To RAS or Not to RAS? The Evidence for and Cautions with Renin-Angiotensin System Inhibition in...

To RAS or Not to RAS? The Evidence for and Cautions

with Renin-Angiotensin System Inhibition in Patients

with Diabetic Kidney Disease

Wendy L. St. Peter, Lauren E. Odum, and Adam T. Whaley-Connell

Substantial morbidity, mortality, and costs are associated with progressivediabetic kidney disease (DKD). A goal of Healthy People 2020 is to reducekidney disease attributable to diabetes mellitus and increase the proportionof patients who receive agents that interrupt the renin-angiotensin system(RAS), such as angiotensin-converting enzyme inhibitors (ACEIs) or angio-tensin receptor blockers (ARBs). The mechanisms that contribute to progres-sive loss of kidney function in patients with diabetes are disrupted byinhibition of the RAS. ACEIs, ARBs and direct renin inhibitors (DRIs) allreduce the effect of angiotensin II, yet each works through a different mecha-nism and displays properties that may or may not be replicated by the oth-ers. As single agents, RAS inhibitors and blockers have been shown to slowthe rate of progression of DKD and to reduce new cases of end-stage renaldisease in various subsets of patients with diabetes and proteinuria (e.g.,albuminuria). However, even with contemporary use of ACEIs, ARBs, and,more recently, DRIs, the burden of kidney disease remains high. Thus inves-tigators sought to explore the utility of combining agents (e.g., dual RAStherapy) in various regimens for cardiovascular and kidney end points.Recent data from the Ongoing Telmisartan Alone and in Combination withRamipril Global Endpoint Trial (ONTARGET) and Aliskiren Trial in Type 2Diabetes Using Cardio-Renal Endpoints (ALTITUDE) studies suggest thatkidney-related outcomes (composite of dialysis initiation, doubling serumcreatinine concentration, or death) were increased with ACEI plus ARB orDRI plus ARB combinations. Consequently, dual therapy should not be rou-tinely prescribed in patients with diabetes until further data become availablefrom other future studies. This review provides an introduction to DKD anda rationale for using RAS inhibition; discusses screening, detection, and mon-itoring of patients with DKD; and summarizes results from meta-analysesand critical reviews and from recent large randomized controlled studiespublished since the meta-analyses or reviews. Finally, we suggest a clinicalapproach for using RAS agents in patients with DKD.Key Words: angiotensin-converting enzyme inhibitors, angiotensin receptorblockers, diabetic kidney disease, renin-angiotensin system inhibition.(Pharmacotherapy 2013;33(5):496–514)

R E V I E W S O F T H E R A P E U T I C S

Diabetic kidney disease (DKD) is estimated tooccur in 20–40% of patients with diabetes mell-itus.1 Diabetes is the leading cause of kidney dis-ease in developed countries, and diabetes andhypertension are the leading causes of chronickidney disease (CKD) and end-stage renal dis-ease (ESRD) in the United States; diabetesaccounted for 44% and hypertension 28% ofincident ESRD in 2009.2 A recent analysis fromthe National Health and Nutrition ExaminationSurvey demonstrated that from 1988 to 2008,the prevalence of DKD increased directly in pro-portion to the prevalence of diabetes.3 Concur-rently, the use of diabetes agents and renin-angiotensin system (RAS) agents increased.3

Accordingly, the prevalence of proteinuriatrended downward (except in patients older than65 years), which may be a result of improvedglycemic control4–6 and RAS inhibition.7–10

Interestingly, estimated glomerular filtration rate(eGFR) also decreased, possibly partially due toimperfect adjustment for serum creatinine assaycalibration over time,3 but this observation addsa cautionary note. Although the rate of age-adjusted new cases of diagnosed diabetes in theUnited States stabilized from 2008 to 2010, theprevalent population continues to increase;20.9 million Americans had diagnosed diabetesin 2010.11 The increasing prevalence of DKD isconcerning from a public health and cost per-spective. Progressive kidney disease is associatedwith considerable societal costs due to morbidityand mortality from cardiovascular disease andESRD.2

Hypertension is one of the most common co-morbid conditions in patients with DKD, andblood pressure management is a critical risk-reduction strategy. Hypertension contributes tothe progression of kidney disease and in turn isa consequence of progressive DKD. RAS agentshave been shown to reduce blood pressure and

proteinuria (e.g., albuminuria) and to slow theprogression of CKD in various subsets ofpatients with diabetes.12, 13 These agents havebeen shown to reduce GFR over the short termthrough hemodynamic effects by attenuatingangiotensin II–induced efferent arteriole vaso-constriction and lowering intraglomerular pres-sure. These short-term reductions in GFR seemto be offset by long-term reduction in GFRdecline. However, recent work suggests thatRAS inhibition may represent a double-edgedsword when used to prevent the progression ofDKD.3

We provide an introduction to the mecha-nisms of DKD and the rationale for using RASagents (angiotensin-converting enzyme inhibi-tors [ACEIs], angiotensin receptor blockers[ARBs], and direct renin inhibitors [DRIs]) toprevent DKD progression; discuss screening,detection, and monitoring of patients with DKDfor complications; and summarize results frommeta-analyses and critical reviews coveringmajor clinical trials7–10, 14 and from recentlarge randomized controlled studies publishedsince the meta-analyses or reviews. We alsohighlight major findings regarding the use ofRAS agents individually and in combinationtherapy in preventing the development and pro-gression of DKD, and we suggest a clinicalapproach for using RAS agents in patients withDKD.

Pathophysiology of Diabetic Kidney Disease

Multiple mechanisms contribute to DKD initi-ation and progression, eventually leading todestruction of nephrons and reduction of kidneymass over time.15–17 An initial adaptive hyperfil-tration phase occurs in response to increases inglomerular capillary pressure and flow derivedfrom elevations in systolic pressure, changes inhydrostatic pressures stemming from obesity,and increases in bioavailable nitric oxide derivedfrom excess insulin under conditions of insulinresistance.These initial mechanisms eventually become

maladaptive and predispose any remainingfunctional nephrons to hypertrophy and thento sclerosis over time. The extent of sclerosisalong the length of the nephron at variouslevels including the glomerular tuft, the proxi-mal tubule, or even the distal tubule isdictated by various proinflammatory and pro-oxidant mechanisms that are derived fromexcess or inappropriate activation of the

From the College of Pharmacy, University of Minne-sota, and Chronic Disease Research Group, MinneapolisMedical Research Foundation, Minneapolis, Minnesota(W.L. St. Peter); the Division of Pharmacy Practice andAdministration, University of Missouri Kansas City Schoolof Pharmacy, Columbia, Missouri (L.E. Odum); and HarryS. Truman Memorial Veterans Hospital, and the Division ofNephrology and Hypertension, University of Missouri-Columbia School of Medicine, Columbia, Missouri (A.T.Whaley-Connell).

For questions or comments, contact Wendy L. St. Peter,Chronic Disease Research Group, Minneapolis MedicalResearch Foundation, 914 South 8th Street, Suite S4.100,Minneapolis, MN 55404; e-mail: [email protected].

RAS INHIBITION IN PATIENTS WITH DIABETIC KIDNEY DISEASE St. Peter et al 497

renin-angiotensin-aldosterone system (RAAS),the sympathetic nervous system, and/or theendothelin system.18

The complex relationship between thesesystems with more advanced stages of CKDpotentiate anatomic and functional abnormali-ties in the vasculature that lead to endothelialdysfunction and to extracellular matrix depo-sition, which contributes to sclerosis, fibrosis,and progressive DKD.15–17 The increases insystemic RAAS are accompanied by intrarenalactivity of the RAAS that collectively promoteboth the initial hyperfiltration phase observedin DKD and subsequent hypertrophy, sclero-sis, and fibrosis.18 Thus interruption of theRAAS at any level has become the preeminentrisk-reduction strategy in preventing andarresting the progression of DKD and CKD ingeneral.In this context, the inappropriate activation

of the RAAS in DKD occurring in the setting ofadequate salt intake and volume expansion hasbeen well characterized. Angiotensin II is aproinflammatory, pro-oxidant peptide thatcontributes substantially to kidney tissue injurybeyond the hemodynamic influences on vascu-lar tone and intraglomerular pressure.19, 20

Angiotensin II is known to activate circulatorycells, facilitate adhesion, and ultimately causeendothelial damage and dysfunction. Thispromotes reactive oxygen species productionand nuclear factor–j B activation21, 22 and pot-entiates hypertension-induced injury to the glo-merular filtration barrier.19, 23 Furthermore,angiotensin II has been noted to promote cellgrowth and fibrosis in the proximal tubule.21

Thus pharmacologic blockade of RAS is benefi-cial in attenuating the mechanisms that dictateprogressive DKD and in reducing systemicblood pressure.Blood pressure regulation in more advanced

stages of CKD and DKD is dictated largely byvolume retention and expansion of extracellularfluid volume. This expansion of the extracellularcompartment is consistent with an impairednatriuretic response with salt loading in patientswith CKD, especially those with diabetes (e.g.,DKD).19, 24 Reductions in the kidney’s ability toexcrete excess salt and water are largely consid-ered to be sequelae of the reduction in nephronmass. Thus the systemic blood pressure loweringpotency of RAS inhibition in isolation may bediminished in DKD, necessitating use of diuret-ics to augment blood pressure reduction in thesetting of RAS inhibition.

Screening, Detection, and Monitoring forDiabetic Kidney Disease

As the prevalence of DKD increases in theUnited States, current practice dictates promo-tion of screening and detection in earlier stagesso interventions that prevent progression can beincorporated into management plans. In thiscontext, some data suggest that targeted screen-ing of patients with diabetes is cost effective.25

However, a recent systematic review by the USPreventive Services Task Force found insufficientevidence supporting routine CKD screening inasymptomatic adults.26 Thus robust research inthis area is greatly needed.The Kidney Disease Outcomes Quality Initiative

(KDOQI), Kidney Disease: Improving Global Out-comes (KDIGO), and American Diabetes Associa-tion (ADA) clinical practice guidelines1, 27–30

advocate for the screening and risk stratificationof patients with diabetes using blood pressure,eGFR based on serum creatinine concentrationand other variables, urine albumin-to-creatinineratio, examination of the urine sediment, and kid-ney imaging studies (Table 1).The most common markers used in clinical

practice to detect DKD are serum creatinineconcentration, eGFR, and proteinuria.1, 27 In theUnited States, the equations most often used tocalculate eGFR for CKD staging in adults are themodification of diet in renal disease (MDRD)study equation32 and the CKD EpidemiologyCollaboration equation.33 Diagnosis and classifi-cation of CKD are based on a set of establishedclinical practice guidelines.27 CKD is defined asabnormalities of kidney structure or function,present for 3 or more months, as established bykidney biopsy or markers of kidney damage(i.e., presence of structural or functional abnor-malities as evidenced by abnormal blood, urine,or imaging studies) with or without decreasedGFR; or GFR less than 60 ml/min/1.73 m2 for 3or more months with or without kidney damage.CKD is stratified by risk into stages G1 to G4based on level of GFR, with declining GFRassociated with worsening CKD. GFR lessthan 15 ml/min/1.73 m2 is considered stage G5kidney failure.27

With eGFR higher than 60 ml/min/1.73 m2,presence of proteinuria is one marker for meet-ing the diagnostic criteria for CKD.27, 30 CurrentKDOQI and KDIGO clinical practice guidelinesprimarily advocate untimed (“spot”) first morn-ing void urine samples to detect and monitorproteinuria in children and adults. Although

498 PHARMACOTHERAPY Volume 33, Number 5, 2013

Table 1. Current screening, treatment, and monitoring guidelines with renin-angiotensin system agents in patients withdiabetic kidney disease

Activity Guidelines

ADA 20131, a KDOQI 2007 Clinical Practice Guidelinesand recommendations for DKD supplementedby KDOQI Clinical Practice Guideline for Diabetesand CKD: 2012 Update and KDIGO 2012Clinical Practice Guideline for the Managementof Blood Pressure in CKD.28, 29, 30, b, c

JNC 7 200431

BP goal <140/80 mm Hg (B),but lower systolictargets may beappropriate in someindividuals (C).

� 140/90 mm Hg in adults withUAE <30 mg/24 hrs (or equivalent)(1B) and � 130/80 mm Hg in adultswith UAE >30 mg/24 hrs (or equivalent) (2D).

< 130/80 mm Hg.

Hypertensiontreatment

Pharmacologic therapyregimen for patientswith diabetes andhypertension shouldinclude an ACEI oran ARB. If one classis not tolerated, theother should besubstituted (C).

Recommend not using ACEI or ARB for primaryprevention of DKD in normotensive,normoalbuminuric patients with diabetes (1A).Suggest that ACEI or ARB be used in adultswith CKD ND with UAE of 30–300 mg/24 hrs(or equivalent) (2D). Recommend that ACEIor ARB be used in adults with CKD ND withUAE >300 mg/24 hrs (or equivalent) (1B).

Advocate usingKDOQIguidelines.

MonitoringBP withACEIs orARBs

Interval of monitoring depends on baselineBP levels. After initiation of ACEI or ARBor increase in dose, 4–12 wks if SBP �120 mm Hg or � 4 wks if SBP < 120 mm Hg.

Screeningforproteinuria

Assess urine albuminexcretion annually inpatients with type 1diabetes duration �5 yrs and in allpatients with type2 diabetes startingat diagnosis (B).

Similar to ADA guideline; additionally, urinaryalbumin excretion should be measured byACR in a spot urine sample, and ACRshould be confirmed in the absence ofurinary tract infection with two additionalfirst-void specimens collected in next 3–6 mo(B). Microalbuminuria defined as ACR30–300 mg/g, and macroalbuminuriadefined as ACR > 300 mg/g; 2 of 3 samplesshould fall within micro- or macroalbuminuriarange to confirm classification.

To avoid inaccuraciesassociated with 24-hrurine collections, spoturine samples may beused and ACRdetermined.Microalbuminuriadefined as spot ACR30–200 mg/g, andmacroalbuminuriadefined as ACR >200 mg/g.

Treatmentforproteinuria

In treatment ofnonpregnant patientwith modestlyelevated(30–299 mg/day)(C) or higher levels(� 300 mg/day)of urinary albuminexcretion (A),either ACEI orARBs arerecommended.

ACEIs and ARBs are effective in slowingprogression of kidney disease characterizedby microalbuminuria in hypertensive patientswith type 1 or 2 diabetes (moderate evidence).ACEIs and ARBs are more effective than otherantihypertensive classes in slowing progressionof kidney disease characterized by macroalbuminuriain hypertensive patients with type 1 diabetes(strong evidence for ACEIs, weak evidence for ARBs).ACEIs and ARBs are more effective than otherantihypertensive classes in slowing progression ofkidney disease characterized by macroalbuminuriain hypertensive patients with type 2 diabetes (strongevidence for ACEIs, weak evidence for ARBs).ACEIs, ARBs, and nondihydropyridine CCBs have agreater antiproteinuric effect than other antihypertensiveclasses in hypertensive patients with DKD(strong evidence).Dihydropyridine CCBs, when used to treat hypertensionin absence of ACEI or ARBs, are less effective thanother agents in slowing progression of DKD(strong evidence).Based on similar mechanisms, the work group suggeststhat ACEI or ARB can be used as alternative agentif preferred agent cannot be used (weak evidence).

(continued)


random sampling and even dipstick results areacceptable, positive test results should undergoconfirmation. Subsequent monitoring should usequantitative measurements of protein (or albu-min-to-creatinine ratio) in spot urine samples.Albuminuria results are stratified based onamount: less than 30 mg/g is considered normalto mildly increased, 30 to 300 mg/g moderatelyincreased, and more than 300 mg/g severelyincreased.The presence of proteinuria is considered a

marker for kidney injury and has been shownover time to be a strong independent predictor

or marker of kidney disease progression and car-diovascular outcomes.27, 34–37 New KDIGO clini-cal practice guidelines for CKD staging,27, 38

have incorporated eGFR and level of proteinuriain the classification to improve prediction ofCKD progression.27, 39

Blood Pressure Control Guidelines in Diabetic

Kidney Disease

Whereas glycemic control is a cornerstone oftherapy for DKD, data suggest that blood pres-sure control is the predominant strategy for

Table 1. (continued)

Activity Guidelines

Screeningfor GFR

Measure SCr at leastannually in all adultswith diabetes,regardless of degreeof urine albuminexcretion. Use SCr toestimate GFR and stageCKD level, ifpresent (E).

Similar to ADA guidelines.

MonitoringSCr (GFR),serumpotassiumlevels

When ACEIs, ARBs,or diuretics are used,monitor SCr andpotassium levels fordevelopment ofincreased SCr andhyperkalemia (E).

Interval for monitoring SCr (GFR) and potassiumlevels depends on baseline levels and whetherACEI or ARB was just initiated, dose wasuptitrated, or dose is stable (B). If GFR �60 ml/min/1.73 m2, early GFR decline < 15%,and serum potassium � 4.5 mEq/L, and ACEIor ARB dose was initiated or increased: 4–12 wks;if dose is stable and BP is at goal: 6–12 mo;if GFR < 60 ml/min/1.73 m2, early GFRdecline � 15%, or potassium > 4.5 mEq/L, anddose was initiated or increased: � 4 wks; if doseis stable and BP is at goal: 1–6 mo.d

Monitoringurinealbumin

Continued monitoringof urine albuminexcretion to assesswhether response totherapy and diseaseprogression arereasonable (E).

Similar to ADA recommendations; use ACR tomonitor urine albumin excretion.

ADA = American Diabetes Association; KDOQI = Kidney Disease Outcome Quality Initiative; JNC 7 = Seventh Report of the Joint NationalCommittee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; DKD = diabetic kidney disease; SBP = systolic bloodpressure; DBP = diastolic blood pressure; CKD = chronic kidney disease; BP = blood pressure; ACEI = angiotensin-converting enzyme inhibi-tor; ARB = angiotensin receptor blocker; ACR = albumin-to-creatinine ratio; CCBs = calcium channel blockers; GFR = glomerular filtrationrate; SCr = serum creatinine concentration; UAE = urine albumin excretion.aLevels of evidence for ADA recommendations: (A) clear evidence from well-conducted generalizable randomized controlled trials that areadequately powered; (B) supportive evidence for well-conducted cohort trials; (C) supportive evidence from poorly controlled or uncon-trolled studies; (E) expert consensus or clinical experience.bRating strength of 2007 KDOQI guidelines: (A) strongly recommended that clinicians routinely follow the guideline for eligible patients andstrong evidence that the practice improves health outcomes; (B) recommended that clinicians routinely follow the guidelines for eligiblepatients and moderately strong evidence that the practice improves health outcomes; (C) recommended that clinicians consider following foreligible patients; recommendation based on weak evidence or on opinions of the work group and reviewers that the practice might improvehealth outcomes.cRating strength of 2012 KDIGO and 2012 KDOQI guidelines: Within each recommendation, the strength of recommendation is indicated asLevel 1: “We recommend,” Level 2: “We suggest” or Ungraded” paired with quality of supporting evidence: A: High, B: Moderate, C: Low, D:Very Low.dIn most patients, ACEI or ARB can be continued if GFR decline over 4 months is < 30% from baseline value (B) or serum potassium levelis � 5.5 mEq/L (B). If GFR declines > 30% from baseline within 4 wk of initiation or uptitration, evaluate causes.


preventing progression and cardiovascular com-plications.6 The aim of secondary prevention isto prevent or decrease the progression frommoderately to severely increased albuminuria,and the aim of tertiary prevention is to decreasethe progression from severely increased albumi-nuria to kidney failure. The ADA, KDOQI,KDIGO and the National High Blood PressureEducation Program have published guidelinesrelating to blood pressure management inpatients with DKD (Table 1).1, 28–31 A KDIGOguideline for blood pressure management inCKD was recently published and suggests a goalsystolic blood pressure (SBP) less than or equalto 130 mm Hg when UAE is greater than orequal to 30 mg/24 hours30, 40 while 2012 ADAguidelines suggest that a goal SBP lower than140 mm Hg is appropriate for most patientswith diabetes (level B recommendation), butlower systolic targets may be appropriate insome individuals based on patient characteristics(level C recommendation).1 Patients with diabe-tes should be treated to a diastolic blood pres-sure (DBP) lower than 80 mm Hg (level Brecommendation)1, a recommendation consistentwith KDIGO guidelines for patients with diabe-tes and CKD with UAE greater than or equal to30 mg/24 hours published in 2012.27 The levelC ADA recommendation for SBP lower than140 mm Hg reflects the uncertainty regardingthis target generated by recent trials or post hocanalyses of hypertension studies in patientswith and without diabetes. Results from theAction to Control Cardiovascular Risk in Diabe-tes (ACCORD) trial showed that intensive bloodpressure lowering (goal SBP less than 120versus less than 140 mm Hg) led to increasedadverse effects and did not reduce cardiovascularevents but did reduce stroke risk.41 Data regard-ing prospectively testing lower blood pressuretargets in patients with CKD are scant. Datafrom the African-American Study of Kidney Dis-ease and Hypertension (AASK) and the MDRDstudies, as well as secondary outcomes derivedfrom the Antihypertensive and Lipid-LoweringTreatment to Prevent Heart Attack Trial (ALL-HAT), suggest that targeting SBP less than130 mm Hg may not improve CKD-related endpoints except in patients with overt proteinuria(more than 300 mg/day).42–45

Additional data from a subgroup analysis ofpatients with and without diabetes from theOngoing Telmisartan Alone and in Combinationwith Ramipril Global Endpoint Trial (ONTAR-GET) showed that, except for stroke, lowering

SBP to less than 130 mm Hg did not reduce fatalor nonfatal cardiovascular outcomes.46 A sub-analysis of the International Verapamil SR-Trandolapril Study (INVEST) showed that anSBP less than 130 mm Hg was not associatedwith improved cardiovascular outcomes com-pared with an SBP of 130–140 mm Hg.47 How-ever, none of these studies specifically focusedon patients with DKD. To date, neither cardio-vascular nor renoprotective effects of loweringSBP to less than 130 mm Hg have been clearlyestablished. The ongoing Systolic Blood PressureIntervention Trial (SPRINT) will provide furtherguidance regarding whether reducing SBP to lessthan 120 mm Hg versus less than 140 mm Hgin patients with stage 3 CKD (no diabetes) willaffect the occurrence of ESRD or cardiovasculardisease.48

To date, the best available evidence recom-mends the use of ACEIs or ARBs in patientswith DKD with moderate or severe albumi-nuria.1, 28–30 KDOQI 2012 guidelines recom-mend not using ACEI or ARBs for primaryprevention of DKD in normotensive, normoalbu-minuric patients (level 1A), but do recommendthese agents in normotensive patients with ACRgreater than or equal to 30 mg/g who are at highrisk for progression (level 2C).30 In addition, aHealthy People 2020 CKD goal is to reduce kid-ney failure due to diabetes and to increase theproportion of patients with DKD who receiverecommended medical treatment with an ACEIor ARB.49 Several meta-analyses and reviews,along with a few new trials, have expandedknowledge regarding application of RAS thera-pies in DKD. Thus we evaluated the literature intwo areas: studies of single RAS therapy com-pared with placebo and studies of dual RAStherapies compared with single RAS therapy.Readers should note that current guidelines usetwo different terminologies for albuminuria, thusthe following terms are used interchangeably:Normal to mildly increased albuminuria (nor-moalbuminuria), moderately increased albumi-nuria (microalbuminuria), severely increasedalbuminuria (macroalbuminuria).

Single Renin-Angiotensin System Agents versusPlacebo in Patients with Diabetic Kidney

Disease

Many trials have evaluated the effects of ACEIor ARB therapy versus placebo on albuminuria(Table 2). Data from a recent meta-analysis9

support a beneficial effect of ACEI or ARB


Table 2. Summary of Meta-Analyses, Reviews, and Recent Studies Evaluating Single-Agent Angiotensin-Converting EnzymeInhibitors, Angiotensin Receptor Blockers, or Renin Inhibitors Versus Placebo in Patients with Diabetes, Chronic KidneyDisease, or Diabetic Kidney Disease

Study Study characteristics Description

Mauer200950

Inclusion criteria DM type 1, normoalbuminuria, normotensive.Exclusion criteria HTN, albuminuria, failure to take 85% of placebo pills during a 2-wk run-in

period, eGFR < 90 ml/min/1.73 m2, retinopathy.No. of patients 256: 86 received enalapril, 85 received losartan, 85 received placebo.Design R, DB, PC, multicenter.Duration 5 yrs.Treatment regimen Enalapril 10–20 mg/day vs losartan 50–100 mg/day vs placebo.Proteinuria/albuminuriaresults

UAER at study end vs baseline: NS for enalapril vs placebo, p=0.04 for losartan vsplacebo.

Blood pressure results(mm Hg)

Mean � SD BP during study: enalapril 113 � 9/66 � 6, losartan 115 � 8/66 � 6,placebo 117 � 8/68 � 5.

Adverse effects Chronic cough; most common in enalapril group.Other results Microalbuminuria progression: placebo 6% vs enalapril 4% (p=0.96) or losartan

17% (p=0.01); change in MFVPG: placebo 0.016 units vs enalapril 0.005 (p=0.38)or losartan 0.026 (p=0.26); retinopathy progression vs placebo: enalapril OR 0.35(95% CI 0.14–0.85), losartan OR 0.30 (95% CI 0.12–0.73).

Limitations Small sample size.

Bilous200951

Inclusion criteria DM type 1 or 2, normoalbuminuria, normotensive.Exclusion criteria Eye conditions precluding ability to analyze retinal photographs; recent stroke or

MI, stenotic valvular heart disease, renal impairment.No. of patients 5231: 3326 with DM type 1 (1662 received candesartan, 1664 received placebo),

1905 with DM type 2 (951 received candesartan, 954 received placebo).Design Three randomized trials of the DIRECT (Diabetic Retinopathy Candesartan Trials)

Program, multicenter.Duration Median 4.7 yrs.Treatment regimen Candesartan 16 mg increased to 32 mg vs placebo.Proteinuria/albuminuriaresults

Annual rate of change in albuminuria for candesartan vs placebo: 5.53% reduction(95% CI 0.73%–10.14%, p=0.024).


Within 3 mo of study and for study entirety, BP was lower in the candesartangroup vs placebo (p<0.005) for patients with both DM type 1 and 2.

Adverse effects NSOther results Risk for microalbuminuria in candesartan vs placebo: HR 0.95 (95% CI 0.78–1.16,

p=0.60).Limitations Patients recruited are at lower vascular risk. Studies were powered for retinal and

not renal end points.

Imai 2011ORIENT52

Inclusion criteria DM type 2, overt nephropathy in Japanese or Chinese patients.Exclusion criteria DM type1, MI/CABG in last 3 mo, PCI/CAD/PAD revascularization in last 6 mo,

stroke/TIA in last year, UA, NYHA HF class III or IV, rapid decline in renaldisease within 3 mo before consent, severe orthostatic hypotension, hypo- orhyperkalemia.

No. of patients 577: 288 received olmesartan, 289 received placebo.Design R, DB, PC, multicenter.Duration Mean 3.2 yrs.Treatment regimen Olmesartan 10–40 mg/day vs placebo.Proteinuria/albuminuriaresults

Percentage change in UPCR from baseline higher in olmesartan group vs placebogroup (p=0.005).


Mean BP at baseline and end of trial: olmesartan 141.7/77.8 and 131.8/72.2;placebo 140.8/77.2 and 136.6/73.6. Time-average difference between olmesartanand placebo group: 2.8/1.6 mm Hg (p<0.01).

Adverse effects CV deaths higher in the olmesartan group vs placebo: 10 vs 3 patients (HR 3.38,95% CI 0.93–12.29).

Other results Composite of doubling of SCr, ESRD, and death: olmesartan vs placebo: HR 0.97(95% CI 0.75–1.24).

Limitations 73.5% of patients received concomitant ACEI therapy (similar between groupsat baseline).

Haller 2011ROADMAP53

Inclusion criteria DM type 2, normoalbuminuria.Exclusion criteria Dual RAS therapy, use of ACEI or ARB � 6 mo before start of trial.No. of patients 4447: 2232 received olmesartan, 2215 received placebo.Design R, DB, PC, multicenter.Duration Median 3.2 yrs.Treatment regimen Olmesartan 40 mg/day vs placebo.Proteinuria/albuminuriaresults

Time to microalbuminuria onset: 722 days for olmesartan vs 576 days for placebo(HR 0.77, 95% CI 0.63–0.94, p=0.01).

(continued)





Mean BP 3/2 mm Hg higher in placebo vs olmesartan group at end of study.

Adverse effects CV deaths higher in olmesartan group vs placebo: 15 vs 3 patients (p=0.01); deathshigher in patients with preexisting CHD.

Other results Nonfatal CV events similar between groups: olmesartan 3.6% vs placebo 4.1%(p=0.37).

Limitations Trial duration; 23% premature withdrawals in both study groups; more patientsreceiving ARB vs placebo achieved goal BP (80% vs 71%).

Hirst20129

Inclusion criteria DM type 1 or 2 with normo- or microalbuminuria.Exclusion criteria Dual RAS therapy, normo- and microalbuminuria not separated, DM type not

separated.No. of patients DM type 1, normoalbuminuria: 7 RCTs (n=4261); DM type 1, microalbuminuria:

15 RCTs (n=1152); DM type 2, normoalbuminuria: 10 RCTs (n=15,661); DMtype 2, microalbuminuria: 24 RCTs (n=13,008).

Design Meta-analysis.Duration At least 72 wks.Treatment regimen ACEI or ARB vs placebo in 84% of the trials in the meta-analysis.Proteinuria/albuminuriaresults

Ratio of mean UAE in ACEI or ARB vs comparator or placebo at end of trial;DM type 1 normoalbuminuria: 4% (ratio of means 0.96, 95% CI 0.94–0.99); DMtype 1, microalbuminuria: 60% (ratio of means 0.40, 95% CI 0.36–0.44); DMtype 2, normoalbuminuria: 12% (ratio of means 0.88, 95% CI 0.84–0.92); DMtype 2, microalbuminuria: 23% (ratio of means 0.77, 95% CI 0.74–0.80).


Not reported.

Adverse effects None reported.Other results Progression of albuminuria in ACEI or ARB vs comparator or placebo;

DM type 1 normoalbuminuria progression to microalbuminuria: RR 0.96 (95% CI0.76–1.23); DM type 1, microalbuminuria progression to macroalbuminuria: onlyACEI studied: RR 0.39 (95% CI 0.23–0.64); DM type 1, microalbuminuriaregression to normoalbuminuria: only ACEI studied: RR 5.81 (95% CI2.05–16.42); DM type 2, normoalbuminuria progression to microalbuminuria: RR0.84 (95% CI 0.79–0.89); DM type 2, microalbuminuria progression tomacroalbuminuria: RR 0.52 (95% CI 0.43–0.63); DM type 2, microalbuminuriaregression to normoalbuminuria: RR 1.20 (95% CI 1.12–1.29).

Limitations Large heterogeneity between trials; effect of BP lowering on outcomes unclear; only1 ARB trial in DM type 1.

Vejakama201214

Inclusion criteria DM type 2, at least 1 of the following outcomes measures: microalbuminuria,macroalbuminuria, albuminuria regression, microvascular complications, SCrdoubling, and/or ESRD.

Exclusion criteria Dual RAS therapy, crossover trials.No. of patients Patients grouped by outcome: ESRD: 4 RCTs (n=10,581); SCr doubling: 4 RCTs

(n=10,594); microvascular complications: 4 RCTs (n=6489); macroalbuminuria: 5RCTs (n=3868); microalbuminuria: 4 RCTs (n=6762); albuminuria regression: 2RCTs (n=1238).

Design Meta-analysis.Duration Ranged from 0.5 to 8.4 yrs.Treatment regimen ACEI or ARB vs placebo.Proteinuria/albuminuriaresults

Not reported.


Not reported.

Adverse effects None reported.Other results ESRD in ACEI or ARB group vs placebo or comparator: RR 0.80 (95% CI 0.69–0.93),

SCr doubling: RR 0.76 (95% CI 0.69–0.84);microvascular complication: RR 0.85 (95% CI 0.74–0.97); macroalbuminuria:RR 0.67 (95% CI 0.54–0.83); microalbuminuria: RR 0.82 (95% CI 0.64–1.05);albuminuria regression RR 1.17 (95% CI 1.00–1.37).

Limitations Large heterogeneity between trials; lack of BP data.

DM = diabetes mellitus; HTN = hypertension; eGFR = estimated glomerular filtration rate; R, DB, PC = randomized double-blind placebo-controlled trial; UAE = urine albumin excretion; UAER = urine albumin excretion rate; NS = not significant; BP = blood pressure;MFVPG = mesangial fractional volume per glomerulus; OR = odds ratio; HR = hazard ratio; CI = confidence interval; ORIENT = OlmesartanReducing Incidence of End Stage Renal Disease in Diabetic Nephropathy Trial; MI = myocardial infarction; CABG = coronary artery bypassgraft; PCI, percutaneous coronary intervention; CAD = coronary artery disease; PAD = peripheral artery disease; TIA = transient ischemicattack; UA = unstable angina; NYHA HF = New York Heart Association heart failure; UPCR = urine protein-to-creatinine ratio; CV = cardio-vascular; SCr = serum creatinine concentration; ESRD = end-stage renal disease; ACEI = angiotensin-converting enzyme inhibitor; ROAD-MAP = Randomized Olmesartan and Diabetes Microalbuminuria Prevention; RAS = renin-angiotensin system; ARB = angiotensin receptorblocker; CHD = coronary heart disease; RCT = randomized controlled trial; RR = risk ratio.


therapy on lowering the urinary albumin excre-tion rate for patients with type 1 diabetes mell-itus with microalbuminuria and type 2 diabeteswith normo- and microalbuminuria; however,the effect in patients with type 1 diabetes andnormoalbuminuria was significant only with afixed-effects model but not with the random-effects model. Thus outcome was sensitive tothe model used. The fixed-effects model doesnot reflect heterogeneity between trials, but therandom-effects model can give too much weightto small studies. Additionally, the meta-analysisfound a beneficial effect of ACEI or ARB therapyon reducing progression of albuminuria forpatients with type 1 diabetes and microalbumin-uria and patients with type 2 diabetes and nor-mo- or microalbuminuria. No significantdifferences between the ACEI or ARB and pla-cebo groups were found regarding progressionfrom normoalbuminuria to microalbuminuria inpatients with type 1 diabetes. A limitation tothis meta-analysis is that whereas most patientswith type 1 diabetes were normotensive or hadcontrolled blood pressure, many patients withtype 2 diabetes were hypertensive at baseline.Therefore, it is difficult to differentiate the anti-hypertensive effect on albuminuria versus thespecific effect of the ACEI or ARB, especially forpatients with type 2 diabetes. Overall, this meta-analysis did confirm the beneficial albumin-low-ering effect of ACEI or ARB therapy comparedwith placebo in patients with type 1 diabetesand microalbuminuria, type 2 diabetes and nor-moalbuminuria, and type 2 diabetes and micro-albuminuria. These meta-analysis results do notsupport the routine use of ACEI or ARB therapyin patients with type 1 diabetes and normoalbu-minuria. However, these patients may haveanother indication (e.g., heart failure) for anACEI or an ARB.Several nonrenal conditions, such as urinary

tract infection, hypertension, and cardiovasculardisease, can affect urinary albumin excretion. In-traindividual fluctuation in urinary albuminexcretion is significant and can be influenced bytime of day, exercise, and uncontrolled bloodglucose, making accurate categorization ofpatients with normo- or microalbuminuria chal-lenging.54, 55 Additionally, the relationshipbetween microalbuminuria and clinically rele-vant renal outcomes, such as ESRD is difficult toassess due to the short duration of most trials.56

A recent meta-analysis14 evaluated hard renaloutcomes from randomized trials of ACEI orARB therapy versus placebo in patients with type

2 diabetes. Treatment with an ACEI or ARBcompared with placebo significantly decreasedthe risk of ESRD, doubling of serum creatinineconcentration, major microvascular complica-tions, macroalbuminuria, and albuminuriaregression. No significant effect was found forrisk of microalbuminuria, but only four trials ofsingle therapy versus placebo for this outcomewere included, and study populations and trialdesigns were dissimilar; three studies measuredprogression from normoalbuminuria to microal-buminuria, and one study measured reductionin urinary albumin excretion in patients whoalready had microalbuminuria. Several trialsincluded in the meta-analysis did not reportblood pressure data, making it difficult to con-clude that outcome differences were driven byrenoprotective effects of the RAS therapy versussystemic blood pressure lowering. Another limi-tation was that the outcomes related to ESRDand doubling of serum creatinine concentrationwere not stratified by baseline albuminuria;patients with normo-, micro-, and macroalbu-minuria were grouped together. Although thereis support for using ACEI or ARB therapy inDKD patients with albuminuria or hypertension,few trials have been designed to evaluate renaloutcomes in normotensive, normoalbuminurictype 2 diabetes patients, and outcomes of thosetrials are mixed.51, 57

Results of two other studies50, 51 do not sup-port the use of ACEI or ARB therapy for renalprotection in normotensive, normoalbuminurictype 1 diabetes patients. A randomized con-trolled trial showed no significant difference innephropathy progression as measured by renalbiopsy with enalapril or losartan versus placebodespite slowed progression of retinopathy.50

Interestingly, progression to microalbuminuriawas significantly higher in the losartan groupversus placebo, a surprising and unexplainedresult.Most trials incorporating aliskiren in patients

with diabetes evaluated aliskiren in combinationwith ACEIs or ARBs. Only one small dose-find-ing crossover trial evaluated aliskiren dosingversus placebo in patients with type 2 diabetes,hypertension, and albuminuria, and it found areduction in albuminuria with aliskiren.58

Two recent randomized controlled trialsraised concerns regarding olmesartan use in type2 diabetes patients because an excess of cardio-vascular deaths was found in the olmesartancompared with placebo group.52, 53 Althoughboth studies were designed to compare olmesar-


tan with placebo, 73.5% of patients in one trial52

were concurrently using ACEIs, but this percent-age was similar at baseline between treatmentarms. The reason for the unexpected rise in fatalcardiovascular events is not fully understood,but chance cannot be ruled out, and furtherevaluation is under way. Currently, the U.S.Food and Drug Administration states thatthe benefits of olmesartan in the treatment ofhypertension in diabetes outweigh the potentialrisks, but it is not recommended as a treatmentstrategy to delay or prevent microalbuminuria inpatients with diabetes and normoalbuminuria.59

Overall, meta-analyses and additional evidencefrom recent single trials support the use of ACEIor ARB therapy in patients with type 1 or type 2diabetes who have albuminuria and/or hyperten-sion. The role of ACEI and ARB therapy in dia-betes patients who are normotensive with eithernormo- or microalbuminuria is more controver-sial and data are limited; a consistent renopro-tective benefit has not been demonstrated inpatients with type 1 diabetes. More research inthis area will help to better define the role ofRAS agents for these patient populations.

Dual Renin-Angiotensin System Therapy

Compared with Single Renin-AngiotensinSystem Agents

Both ACEIs and ARBs have demonstrated ben-efit as primary therapy for patients with DKD,particularly those with proteinuria. ACEIs andARBs have long been regarded as alternatives forone another largely based on tolerability, despitemore evidence supporting ACEIs than ARBs in

patients with type 1 diabetes and vice versa inpatients with type 2 diabetes.1, 28 Many attemptsto differentiate the two classes based on variousend points have shown little success. One suchstudy is the 5-year randomized double-blindDiabetes Exposed to Telmisartan and EnalaprilTrial (DETAIL), which directly compared enalap-ril 10–20 mg per day to telmisartan 40–80 mg/day in type 2 diabetes patients. Results demon-strated the noninferiority of telmisartan com-pared with enalapril on the primary end point ofGFR decline and support the notion that thetwo RAS classes provide the same degree of ren-oprotection.60 Thus although ACEIs and ARBsdiffer somewhat in pharmacologic actions(Table 3),61 these differences have not yet beenproven to modify their clinical effect in singleuse in humans.Alternatively, investigators have explored the

impact of dual blockade in both diabetic andnondiabetic patients with hypertension andCKD. The first fair-size study to evaluate dualblockade on hard renal outcomes was the Com-bination Treatment of Angiotensin-II ReceptorBlocker and Angiotensin-Converting EnzymeInhibitor in Nondiabetic Renal Disease (COOP-ERATE) trial.62 Results showed a favorable effectof dual treatment versus ACEIs or ARBs aloneon the primary end point (doubling of serumcreatinine concentration or development ofESRD). However, a retraction of this study waspublished in 2009 after an investigation showedserious scientific misconduct.63

Subsequent studies in patients with diabetesfocused on short-term reduction in proteinuria,not long-term reduction in blood pressure or

Table 3. Advantages and Disadvantages of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers61

Advantages of ACEIs Advantages of ARBs

Reduced angiotensin II production leads to reduced AT1

receptor activation, preventing vasoconstriction, aldosteronesecretion, and subsequent renal sodium reabsorption.

Complete blockade of AT1 receptor throughout body,preventing vasoconstriction, aldosterone secretion, andsubsequent renal sodium reabsorption.

Inhibits breakdown of bradykinin, a vasodilator. No angiotensin II or aldosterone escape.Partial preservation of angiotensin II–relatedfeedback on renin release.

Does not block angiotensin II stimulation of AT2 receptor,resulting in vasodilation.

Disadvantages of ACEIs Disadvantages of ARBs

Angiotensin I production can continue through nonreninpathways (e.g., tissue plasminogen activator, cathepsin, tonin).Angiotensin II production can continue through non-ACEpathways (e.g., chymase, cathepsin).Minimal effect on local angiotensin II production.No inhibition of intrarenal ACE.

Increased renin levels and angiotensin II; angiotensin II canbind to AT2, AT3, and AT4 receptors (unclearconsequences for stimulation of AT3 and AT4 receptors).Stimulation of AT2 receptor by angiotensin II may result inaccelerated apoptosis, proinflammatory signal transduction,or chemokine induction.

ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; AT1, AT2, AT3, or AT4 = angiotensin II type 1, 2, 3,or 4 receptor.


slowing the progression of kidney disease. Ameta-analysis that included randomized con-trolled studies published before 2007, comparingdual ACEI and ARB therapy with ACEIs or ARBsalone in patients with or without diabetes,showed further reduction in proteinuria whendual therapy was applied over relatively shortfollow-up times of 1 to 12 months.10 However,patients receiving dual therapy were four toalmost six times more likely to discontinue ther-apy than patients receiving monotherapy, andadverse effects were not uniformly reported inthese studies. An earlier systematic review ofstudies conducted in hypertensive patients sug-gested that dual ACEI-ARB therapy resulted inan approximate 4 and 3 mm Hg greater reduc-tion in SBP and DBP, respectively, over a 24-hour period than monotherapy alone, but anumber of the included studies failed to maxi-mize the doses of the drugs used for monothera-py.64 Thus, whether the greater reduction inproteinuria simply stemmed from better bloodpressure control in the dual therapy groupscompared with the monotherapy groups remainsunclear. More importantly, the larger questionsof whether dual therapy is more effective inreducing progression of DKD or cardiovascularevents were not addressed in either of thesemeta-analyses or subsequent small trials withdual therapies in patients with diabetes(Table 4).10, 65–68

The most significant trial to date thataddresses dual ACEI-ARB therapy in patientswith and without diabetes is the ONgoing Tel-misartan Alone and in combination with Rami-pril Global Endpoint Trial (ONTARGET).66

More than 25,000 patients with diabetes andend-organ damage or with atherosclerotic vascu-lar disease were randomized to treatment withtelmisartan 80 mg/day, ramipril 10 mg/day, orboth. The primary study outcome was a com-bined end point of doubling of serum creatinineconcentration, hemodialysis initiation, or death.The secondary endpoint (doubling of serumcreatinine and dialysis initiation) was statisticallysignificantly higher when dual therapy was com-pared with the single agents. No blood pressuregoal was stated, and no other antihypertensiveagents were used.The ONTARGET trial showed a greater reduc-

tion in eGFR with dual than with single therapy,despite a more significant decrease in albumin-uria in the dual therapy group. Despite validity ofthe trial, a significant limitation in interpretingthe results may be lack of inclusion of patients

with proteinuria; only 16% of patients demon-strated any level of micro- or macroalbuminuria,and mean eGFR was ~74 ml/min/1.73 m2 in theincluded patients, suggesting that the populationrecruited may have been low risk and susceptibleto significant misclassification of eGFR based onthe estimating equation used (Table 4).10, 65–68

Additionally, a third of patients did not havehypertension at study initiation (mean SBP~142 mm Hg); more hypotensive episodes in thedual therapy group may have contributed to morerenal ischemia (and larger reduction in eGFR).Although some concerns linger about this

study for evaluation of kidney-related end points(not powered for kidney-related end points, rela-tively low percentage of patients with albumin-uria or eGFR less than 60 ml/min/1.73 m2,acute and long-term hemodialysis events couldnot be reliably separated, and albuminuria moni-toring may have been lax),69 experts have cau-tioned that dual ACEI-ARB therapy should notbe routinely prescribed in the primary care set-ting, and if used, it should be done under thecare of specialists and monitored carefully toavoid unreasonable reductions in eGFR or thedevelopment of hyperkalemia. However, otherexperts have pointed out that the renoprotectiveeffect of proteinuria reduction increases withincreasing levels of baseline proteinuria. Dualblockade may not be necessary in patients withlow urinary albumin excretion but may be usefulin those with high excretion.70

It was expected that the Veterans Affairs (VA)NEPHROpathy iN Diabetes (NEPHRON-D)study71 would address many of the limitations ofearlier dual ACEI-ARB therapy studies includingthe ONTARGET trial. It was a mid-size(n=1644), long-term (up to 5 years), random-ized double-blind multicenter trial assessing dualtherapy with losartan and lisinopril versus lisin-opril alone, specifically in patients with stage 2and 3 CKD, diabetes, and macroalbuminuria onthe hard end point of time to reduction in eGFR(degree based on entry GFR) and progression toESRD. Investigators stratified by baseline albu-minuria and eGFR less than 60 versus morethan 60 ml/min/1.73 m2 because eGFR andalbuminuria are independent predictors of kid-ney disease progression and may also modify theeffect of RAS agents on disease progression. Thisstudy evaluated the prevalence of serious hyper-kalemia and all-cause mortality. Study enroll-ment began in 2008; estimated completion datewas 2014.72 However, the study was terminatedearly on recommendations of the Data Monitoring


Table 4. Summary of Meta-Analyses, Reviews, and Recent Studies Evaluating Dual versus Single Renin Angiotensin SystemAgents in Patients with Diabetes, Chronic Kidney Disease, or Diabetic Kidney Disease


Kunz R 200810 Inclusion criteria DM, non-DM with micro- or macroalbuminuria.Exclusion criteria No evidence of microalbuminuria or proteinuria.No. of patients 16 RCTs (n=571): DM type 1: 1 RCT (n=18); DM type 2: 5 RCTs (n=297);

non-DM: 10 RCTs (n=256).Design Meta-analysis (evaluated studies through September 2006).Duration Ranged from 1–12 mo.Treatment regimen Dual therapy with ACEI + ARB vs ARB alone.Proteinuria/albuminuriaresults

Ratio of means for dual vs ARB: 0.76 (95% CI, 0.68–0.85) over months1–4, 0.75 (95% CI, 0.61–0.92) over months 5–12.


Not reported.

Adverse effects Patients receiving dual therapy were four times more likely to discontinuetherapy than patients receiving ARB alone.

Other results Dual ACEI + ARB therapy significantly more effective in reducingalbuminuria than ARB alone.

Limitations Most studies had small sample sizes and short-term, variable qualityand did not provide reliable data on adverse effects. Proteinuria is onlya surrogate for kidney disease progression.

Kunz R 200810 Inclusion criteria DM, non-DM with micro-or macroalbuminuria.Exclusion criteria No evidence of microalbuminuria or proteinuria.No. of patients 23 RCTs (n=711): DM type 1: 3 RCTs (n=63); DM type 2: 7 RCTs (n=330);

mixed DM–non-DM: 3 RCTs (n=117); non-DM: 10 RCTs (n=201).Design Meta-analysis (evaluated studies through September 2006).Duration Ranged from 1–12 mo.Treatment regimen Dual therapy with ACEI + ARB vs ACEI alone.Proteinuria/albuminuriaresults

Ratio of means for dual vs ACEI: 0.78 (95% CI, 0.72–0.84)over months 1–4, 0.82 (95% CI, 0.67–1.01) over months 5–12.


Not reported.

Adverse effects Patients receiving dual therapy were almost six times more likely to discontinuethan patients receiving ACEI alone.

Other results Dual ACEI + ARB therapy significantly more effective in reducing albuminuriathan ACEI alone.

Limitations Most studies had small sample sizes and short-term, variable quality and did notprovide reliable data on adverse effects. Proteinuria is only a surrogatefor kidney disease progression.

IMPROVE200765

Inclusion criteria Age � 55 yrs, increased CV risk (e.g., DM), BP > 140/90 mm Hg, albuminuria,receiving ACEI.

Exclusion criteria SBP < 115 or � 200 mm Hg and/or DBP � 115 mm Hg.No. of patients 405: 201 receiving ramipril, 204 receiving ramipril + irbesartan.Design R, DB, PC, parallel-group.Duration 20 wks.Treatment regimen Ramipril 10 mg/day + irbesartan 150–300 mg/day or ramipril 10 mg/day +

placebo; BP goal < 130/80.Proteinuria/albuminuriaresults

Overall, no significant difference in albuminuria; higher percent change inUAER in dual vs single treatment in macroalbuminuria subgroup.


More patients receiving dual vs single treatment achieved goal BP(35.5% vs 10.8%).

Adverse effects Discontinue rate similar between groups: 2.5% with hyperkalemia in in eachgroup, ~3% with high SCr in each group.

Other results 66% DM in single treatment group, 77% DM in dual treatment group.Limitations Underpowered for main outcome (albuminuria); short duration.

(continued)




ONTARGET200866

Inclusion criteria Age > 55 yrs, either DM with end-organ damage or atherosclerotic disease.Exclusion criteria Renal artery stenosis, SCr > 3 mg/dL, SBP > 160 mm Hg or DBP > 100 mm Hg.No. of patients 25,620: 8576 received ramipril, 8542 received telmisartan, 8502 received dual

treatment.Design R, DB, PC, multicenter.Duration 56 mo.Treatment regimen Ramipril 10 mg/day, telmisartan 80 mg/day, or both ramipril + telmisartan; no

BP goal.Proteinuria/albuminuriaresults

Increase in UAE less with telmisartan or dual treatment vs ramipril.


Mean SBP was 2–3 mm Hg lower with dual treatment vs ramipril.

Adverse effects 784 patients discontinued treatment due to hypotension (406 dual treatment,149 ramipril, 229 telmisartan).

Other results Secondary end point (composite of dialysis, SCr doubling, and death) similarwith single treatments (HR 1.0, 95% CI 0.92–1.09) but higher withdual treatment (HR 1.09, 95% CI 1.01–1.18); secondary outcome(dialysis or SCr doubling) similar with single treatments(HR 1.09, 95% CI 0.89–1.34) but higher with dual treatment(HR 1.24, 95% CI 1.01–1.51); eGFR declined least with ramipril(�2.82 ml/min/1.73 m2) vs telmisartan and dual treatment (�4.12 and �6.11ml/min/1.73 m2, respectively).

Limitations Only ~15.5% and ~23.5% of patients had micro- or macroalbuminuria or eGFR< 60 ml/min/1.73 m2, respectively; thus results may not apply to patients withDM and albuminuria or low GFR; SCr was not calibrated to a standard.

Krairittichai,Chaisuvannarat,200967

Inclusion criteria DM type 2 with UPCR > 500 mg/g receiving maximum dose enalapril40 mg/day for 3 mo.

Exclusion criteria Serum potassium level > 5.5 mEq/L, age < 18 yrs, SBP < 100,eGFR < 15 ml/min/1.73 m2.

No. of patients 80: 40 receiving enalapril, 40 receiving enalapril + telmisartan.Design Prospective RCT.Duration 24 wks.Treatment regimen Enalapril 40 mg/day + telmisartan 80 mg/day or enalapril 40 mg/day; BP goal

< 130/80 mm Hg.Proteinuria/albuminuriaresults

Dual treatment showed additional 29% reduction in proteinuria compared withACEI alone.


SBP reduced more in dual treatment vs enalapril alone (SBP reduction of 12.8 vs7.1 mm Hg).

Adverse effects Serum potassium level increased in dual and decreased in ACEI-alone group(+0.07 mEq/L vs �0.2 mEq/L); no serious events or cough reported.

Other results eGFR reduced more in dual treatment vs ACEI alone (eGFR reduction of 3.9 vs1.0 ml/min/1.73 m2).

Limitations Small sample size, no placebo control, baseline diabetes duration longer, UPCRhigher, eGFR lower in dual treatment than in single treatment group; thusresults may be unreliable.

AVOID 2008,68

201073Inclusion criteria DM type 2, age 18–85 yrs, nephropathy (UACR > 300 mg/g or > 200 mg/g),

receiving RAS agents.Exclusion criteria UACR > 3500 mg/g, eGFR < 30 ml/min/1.73 m2, potassium level > 5.1 mEq/L.No. of patients 599: 301 receiving aliskiren + losartan, 298 receiving placebo + losartan.Design R, DB, PC, multicenter.Duration 24 wks.Treatment regimen Losartan 100 mg/day + other antihypertensive drugs to reach BP goal < 130/80

then randomized to aliskiren 150–300 mg/day or placebo.Proteinuria/albuminuriaresults

Dual treatment showed additional 20% reduction in UACR vs losartan alone.


SBP 2 mm Hg lower and DBP 1 mm Hg lower with dual treatment vs ARB alone.

Adverse effects Higher rate of hyperkalemia in stage 3 CKD group with aliskiren vs placebo.Other results Lower rate of kidney dysfunction in stage 3 CKD group with aliskiren vs placebo.Limitations Surrogate end point only (proteinuria reduction).

DM = diabetes mellitus; RCT = randomized controlled trial; ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptorblocker; CI = confidence interval; IMPROVE = Irbesartan in the Management of PROteinuric patients at high risk for Vascular Events trial;CV = cardiovascular; BP = blood pressure; SBP = systolic blood pressure; DBP = diastolic blood pressure; R, DB, PC = randomized double-blind placebo-controlled; UAER = urine albumin excretion rate; SCr = serum creatinine concentration; ONTARGET = ONgoing TelmisartanAlone and in combination with Ramipril Global Endpoint Trial; UAE = urine albumin excretion; HR = hazard ratio; eGFR = estimated glo-merular filtration rate; GFR = glomerular filtration rate; UPCR = urine protein-to-creatinine ratio; AVOID = Aliskiren in the Evaluation ofProteinuria in Diabetes; UACR = urine albumin-to-creatinine ratio; RAS = renin-angiotensin system; CKD = chronic kidney disease;


Committee based on a greater number ofobserved acute kidney injury (AKI) events andhyperkalemia in dual therapy group as comparedto ARB plus placebo. Full results are pending.(personal communication Dr. Linda Fried, Febru-ary 21, 2013).

Dual Therapy Including Renin Inhibitors

The ONTARGET results led to the question ofwhether a similar negative effect on kidney-related outcomes may occur with dual RAStherapy with a DRI in patients with DKD. Aliski-ren, the first commercially available DRI,entered the U.S. market in 2007 for treatinghypertension. DRIs inhibit the first step in theRAS cascade, the conversion of angiotensinogento angiotensin I, thus reducing subsequent syn-thesis of all downstream components of the cas-cade, whereas ACEIs and ARBs lead to acompensatory increase in plasma renin activity.A post hoc analysis of the Aliskiren in the Eval-uation of Proteinuria in Diabetes (AVOID)study68 of 599 patients with type 2 diabetes andnephropathy demonstrated that aliskiren addedto losartan and optimal antihypertensive therapyreduced albuminuria further than placebo addedto losartan. The reduction was independent ofbaseline kidney function and changes in bloodpressure.73 However, the drawback was a higherincidence of severe hyperkalemia in CKD stage3 patients in the aliskiren group. Overall, thistrial set the stage for the Aliskiren Trial in Type2 Diabetes Using Cardio-Renal Endpoints (ALTI-TUDE) study.The ALTITUDE study was designed to deter-

mine whether aliskiren 300 mg/day added toconventional treatment with an ACEI or ARBreduced a composite cardiorenal end point (car-diovascular death, resuscitated death, myocardialinfarction, stroke, heart failure hospitalization,onset of ESRD, or doubling of serum creatinineconcentration) in patients with type 2 diabetesat high risk for cardiorenal outcomes includingpatients with albuminuria and GFR 30–60 ml/min/1.73 m2.74 This large well-designed trialwas terminated early (December 2011) after thedata monitoring committee found an increasedrisk of hypotension, kidney impairment, andhyperkalemia along with a trend for higher car-diovascular event rates (death or stroke) inpatients given aliskiren versus placebo.75 Conse-quently, the U.S. Food and Drug Administrationissued a safety communication in April 2012warning of possible risks of dual therapy

with DRIs along with ACEIs or ARBs in patientswith diabetes or GFR less than 60 ml/min/1.73 m2.76

Based on data from the ONTARGET andALTITUDE trials and emerging results from theVA NEPHRON-D study, it is becoming increas-ingly clear that dual RAS blockade should beavoided. Thus patients with DKD should notroutinely be prescribed dual RAS agents to pre-vent progression of kidney disease or for preven-tion of cardiovascular end points.

Treatment Approach with Renin-AngiotensinSystem Agents

Current clinical practice guidelines supportusing ACEIs or ARBs as primary agents toreduce risk of CKD progression in patients withDKD with or without hypertension if the patientexhibits micro- or macroalbuminuria. However,use of RAS agents in patients with DKD is notwithout risks. All of these agents, throughreduction of angiotensin II formation or throughblockade of the receptor, decrease compensatoryvasoconstriction in the glomerular efferent arte-riole, effectively lowering glomerular pressure(Figure 1).77 This kidney-specific action, whichis not shared by other antihypertensive classes,is thought to be responsible for the observationthat glomerular protection is independent of thelowering effects of systemic blood pressure.Studies have shown that the use of RAS agentsresults in a mean rise in serum creatinine con-centration (and lowering of GFR) relative to di-hydropyridine calcium channel blockers.However, over time, the rate of GFR reductionis less than in patients receiving dihydropyridinecalcium channel blockers.42

The message is that short-term changes in GFRare offset by long-term slowing of GFR decline.However, excessive reduction in GFR can occurwith use of RAS agents, resulting in AKI. Risk ofAKI is increased in states of relative intravascularvolume depletion (congestive heart failure, dehy-dration, diuretic use) and with use of other poten-tial nephrotoxins that affect interglomerularhemodynamics (e.g., nonsteroidal anti-inflamma-tory drugs, contrast media) (Figure 1).77 In addi-tion, suppression of angiotensin II effect and ofaldosterone production with RAS agents contrib-utes to increased renal sodium excretion andpotassium reabsorption that can result in hyper-kalemia. Importantly, patients receiving potas-sium-sparing diuretics or potassium supplements,or who have lower baseline GFRs, are more prone


to develop hyperkalemia. The following RAS useand monitoring suggestions, guided by publishedstudies and by methods used in the VA NEPH-RON-D study,71 represent a reasonable approachto maximizing efficacy and reducing the possibil-ity of harm in patients with DKD:

• Blood pressure goal less than or equal to 130/80 mm Hg may be reasonable for many patientswith DKD and micro- or macro-albuminuria,but a higher goal (e.g., less than or equal to140/90 mm Hg) may be appropriate in thosewith normoalbuminuria, for elderly patients orthose with significant cardiovascular disease;therefore, individualize the blood pressure goal.

• Consider use of ACEIs or ARBs as single-agentprimary therapy in all patients with DKD, par-

ticularly those with concurrent hypertensionandmicro- or macroalbuminuria.

• Do not institute dual RAS therapy exceptunder the care or recommendation of a spe-cialist (endocrinologist, nephrologist, or dia-betologist).

• Do not initiate RAS therapy in patients withpotassium levels higher than 5.5 mEq/L orwith diagnosed or suspected bilateral renalartery stenosis.

• Assess serum creatinine and serum potas-sium concentrations before ACEI or ARB ini-tiation and with each dose increase.

• Initiate using lowest doses of ACEIs orARBs; consider halving the lowest dosein patients at high risk for RAS agent–induced AKI (elderly patients, patients with

Figure 1. Intrarenal mechanisms for autoregulation of glomerular filtration rate (GFR) under normal conditions andsituations of decreased perfusion pressure and GFR reduction in the presence of renin-angiotensin system (RAS) agents andnonsteroidal anti-inflammatory drugs (NSAIDs). Panel A shows normal conditions, with normal GFR. Panel B showsdecreased perfusion pressure and normal kidney autoregulation. Normal GFR is maintained by afferent arteriole vasodilationand efferent arteriole vasoconstriction. Panel C shows decreased perfusion pressure with use of NSAIDs in the presence ofdecreased kidney perfusion. NSAIDs reduce vasodilatory prostaglandins, leading to narrowing of afferent arterioles andfurther reduced glomerular pressure and lower GFR. Panel D shows decreased perfusion pressure with RAS agents.Reduction in angiotensin II action, essential for the autoregulatory mechanism to maintain glomerular pressure in situationsof decreased kidney perfusion, results in decreased glomerular capillary pressure and reduced GFR. (From reference 77 withpermission.)


atherosclerosis, or patients using diuretics orare dehydrated).

• Maximize ACEI or ARB dose by titrating upas frequently as every 2 to 4 weeks until themaximum dose is achieved or hypotensionor other adverse effects occur (see potassiumand serum creatinine concentration monitor-ing guidelines below).

• Reassess potassium and serum creatinineconcentration within 2 weeks of initiatingRAS agent or dose increase.

○ Recommendations regarding changes inserum creatinine concentrations:

■ If the dose is tolerated with 30% or lessincrease in baseline serum creatinine or 30% orless increase in baseline eGFR, consider doseincrease.■ If the serum creatinine increases more than30% from baseline or GFR is reduced morethan 30% from baseline anytime within4 months of RAS initiation, decrease the dose(or stop the RAS agent if at lowest dose).

○ Recommendation regarding serum potas-sium levels:

■ If the potassium level is at or increases to5.0 mEq/L, prescribe a low-potassium diet.■ If the potassium level increases to 5.5 mEq/L,measures such as adjustment in diuretics,administration of long-term alkali supplements,liberalizing salt intake, or long-term use of low-dose sodium polystyrene sulfonate may be indi-cated.■ If the potassium level increases to 6.0 toless than 6.5 mEq/L, stop the RAS agent andreinstitute at 50% of the prior dose whenpotassium is less than 5.5 mEq/L.■ If potassium increases to 6.5 mEq/L ormore, permanently discontinue the RAS agent.

Patients with DKD are complex from thestandpoint of multiple concurrent comorbidconditions (e.g., hypertension, atherosclerosis,congestive heart failure, other cardiovasculardisorders, and peripheral neuropathy), multipleantihypertensive and other medications, andkidney dysfunction that can alter the pharmaco-kinetics and pharmacodynamics of drugs. Arecent review showed that blood pressure con-trol is not achieved in many CKD patients, andseveral lines of evidence in the general andCKD populations show that pharmacists work-ing in collaboration with physicians canimprove blood pressure control compared with

usual care.78 The major roles of the pharmacistare to intensify antihypertensive regimens andimprove medication adherence. A population ofDKD patients, whose blood pressure goal is amoving target and who often need multiplemedications in addition to RAS agents to man-age blood pressure, presents an opportunity forpharmacists to use their knowledge and skillsto improve care.

Conclusion

Blood pressure management and ACEI or ARBuse are key strategies in reducing progression ofkidney disease in patients with DKD. Evidencesupports use of ACEI or ARB therapy to reduceprogression of kidney disease in patients withtype 1 or type 2 diabetes and micro- or macroal-buminuria and/or hypertension. However,whether or not microalbuminuria in normoten-sive patients will progress to ESRD has createdcontroversy. The role of ACEI or ARB therapy innormotensive and normoalbuminuric patients isnot recommended because a consistent renopro-tective benefit has not been demonstrated inpatients especially with type 1 diabetes. There isa paucity of evidence for use of the DRI aliskirenas a single agent to decrease progression of kid-ney disease. Results from recent trials evaluatingthe effectiveness of dual therapy with an ACEIand ARB or a DRI and ARB suggest that thesecombinations may increase rather than decreasekidney-related outcomes, particularly in patientswith lower kidney disease progression risk. Thusdual therapy should not be routinely prescribedin diabetic patients until further studies are con-ducted. RAS therapy can be a double-edgedsword in DKD management. Evidence showsthat RAS therapy can slow progression of DKD;however, overly aggressive use in patients at riskfor RAS-related adverse effects and/or inadequatemonitoring can result in AKI. The treatmentapproach we suggest represents a reasonable oneto maximize efficacy and reduce the possibilityof harm in patients with DKD. Practitionersshould keep abreast of new clinical practiceguideline development through the NationalKidney Foundation KDOQI (www.kidney.org/professionals/kdoqi/), Kidney Disease ImprovingGlobal Outcomes (KDIGO;www.KDIGO.org),American Diabetes Association (www.diabetes.org/), and Joint National Committee on Preven-tion, Detection, Evaluation, and Treatment ofHigh Blood Pressure (http://www.nhlbi.nih.gov/guidelines/hypertension/) guidelines.


Acknowledgments

The authors thank Chronic Disease ResearchGroup colleagues Dana Knopic and Anne C. Shawfor their assistance in preparing this manuscript forpublication from the authors’ original, and NanBooth for manuscript editing.

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