respectively (Fig 3).ean blood pressure was lowered to 103 mm Hg
n the placebo and in the 150 mg irbesartan group,hereas mean blood pressure was 102 mm Hg in
he 300 mg irbesartan group (P � 0.004). Impor-antly, a substudy of 24-hour blood pressure levelsevealed no differences between the three arms.63
n the placebo group, there was a 2% reduction,50 mg irbesartan had a 24% reduction, and the00 mg irbesartan group had a 38% reduction inrinary albumin excretion during the whole studyeriod. The rapid and sustained response to irbe-artan and the continuing divergence in renal out-omes between the 300-mg group and the placeboroup in our study suggest that longer-term therapyould result in an even better prognosis. The rate ofrogression to diabetic nephropathy in the placeboroup in our study corresponds with other studiesonducted in similar populations. Nonfatal cardio-ascular events were slightly more frequent in thelacebo group (8.7% vs. 4.5% in the 300-mg
Fig 3. Incidence of progression to diabetic nephroprbesartan daily, or placebo in hypertensive patientsifference between the placebo group and the 150-mghe difference between the placebo group and the 30eprinted from the New England Journal of Medicine
roup; P � 0.11). Recently, we evaluated whether o
he reduction in microalbuminuria is reversiblehemodynamic) or persistent (structural/biochemi-al normalization) after prolonged antihyperten-ive treatment. After 2 years, all antihypertensivereatment was stopped for a month in the threerms of IRMA 2.64 Compared with baseline, therinary albumin excretion rate was increased in thelacebo group and the 150 mg irbesartan dailyroup, but persistently reduced by 47% (24-73%)n the 300 mg irbesartan daily group. This coulduggest that high-dose irbesartan treatment confersong-term renoprotective effects.
In conclusion, ARB can prevent/delay develop-ent of diabetic nephropathy independent of its
eneficial blood pressure-lowering effect in pa-ients with type 2 diabetes and microalbuminuria.
PROTECTION AGAINST END-STAGE RENALDISEASE WITH ANGIOTENSIN RECEPTOR
f renal disease in patients with type 1 diabetes, but
upvntcwrmbdRwvTabsTcsdpct
tic
dtb
ilrlhlictnuimoabLscbdg6mptih((bfii
DDEDE
Id
PARVING ET AL154
ntil recently, similar data is not available foratients with type 2 diabetes as reviewed by Par-ing.62 Against this background, two large multi-ational, double-blind, randomized, placebo-con-rolled trials with ARBs were carried out inomparable populations of hypertensive patientsith type 2 diabetes, proteinuria, and elevated se-
um creatinine levels.12,13 In both trials, the pri-ary outcome was the composite of a doubling of
aseline serum creatinine concentration, ESRD, oreath. A comparison of the benefits obtained in theENAAL (Reduction of end points in NIDDMith the Angiotensin II Antagonist Losartan) studyersus the IDNT (Irbesartan Diabetic Nephropathyrial) is shown in Table 2. Side effects were low,nd less than 2% of the patients had to stop ARBecause of severe hyperkalemia. The number ofudden deaths in the different groups was alike.he two landmark studies led to the followingonclusion: “Losartan and Irbesartan conferredignificant renal benefits in patients with type 2iabetes and nephropathy. This protection is inde-endent of the reduction in blood pressure itauses. The ARB’s are generally safe and wellolerated.”
Finally, treatment with ARBs in patients withype 2 diabetes and nephropathy not only reducesncidence of ESRD, but also results in substantialost savings.65
IMPACT OF ANGIOTENSIN RECEPTORBLOCKADES ON CARDIOVASCULAR EVENTS
Proteinuria is an established risk marker for car-iovascular morbidity and mortality.2,62 The rela-ive cardiovascular mortality in young type 1 dia-
Table 2. RENAAL and IDNT Results: Compariso
Composite End PointLosartan vs.Placebo (80)
sCr, ESRD, death 16 (2, 28) 2oubling of s-Cr 25 (8, 39) 3SRD 28 (11, 42) 2eath �2 (�27, 19)SRD or death 20 (5, 32)
Abbreviations: RENAAL, Reduction of End points in Nrbesartan Diabetic Nephropathy Trial; CI, confidence inteisease.
etic patients with proteinuria is nearly 40-fold d
ncreased as compared with the background popu-ation.5 In proteinuric type 2 patients, the yearlyate of cardiovascular death or major cardiovascu-ar events such as stroke, myocardial infarction,eart failure, and reduced peripheral perfusioneading to foot ulcers and amputations are approx-mately 7% to 12% yearly.6 The relative mortalityompared with the background population is six-o ninefold increased in type 2 patients with overtephropathy.6 Recently, we evaluated if protein-ria not only is a marker of cardiovascular diseasen type 2 diabetic patients, but also a target toonitor the therapeutic cardioprotective efficacy
f renin–angiotensin system intervention. We an-lyzed data from the RENAAL study, a double-lind, randomized trial to examine the effect ofosartan on the composite end point of doubling oferum creatinine, ESRD, or death and cardiovas-ular morbidity and mortality in 1513 type 2 dia-etic patients with nephropathy.13 Losartan re-uced albuminuria by 28%, whereas in the placeboroup, proteinuria increased by 4% during the first
months of therapy. Modeling of the initial 6onths change in different risk parameters for
redicting the long-term cardiac risk showed thathe initial albuminuria reduction is the strongestndependent predictor of cardiovascular outcome:azard ratio for a cardiovascular end point of 1.1395% CI, 1.04-1.23) and for heart failure 1.2195% CI, 1.8-1.36).66 Every 50% reduction in al-uminuria during the first 6 months halved the riskor cardiovascular end points and heart failure dur-ng the 3-year follow-up period. The study thusndicates that reduction in proteinuria affords car-
ith the Angiotensin II Antagonist Losartan study; IDNT,Cr, doubling of serum creatinine; ESRD, end-stage renal
n of P
R
Irbesavs. Pla
(81
0 (3, 33 (13,3 (�3,8 (�31
—
IDDM wrval; Ds
iovascular protection: the more reduction, the
mtrttmta
rshhsATbmtrsfnmtd
itmciAb
e
pt
c
IS
dt
Vrw
dm
Pm
a
h6
Edi
aa
RoN
tp
L
ANGIOTENSIN BLOCKERS IN DIABETIC NEPHROPATHY 155
ore protection. This specific cardiovascular pro-ective effect of therapy in that study overlaps theenoprotective effect and appears to be marked linko its antiproteinuric potential. Consequently, pro-einuria should not only be considered a riskarker for cardiovascular morbidity, but also a
arget for therapy in type 2 patients with nephrop-thy.
The RENAAL study showed an insignificanteduction in myocardial infarction (28%) but aignificant reduction in first hospitalization foreart failure with 32% (P � 0.0005). Similar dataas been presented in the other major landmarktudy dealing with kidney protection applying theRB, Irbesartan (Irbesartan Diabetic Nephropathyrial [IDNT]).12,67 Furthermore, a metaanalysisased on these two studies and the previouslyentioned IRMA 2 revealed a relative risk reduc-
ion of 15% for cardiovascular events comparingeceptor blockade with conventional blood pres-ure-lowering therapy.68 There was a similar trendor death with a risk reduction of 11% but this wasot statistically significant. The impact of treat-ent with ARB on cardiovascular events in hyper-
ensive type 2 diabetic patients with13 and withoutiabetic nephropathy69 is presented in Table 3.
Recently, we have demonstrated that long-term,ntensified intervention aimed at multiple risk fac-ors in patients with type 2 diabetes and microalbu-inuria reduces the risk of cardiovascular and mi-
rovascular events by approximately 50%.70 Thentensively treated patients all received ACEI orRBs and in 30% of the patients dual RAASlockade.In conclusion, ARBs reduce cardiovascular
* Kidney death and all-cause mortality.Abbreviations: RENAAL, Reduction of End points in N
osartan Intervention For Endpoint reduction in hypertenNOTE. (95% confidence interval).
vents mainly because of a reduction in first hos- 3
italization for congestive heart failure in hyper-ensive type 2 diabetic patients with albuminuria.
REFERENCES
1. Kussman MJ, Goldstein HH, Gleason RE: The clinicalourse of diabetic nephropathy. JAMA 236:1861-1863, 1976
2. Parving H-H, Østerby R, Ritz E: Diabetic nephropathy,n: Brenner BM, (ed). The Kidney, 6th ed. Philadelphia: WBaunders, 2000:1731-17733. Mogensen CE: Progression of nephropathy in long-term
iabetics with proteinuria and effect of initial antihypertensivereatment. Scand J Clin Lab Invest 36:383-388, 1976
4. Parving H-H, Smidt UM, Friisberg B, Bonnevie-Nielsen, Andersen AR: A prospective study of glomerular filtration
ate and arterial blood pressure in insulin-dependent diabeticsith diabetic nephropathy. Diabetologia 20:457-461, 19815. Borch-Johnsen K, Kreiner S: Proteinuria: Value as pre-
ictor of cardiovascular mortality in insulin dependent diabetesellitus. BMJ 294:1651-1654, 19876. Gall M-A, Borch-Johnsen K, Hougaard P, Nielsen FS,
arving H-H: Albuminuria and poor glycemic control predictsortality in NIDDM. Diabetes 44:1303-1309, 19957. Parving H-H, Hommel E: Prognosis in diabetic nephrop-
arly aggressive antihypertensive treatment reduces rate ofecline in kidney function in diabetic nephropathy. Lancet:1175-1179, 1983
10. Lewis E, Hunsicker L, Bain R, Rhode R: The effect ofngiotensin-converting-enzyme inhibition on diabetic nephrop-thy. N Engl J Med 329:1456-1462, 1993
11. Parving H-H, Lehnert H, Brochner-Mortensen J, Gomis, Andersen S, Arner P: The effect of Irbesartan on the devel-pment of diabetic nephropathy in patients with type 2 diabetes.
Engl J Med 345:870-878, 200112. Lewis EJ, Hunsicker LG, Clarke WR, et al: Renoprotec-
ive effect of the angiotensin-receptor antagonist irbesartan inatients with nephropathy due to type 2 diabetes. N Engl J Med
ith the Angiotensin II Antagonist Losartan Study, LIFE,udy.
vascul
REN
12
32
IDDM wsion st
45:851-860, 2001
Mcn
Hdn
qK
p1
od1
cm1
dd6
po(
ttp
ale
orp
pt
H7
t3
vtC
chI
H
i5
PtT
TrT
fn2
Ho
hp
Crt
tiz
eo
Pir
Hn
rS
rp2
Erl
cpdm
m
Dpt
PARVING ET AL156
13. Brenner BM, Cooper ME, de Zeeuw D, Keane WF,itch WE, Parving H-H: Effects of Losartan on renal and
ardiovascular outcomes in patients with type 2 diabetes andephropathy. N Engl J Med 345:861-869, 200114. Hovind P, Rossing P, Tarnow L, Smidt UM, Parving
-H: Remission and regression in the nephropathy of type 1iabetes when blood pressure is controlled aggressively. Kid-ey Int 60:277-283, 200115. Remuzzi G, Bertani T: Is glomerulosclerosis a conse-
uence of altered glomerular permeability to macromolecules?idney Int 38:384-394, 199016. Rossing P: Promotion, prediction, and prevention of
rogression in diabetic nephropathy. Diabet Med 15:900-919,99817. Rossing P, Hommel E, Smidt UM, Parving H-H: Impact
f arterial blood pressure and albuminuria on the progression ofiabetic nephropathy in IDDM patients. Diabetes 42:715-719,99318. Peterson JC, Adler S, Burkart JM, et al: Blood pressure
ontrol, proteinuria, and the progression of renal disease. Theodification of diet in renal disease study. Ann Intern Med
23:754-762, 199519. Keane WF, Brenner BM, de Zeeuw D, et al: The risk of
eveloping end-stage renal disease in patients with type 2iabetes and nephropathy: the RENAAL study. Kidney Int3:1499-1507, 200320. Atkins RC, Briganti E, Wiegmann TB: Effect of baseline
roteinuria and change in proteinuria with treatment on the riskf renal endpoints in the Irbesartan Diabetic Nephropathy TrialIDNT). J Am Soc Nephrol 13:17A, 2002 (abstr)
21. Rossing P, Hommel E, Smidt UM, Parving H-H: Reduc-ion in albuminuria predicts a beneficial effect on diminishinghe progression of human diabetic nephropathy during antihy-ertensive treatment. Diabetologia 37:511-516, 199422. Apperloo AJ, de Zeeuw D, de Jong PE: Short-term
ntiproteinuric response to antihypertensive treatment predictsong-term GFR decline in patients with non-diabetic renal dis-ase. Kidney Int 45:S174-S178, 1994 (suppl 45)
23. The GISEN Group: Randomised placebo-controlled trialf effect of ramipril on decline in glomerular filtration rate andisk of terminal renal failure in proteinuric, non-diabetic ne-hropathy. Lancet 349:1857-1863, 199724. Shahinfar S, Dickson TZ, Ahmed T, et al: Losartan in
atients with type 2 diabetes and proteinuria: Observations fromhe RENAAL study. Kidney Int Suppl 64-67, 2002
25. Hovind P, Rossing P, Tarnow L, Smidt UM, Parving-H: Progression of diabetic nephropathy. Kidney Int 59:702-09, 200126. de Jong PE, Navis GJ, de Zeeuw D: Renoprotective
herapy: Titration against urinary protein excretion. Lancet 354:52-353, 199927. Muirhead N, Feagan B, Mahon J, et al: The effects of
alsartan and captopril on reducing microalbuminuria in pa-ients with type 2 diabetes mellitus: A placebo-controlled trial.urrent Therapeutic Research 60:650-660, 200228. Lacourciere Y, Belanger A, Godin C, et al: Long-term
omparison of Losartan and enalapril on kidney function inypertensive type 2 diabetics with early nephropathy. Kidneynt 58:762-769, 2000
-H: Renoprotective effects of angiotensin II receptor blockade
n type 1 diabetic patients with diabetic nephropathy. Kidney Int7:601-606, 200030. Andersen S, Jacobsen P, Tarnow L, Rossing P, Juhl TR,
arving H-H: Time course of the antiproteinuric and antihyper-ensive effect of Losartan in diabetic nephropathy. Nephrol Dialransplant 18:293-297, 200331. Buter H, Navis G, Dullaart RP, de Zeeuw D, de Jong PE:
ime course of the antiproteinuric and renal haemodynamicesponses to losartan in microalbuminuric IDDM. Nephrol Dialransplant 16:771-775, 200132. Bos H, Andersen S, Rossing P, et al: Role of patient
actors in therapy resistance to antiproteinuric intervention inondiabetic and diabetic nephropathy. Kidney Int 57:S32-S37,00033. Andersen S, Blouch K, Bialek J, Deckert M, Parving
-H, Myers BD: Glomerular permselectivity in early stages ofvert diabetic nephropathy. Kidney Int 58:2129-2137, 200034. Imanishi M, Yoshioka K, Konishi Y, et al: Glomerular
ypertension as one cause of albuminuria in type II diabeticatients. Diabetologia 42:999-1005, 199935. Bonnet F, Cooper ME, Kawachi H, Allen TJ, Boner G,
ao Z: Irbesartan normalises the deficiency in glomerular neph-in expression in a model of diabetes and hypertension. Diabe-ologia 44:874-877, 2001
36. Langham RG, Kelly DJ, Cox AJ, et al: Proteinuria andhe expression of the podocyte slit diaphragm protein, nephrin,n diabetic nephropathy: Effects of angiotensin converting en-yme inhibition. Diabetologia 45:1572-1576, 2002
37. Peters H, Border WA, Noble NA: Targeting TGF over-xpression in renal disease. Maximizing the antifibrotic actionf angiotensin II blockade. Kidney Int 54:1570-1580, 200038. Rossing K, Christensen PK, Hansen BV, Carstensen B,
arving H-H: Optimal dose of Candesartan for renoprotectionn type 2 diabetic patients with nephropathy: A double-blindandomized crossover study. Diabetes Care 26:150-155, 2003
39. Andersen S, Rossing P, Juhl TR, Deinum J, Parving-H: Optimal dose of losartan for renoprotection in diabeticephropathy. Nephrol Dial Transplant 17:1413-1418, 200240. Hilgers KF, Mann JF: ACE inhibitors versus AT(1)
eceptor antagonists in patients with chronic renal disease. J Amoc Nephrol 13:1100-1108, 200241. Cao Z, Bonnet F, Candido R, et al: Angiotensin type 2
eceptor antagonism confers renal protection in a rat model ofrogressive renal injury. J Am Soc Nephrol 13:1773-1787,00242. Komine N, Khang S, Wead LM, Blantz RC, Gabbai FB:
ffect of combining an ACE inhibitor and an angiotensin IIeceptor blocker on plasma and kidney tissue angiotensin IIevels. Am J Kidney Dis 39:159-164, 2002
43. Mogensen CE, Neldam S, Tikkanen I, et al: Randomisedontrolled trial of dual blockade of renin-angiotensin system inatients with hypertension, microalbuminuria, and non-insulinependent diabetes: the candesartan and lisinopril microalbu-inuria (CALM) study. BMJ 321:1440-1444, 200044. Agarwal R: Add-on angiotensin receptor blockade withaximized ACE inhibition. Kidney Int 59:2282-2289, 200145. Rossing K, Christensen PK, Jensen BR, Parving H-H:
ual blockade of the renin–angiotensin system in diabetic ne-hropathy: a randomized double-blind crossover study. Diabe-es Care 25:95-100, 2002
-H: Dual blockade of the renin-angiotensin system in type 1atients with diabetic nephropathy. Nephrol Dial Transplant7:1019-1024, 200247. Jacobsen P, Andersen S, Jensen BR, Parving H-H: Ad-
itive effect of ACE-inhibition and angiotensin II receptorlockade in type I diabetic patients with diabetic nephropathy.Am Soc Nephrol 14:992-999, 200348. Jacobsen P, Andersen S, Rossing K, Jensen BR, Parving
-H: Dual blockade of the renin–angiotensin system versusaximal recommended dose of ACE inhibition in diabetic
enoprotective effects of adding angiotensin II receptor blockero maximal recommended doses of ACE-inhibitor in diabeticephropathy. A randomized double-blind cross-over trial. Dia-etes Care 26:2268-2274, 200350. Nakao N, Yoshimura A, Morita H, Takada M, Kayano T,
deura T: Combination treatment of angiotensin-II receptorlocker and angiotensin-converting-enzyme inhibitor in non-iabetic renal disease (COOPERATE): A randomised con-rolled trial. Lancet 361:117-124, 2003
51. Palmer BF: Renal dysfunction complicating the treat-ent of hypertension. N Engl J Med 347:1256-1261, 200252. Parving H-H, Kastrup J, Smidt UM, Andersen AR,
eldt-Rasmussen B, Christiansen JS: Impaired autoregulationf glomerular filtration rate in type 1 (insulin-dependent) dia-etic patients with nephropathy. Diabetologia 27:547-552, 198453. Christensen PK, Hansen HP, Parving H-H: Impaired
utoregulation of GFR in hypertensive non-insulin dependentiabetic patients. Kidney Int 52:1369-1374, 199754. Christensen PK, Lund S, Parving H-H: Autoregulated
lomerular filtration rate during candesartan treatment in hy-ertensive type 2 diabetic patients. Kidney Int 60:1435-1442,00155. Christensen PK, Akram K, Konig KB, Parving H-H:
utoregulation of glomerular filtration rate in patients with typediabetes during isradipine therapy. Diabetes Care 26:156-162,00356. Parving H-H, Jacobsen P, Tarnow L, et al: Effect of
eletion polymorphism of angiotensin converting enzyme genen progression of diabetic nephropathy during inhibition ofngiotensin converting enzyme: observational follow up study.MJ 313:591-594, 199657. Jacobsen P, Rossing K, Rossing P, et al: Angiotensin
onverting enzyme gene polymorphism and ACE inhibition iniabetic nephropathy. Kidney Int 53:1002-1006, 199858. Penno G, Chaturvedi N, Talmud PJ, et al: Effect of
ngiotensin-converting enzyme (ACE) gene polymorphism onrogression of renal disease and the influence of ACE inhibitionn IDDM patients: Findings from the EUCLID Randomized
59. Jacobsen P, Tarnow L, Carstensen B, Hovind P, Poirier, Parving H-H: Genetic variation in the renin–angiotensin
ystem and progression of diabetic nephropathy. J Am Socephrol 19:2843-2850, 200360. Andersen S, Tarnow L, Cambien F, et al: Long-term
enoprotective effects of Losartan in diabetic nephropathy: In-eraction with ACE insertion/deletion genotype? Diabetes Care6:1501-1506, 200261. Andersen S, Tarnow L, Cambien F, et al: Renoprotective
ffects of losartan in diabetic nephropathy: Interaction withCE insertion/deletion genotype? Kidney Int 62:192-198, 200262. Parving H-H: Renoprotection in diabetes: Genetic and
ansen HP, Parving H-H: Comparative effects of Irbesartan onmbulatory and office blood pressure: A substudy of ambula-ory blood pressure from the Irbesartan in Patients with Type 2iabetes and Microalbuminuria Study. Diabetes Care 26:569-74, 200364. Andersen S, Brochner-Mortensen J, Parving H-H: Kid-
ey function after withdrawal of long-term antihypertensivereatment in patients with type 2 diabetes and microalbumin-ria. Diabetes Care 26:3296-3302, 200365. Gerth WC, Remuzzi G, Viberti G, et al: Losartan reduces
he burden and cost of ESRD: Public health implications fromhe RENAAL study for the European Union. Kidney Int 62:68-2, 2002 (suppl 82)66. de Zeeuw D, Remuzzi G, Parving H-H, et al: Proteinuria
eduction during antihypertensive therapy predicts renal andardio-vascular protection in patients with type 2 diabetic ne-hropathy. Diabetologia 46:A339, 2003 (suppl 2, abstr)67. Berl T, Hunsicker LG, Lewis JB, et al: Cardiovascular
utcomes in the Irbesartan Diabetic Nephropathy Trial of Pa-ients with Type 2 Diabetes and Overt Nephropathy. Ann Intern
ed 138:542-549, 200368. Pourdjabbar A, Lapointe N, Rouleau JL: Angiotensin
eceptor blockers: powerful evidence with cardiovascular out-omes? Can J Cardiol 18:7A-14A, 2002 (suppl A)
69. Dahlof B, Devereux RB, Kjeldsen SE, et al: Cardiovas-ular morbidity and mortality in the Losartan Intervention Forndpoint reduction in hypertension study (LIFE): A random-
sed trial against atenolol 2790. Lancet 359:995-1003, 200270. Gaede P, Vedel P, Larsen N, Jensen GV, Parving H-H,
edersen O: Multifactorial intervention and cardiovascular dis-ase in patients with type 2 diabetes. N Engl J Med 348:383-93, 2003
![[Maintenance tocolysis with calcium channel blockers]](https://static.documents.pub/doc/80x56/63592c71ca12adf96502e719/maintenance-tocolysis-with-calcium-channel-blockers.jpg)
