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Antihypertensive agents for preventing diabetic kidney

disease (Review)

Lv J, Perkovic V, Foote CV, Craig ME, Craig JC, Strippoli GFM

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2012, Issue 12

http://www.thecochranelibrary.com

Antihypertensive agents for preventing diabetic kidney disease (Review)

Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

11DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

12AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

12ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

12REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

21CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

55DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 ACEi versus placebo/no treatment, Outcome 1 Normo- to micro- or macroalbuminuria. 57

Analysis 1.2. Comparison 1 ACEi versus placebo/no treatment, Outcome 2 All-cause mortality. . . . . . . . . 58

Analysis 1.3. Comparison 1 ACEi versus placebo/no treatment, Outcome 3 Doubling of SCr. . . . . . . . . 59

Analysis 1.4. Comparison 1 ACEi versus placebo/no treatment, Outcome 4 ESKD. . . . . . . . . . . . . 60

Analysis 1.5. Comparison 1 ACEi versus placebo/no treatment, Outcome 5 Adverse events. . . . . . . . . . 61

Analysis 1.6. Comparison 1 ACEi versus placebo/no treatment, Outcome 6 Blood pressure. . . . . . . . . . 62

Analysis 2.1. Comparison 2 ARB versus placebo/no treatment, Outcome 1 Normo- to micro- or macroalbuminuria. 63

Analysis 2.2. Comparison 2 ARB versus placebo/no treatment, Outcome 2 All-cause mortality. . . . . . . . . 64

Analysis 2.3. Comparison 2 ARB versus placebo/no treatment, Outcome 3 Doubling of SCr. . . . . . . . . 65

Analysis 2.4. Comparison 2 ARB versus placebo/no treatment, Outcome 4 ESKD. . . . . . . . . . . . . 66

Analysis 2.5. Comparison 2 ARB versus placebo/no treatment, Outcome 5 Adverse events. . . . . . . . . . 67

Analysis 2.6. Comparison 2 ARB versus placebo/no treatment, Outcome 6 Blood pressure. . . . . . . . . . 68

Analysis 3.1. Comparison 3 ACEi versus ARB, Outcome 1 Normo- to micro- or macroalbuminuria. . . . . . . 69

Analysis 3.2. Comparison 3 ACEi versus ARB, Outcome 2 All-cause mortality. . . . . . . . . . . . . . 69

Analysis 4.1. Comparison 4 ACEi versus CCB, Outcome 1 Normo to micro or macroalbuminuria. . . . . . . 70

Analysis 4.2. Comparison 4 ACEi versus CCB, Outcome 2 All-cause mortality. . . . . . . . . . . . . . 71

Analysis 4.3. Comparison 4 ACEi versus CCB, Outcome 3 Doubling of SCr. . . . . . . . . . . . . . . 72

Analysis 4.4. Comparison 4 ACEi versus CCB, Outcome 4 ESKD. . . . . . . . . . . . . . . . . . 73

Analysis 4.5. Comparison 4 ACEi versus CCB, Outcome 5 Blood pressure. . . . . . . . . . . . . . . . 74

Analysis 5.1. Comparison 5 Prevention of kidney disease: other agents, Outcome 1 ACEi + ARB versus ACEi. . . . 75

Analysis 5.2. Comparison 5 Prevention of kidney disease: other agents, Outcome 2 ACEi versus BB. . . . . . . 75

Analysis 5.3. Comparison 5 Prevention of kidney disease: other agents, Outcome 3 ACEi + CCB versus ACEi. . . 76

Analysis 5.4. Comparison 5 Prevention of kidney disease: other agents, Outcome 4 CCB versus placebo. . . . . . 76

76ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

80APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

88FEEDBACK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

89WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

89HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

89CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

89DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

90INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iAntihypertensive agents for preventing diabetic kidney disease (Review)


[Intervention Review]

Antihypertensive agents for preventing diabetic kidney disease

Jicheng Lv1, Vlado Perkovic1, Celine V Foote1, Maria E Craig2, Jonathan C Craig3, Giovanni FM Strippoli3,4,5,6,7

1Renal and Metabolic Division, The George Institute for Global Health, Camperdown, Australia. 2Divison of Women’s and Children’s

Health, University of New South Wales, Kogarah, Australia. 3Cochrane Renal Group, Centre for Kidney Research, The Children’s

Hospital at Westmead, Westmead, Australia. 4Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.5Department of Clinical Pharmacology and Epidemiology, Mario Negri Sud Consortium, Santa Maria Imbaro, Italy. 6Sydney School

of Public Health, The University of Sydney, Sydney, Australia. 7Medical-Scientific Office, Diaverum, Lund, Sweden

Contact address: Giovanni FM Strippoli, [email protected].

Editorial group: Cochrane Renal Group.

Publication status and date: New search for studies and content updated (conclusions changed), published in Issue 12, 2012.

Review content assessed as up-to-date: 24 January 2011.

Citation: Lv J, Perkovic V, Foote CV, Craig ME, Craig JC, Strippoli GFM. Antihypertensive agents for preventing diabetic kidney

disease. Cochrane Database of Systematic Reviews 2012, Issue 12. Art. No.: CD004136. DOI: 10.1002/14651858.CD004136.pub3.


A B S T R A C T

Background

Various blood pressure-lowering agents, and particularly inhibitors of the renin-angiotensin system (RAS), are widely used for people

with diabetes to prevent the onset of diabetic kidney disease (DKD) and adverse cardiovascular outcomes. This is an update of a

Cochrane review first published in 2003 and updated in 2005.

Objectives

This systematic review aimed to assess the benefits and harms of blood pressure lowering agents in people with diabetes mellitus and a

normal amount of albumin in the urine (normoalbuminuria).

Search methods

In January 2011 we searched the Cochrane Renal Group’s Specialised Register through contact with the Trials Search Co-ordinator.

Selection criteria

Randomised controlled trials (RCTs) comparing any antihypertensive agent with placebo or another agent in hypertensive or nor-

motensive patients with diabetes and no kidney disease (albumin excretion rate < 30 mg/d) were included.

Data collection and analysis

Two investigators independently extracted data on kidney and other patient-relevant outcomes (all-cause mortality and serious cardio-

vascular events), and assessed study quality. Analysis was by a random effects model was applied to analyse results which were expressed

as risk ratio (RR) and 95% confidence intervals (CI).

Main results

We identified 26 studies that enrolling 61,264 participants. Angiotensin-converting enzyme inhibitors (ACEi) reduced the risk of new

onset of microalbuminuria, macroalbuminuria or both when compared to placebo (8 studies, 11,906 patients: RR 0.71, 95% CI 0.56

to 0.89), with similar benefits in people with and without hypertension (P = 0.74), and when compared to calcium channel blockers

(5 studies, 1253 participants: RR 0.60, 95% CI 0.42 to 0.85). ACEi reduced the risk of death when compared to placebo (6 studies,

11,350 participants: RR 0.84, 95% CI 0.73 to 0.97). No effect was observed for angiotensin receptor blockers (ARB) when compared

1Antihypertensive agents for preventing diabetic kidney disease (Review)


mailto:[email protected]

to placebo for new microalbuminuria, macroalbuminuria or both (5 studies, 7653 participants: RR 0.90, 95% CI 0.68 to 1.19) or

death (5 studies, 7653 participants: RR 1.12, 95% CI 0.88 to 1.41); however, meta-regression suggested possible benefits from ARB for

preventing kidney disease in high risk patients. There was a trend towards benefit from use of combined ACEi and ARB for prevention

of DKD compared with ACEi alone (2 studies, 4171 participants: RR 0.88, 95% CI 0.78 to 1.00).The risk of cough was significantly

increased with ACEi when compared to placebo (6 studies, 11,791 patients: RR 1.84, 95% CI 1.24 to 2.72), however there was no

significant difference in the risk of headache or hyperkalaemia. There was no significant difference in the risk of cough, headache

or hyperkalaemia when ARB was to placebo. On average risk of bias was judged to be either low (27% to 69%) or unclear (i.e. no

information available) (8% to 73%). Blinding of participants, incomplete outcome data and selective reporting were judged to be high

in 23%, 31% and 31% of studies, respectively.

Authors’ conclusions

ACEi were found to prevent new onset DKD and death in normoalbuminuric people with diabetes, and could therefore be used in

this population. More data are needed to clarify the role of ARB and other drug classes in preventing DKD.

P L A I N L A N G U A G E S U M M A R Y

Drugs for preventing kidney disease in people with diabetes

Many people with diabetes (around 20% to 60%) are are affected by high blood pressure (hypertension) and need drugs (antihypertensive

agents) to treat this condition. These drugs also help to prevent development of kidney disease both in people with diabetes who have

normal blood pressure and those whose blood pressure is high. Many people with diabetic kidney disease (DKD) (20% to 40%) go

on to develop end-stage kidney disease (ESKD), and many others die from heart disease or other circulatory problems before ESKD

develops.

We reviewed the literature to determine the benefits and harms of antihypertensive treatment in people with diabetes who did not have

signs of kidney disease. We found 26 studies involving 61,264 participants that compared antihypertensive drugs with placebo (an

neutral agent with no therapeutic benefits or harms), no treatment, and other antihypertensive drugs. A family of drugs called ACEi

(angiotensin-converting enzyme inhibitors) has been shown to prevent new onset of kidney disease and reduce the numbers of deaths

in people with diabetes who have normal levels of albumin in their urine compared with placebo or calcium channel blocking drugs.

We found no significant effect from angiotensin receptor blocker (ARB) drugs on either development of ESKD or death.

Subgroup analyses that suggested similar benefits from ARB for people with type 2 diabetes who were at high risk of heart disease or

should be interpreted cautiously. Direct comparison of ACEi and ARB in this population showed no difference in preventing DKD.

The benefits of ACEi are consistent, and ACEi could be the first choice intervention for primary prevention of DKD.

B A C K G R O U N D

Description of the condition

Diabetes is a major global epidemic and responsible for most diag-

noses of end-stage kidney disease (ESKD). Diabetes is also a ma-

jor cause of death in many countries (IDF 2009; USRDS 2009).

Diabetic kidney disease (DKD) (also called diabetic nephropathy)

develops slowly, and the first clinically-evident feature of kidney

involvement is often development of microalbuminuria (urinary

albumin excretion > 30 mg/d). DKD occurs in 20% to 40% of

patients within 10 to 15 years of diabetes onset and typically pro-

gresses to macroalbuminuria before kidney function starts to de-

cline. Micro- and macroalbuminuria are both risk factors for kid-

ney failure, cardiovascular disease and death (Ninomiya 2009; Ritz

1999; Ruggenenti 1997).

Description of the intervention

Hypertension and proteinuria contribute to a progressive dete-

rioration of kidney function in patients with DKD (Hasslacher

1985; Mogensen 1976) and most antihypertensive agents are used

both for the treatment of hypertension and in an effort to slow



the progression of kidney damage in patients with DKD. Antihy-

pertensive agents used in this scenario include angiotensin-con-

verting enzyme inhibitors (ACEi), angiotensin receptor blockers

(ARB), calcium channel blockers (CCBs), beta-blockers and di-

uretics. These have been used both alone or in combination.

How the intervention might work

For patients with established DKD, inhibitors of the renin-an-

giotensin system (RAS) have been shown to retard progressive

kidney impairment and prevent ESKD onset (Strippoli 2004).

Based on data from completed studies, most guideline groups have

recommended the use of ACEi or angiotensin receptor block-

ers (ARB) equally in patients who have diabetes with micro- or

macroalbuminuria, interchangeably (Table 1).

Why it is important to do this review

Our original review suggested that ACEi may reduce the risk of

nephropathy developing in normoalbuminuric patients with dia-

betes (Strippoli 2005). However, relatively few data were available

about the effects of other classes of antihypertensives at that time,

which contributed to some persisting uncertainty. A number of

new studies have examined the efficacy of blood pressure lowering

for the primary prevention of DKD, albeit with conflicting results

(ADVANCE Study 2009; DIRECT Studies 2009; RASS Study

2002; TRANSCEND Study 2009). This updated systematic re-

view was therefore undertaken to evaluate the relative effects of

blood pressure lowering agents on the primary prevention of new-

onset kidney disease in patients who have diabetes.

O B J E C T I V E S

The objectives of this review were to assess the effects of antihy-

pertensive agents for prevention of diabetes in people with kidney

disease who were normoalbuminuric. We aimed to evaluate:

1. the benefits and harms of different antihypertensive agents

such as ACEi, ARB, calcium channel blockers (CCB), beta-

blockers (BB), and diuretics in preventing DKD in diabetic

patients without kidney disease (defined as an albumin excretion

rate < 30 mg/d, that is, no microalbuminuria);

2. if combination therapy with different antihypertensive

agents was better than monotherapy with a single agent if study

data were available; and

3. the variation of effects of interventions according to:

◦ diabetes type 1 or type 2

◦ duration of diabetes at initiation of antihypertensive

treatment (time of study entry)

◦ presence or absence of hypertension.

M E T H O D S

Criteria for considering studies for this review

Types of studies

Any randomised controlled trials (RCTs) and quasi-RCTs (RCTs

in which allocation to treatment was obtained by alternation, use of

alternate medical records, date of birth or other predictable meth-

ods) that evaluated the effect of any antihypertensive agent admin-

istered to diabetic patients who did not have kidney disease (de-

fined as an albumin excretion rate < 30 mg/d on a timed specimen

confirmed with three serial measurements) were included. Studies

in non-diabetic patients were excluded. Studies that were under-

taken in populations with mixed-causation hypertension and in-

cluded a proportion of diabetic patients were included if the raw

data relating to diabetic patients could be obtained from the study

investigators.

Types of participants

Adults aged 18 years and over with type 1 or type 2 diabetes, with-

out diagnoses of kidney disease, and who were normoalbumin-

uria, and irrespective of blood pressure status. Normoalbuminuria

was defined as an albumin excretion rate < 30 mg/d on a timed

specimen confirmed with three serial measurements.

Types of interventions

Antihypertensive agents compared with placebo, no treatment or

another antihypertensive agent for prevention of DKD, irrespec-

tive of class, administered at any dose and for a duration of at least

six months.

Types of outcome measures

• Number of patients who develop microalbuminuria/

macroalbuminuria

◦ progression from normo- to micro or

macroalbuminuria

◦ Albuminuria (mg/24 h or µg/min), macroalbuminuria

(mg/24 h or µg/min) or proteinuria (mg/24 h) at end of

treatment or change between beginning and end of treatment

• Death

◦ all-cause mortality



◦ cardiovascular

• Doubling of serum creatinine

• ESKD

• Blood pressure (mm Hg) (systolic, diastolic, mean arterial

pressure (MAP)) at end of treatment or change between the

beginning and end of treatment

• Adverse events (as reported by the studies)

• Lipid profile

• Glycaemic control (HbA1c%)

• Urinary albumin/creatinine ratio (mg albumin/mmol

creatinine)

Search methods for identification of studies

For this review update we searched the Cochrane Renal Group’s

Specialised Register (24 January 2011) through contact with the

Trials’ Search Co-ordinator using search terms relevant to this

review.

The Cochrane Renal Group’s Specialised Register contains studies

identified from:

1. Quarterly searches of the Cochrane Central Register of

Controlled Trials CENTRAL

2. Weekly searches of MEDLINE OVID SP

3. Handsearching of renal-related journals and the

proceedings of major renal conferences

4. Searching of the current year of EMBASE OVID SP

5. Weekly current awareness alerts for selected renal journals

6. Searches of the International Clinical Trials Register

(ICTRP) Search Portal and ClinicalTrials.gov.

Studies contained in the Specialised register are identified through

search strategies for CENTRAL, MEDLINE, and EMBASE based

on the scope of the Cochrane Renal Group. Details of these strate-

gies as well as a list of handsearched journals, conference proceed-

ings and current awareness alerts are available in the specialised

register section of information about the Cochrane Renal Group.

See Appendix 1 for search terms used in strategies for this review.

The original search strategies can be found in Strippoli 2005.

Data collection and analysis

Selection of studies

Two authors (original review GFMS, MC; review update JL, CF)

undertook selection of studies. Authors independently assessed

retrieved abstracts, and wherever necessary the full text of studies,

to determine which satisfied the inclusion criteria. Disagreements

were resolved in all cases by discussion among author teams.

Data extraction and management

Data extraction was carried out by the same authors independently

using standard data extraction forms. It was planned that any stud-

ies reported in non-English language journals would be translated

before assessment. Where more than one report of one study ex-

isted, the reports were grouped together and the report with most

complete data was used in the analyses. Where relevant outcomes

were only published in other reports these data was used.

Assessment of risk of bias in included studies

For this review update the following items were independently

assessed by two authors using the risk of bias assessment tool (

Higgins 2011) (see Appendix 2).

• Was there adequate sequence generation (selection bias)?

• Was allocation adequately concealed (selection bias)?

• Was knowledge of the allocated interventions adequately

prevented during the study (detection bias)?

◦ Participants and personnel

◦ Outcome assessors

• Were incomplete outcome data adequately addressed

(attrition bias)?

• Are reports of the study free of suggestion of selective

outcome reporting (reporting bias)?

• Was the study apparently free of other problems that could

put it at a risk of bias?

Measures of treatment effect

Data entry was carried out by two authors (original review GFMS,

MC; review update: JL, CF). For dichotomous outcomes results

were expressed as risk ratio (RR) with 95% confidence intervals

(CI). Where continuous scales of measurement were used to assess

the effects of treatment (microalbuminuria, blood pressure) the

mean difference (MD) was used.

Dealing with missing data

Any further information required from the original author was

requested by written correspondence (e.g. emailing and/or writing

to corresponding author/s) and any relevant information obtained

in this manner was included and noted in the Characteristics of

included studies table.

Assessment of heterogeneity

Heterogeneity was analysed using a Chi² test on N-1 degrees of

freedom, with an alpha of 0.05 used for statistical significance and

with the I² test (Higgins 2003). I² values of 25%, 50% and 75%

correspond to low, medium and high levels of heterogeneity.



http://onlinelibrary.wiley.com/o/cochrane/clabout/articles/RENAL/frame.html



Assessment of reporting biases

It was planned that if sufficient RCTs were identified, an attempt

would be made to examine for publication bias using a funnel plot

(Higgins 2011). It was also planned that when different treatment

options had not been compared directly within available RCTs,

conclusions on relative efficacy would be based on indirect com-

parisons where applicable (Bucher 1997; Song 2000). STATA ver-

sion 10.0 was used to test for interaction.

Data synthesis

Data were pooled using the random-effects model but the fixed-

effect model was also used to investigate robustness of the model

chosen and susceptibility to outliers.

Subgroup analysis and investigation of heterogeneity

Subgroup analyses were used to explore possible sources of hetero-

geneity. Heterogeneity among participants could be related to age,

baseline presence or absence of hypertension, renal pathology and

glycaemic control. Heterogeneity in treatments could be related to

dose and duration of therapies administered to study participants.

These aspects were analysed and tabulated or computed when-

ever applicable. Adverse effects were tabulated and assessed using

descriptive techniques because of differences among the various

agents investigated. Where possible, the risk difference with 95%

CI was calculated for each adverse effect, either compared with no

treatment or another agent.

R E S U L T S

Description of studies

See: Characteristics of included studies; Characteristics of excluded

studies.

Results of the search

The literature search identified 5073 articles, of which 4748

were excluded after title and abstract review (Figure 1). Full-text

assessment of 325 potentially eligible reports identified 26 el-

igible studies (143 publications) enrolling 61,264 patients, in-

cluding 33,735 who were normoalbuminuric at baseline (ABCD

Study 2002; ABCD-2V Study 2004; ADVANCE Study 2009;

Baba 2001; BENEDICT Study 2004; CALM II Study 2005;

Chan 1992; Crepaldi 1995; DIRECT Studies 2009 (DIRECT-

Prevent 1, DIRECT-Protect 1, DIRECT-Protect 2); EUCLID

Study 1997; FACET Study 1998; HOPE Study 2000; Joglekar

1998; Kavgaci 2002; Kvetny 2001; Lin 1995; ONTARGET Study

2008; Perrin 2008; RASS Study 2002; Ravid 1998; ROADMAP

Study 2009; Scognamiglio 1997; TRANSCEND Study 2009;

Tuominen 1998; UKPDS Study 1998; Velussi 1996).



Figure 1. Study flow diagram.



Included studies

Supplemental data on design features and outcomes were asked

of all authors of the studies. Authors of the 16 studies that en-

rolled both patients with and without kidney disease were also

asked for data sets of normoalbuminuric patients only, with 12

replying to our requests (ADVANCE Study 2009; Baba 2001;

CALM II Study 2005; Chan 1992; HOPE Study 2000; Kvetny

2001; ONTARGET Study 2008; RASS Study 2002; Ravid 1998;

TRANSCEND Study 2009; Tuominen 1998; Velussi 1996). Un-

fortunately, several studies did not contain any raw data or data

in an extractable format, only summary statistics and overall esti-

mates of the results. These studies therefore could not contribute

to our analyses, in particular to the meta-analyses.

The characteristics of the populations and interventions of

the studies included in this systematic review are presented in

Characteristics of included studies.

• Nine studies or study arms (16,463 patients) compared

ACEi versus placebo or no treatment

• Seven studies or study arms (1804 patients) compared

ACEi versus CCBs

• Four studies (10,517 patients) compared ARB versus

placebo

• Three studies or study arms (17,436 patients) compared

ACEi versus ARB

• One study compared ACEi with beta-blockers (1148

patients)

• Two studies combined ACEi and ARB and compared to

ACEi or ARB (25,695 patients)

• One study combined ACEi and CCB and compared to

ACEi, CCB or placebo (901 patients)

• One study compared ACEi to alpha-blockers (89 patients)

• Two studies compared CCB with placebo (5831 patients).

Most studies enrolled only type 2 diabetic patients (17 studies;

26,342 patients; DIRECT-Prevent 1); seven studies only enrolled

type 1 diabetic patients (2921 patients; DIRECT-Protect 1 and

DIRECT-Protect 2); one study enrolled both type 1 and type 2

diabetic patients (74 patients) and type of diabetes was unknown

in three studies (16,921 patients). Fifteen studies enrolled mixed

populations of normo- and micro-macroalbuminuric subjects.

Follow-up ranged from six to 72 months.

Cointerventions for blood glucose control were administered in

all but one study but the agents used were often not specified.

In general, tight control of blood glucose was addressed with end

of treatment values of HbA1c reported in 20 studies and ranging

between 5% and 9%.

Risk of bias in included studies

Risk of bias was variable as illustrated in Figure 2 and Figure 3.

Figure 2. Risk of bias graph: review authors’ judgements about each risk of bias item presented as

percentages across all included studies.



Figure 3. Risk of bias summary: review authors’ judgements about each risk of bias item for each included

study.



Allocation

Random sequence generation

Random sequence generation was judged to be of low risk in 13/

26 (50%) studies (ABCD-2V Study 2004; ABCD Study 2002;

ADVANCE Study 2009; Baba 2001; Chan 1992; EUCLID Study

1997; FACET Study 1998; Lin 1995; ONTARGET Study 2008;

RASS Study 2002; Ravid 1998; ROADMAP Study 2009; UKPDS

Study 1998) and unclear in 13/26 studies (BENEDICT Study

2004; CALM II Study 2005; Crepaldi 1995; DIRECT Studies

2009; HOPE Study 2000; Joglekar 1998; Kavgaci 2002; Kvetny

2001; Perrin 2008; Scognamiglio 1997; TRANSCEND Study

2009; Tuominen 1998; Velussi 1996).

Allocation concealment

Allocation concealment was judged to be of low risk in 12/

26 (46%) studies (ABCD-2V Study 2004; ABCD Study 2002;

ADVANCE Study 2009; Baba 2001; DIRECT Studies 2009;

EUCLID Study 1997; FACET Study 1998; ONTARGET Study

2008; Ravid 1998; ROADMAP Study 2009; TRANSCEND

Study 2009; UKPDS Study 1998) and unclear in 14/26 (54%)

studies (BENEDICT Study 2004; CALM II Study 2005; Chan

1992; Crepaldi 1995; HOPE Study 2000; Joglekar 1998; Kavgaci

2002; Kvetny 2001; Lin 1995; Perrin 2008; RASS Study 2002;

Scognamiglio 1997; Tuominen 1998; Velussi 1996).

Blinding

Blinding of participants and personnel (performance bias) was

judged to be of low risk in 18/26 (69%) studies (ABCD-2V Study

2004; ABCD Study 2002; ADVANCE Study 2009; BENEDICT

Study 2004; CALM II Study 2005; Crepaldi 1995; DIRECT

Studies 2009; EUCLID Study 1997; HOPE Study 2000; Kvetny

2001; ONTARGET Study 2008; Perrin 2008; RASS Study 2002;

Ravid 1998; ROADMAP Study 2009; TRANSCEND Study

2009; Tuominen 1998; Velussi 1996); unclear in 2/26 (8%) stud-

ies (Chan 1992; Joglekar 1998); and of high risk in 6/26 (23%)

studies (Baba 2001; FACET Study 1998; Kavgaci 2002; Lin 1995;

Scognamiglio 1997; UKPDS Study 1998).

Blinding of outcome assessors (detection bias) was judged to be of

low risk in 7/26 (27%) studies (ABCD-2V Study 2004; ABCD

Study 2002; ADVANCE Study 2009; Chan 1992; EUCLID

Study 1997; RASS Study 2002; UKPDS Study 1998), and un-

clear in 19/26 (73%) studies (Baba 2001; BENEDICT Study

2004; CALM II Study 2005; Crepaldi 1995; DIRECT Studies

2009; FACET Study 1998; HOPE Study 2000; Joglekar 1998;

Kavgaci 2002; Kvetny 2001; Lin 1995; ONTARGET Study

2008; Perrin 2008; RASS Study 2002; Ravid 1998; ROADMAP

Study 2009; Scognamiglio 1997; TRANSCEND Study 2009;

Tuominen 1998; Velussi 1996).

Incomplete outcome data

Incomplete data was judged to be of low risk in 14/26 (54%)

studies (ABCD-2V Study 2004; ADVANCE Study 2009;

BENEDICT Study 2004; CALM II Study 2005; Chan 1992;

Crepaldi 1995; Kavgaci 2002; ONTARGET Study 2008; RASS

Study 2002; ROADMAP Study 2009; Scognamiglio 1997;

TRANSCEND Study 2009; Tuominen 1998; UKPDS Study

1998); unclear in 4/26 (15%) studies (ABCD Study 2002; Baba

2001; HOPE Study 2000; Lin 1995); and of high risk in 8/26

(31%) studies (DIRECT Studies 2009; EUCLID Study 1997;

FACET Study 1998; Joglekar 1998; Kvetny 2001; Perrin 2008;

Ravid 1998; Velussi 1996).

Selective reporting

Incomplete data was judged to be of low risk in 15/26 (57%)

studies (ADVANCE Study 2009; Baba 2001; BENEDICT Study

2004; Chan 1992; DIRECT Studies 2009; EUCLID Study

1997; FACET Study 1998; HOPE Study 2000; Kvetny 2001;

ONTARGET Study 2008; Perrin 2008; RASS Study 2002; Ravid

1998; TRANSCEND Study 2009; UKPDS Study 1998); un-

clear in 3/26 (12%) studies (ROADMAP Study 2009; Tuominen

1998; Velussi 1996); and of high risk in 8/26 (31%) studies

(ABCD-2V Study 2004; ABCD Study 2002; CALM II Study

2005; Crepaldi 1995; Joglekar 1998; Kavgaci 2002; Lin 1995;

Scognamiglio 1997).

Other potential sources of bias

Intention-to-treat analysis

Intention-to-treat analysis was used in 12/26 (43%) studies (Baba

2001; EUCLID Study 1997; HOPE Study 2000; ABCD-2V

Study 2004; ADVANCE Study 2009; DIRECT Studies 2009;

ONTARGET Study 2008; Perrin 2008; RASS Study 2002;

TRANSCEND Study 2009).

Loss to follow-up

The percentage of patients lost to follow-up ranged between 0%

and 17.2%.



Effects of interventions

Prevention of microalbuminuria and

macroalbuminuria or both

ACEi versus placebo

Compared to placebo or no treatment, ACEi significantly reduced

the risk for new onset of microalbuminuria or macroalbuminuria

by 29% (Analysis 1.1 (8 studies, 11906 participants): RR 0.71,

95% CI 0.56 to 0.89, P = 0.004) with no evidence of heterogene-

ity in the magnitude of effect across the included studies (Chi² =

10.20, I² = 31%, P = 0.18). This analysis was dominated by the

ADVANCE Study 2009 which contributed 45.5% of the weight

to the summary estimate, but exclusion of this study did not sub-

stantially change the overall estimate (RR 0.63, 95% CI 0.48 to

0.83, P = 0.0009). Subgroup analysis and meta-regression revealed

a larger estimate of effect was reported in studies that were small,

did not have adequate allocation concealment or use intention-

to-treat analysis (P < 0.05, Table 2)

ARB versus placebo

Compared with placebo or no treatment, no significant effect on

new onset microalbuminuria or macroalbuminuria was observed

for ARB (Analysis 2.1 (5 studies, 7653 patients): RR 0.90, 95% CI

0.68 to 1.19, P = 0.45). There was some evidence of heterogeneity

in the effect across the included studies (Chi² = 11.16, I² = 56%,

P = 0.06). Subgroup analysis suggested a greater likelihood of

benefit in studies recruiting patients with previous cardiovascular

disease or risk factors, type 2 rather than type 1 diabetes, higher

baseline risk of albuminuria progression, and adequate allocation

concealment (P < 0.05, Table 2).

ACEi versus ARB

Only two studies compared between ACEi and ARB on new onset

albuminuria, and no clear difference was observed (Analysis 3.1

(2 studies, 4303 patients): RR 0.57, 95% CI 0.14 to 2.23, P =

0.42). There was evidence of heterogeneity in the magnitude of

effect between the two studies (Chi² = 6.76, I² = 85%, P = 0.009).

A third study (Kavgaci 2002) did not provide detailed data for

new onset albuminuria and could therefore not be included in the

meta-analysis.

Combination ACEi and ARB therapy

Two studies combined ACEi and ARB and compared to ACEi

alone (Analysis 5.1 (2 studies, 4171 patients): RR 0.88, 95% CI

0.73 to 1.00, P = 0.051). One of these studies (CALM II Study

2005) reported urinary albumin excretion levels remained stable

through the follow-up period.

ACEi versus other active agents

ACEi significantly reduced the risk for new onset of microalbu-

minuria or macroalbuminuria when compared to CCBs (Analysis

4.1 (5 studies, 1253 patients); RR 0.60, 95% CI 0.42 to 0.85, P =

0.004) with no evidence of heterogeneity (Chi² = 1.37, I² = 0.0%,

P = 0.71) .

There was no clear difference in the risk of new onset albuminuria

with ACEi compared with beta-blockers (Analysis 5.2 (1 study,

299 patients): RR, 1.01; 95% CI, 0.74 to 1.37), or ACEi plus

calcium channel blockers versus ACEi (Analysis 5.3 (1 study, 603

patients): RR 1.05, 95% CI 0.55 to 2.01), but the amount of data

available were limited.

CCBs versus placebo

Only one study compared a CCB (verapamil) with placebo and

no significant difference was seen in the risk of new onset microal-

buminuria (Analysis 5.4 (1 study, 603 patients): RR 1.19, 95%

CI 0.75 to 1.88).

All-cause mortality

Twelve studies provided information on the risk of death with

ACEi compared to placebo or no treatment. All-cause mortality

was reduced (Analysis 1.2 (6 studies, 11,350 patients): RR 0.84,

95% CI 0.73 to 0.97) in the ACEi group compared to those re-

ceiving placebo or no treatment, with no evidence of heterogeneity

(Chi² = 1.27, I² = 0%, P = 0.87). No clear reduction in the risk of

death was observed in the five studies (7653 patients) comparing

ARB with placebo or no treatment (Analysis 2.2: RR 1.36, 95%

CI 0.64 to 1.41) with no evidence of heterogeneity (Chi² = 2.66,

I² = 0%, P = 0.45). Similar rates of death were observed in a di-

rect comparison between ACEi and ARB (Analysis 3.2 (2 studies,

4303 patients): RR 1.02, 95% CI 0.85 to 1.22; I² = 0%). The risk

of death was also similar in the five studies (1284 patients) that

compared ACEi and CCBs (Analysis 4.2: RR 0.84, 95% CI 0.26

to 2.73; Chi² = 0.02, I² = 0%, P = 0.89).

Doubling of serum creatinine and progression to

ESKD

Very few patients in these studies progressed to the end point of

doubling of serum creatinine or ESKD. As a result, no significant

difference in the risk for doubling serum creatinine (Analysis 1.3

(5 studies, 10,749 patients): RR 0.77, 95% CI 0.39 to 1.49; Chi²

= 4.15, I² = 52%, P = 0.13) or ESKD (Analysis 1.4 (3 studies,

10,504 patients): RR 1.94, 95% CI 0.6 to 5.70; Chi² = 0.09, I²

= 0%, P = 0.76) was found with ACEi compared with placebo.

Pooled analysis for doubling serum creatinine or ESKD were not

able to be calculated from the studies of ACEi compared with

CCBs since no such events were reported in the four relevant

studies (680 patients).



Three studies (6217 patients) comparing ARB with placebo

showed no significant reduction in the risk for doubling serum

creatinine (Analysis 2.3: RR 0.1.36, 95% CI 0.64 to 2.88). Only

four patients in one of these three studies progressed to ESKD

(Analysis 2.4).

Adverse effects

The risk of cough was significantly increased with ACEi compared

with placebo/no treatment (Analysis 1.5.1 (6 studies, 11,791 pa-

tients): RR 1.84, 95% CI 1.24 to 2.72; Chi² = 5.15, I² = 3%, P

= 0.40), whereas there was no significant difference for headache

(Analysis 1.5.2) and hyperkalaemia (Analysis 1.5.3).

No significant difference in the risk of cough, headache or hyper-

kalaemia was found for ARB compared to placebo (Analysis 2.5).

Blood pressure

Systolic BP was significantly lower in the ACEi group (Analysis

1.6.1 (2 studies, 7526 patients): MD -5.37 mm Hg, 95% CI -

7.12 to -3.62), and ARB group (Analysis 2.6.1 (2 studies, 1770

patients): MD -3.28 mm Hg, 95% CI -5.29 to -2.90) when com-

pared to placebo. CCB significantly lowered systolic BP when

compared to ACEi (Analysis 4.5.1 (2 studies, 430 participants):

MD 4.00 mm Hg, 95% CI -1.59 to 6.41).

Diastolic BP was significantly lower in the ACEi group (Analysis

1.6.2 (2 studies, 7526 patients): MD -1.50 mm Hg, 95% CI -

1.50 to -1.50), and ARB group (Analysis 2.6.2 (2 studies, 1770

patients): MD -2.00 mm Hg, 95% CI -2.64 to -1.36) when com-

pared to placebo. There was no significant difference between CCB

and ACEi (Analysis 4.5.2 (2 studies, 430 participants): MD 1.22

mm Hg, 95% CI -0.42 to 2.85).

Other outcomes

Lipid profile, glycaemic control and urinary albumin/creatinine

ratio were either poorly reported or not reported and we therefore

could not perform meta-analyses for these outcomes.

D I S C U S S I O N

Summary of main results

Individuals with diabetes who develop kidney disease are at in-

creased risk of kidney failure, cardiovascular events and death

(Ninomiya 2009; Perkovic 2008). Current treatments provide

modest benefits once kidney diease is established, so primary pre-

vention has been the focus of much attention in recent years

(DIRECT Studies 2009; RASS Study 2002; ROADMAP Study

2009; Parfrey 2009). This updated systematic review has several

times more data than a previous analysis, and has shown that ACEi

reduced the risk of new onset kidney disease by 29% and the risk

of death by 16% in people with diabetes. Clear renal benefits were

observed among individuals without hypertension at baseline, and

in comparison to CCBs. These effects are also consistent across

a broad spectrum of people with diabetes, including individuals

with type 1 or type 2 diabetes, with or without hypertension, and

in placebo controlled studies or those comparing ACEi to other

blood pressure agents. Other studies have suggested ACEi also

prevent new onset diabetic retinopathy in patients without albu-

minuria (EUCLID Study 1997; RASS Study 2002). In contrast

we were unable demonstrate similar overall benefits for ARB over-

all, although it remains possible that benefits may be present for

high risk individuals. These results suggest that ACEi could be

routinely considered for the primary prevention of microvascular

disease and death in people with diabetes regardless of blood pres-

sure levels, although further study is needed to evaluate the cost

effectiveness of this approach.

Potential biases in the review process

The main limitation of this study was that the effects of blood

pressure lowering agents on ESKD could not be ascertained, pos-

sibly due to the slowly progressive nature of DKD, and the re-

sultant low incidence of ESKD in the population. As the use of

ACEi in this population also reduced the risk of death from any

cause, the impact of this limitation for this drug class is likely to be

modest. It has been generally accepted that the onset of albumin-

uria precedes kidney failure and is thus a reliable sign of DKD,

but this notion has been challenged by reports of diabetic patients

with decreased renal function but without albuminuria (DIRECT

Studies 2009). Although observational studies show a strong and

graded relationship between albuminuria levels and the risk of de-

creasing GFR and the development of kidney failure (Adler 2003;

Gerstein 2001; Messent 1992). The available clinical studies have

not demonstrated that preventing microalbuminuria will neces-

sarily lead to reductions in kidney failure. This is mainly a result

of the slow rate of decline in kidney function in diabetes, meaning

that very long follow up would be required in people with diabetes

and normoalbuminuria (Levey 2009). Further study is needed to

confirm whether the prevention of microalbuminuria would lead

to fewer kidney failure or cardiovascular events (Klausen 2004).

Agreements and disagreements with otherstudies or reviews

ACEi and ARB have been recommended interchangeably in most

guidelines for the treatment of people with diabetes (Table 1).The

available data, summarized in this review, suggest that the benefits

of ACEi for the prevention of DKD as well as death were clear,

while as for ARB no clear effects on mortality was observed and



renal benefits were only found in subgroup analyses. ACEi were

also superior to calcium channel blockers in head to head compar-

isons, but little data was available for other drug classes. Studies in

people with DKD have identified clear benefit for ARB in the pre-

vention of ESKD, but have similarly failed to show any benefit for

cardiovascular outcomes or death (Strippoli 2004).Other studies

have also demonstrated consistent preventive effects of ARB on

diabetic retinopathy (Chaturvedi 2008; RASS Study 2002; Sjølie

2008). Caution is required in interpreting potential differences in

the effects of ACEi and ARB. Most ARB studies (DIRECT Studies

2009; RASS Study 2002) in this meta-analysis recruited mainly

normotensive patients at low renal and vascular risk, so event rates

were modest limiting study power. Metaregression also identified

baseline renal and cardiovascular risk as a significant effect modi-

fier for ARB in the prevention of kidney disease, with evidence of

benefit in high risk individuals that was similar in magnitude to

that reported for ACEi. The likelihood of similar effects of the two

classes is further supported by the results of the large ONTARGET

Study 2008 in which a head-to-head comparison demonstrated

that ARB and ACEi were equivalent for the prevention of DKD

in individuals at high cardiovascular risk, and that also suggested

additional benefit for new onset albuminuria when the two classes

of drugs were combined (ONTARGET Study 2008). The consis-

tency of effect demonstrated for ACEi, as well as the clear mortal-

ity benefits observed, suggest that these agents should be the first

choice for the primary prevention intervention of DKD, while

ARB appear a reasonable alternative in high risk individuals who

are unable to tolerate ACEi.

Another finding in this meta-analysis was that the benefits for pri-

mary prevention of DKD were similar in people with and without

hypertension at baseline, so that ACEi were effective even among

groups that are considered normotensive. As RAS blockade has

already been proven to be effective at preventing ESKD in indi-

viduals with established DKD (Strippoli 2004), these results sug-

gest that ACEi are likely to be beneficial for all individuals with

diabetes who are able to tolerate these agents.

Treatment with ACEi could therefore be recommended in nor-

moalbuminuric patients with diabetes for at least two purposes:

the primary prevention of kidney disease, as well as reduction in

the risk of death in this population. ACEi may be used in prefer-

ence to ARB based on the stronger data available for this class of

agents. If these data are applied to a broad population of people

with diabetes, the large excess burden of morbidity and mortality

suffered by these individuals may be substantially reduced.

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

Our data therefore suggest that ACEi could prevent new onset

kidney disease and also reduce the risk of death in diabetics with

normoalbuminuria so should be the treatment of choice in this

population.

Implications for research

Future studies of antihypertensive agents in diabetic patients with

no kidney disease should report microalbuminuria and other re-

nal outcomes as well as the usually reported outcomes - all-cause

mortality and cardiovascular endpoints.

A C K N O W L E D G E M E N T S

We acknowledge the editorial and administrative support of

Narelle Willis and Gail Higgins, trial search coordinators of the

Cochrane Renal Group, provided search strategies for this review.

We are particularly indebted to Janice Pogue and the HOPE in-

vestigators; Michael Mauer and the RASS investigators; Drs An-

dersen, Ravid, Kvetny, Tuominen, Baba, Velussi, and Lin, who

provided data of normoalbuminuric patients with diabetes in their

study or information about study design and conduct upon re-

quest.

R E F E R E N C E S

References to studies included in this review

ABCD-2V Study 2004 {published data only}

Estacio RO, Coll JR, Tran ZV, Schrier RW. Effect of

intensive blood pressure control with valsartan on urinary

albumin excretion in normotensive patients with type 2

diabetes. American Journal of Hypertension 2006;19(12):

1241–8. [MEDLINE: 17161769]

Estacio RO, Esler A, Lundgren R, Schrier RW. Aggressive

blood pressure control with valsartan in normotensive Type

2 diabetic patients results in regression of albuminuria.

[abstract]. Journal of the American Society of Nephrology

2004;15(Oct):568A.

ABCD Study 2002 {published data only}

Estacio RO, Jeffers B, Biggerstaff S, Schrier RW. Effects of

a calcium channel antagonist versus an ace inhibitor on

diabetic nephropathy [abstract]. Journal of the American

Society of Nephrology 1998;9(Program & Abstracts):114A.

Estacio RO, Jeffers BW, Gifford N, Schrier RW. Effect

of blood pressure control on diabetic microvascular

complications in patients with hypertension and type

2 diabetes. Diabetes Care 2000;23(Suppl 2):B54–64.



[MEDLINE: 10860192]

Estacio RO, Jeffers BW, Hiatt WR, Biggerstaff SL, Gifford

N, Schrier RW. The effect of nisoldipine as compared with

enalapril on cardiovascular outcomes in patients with non-

insulin-dependent diabetes and hypertension. New England

Journal of Medicine 1998;338(10):645–52. [MEDLINE:

9486993]

Estacio RO, Mehler P, Esler A, Schrier RW. Aggressive

lowering of blood pressure in normotensive type 2

diabetic patients: beneficial effects on stroke, progression

of retinopathy and nephropathy [abstract]. Journal of

the American Society of Nephrology 2001;12(Program &

Abstracts):146A.

Estacio RO, Savage S, Nagel NJ, Schrier RW. Baseline

characteristics of participants in the Appropriate Blood

Pressure Control in Diabetes trial. Controlled Clinical Trials

1996;17(3):242–57. [MEDLINE: 8877260]

Estacio RO, Schrier RW. Antihypertensive therapy in type

2 diabetes: implications of the appropriate blood pressure

control in diabetes (ABCD) trial. American Journal of

Cardiology 1998;82(9B):9R–14R. [MEDLINE: 9822137]

Savage S, Estacio RO, Jeffers B, Schrier RW. Urinary

albumin excretion as a predictor of diabetic retinopathy,

neuropathy, and cardiovascular disease in NIDDM. Diabetes

Care 1996;19(11):1243–8. [MEDLINE: 8908388]∗ Schrier RW, Estacio RO, Esler A, Mehler P. Effects of

aggressive blood pressure control in normotensive type 2

diabetic patients on albuminuria, retinopathy and strokes.

Kidney International 2002;61(3):1086–97. [MEDLINE:

11849464]

Schrier RW, Estacio RO, Jeffers B. Appropriate Blood

Pressure Control in NIDDM (ABCD) Trial. Diabetologia

1996;39(12):1646–54. [MEDLINE: 8960857]

Stabler SP, Estacio R, Jeffers BW, Cohen JA, Allen

RH, Schrier RW. Total homocysteine is associated

with nephropathy in non-insulin-dependent diabetes

mellitus. Metabolism: Clinical & Experimental 1999;48(9):

1096–101. [MEDLINE: 10484047]

ADVANCE Study 2009 {published data only}

ADVANCE Collaborative Group. ADVANCE--Action in

Diabetes and Vascular Disease: patient recruitment and

characteristics of the study population at baseline. Diabetic

Medicine 2005;22(7):882–8. [MEDLINE: 15975103]

ADVANCE Collaborative Group, Patel A, MacMahon S,

Chalmers J, Neal B, Billot L, et al.Intensive blood glucose

control and vascular outcomes in patients with type 2

diabetes. New England Journal of Medicine 2008;358(24):

2560–72. [MEDLINE: 18539916]

ADVANCE Management Committee. Study rationale

and design of ADVANCE: action in diabetics and vascular

disease - preterax and diamicron MR controlled evaluation.

Diabetologia 2001;44(9):1118–20. [MEDLINE:

11596665]

Anonymous. Rationale and design of the ADVANCE

study: a randomised trial of blood pressure lowering and

intensive glucose control in high-risk individuals with type 2

diabetes mellitus. Action in Diabetes and Vascular Disease:

PreterAx and DiamicroN Modified-Release Controlled

Evaluation. Journal of Hypertension - Supplement 2001;19

(4):S21–8. [MEDLINE: 11848259]

Chalmers J. ADVANCE Study: objectives, design and

current status [Etude ADVANCE : objectifs, protocole

et état actuel]. Drugs 2003;63 Spec No. 1:39–44.

[MEDLINE: 12708881]

de Galan BE, Ninomiya T, Perrovic V, Pillai A, Patel A,

Neal AC, et al.Renoprotective effects of blood pressure

lowering with perindopril-indapamide below current targets

in people with type 2 diabetes mellitus: Results of the

ADVANCE trial [abstract]. Diabetes 2008;57(Suppl 1):

A218–9.∗ de Galan BE, Perkovic V, Ninomiya T, Pillai A, Patel A,

Cass A, et al.Lowering blood pressure reduces renal events in

type 2 diabetes. Journal of the American Society of Nephrology

2009;20(4):883–92. [MEDLINE: 19225038]

Heerspink HJ, Ninomiya T, Perkovic V, Woodward M,

Zoungas S, Cass A, et al.Effects of a fixed combination of

perindopril and indapamide in patients with type 2 diabetes

and chronic kidney disease. European Heart Journal 2010;

31(23):2888–96. [MEDLINE: 20501479]

Jardine M, Ninomiya T, Perkovic V, Woodward M, Pillai

A, Cass A, et al.Predictive baseline factors for major

renal events: a proportional hazards model based on the

Advance Study [abstract]. Journal of the American Society of

Nephrology 2008;19(Abstracts Issue):543A.

Ninomiya T, Zoungas S, Neal B, Woodward M, Patel

A, Perkovic V, et al.Efficacy and safety of routine blood

pressure lowering in older patients with diabetes: results

from the ADVANCE trial. Journal of Hypertension 2010;28

(6):1141–9. [MEDLINE: 20486273]

Patel A, MacMahon S, Chalmers J, Neal B, Woodward M,

Billot L, et al.Effects of a fixed combination of perindopril

and indapamide on macrovascular and microvascular

outcomes in patients with type 2 diabetes mellitus (the

ADVANCE trial): a randomised controlled trial. Lancet

2007;370(9590):829–40. [MEDLINE: 17765963]

Perkovic V, de Galan B, Chalmers J, Ninomiya T, Patel A,

Cass A, et al.Renoprotection with perindopril-indapamide

below current recommended blood pressure targets in

patients with type 2 diabetes mellitus: results of the

ADVANCE trial [abstract]. Nephrology 2008;13(Suppl 3):

A121.

Perkovic V, Ninomiya T, de Galan BE, Zoungas S, Cass A,

Patel A, et al.Joint effects of routine blood pressure lowering

and intensive glucose control in the ADVANCE trial

[abstract no: LB-002]. American Society of Nephrology

(ASN) Renal Week; 2008 Nov 4-9; Philadelphia, PA. 2008.

Perkovic V, Zoungas S, Heerspink HL, Woodward M,

Jun M, Cass A, et al.Intensive glucose lowering and end

stage kidney disease - new data from the ADVANCE trial

[abstract]. Nephrology 2011;16(Suppl 1):42.

Poulter NR. Blood pressure and glucose control in subjects

with diabetes: new analyses from ADVANCE. Journal of

Hypertension - Supplement 2009;27(1):S3–8. [MEDLINE:



19483505]

Zoungas S, de Galan BE, Ninomiya T, Grobbee D, Hamet

P, Heller S, et al.Combined effects of routine blood pressure

lowering and intensive glucose control on macrovascular and

microvascular outcomes in patients with type 2 diabetes:

New results from the ADVANCE trial. Diabetes Care 2009;

32(11):2068–74. [MEDLINE: 19651921]

Baba 2001 {published data only}

Baba S, The J-MIND Study Group. Nifedipine and

enalapril equally reduce the progression of nephropathy in

hypertensive type 2 diabetics. Diabetes Research & Clinical

Practice 2001;54(3):191–201. [MEDLINE: 11689274]

BENEDICT Study 2004 {published data only}

BENEDICT G. The BErgamo NEphrologic DIabetes

Complications Trial (BENEDICT): design and baseline

characteristics. Controlled Clinical Trials 2003;24(4):

442–61. [MEDLINE: 12865039]

De Cosmo S, Motterlini N, Prudente S, Pellegrini F,

Trevisan R, Bossi A, et al.Impact of the PPAR-gamma2

Pro12Ala polymorphism and ACE inhibitor therapy

on new-onset microalbuminuria in type 2 diabetes:

evidence from BENEDICT. Diabetes 2009;58(12):2920–9.

[MEDLINE: 19720797]

Remuzzi G, Macia M, Ruggenenti P. Prevention and

treatment of diabetic renal disease in type 2 diabetes:

the BENEDICT study. Journal of the American Society

of Nephrology 2006;17(4 Suppl 2):S90–7. [MEDLINE:

16565256]

Ruggenenti P, Fassi A, Ilieva AP, Iliev IP, Chiurchiu C,

Rubis N, et al.Effects of verapamil added-on trandolapril

therapy in hypertensive type 2 diabetes patients with

microalbuminuria: the BENEDICT-B randomized trial.

Journal of Hypertension 2011;29(2):207–16. [MEDLINE:

21243736]∗ Ruggenenti P, Fassi A, Parvanova Ilieva A, Bruno

Petrov Iliev I, Brusegan V, Rubis N, et al.Preventing

microalbuminuria in type 2 diabetes. New England


15516697]

Ruggenenti P, Iliev I, Costa GM, Parvanova A, Perna A,

Giuliano GA, et al.Preventing left ventricular hypertrophy

by ACE inhibition in hypertensive patients with type 2

diabetes: a prespecified analysis of the Bergamo Nephrologic

Diabetes Complications Trial (BENEDICT). Diabetes Care

2008;31(8):1629–34. [MEDLINE: 18443191]

Ruggenenti P, Perna A, Ganeva M, Ene-Iordache B,

Remuzzi G, BENEDICT Study Group. Impact of blood

pressure control and angiotensin-converting enzyme

inhibitor therapy on new-onset microalbuminuria in type

2 diabetes: a post hoc analysis of the BENEDICT trial.

Journal of the American Society of Nephrology 2006;17(12):

3472–81. [MEDLINE: 17082240]

Ruggenenti P, Remuzzi G. Primary prevention of renal

failure in diabetic patients: the Bergamo Nephrologic

Diabetes Complication Trial. Journal of Hypertension -

Supplement 1998;16(1):S95–7. [MEDLINE: 9534106]

CALM II Study 2005 {published data only}

Andersen NH, Knudsen ST, Poulsen PL, Poulsen SH,

Helleberg K, Eiskjaer H, et al.Dual blockade with

candesartan cilexetil and lisinopril in hypertensive patients

with diabetes mellitus: rationale and design. Journal of

the Renin-Angiotensin-Aldosterone System 2003;4(2):96–9.

[MEDLINE: 12806591]∗ Andersen NH, Poulsen PL, Knudsen ST, Poulsen SH,

Eiskjaer H, Hansen KW, et al.Long-term dual blockade

with candesartan and lisinopril in hypertensive patients with

diabetes: the CALM II study. Diabetes Care 2005;28(2):

273–7. [MEDLINE: 15677778]

Knudsen ST, Andersen NH, Poulsen SH, Eiskjaer H,

Hansen KW, Helleberg K, et al.Pulse pressure lowering

effect of dual blockade with candesartan and lisinopril vs.

high-dose ACE inhibition in hypertensive type 2 diabetic

subjects: a CALM II study post-hoc analysis. American


18188164]

Chan 1992 {published data only}

Chan JC, Cockram CS, Nicholls MG, Cheung CK,

Swaminathan R. Comparison of enalapril and nifedipine

in treating non-insulin dependent diabetes associated with

hypertension: one year analysis. BMJ 1992;305(6860):

981–5. [MEDLINE: 1458144]∗ Chan JC, Ko GT, Leung DH, Cheung RC, Cheung MY,

So WY, et al.Long-term effects of angiotensin-converting

enzyme inhibition and metabolic control in hypertensive

type 2 diabetic patients. Kidney International 2000;57(2):

590–600. [MEDLINE: 10652036]

Chan JC, Nicholls MG, Cheung CK, Law LK, Swaminathan

R, Cockram CS. Factors determining the blood pressure

response to enalapril and nifedipine in hypertension

associated with NIDDM. Diabetes Care 1995;18(7):

1001–6. [MEDLINE: 7555530]

Chan JC, Yeung VT, Leung DH, Tomlinson B, Nicholls

MG, Cockram CS. The effects of enalapril and nifedipine

on carbohydrate and lipid metabolism in NIDDM. Diabetes

Care 1994;17(8):859–62. [MEDLINE: 7956631]

Crepaldi 1995 {published data only}

Crepaldi G, Carraro A, Brocco E, Adezati L, Andreani

D, Bompiani G, et al.Hypertension and non-insulin-

dependent diabetes. Acta Diabetologica 1995;32(3):203–8.

[MEDLINE: 8590792]

DIRECT Studies 2009 {published data only}∗ Bilous R, Chaturvedi N, Sjolie AK, Fuller J, Klein R,

Orchard T, et al.Effect of candesartan on microalbuminuria

and albumin excretion rate in diabetes: three randomized

trials. Annals of Internal Medicine 2009;151(1):11-20, W3-

4. [MEDLINE: 19451554]

Bilous RW, Parving H, Nishi C. DIRECT-Renal: The effect

of the angiotensive type 1 receptor blocker candesartan

on the development of microalbuminuria in type 1 and

type 2 diabetes [abstract]. Journal of the American Society of

Nephrology 2008, (Abstracts Issue).

Chaturvedi N, Porta M, Klein R, Orchard T, Fuller J,

Parving HH, et al.Effect of candesartan on prevention



(DIRECT-Prevent 1) and progression (DIRECT-Protect

1) of retinopathy in type 1 diabetes: randomised, placebo-

controlled trials. Lancet 2008;372(9647):1394–402.

[MEDLINE: 18823656]

Chaturvedi N, Sjoelie AK, Svensson A, DIRECT

Programme Study Group. The DIabetic Retinopathy

Candesartan Trials (DIRECT) Programme, rationale and

study design. Journal of the Renin-Angiotensin-Aldosterone

System 2002;3(4):255–61. [MEDLINE: 12584669]

Hirsch HH, Tuncer M, Friman S, Wiececk A, Citterio

F, Klinger M, et al.Prospective study of polyomavirus

BK viruria and viremia in de novo renal transplantation

[abstract]. American Journal of Transplantation 2005;5

(Suppl 11):272.

Hirsch HH, Vincenti F, Friman S, Wiecek A, Pescovitz MD,

Jenssen T, et al.Polomarvirus BK viruria and viremia in de

novo renal transplantation comparing cyclosporine and

tacrolimus: a multivariate analysis for the DIRECT Study


2009, (Abstract Issue):85–6.

Jenssen T, Campistol J, Uchida K, Pescovitz M, Citterio F.

Insulin release and insulin sensitivity in patients developing

glucose abnormalities post-transplant: the relative effects of

tacrolimus and cyclosporine [abstract]. American Journal of

Transplantation 2006;6(Suppl 2):356.

Jenssen T, Campistol J, Uchida K, Pescovitz M, Citterio

F, DIRECT Study Group. Insulin release and insulin

sensitivity in patients developing glucose abnormalities

post-transplant: the relative effects of tacrolimus and

cyclosporine [abstract]. Journal of the American Society of

Nephrology 2006;17(Abstracts):233A.

Marchetti P, Tuncer M, Wiecek A, Chadban S, El-Shahawy

M, Budde K, et al.Steroid dose affects risk of glucose

metabolism abnormalities differently with cyclosporine

or tacrolimus in renal transplant recipients [abstract].

American Journal of Transplantation 2006;6(Suppl 2):357.

Marchetti P, Vincenti F, Jenssen T, Friman S. 6-month results

from randomized, international trial of cyclosporine versus

tacrolimus in de novo renal transplant patients: progression

of pre-existing diabetes and glucose abnormalities [abstract].

Transplant International 2007;20(Suppl 2):114.

Rostaing L, Vincenti F, Friman S, Scheuermann E,

DIRECT Study Group. Glucose metabolism disorders

after renal transplantation: results of an international,

randomized trial comparing cyclosporine versus tacrolimus


2006;17(Abstracts):231A.

Rostaing L, Vincenti F, Friman S, Scheuermann E, Rostaing

L. Glucose metabolism disorders after renal transplantation:

results of an international, randomized trial comparing

cyclosporine versus tacrolimus [abstract]. American Journal

of Transplantation 2006;6(Suppl 2):83.

Sjolie AK, Klein R, Porta M, Orchard T, Fuller J, Parving

HH, et al.Effect of candesartan on progression and

regression of retinopathy in type 2 diabetes (DIRECT-

Protect 2): a randomised placebo-controlled trial. Lancet

2008;372(9647):1385–93. [MEDLINE: 18823658]

Sjolie AK, Porta M, Parving HH, Bilous R, Klein R,

DIRECT Programme Study Group. The DIabetic

REtinopathy Candesartan Trials (DIRECT) Programme:

baseline characteristics. Journal of the Renin-Angiotensin-

Aldosterone System 2005;6(1):25–32. [MEDLINE:

16088848]

Vincenti F, Friman S, Scheuermann E, Rostaing L,

Jenssen T, Campistol JM, et al.Results of an international,

randomized trial comparing glucose metabolism disorders

and outcome with cyclosporine versus tacrolimus.

American Journal of Transplantation 2007;7(6):1506–14.

[MEDLINE: 17359512]

Vincenti F, Pescovitz MD, El-Shahawy M. Glucose

metabolism disorders in non-white renal transplant patients

receiving cyclosporine or tacrolimus in an international,

randomized trial [abstract]. Transplant International 2007;

20(Suppl 2):115.

Vincenti F, Rostaing L, DIRECT (Diabetes Incidence

after REnal Transplantation: Neoral C2 monitoring

versus Tacrolimus) investigators. Rationale and design

of the DIRECT study: a comparative assessment of the

hyperglycemic effects of tacrolimus and cyclosporine

following renal transplantation. Contemporary Clinical

Trials 2005;26(1):17–24. [MEDLINE: 15837449]

Vincenti F, Tuncer M, Castagneto M, Klinger M, Friman

S, Scheuermann EH, et al.Prospective, multicenter,

randomized trial to compare incidence of new-onset diabetes

mellitus and glucose metabolism in patients receiving

cyclosporine microemulsion versus tacrolimus after de novo

kidney transplantation. Transplantation Proceedings 2005;

37(2):1001–4. [MEDLINE: 15848604]

Vincenti F, Tuncer M, Castagneto M, Klinger M, Friman

S, Scheuermann EH, et al.Prospective, multicenter,

randomized trial to compare incidence of new-onset diabetes

mellitus and glucose metabolism in patients receiving

cyclosporine microemulsion versus tacrolimus after de novo

kidney transplantation [abstract]. Transplantation 2004;78

(2):141.

EUCLID Study 1997 {published data only}

Chaturvedi N, Sjolie AK, Stephenson JM, Abrahamian

H, Keipes M, Castellarin A, et al.Effect of lisinopril

on progression of retinopathy in normotensive people

with type 1 diabetes. The EUCLID Study Group.

EURODIAB Controlled Trial of Lisinopril in Insulin-

Dependent Diabetes Mellitus. Lancet 1998;351(9095):

28–31. [MEDLINE: 9433426]∗ Chaturvedi N, Stevenson J, Fuller JH, Rottiers R, Ferriss B,

Karamanos B, et al.Randomised placebo-controlled trial of

lisinopril in normotensive patients with insulin-dependent

diabetes and normoalbuminuria or microalbuminuria. The

EUCLID Study Group. Lancet 1997;349(9068):1787–92.

[MEDLINE: 9269212]

Fuller JH, Anzalone D and EUCLID Study Group. Renal

effect of lisinopril in insulin dependent diabetes mellitus

(IDDM) without hypertension [abstract]. Journal of the



American Society of Nephrology 1996;7(9):1357.

Penno G, Chaturvedi N, Talmud PJ, Cotroneo P, Manto A,

Nannipieri M, et al.Effect of angiotensin-converting enzyme

(ACE) gene polymorphism on progression of renal disease

and the influence of ACE inhibition in IDDM patients:

findings from the EUCLID Randomized Controlled Trial.

EURODIAB Controlled Trial of Lisinopril in IDDM.

Diabetes 1998;47(9):1507–11. [MEDLINE: 9726242]

Schalkwijk CG, Chaturvedi N, Twaafhoven H, van

Hinsbergh VW, Stehouwer CD, EUCLID Study

Group. Amadori-albumin correlates with microvascular

complications and precedes nephropathy in type 1 diabetic

patients. European Journal of Clinical Investigation 2002;32

(7):500–6. [MEDLINE: 12153550]

Sjolie AK, Chaturvedi N, Fuller J. Effect of lisinopril

on progression of retinopathy and microalbuminuria in

normotensive subjects with insulin-dependent diabetes

mellitus. Ugeskrift for Laeger 1999;161(7):949–52.

[MEDLINE: 10051804]

FACET Study 1998 {published data only}

Tatti P, Pahor M, Byington RP, Di Mauro P, Guarisco R,

Strollo G, et al.Outcome results of the Fosinopril Versus

Amlodipine Cardiovascular Events Randomized Trial

(FACET) in patients with hypertension and NIDDM.

Diabetes Care 1998;21(4):597–603. [MEDLINE:

9571349]

HOPE Study 2000 {published data only}

Anonymous. The HOPE (Heart Outcomes Prevention

Evaluation) Study: the design of a large, simple randomized

trial of an angiotensin-converting enzyme inhibitor

(ramipril) and vitamin E in patients at high risk of

cardiovascular events. The HOPE study investigators.

Canadian Journal of Cardiology 1996;12(2):127–37.

[MEDLINE: 8605634]

Gerstein HC. Diabetes and the HOPE study: implications

for macrovascular and microvascular disease. International

Journal of Clinical Practice 2001;117(Suppl):8–12.

[MEDLINE: 21572783]

Gerstein HC, Bosch J, Pogue J, Taylor DW, Zinman B,

Yusuf S. Rationale and design of a large study to evaluate

the renal and cardiovascular effects of an ACE inhibitor and

vitamin E in high-risk patients with diabetes. The MICRO-

HOPE Study. Microalbuminuria, cardiovascular, and

renal outcomes. Heart Outcomes Prevention Evaluation.

Diabetes Care 1996;19(11):1225–8. [MEDLINE:

8908384]

Gerstein HC, Pogue J, Mann JF, Lonn E, Dagenais GR,

McQueen M, et al.The relationship between dysglycaemia

and cardiovascular and renal risk in diabetic and non-

diabetic participants in the HOPE study: a prospective

epidemiological analysis. Diabetologia 2005;48(9):

1749–55. [MEDLINE: 16059716]∗ Heart Outcomes Prevention Evaluation (HOPE) Study

Investigators. Effects of ramipril on cardiovascular and

microvascular outcomes in people with diabetes mellitus:

results of the HOPE study and MICRO-HOPE substudy.

Lancet 2000;335(9200):253–9. [MEDLINE: 10675071]

Hoogwerf BJ, Young JB. The HOPE study. Ramipril

lowered cardiovascular risk, but vitamin E did not.

Cleveland Clinic Journal of Medicine 2000;67(4):287–93.

[MEDLINE: 10780101]

Lamy A, Yusuf S, Pogue J, Gafni A, Heart Outcomes

Prevention Evaluation Investigators. Cost implications

of the use of ramipril in high-risk patients based on the

Heart Outcomes Prevention Evaluation (HOPE) study.

Circulation 2003;107(7):960–5. [MEDLINE: 12600907]

Lonn E, Mathew J, Pogue J, Johnstone D, Danisa K,

Bosch J, et al.Relationship of electrocardiographic left

ventricular hypertrophy to mortality and cardiovascular

morbidity in high-risk patients. European Journal of

Cardiovascular Prevention & Rehabilitation 2003;10(6):

420–8. [MEDLINE: 14671464]

Lonn E, Yusuf S, Hoogwerf B, Pogue J, Yi Q, Zinman B, et

al.Effects of vitamin E on cardiovascular and microvascular

outcomes in high-risk patients with diabetes: results of the

HOPE study and MICRO-HOPE substudy. Diabetes Care

2002;25(11):1919–27. [MEDLINE: 12401733]

Mann JF, Gerstein HC, Pogue J, Bosch J, Yusuf S. Renal

insufficiency (RI) as predicator of cardiovascular (CV)

outcomes and impact of ramipril: the HOPE study


2000;11(Sept):156A.

Mann JF, Gerstein HC, Pogue J, Bosch J, Yusuf S. Renal

insufficiency as a predictor of cardiovascular outcomes and

the impact of ramipril: the HOPE randomized trial. Annals

of Internal Medicine 2001;134(8):629–36. [MEDLINE:

11304102]

Mann JF, Gerstein HC, Yi QL, Franke J, Lonn EM,

Hoogwerf BJ, et al.Progression of renal insufficiency in type

2 diabetes with and without microalbuminuria: results of

the Heart Outcomes and Prevention Evaluation (HOPE)

randomized study. American Journal of Kidney Diseases

2003;42(5):936–42. [MEDLINE: 14582037]

Mann JF, Gerstein HC, Yi QL, Lonn EM, Hoogwerf BJ,

Rashkow A, et al.Development of renal disease in people at

high cardiovascular risk: results of the HOPE randomized

study. Journal of the American Society of Nephrology 2003;14

(3):641–7. [MEDLINE: 12595499]

Mann JF, Lonn EM, Yi Q, Gerstein HC, Hoogwerf BJ,

Pogue J, et al.Effects of vitamin E on cardiovascular outcomes

in people with mild-to-moderate renal insufficiency: results

of the HOPE study. Kidney International 2004;65(4):

1375–80. [MEDLINE: 15086477]

Mann JF, Yi QL, Sleight P, Dagenais GR, Gerstein HC,

Lonn EM, et al.Serum potassium, cardiovascular risk, and

effects of an ACE inhibitor: results of the HOPE study.

Clinical Nephrology 2005;63(3):181–7. [MEDLINE:

15786818]

Mathew J, Sleight P, Lonn E, Johnstone D, Pogue J, Yi

Q, et al.Reduction of cardiovascular risk by regression of

electrocardiographic markers of left ventricular hypertrophy

by the angiotensin-converting enzyme inhibitor ramipril.

Circulation 2001;104(14):1615–21. [MEDLINE:



11581138]

McQueen MJ, Lonn E, Gerstein HC, Bosch J, Yusuf S.

The HOPE (Heart Outcomes Prevention Evaluation) Study

and its consequences. Scandinavian Journal of Clinical and

Laboratory Investigation Supplement 2005;240:143–56.

[MEDLINE: 6112972]

Sleight P, Yusuf S, Pogue J, Tsuyuki R, Diaz R, Probstfield

J, et al.Blood-pressure reduction and cardiovascular

risk in HOPE study. Lancet 2001;358(9299):2130–1.

[MEDLINE: 11784631]

Smieja M, Gnarpe J, Lonn E, Gnarpe H, Olsson G, Yi Q, et

al.Multiple infections and subsequent cardiovascular events

in the Heart Outcomes Prevention Evaluation (HOPE)

Study. Circulation 2003;107(2):251–7. [MEDLINE:

12538424]

Veres A, Fust G, Smieja M, McQueen M, Horvath

A, Yi Q, et al.Relationship of anti-60 kDa heat shock

protein and anti-cholesterol antibodies to cardiovascular

events. Circulation 2002;106(22):2775–80. [MEDLINE:

12451002]

Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais

G. Effects of an angiotensin-converting-enzyme inhibitor,

ramipril, on cardiovascular events in high-risk patients. The

Heart Outcomes Prevention Evaluation Study Investigators.

New England Journal of Medicine 2000; Vol. 342, issue 3:

145–53. [MEDLINE: 10639539]

Joglekar 1998 {published data only}

Joglekar SJ, Nanivadekar AS. A randomized, controlled,

multicenter study to compare prazosin GITS with enalapril

in hypertensive patients with diabetes mellitus. Bombay

Hypertension Study Group. Journal of the Association of

Physicians of India 1998;Suppl 1:52–62. [MEDLINE:

11233387]

Kavgaci 2002 {published data only}

Kavgaci H, Sahin A, Onder EH, Erem C, Ozdemir F.

The effects of losartan and fosinopril in hypertensive type

2 diabetic patients. Diabetes Research & Clinical Practice

2002;58(1):19–25. [MEDLINE: 12161053]

Kvetny 2001 {published data only}

Kvetny J, Gregersen G, Smith Pedersen R. Randomized

placebo-controlled trial of perindopril in normotensive,

normoalbuminuric patients with type 1 diabetes mellitus.

Qjm 2001;94(2):89–94. [MEDLINE: 11181984]

Lin 1995 {published data only}

Lin M, Yang YF, Chiang HT, Lee D, Wang SP, Chang MS,

et al.Beneficial effects of angiotensin-converting enzyme

inhibitors on cardiovascular and renal functions in patients

with hypertension and diabetes. Acta Cardiologica Sinica

1995;11(1):30–8. [EMBASE: 1995122137]

ONTARGET Study 2008 {published data only}

Barzilay JI, Gao P, O’Donnell M, Mann JF, Anderson

C, Fagard R, et al.Albuminuria and decline in cognitive

function: The ONTARGET/TRANSCEND studies.

Archives of Internal Medicine 2011;171(2):142–50.

[MEDLINE: 21263104]

Cukierman-Yaffe T, Gerstein HC, Anderson C, Zhao

F, Sleight P, Hilbrich L, et al.Glucose intolerance and

diabetes as risk factors for cognitive impairment in people

at high cardiovascular risk: results from the ONTARGET/

TRANSCEND research programme. Diabetes Research &

Clinical Practice 2009 Mar;83(3):387–93. [MEDLINE:

19157618]

Gallieni M, Cozzolino M, Brancaccio D, Giovannini M.

Renal outcomes in the ONTARGET study. Lancet 2008;

372(9655):2019–21. [MEDLINE: 19070732]

Mancia G, Schumacher H, Redon J, Verdecchia P,

Schmieder R, Jennings G, et al.Blood pressure targets

recommended by guidelines and incidence of cardiovascular

and renal events in the Ongoing Telmisartan Alone and

in Combination With Ramipril Global Endpoint Trial

(ONTARGET). Circulation 2011;124(16):1727–36.

[MEDLINE: 21947289]∗ Mann JF, Schmieder RE, McQueen M, Dyal L,

Schumacher H, Pogue J, et al.Renal outcomes with

telmisartan, ramipril, or both, in people at high vascular

risk (the ONTARGET study): a multicentre, randomised,

double-blind, controlled trial. Lancet 2008;372(9638):

547–53. [MEDLINE: 18707986]

Mann JF, Schmieder RE, McQueen MM, Dyal L,


telmisartan, ramipril, or both in people at high vascular risk:

results from the ONTARGET trial [abstract]. Journal of the

American Society of Nephrology 2008;17(Abstracts Issue):

48A.

Mann JF, Schmieder RE, McQueen MM, Dyal L,


telmisartan, ramipril, or both in people at high vascular risk:

results from the ONTARGET trial [abstract]. Journal of the

American Society of Nephrology 2008;19(Abstracts Issue):

48A.

Narayanan RM, Chi LS, Choo LL, Ying YL, Fang SC.

Renal outcomes in the ONTARGET study. Lancet 2008;

372(9655):2020–1. [MEDLINE: 19070735]

Nonoguchi H, Nanami M, Hasuike Y, Kuragano T,

Nakanishi T. Renal outcomes in the ONTARGET study.

Lancet 2008;372(9655):2019–20. [MEDLINE: 19070731]

ONTARGET Investigators, Yusuf S, Teo KK, Pogue J, Dyal

L, Copland I, et al.Telmisartan, ramipril, or both in patients

at high risk for vascular events. New England Journal of


Ruilope LM, Redon J, Schmieder R. Cardiovascular risk

reduction by reversing endothelial dysfunction: ARBs, ACE

inhibitors, or both? Expectations from the ONTARGET

Trial Programme. Vascular Health & Risk Management

2007;3(1):1–9. [MEDLINE: 17583170]

Schmieder RE, Mann JFE, Dyal L, Pogue J, Copland I,

Teo KK, et al.ONTARGET: cardiovascular outcome in

patients at high cardiovascular risk and with chronic kidney

disease (CKD) [abstract]. Journal of the American Society of

Nephrology 2008;19(Abstracts Issue):309A.

Sleight P. Clinical evidence from ONTARGET: the value

of an angiotensin II receptor blocker and an angiotensin-

converting enzyme inhibitor. Journal of Hypertension

- Supplement 2009;27(Suppl 5):S23–9. [MEDLINE:



19587551]

Sleight P, Redon J, Verdecchia P, Mancia G, Gao P, Fagard

R, et al.Prognostic value of blood pressure in patients with

high vascular risk in the Ongoing Telmisartan Alone and in

combination with Ramipril Global Endpoint Trial study.


19506526]

Teo K, Yusuf S, Sleight P, Anderson C, Mookadam F, Ramos

B, et al.Rationale, design, and baseline characteristics of

2 large, simple, randomized trials evaluating telmisartan,

ramipril, and their combination in high-risk patients: the

Ongoing Telmisartan Alone and in Combination with

Ramipril Global Endpoint Trial/Telmisartan Randomized

Assessment Study in ACE Intolerant Subjects with

Cardiovascular Disease (ONTARGET/TRANSCEND)

trials. American Heart Journal 2004;148(1):52–61.

[MEDLINE: 15215792]

Wetzels JF. Renal outcomes in the ONTARGET study.

Lancet 2008;372(9655):2020–1. [MEDLINE: 19070734]

Perrin 2008 {published data only}

Perrin NE, Jaremko GA, Berg UB. The effect of candesartan/

placebo treatment on renal function and morphology in

diabetes type 1 [abstract]. Journal of the American Society of

Nephrology 2007;18(Abstracts):327A.∗ Perrin NE, Jaremko GA, Berg UB. The effects of

candesartan on diabetes glomerulopathy: a double-blind,

placebo-controlled trial. Pediatric Nephrology 2008;23(6):

947–54. [MEDLINE: 18270751]

RASS Study 2002 {published and unpublished data}

Donnelly S, Goodyear P, Ly J, Klein R, Moss S, Sinsiko A, et

al.Renal biopsy complications in the RASS study [abstract].

Journal of the American Society of Nephrology 2005;16:559A.

Donnelly S, Sinaiko A, Strand T, Zinman B, Drummond

K, Gardiner R, et al.Effects of renin angiotensin system

(RAS) blockade on diabetic nephropathy (DN)-a primary

prevention trial: study design and baseline results [abstract].

Journal of the American Society of Nephrology 2002;13

(Program & Abstracts):651A.

Katavetin P, Katavetin P. Renal and retinal effects of enalapril

and losartan in type 1 diabetes. New England Journal of


Mauer M, Strand T, Zinman B, Gardiner R, Suissa S,

Sinaiko A, et al.The Renin Angiotensin System Study

(RASS): compliance in a long-term kidney biopsy based

diabetic nephropathy (DN) primary prevention trial in

Type 1 diabetes mellitus (T1DM) patients (pts) [abstract].

Journal of the American Society of Nephrology 2005;16:554A.

Mauer M, Zinman B, Gardiner R, Drummond KN, Suissa

S, Donnelly SM, et al.ACE-I and ARBs in early diabetic

nephropathy. Journal of the Renin-Angiotensin-Aldosterone

System 2002;3(4):262–9. [MEDLINE: 12584670]∗ Mauer M, Zinman B, Gardiner R, Suissa S, Sinaiko A,

Strand T, et al.Renal and retinal effects of enalapril and

losartan in type 1 diabetes. New England Journal of Medicine

2009;361(1):40–51. [MEDLINE: 19571282]

Robiner WN, Yozwiak JA, Bearman DL, Strand TD,

Strasburg KR. Barriers to clinical research participation in a

diabetes randomized clinical trial. Social Science & Medicine

2009;68(6):1069–74. [MEDLINE: 19167143]

Suissa S. Renin angiotensin system study (RASS) of diabetic

nephropathy. (study protocol).

Tamsma JT. Renal and retinal effects of enalapril and

losartan in type 1 diabetes. New England Journal of Medicine

2009;361(14):1410. [MEDLINE: 19797291]

Ravid 1998 {published data only}

Ravid M, Brosh D, Levi Z, Bar-Dayan Y, Ravid D,

Rachmani R. Use of enalapril to attenuate decline in renal

function in normotensive, normoalbuminuric patients with

type 2 diabetes mellitus: a randomized, controlled trial.

Annals of Internal Medicine 1998;128(12 Pt 1):982–8.

[MEDLINE: 9625684]

ROADMAP Study 2009 {published data only}∗ Haller H, Ito S, Izzo JL, Januszewicz A, Katayama S,

Menne J, et al.Olmesartan for the delay or prevention

of microalbuminuria in type 2 diabetes. New England


21388309]

Haller H, Viberti GC, Mimran A, Remuzzi G, Rabelink

AJ, Ritz E, et al.Preventing microalbuminuria in patients

with diabetes: rationale and design of the Randomised

Olmesartan and Diabetes Microalbuminuria Prevention

(ROADMAP) study. Journal of Hypertension 2006;24(2):

403–8. [MEDLINE: 16508590]

Haller HG, Viberti GV, Ritz E, Ruilope LM, Rabelink

TJ, for the ROADMAP Steering Committee Members.

Prevention of albuminuria and cardiovascular morbidity

with olmesartan, the ROADMAP trial. ASN Renal Week.

2009:LB–005.

Januszewicz A, Ritz E, Viberti G, Mimran A, Rabelink

AJ, Rump LC, et al.Office and ambulatory pulse

pressure--association with clinical characteristics and

cardiovascular risk factors in normoalbuminuric patients

with type 2 diabetes (ROADMAP study). Journal of

Human Hypertension 2011;25(11):679–85. [MEDLINE:

21150933]

Menne J, Izzo JL Jr, Ito S, Januszewicz A, Katayama S,

Chatzykirkou C, et al.Prevention of microalbuminuria in

patients with type 2 diabetes and hypertension. Journal of

Hypertension 2012;30(4):811–8. [MEDLINE: 22418908]

Ritz E, Viberti GC, Ruilope LM, Rabelink AJ, Izzo JL

Jr, Katayama S, et al.Determinants of urinary albumin

excretion within the normal range in patients with type

2 diabetes: the Randomised Olmesartan and Diabetes

Microalbuminuria Prevention (ROADMAP) study.

Diabetologia 2010;53(1):49–57. [MEDLINE: 19876613]

Scognamiglio 1997 {published data only}

Scognamiglio R, Nosadini R, Marin M, Nisti S, Fasoli G,

Palisi M, et al.Evaluation of the efficacy and tolerability of

nitrendipine in reducing both pressure and left ventricular

mass in hypertensive type 2 diabetic patients. Diabetes Care

1997;20(8):1290–2. [MEDLINE: 9250456]

TRANSCEND Study 2009 {published data only}

Barzilay JI, Gao P, O’Donnell M, Mann JF, Anderson

C, Fagard R, et al.Albuminuria and decline in cognitive



function: The ONTARGET/TRANSCEND studies.

Archives of Internal Medicine 2011;171(2):142–50.

[MEDLINE: 21263104]

Cukierman-Yaffe T, Gerstein HC, Anderson C, Zhao

F, Sleight P, Hilbrich L, et al.Glucose intolerance and

diabetes as risk factors for cognitive impairment in people

at high cardiovascular risk: results from the ONTARGET/

TRANSCEND research programme. Diabetes Research

& Clinical Practice 2009;83(3):387–93. [MEDLINE:

19157618]

Held C, Gerstein HC, Yusuf S, Zhao F, Hilbrich L,

Anderson C, et al.Glucose levels predict hospitalization for

congestive heart failure in patients at high cardiovascular

risk. Circulation 2007;115(11):1371–5. [MEDLINE:

17339550]∗ Mann JF, Schmieder RE, Dyal L, McQueen MJ,

Schumacher H, Pogue J, et al.Effect of telmisartan on renal

outcomes: a randomized trial. Annals of Internal Medicine

2009;151(1):1–10. [MEDLINE: 19451556]

Telmisartan Randomised AssessmeNt Study in ACE

iNtolerant subjects with cardiovascular Disease

(TRANSCEND) Investigators. Yusuf S. Teo K. Anderson

C. Pogue J. Dyal L, et al.Effects of the angiotensin-receptor

blocker telmisartan on cardiovascular events in high-

risk patients intolerant to angiotensin-converting enzyme

inhibitors: a randomised controlled trial. Lancet 2008;372

(9644):1174–83. [MEDLINE: 18757085]

Teo K, Yusuf S, Sleight P, Anderson C, Mookadam F, Ramos

B, et al.Rationale, design, and baseline characteristics of

2 large, simple, randomized trials evaluating telmisartan,

ramipril, and their combination in high-risk patients: the

Ongoing Telmisartan Alone and in Combination with

Ramipril Global Endpoint Trial/Telmisartan Randomized

Assessment Study in ACE Intolerant Subjects with

Cardiovascular Disease (ONTARGET/TRANSCEND)

trials. American Heart Journal 2004;148(1):52–61.

[MEDLINE: 15215792]

Tuominen 1998 {published data only}

Tuominen JA, Ebeling P, Koivisto VA. Long-term

lisinopril therapy reduces exercise-induced albuminuria in

normoalbuminuric normotensive IDDM patients. Diabetes

Care 1998;21(8):1345–8. [MEDLINE: 9702445]

UKPDS Study 1998 {published data only}

Anonymous. UK Prospective Diabetes Study (UKPDS).

VIII. Study design, progress and performance. Diabetologia

1991;34(12):877–90. [MEDLINE: 1778353]∗ Holman R, Turner R, Stratton I, Cull C, Frighi V, Manley

S, et al.Efficacy of atenolol and captopril in reducing risk

of macrovascular and microvascular complications in type

2 diabetes: UKPDS 39. UK Prospective Diabetes Study

Group. BMJ 1998;317(7160):713–20. [MEDLINE:

9732338]

UK PDS Group. Intensive blood-glucose control with

sulphonylureas or insulin compared with conventional

treatment and risk of complications in patients with

type 2 diabetes (UKPDS 33). UK Prospective Diabetes

Study (UKPDS) Group. Lancet 1998;352(9131):837–53.

[MEDLINE: 9742976]

UK PDS Group. Tight blood pressure control and risk

of macrovascular and microvascular complications in type

2 diabetes: UKPDS 38. UK Prospective Diabetes Study

Group. BMJ 1998;317(7160):703–13. [MEDLINE:

9732337]

Velussi 1996 {published data only}

Velussi M, Brocco E, Frigato F, Zolli M, Muollo B, Maioli

M, et al.Effects of cilazapril and amlodipine on kidney

function in hypertensive NIDDM patients. Diabetes 1996;

45(2):216–22. [MEDLINE: 8549868]

References to studies excluded from this review

ALLHAT 2002 {published data only}

ALLHAT Officers and Coordinators for the ALLHAT

Collaborative Research Group. The Antihypertensive

and Lipid-Lowering Treatment to Prevent Heart Attack

Trial. Major outcomes in high-risk hypertensive patients

randomized to angiotensin-converting enzyme inhibitor or

calcium channel blocker vs diuretic: The Antihypertensive

and Lipid-Lowering Treatment to Prevent Heart Attack Trial

(ALLHAT). JAMA 2002;288(23):2981–97. [MEDLINE:

12479763]

Messerli HF. Implications of discontinuation of doxazosin

arm of ALLHAT. Antihypertensive and Lipid-Lowering

Treatment to Prevent Heart Attack Trial. Lancet 2000;355

(9207):863–4. [MEDLINE: 10752699]

CAPPP 1999 {published data only}

Hansson L, Lindholm LH, Niskanen L, Lanke J, Hedner

T, Niklason A, et al.Effect of angiotensin-converting-

enzyme inhibition compared with conventional therapy on

cardiovascular morbidity and mortality in hypertension: the

Captopril Prevention Project (CAPPP) randomised trial.

Lancet 1999;353(9153):611–6. [MEDLINE: 10030325]

Hansson 1999 {published data only}

Hansson L, Lindholm LH, Ekbom T, Dahlof B, Lanke

J, Schersten B, et al.Randomised trial of old and new

antihypertensive drugs in elderly patients: cardiovascular

mortality and morbidity the Swedish Trial in Old Patients

with Hypertension-2 study. Lancet 1999;354(9192):

1751–6. [MEDLINE: 10577635]

HOT 1998 {published data only}

Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt

D, Julius S, et al.Effects of intensive blood-pressure lowering

and low-dose aspirin in patients with hypertension:

principal results of the Hypertension Optimal Treatment

(HOT) randomised trial. Lancet 1998;351(9118):1755–62.

[MEDLINE: 9635947]

INSIGHT 2000 {published data only}

Brown MJ, Palmer CR, Castaigne A, de Leeuw PW,

Mancia G, Rosenthal T, et al.Morbidity and mortality

in patients randomised to double-blind treatment with

a long-acting calcium-channel blocker or diuretic in the

International Nifedipine GITS study: Intervention as a

Goal in Hypertension Treatment (INSIGHT). Lancet 2000;

356(9227):366–72. [MEDLINE: 10972368]



NORDIL 2000 {published data only}

Hansson L, Hedner T, Lund-Johansen P, Kjeldsen SE,

Lindholm LH, Syvertsen JO, et al.Randomised trial of

effects of calcium antagonists compared with diuretics and

beta-blockers on cardiovascular morbidity and mortality

in hypertension: the Nordic Diltiazem (NORDIL) study.

Lancet 2000;356(9227):359–65. [MEDLINE: 10972367]

Tuomilehto 1999 {published data only}

Tuomilehto J, Rastenyte D, Birkenhager WH, Thijs L,

Antikainen R, Bulpitt CJ, et al.Effects of calcium-channel

blockade in older patients with diabetes and systolic

hypertension. Systolic Hypertension in Europe Trial

Investigators. New England Journal of Medicine 1999;340

(9):677–84. [MEDLINE: 10053176]

Additional references

ADA 2010

American Diabetes Association. Standards of Medical Care

in Diabetes-2010. Diabetes Care 2010;33(Suppl 1):S11–61.

[MEDLINE: 14693929]

Adler 2003

Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA,

Holman RR. Development and progression of nephropathy

in type 2 diabetes: The United Kingdom Prospective

Diabetes Study (UKPDS 64). Kidney International 2003;63

(1):225–32. [MEDLINE: 12472787]

Bucher 1997

Bucher HC, Guyatt GH, Griffith LE, Walter SD. The

results of direct and indirect treatment comparisons in meta-

analysis of randomized controlled trials. Journal of Clinical

Epidemiology 1997;50(6):683–91. [MEDLINE: 9250266]

CDA 2008

Canadian Diabetes Association Clinical Practice Guidelines

Expert Committee. Canadian Diabetes Association

2008 clinical practice guidelines for the prevention and

management of diabetes in Canada. Canadian Journal of

Diabetes 2008; Vol. 32, issue Suppl 1:S1–S201.

Chadban 2010

Chadban S, Howell M, Twigg S, Thomas M, Jerums G,

Cass A, et al.Prevention and management of chronic kidney

disease in type 2 diabetes. Nephrology 2010;15:S162–94.

[DOI: 10.1111/j.1440-1797.2010.01240.x]

Chaturvedi 2008

Chaturvedi N, Porta M, Klein R, Orchard T, Fuller J,

Parving HH, et al.Effect of candesartan on prevention

(DIRECT-Prevent 1) and progression (DIRECT-Protect

1) of retinopathy in type 1 diabetes: randomised, placebo-

controlled trials. Lancet 2008;372(9647):1394–402.

[MEDLINE: 18823656]

Chobanian 2003

Chobanian AV, Bakris GL, Black HR, Cushman WC,

Green LA, Izzo JL Jr, et al.The Seventh Report of the Joint

National Committee on Prevention, Detection, Evaluation,

and Treatment of High Blood Pressure: the JNC 7 report.

JAMA 2003;289(19):2560–72. [MEDLINE: 12748199]

ESH-ESC 2007

Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard

R, Germano G, et al.2007 ESH-ESC Practice Guidelines

for the Management of Arterial Hypertension: ESH-ESC

Task Force on the Management of Arterial Hypertension.


17762635]

Gerstein 2001

Gerstein HC, Mann JF, Yi Q, Zinman B, Dinneen SF,

Hoogwerf B, et al.Albuminuria and risk of cardiovascular

events, death, and heart failure in diabetic and nondiabetic

individuals. JAMA 2001;286(4):421–6. [MEDLINE:

11466120]

Hasslacher 1985

Hasslacher C, Ritz E, Terpstra J, Gallasch G, Kunowski G,

Rall C. Natural history of nephropathy in type I diabetes.

Relationship to metabolic control and blood pressure.

Hypertension 1985;7(6 Pt 2):74–8. [MEDLINE: 4077240]

Higgins 2003

Higgins JP, Thompson SG, Deeks JJ, Altman DG.

Measuring inconsistency in meta-analyses. BMJ 2003;327

(7414):557–60. [MEDLINE: 12958120]

Higgins 2011

Higgins JPT, Green S (editors). Cochrane Handbook

for Systematic Reviews of Interventions Version 5.1.0

[updated March 2011]. The Cochrane Collaboration,

2011. Available from www.cochrane-handbook.org.

IDF 2009

International Diabetes Federation. IDF Diabetes Atlas.

http://www.idf.org/diabetesatlas/ (accessed 26 September

2012).

KDOQI 2007

American Kidney Foundation. KDOQI clinical practice

guidelines and clinical practice recommendations for

diabetes and chronic kidney disease. http://www.kidney.org/

professionals/KDOQI/guideline˙diabetes/guide3.htm

(accessed 26 September 2012).

Klausen 2004

Klausen K, Borch-Johnsen K, Feldt-Rasmussen B, Jensen

G, Clausen P, Scharling H, et al.Very low levels of

microalbuminuria are associated with increased risk of

coronary heart disease and death independently of renal

function, hypertension, and diabetes. Circulation 2004;110

(1):32–5. [MEDLINE: 15210602]

Levey 2009

Levey AS, Cattran D, Friedman A, Miller WG, Sedor

J, Tuttle K, et al.Proteinuria as a surrogate outcome in

CKD: report of a scientific workshop sponsored by the

National Kidney Foundation and the US Food and Drug

Administration. American Journal of Kidney Diseases 2009;

54(2):205–26. [MEDLINE: 19577347]

Messent 1992

Messent JW, Elliott TG, Hill RD, Jarrett RJ, Keen H,

Viberti GC. Prognostic significance of microalbuminuria

in insulin-dependent diabetes mellitus: a twenty-three year



follow-up study. Kidney International 1992;41(4):836–9.

[MEDLINE: 1513106]

Mogensen 1976

Mogensen CE. Progression of nephropathy in long-

term diabetics with proteinuria and effect of initial anti-

hypertensive treatment. Scandinavian Journal of Clinical &

Laboratory Investigation 1976;36(4):383–8. [MEDLINE:

959756]

Ninomiya 2009

Ninomiya T, Perkovic V, de Galan BE, Zoungas S, Pillai

A, Jardine M, et al.Albuminuria and kidney function

independently predict cardiovascular and renal outcomes in

diabetes. Journal of the American Society of Nephrology 2009;

20(8):1813–21. [MEDLINE: 19443635]

Parfrey 2009

Parfrey PS. Angiotensin-receptor blockers in the prevention

or treatment of microalbuminuria. Annals of Internal


Perkovic 2008

Perkovic V, Verdon C, Ninomiya T, Barzi F, Cass A, Patel

A, et al.The relationship between proteinuria and coronary

risk: a systematic review and meta-analysis. PLoS Medicine

/ Public Library of Science 2008;5(10):e207. [MEDLINE:

18942886]

Ritz 1999

Ritz E, Orth SR. Nephropathy in patients with type 2

diabetes mellitus. New England Journal of Medicine 1999;

341(15):1127–33. [MEDLINE: 10511612]

Ruggenenti 1997

Ruggenenti P, Remuzzi G. The diagnosis of renal

involvement in non-insulin-dependent diabetes mellitus.

Current Opinion in Nephrology & Hypertension 1997;6(2):

141–5. [MEDLINE: 9146975]

Sjølie 2008

Sjølie AK, Klein R, Porta M, Orchard T, Fuller J, Parving

HH, et al.Effect of candesartan on progression and

regression of retinopathy in type 2 diabetes (DIRECT-

Protect 2): a randomised placebo-controlled trial. Lancet

2008;372(9647):1385–93. [MEDLINE: 18823658]

Song 2000

Song F, Glenny AM, Altman DG. Indirect comparison

in evaluating relative efficacy illustrated by antimicrobial

prophylaxis in colorectal surgery. Controlled Clinical Trials

2000;21(5):488–97. [MEDLINE: 11018565]

Strippoli 2004

Strippoli GF, Craig M, Deeks JJ, Schena FP, Craig JC.

Effects of angiotensin converting enzyme inhibitors and

angiotensin II receptor antagonists on mortality and renal

outcomes in diabetic nephropathy: systematic review. BMJ

2004;329(7370):828–31. [MEDLINE: 15459003]

USRDS 2009

U S Renal Data System. USRDS 2009 Annual Data Report:

Atlas of Chronic Kidney Disease and End-Stage Renal

Disease in the United States, National Institutes of Health,

National Institute of Diabetes and Digestive and Kidney

Diseases, Bethesda, MD, 2009. http://www.usrds.org/

atlas09.aspx (accessed 25 September 2012).

Williams 2004

Williams B, Poulter NR, Brown MJ, Davis M, McInnes

GT, Potter JF, et al.British Hypertension Society guidelines

for hypertension management 2004 (BHS-IV): summary.

BMJ 2004;328(7440):634–40. [MEDLINE: 15016698]

References to other published versions of this review

Strippoli 2003

Strippoli GFM, Craig M, Schena FP, Craig JC.

Antihypertensive agents for preventing diabetic kidney

disease. (Protocol). Cochrane Database of Systematic Reviews

2003, Issue 2. [DOI: 10.1002/14651858.CD004136]

Strippoli 2005

Strippoli GF, Craig M, Craig JC. Antihypertensive agents

for preventing diabetic kidney disease. Cochrane Database

of Systematic Reviews 2005, Issue 4. [DOI: 10.1002/

14651858.CD004136.pub2]∗ Indicates the major publication for the study



C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

ABCD Study 2002

Methods • Study design: parallel RCT

• Follow-up period: 63.6 months

Participants Inclusion criteria

• Country: USA

• Setting: University

• Proportion of diabetic subjects with normoalbuminuria, microalbuminuria or

macroalbuminuria not available; all type 2 diabetes; all hypertensive

• Number: treatment group (119); control group (127)

• Mean age ± SD (years): treatment group (8.8 ± 6.3); control group (9.2 ± 7.6)

• Sex (M/F): 131/115

Exclusion criteria

• Known allergy to dihydropyridines or ACEi; a myocardial infarction or cerebral

vascular accident within the previous 6 months; coronary artery bypass surgery within

the previous 3 months; unstable angina pectoris within the previous 6 months; Class

III or IV New York Heart Association classification of congestive heart failure;

demonstrated an absolute need for ACEi or calcium channel blockers; receiving

haemo- or peritoneal dialysis and/or had a SCr > 3 mg/dL

Interventions Treatment group

• Enalapril: 5 to 40 mg/d

Control group

• Placebo

Outcomes • Death

• Cardiovascular death

• Myocardial infarction

• BP

Notes • BP target equalisation not achieved in study (no use of other antihypertensive co-

interventions)

• End of treatment HbA1c not available

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Low risk Using permuted block randomisation

within strata

Allocation concealment (selection bias) Low risk Assignment through telephone by the co-

ordinator centres



ABCD Study 2002 (Continued)

Blinding of participants and personnel

(performance bias)

All outcomes

Low risk Placebo was used; study nurses were

blinded to the use of enalapril versus nisol-

dipine, but could not be blinded with re-

spect to intensive versus moderate BP con-

trol

Blinding of outcome assessment (detection

bias)

All outcomes

Low risk Endpoint committee were blinded to the

patient assignment

Incomplete outcome data (attrition bias)

All outcomes

Unclear risk Not described

Selective reporting (reporting bias) High risk Reported the pre-specified outcomes in the

protocol. Albuminuria change was not re-

ported in detail for the data to be included

in the meta-analysis

ABCD-2V Study 2004


• Follow-up period: 22.8 months


• Country: USA

• Setting: single centre, university

• Diabetic subjects with normoalbuminuria (102), microalbuminuria (26),

macroalbuminuria (1); all type 2 diabetes; all normotensive



• Sex (M/F): treatment group (44/22); control group (43/20)

Exclusion criteria

• Pregnant or lactating women; need for any antihypertensive medications;

documented myocardial infarction or cerebrovascular accident within the past 6

months; severe peripheral vascular disease; history of bilateral renal artery stenosis or

stenosis in a solitary kidney; evidence of severe liver disease; hyperkalaemia; history of

active cancer


• Valsartan: 80 to 160 mg/d

Control group

• Placebo

Outcomes • Death

• Cardiovascular event

• BP



ABCD-2V Study 2004 (Continued)

Notes • BP target equalization not achieved in study

• Change in end of treatment HbA1c -0.67% versus -0.33% in treatment and

control group

• ’Study terminated due to funding restraints The extended recruitment period (4

years) and study termination after a total of 5 years resulted in a differential follow-up

ranging from 1 year to 4 years, with 12 patients having 4 years of follow-up. The mean

follow-up was 1.9 ± 1.0 years for the study group. Because the follow-up period was

shorter than anticipated and did not reach the initial study recruitment goals, the

primary outcome was redefined as the change in UAE. The progression/regression of

retinopathy and neuropathy as well as the incidence of cardiovascular events were also

evaluated’

Risk of bias



bias)

Low risk Generated the randomisation list using

SAS, stratified by sex and SCr

Allocation concealment (selection bias) Low risk Randomisation list was secured within the

Data Coordinating Center


(performance bias)

All outcomes

Low risk Placebo was used; the study nurses by ne-

cessity knew the BP treatment categories

for their individual patients


bias)

All outcomes

Low risk Endpoint committee was blinded to the in-

tervention arm


All outcomes

Low risk Five patients were lost follow-up, and com-

parable between the two intervention arms

(2 in intervention group and 3 in the con-

trol group)

Selective reporting (reporting bias) High risk Reporting all outcomes that described in

the method. Albuminuria change was not

reported in detail for the data to be included

in the meta-analysis

ADVANCE Study 2009


• Follow-up: 51.6 months


• Country: 20 countries

• Setting: 215 collaborating clinical centres



ADVANCE Study 2009 (Continued)

• Diabetic subjects with normoalbuminuria (7877), microalbuminuria (2862),

macroalbuminuria (401); 68.7% were hypertensive; all type 2 diabetes


• Mean age ± SD (years): treatment group (66 ± 6); control group (66 ± 7)


Exclusion criteria

• Indication for long-term insulin therapy


• Perindopril: 4 mg

• Indapamide: 1.25 mg/d

Control group

• Placebo

Outcomes • Death

• ESKD

• Doubling SCR

• New onset of albuminuria

• BP

Notes • Additional outcome data obtained from author

• BP target equalization not achieved in study

• No difference in end of treatment HbA1c values

Risk of bias



bias)

Low risk Centre randomisation stratified by study

centre, history macrovascular/microvascu-

lar disease and and background use of

perindopril at baseline

Allocation concealment (selection bias) Low risk Randomisation service accessible by Inter-

net, telephone, and facsimile


(performance bias)

All outcomes

Low risk Double blind fashion


bias)

All outcomes

Low risk An Endpoint Adjudication Committee was

masked to treatment allocation


All outcomes

Low risk Only 15 patients (0.1%) were lost follow-

up, 4 in the intervention group and 11 in

the placebo group



ADVANCE Study 2009 (Continued)

Selective reporting (reporting bias) Low risk Reported all the outcomes described in the

protocol

Baba 2001


• Follow-up: 24 months


• Country: Japan

• Setting: multicentre study

• Proportion of diabetic subjects with normo or micro/macroalbuminuria in study

not available; all had type 2 diabetes; all were hypertensive




Exclusion criteria

• Poor glycaemic control (HbA1c 12%); malignant hypertension; renal artery

stenosis; overt proteinuria


• Enalapril: 5 to 20 mg/d

Control group

• Nifedipine: 20 to 60 mg/d

Outcomes • Death

• ESKD

• Doubling of SCr


• BP target equalization achieved in study by use of other antihypertensive co-

interventions


Risk of bias



bias)

Low risk ’A block of 4 patients (2 per group) was

assigned’. Possible generated by computer

or randomisation table

Allocation concealment (selection bias) Low risk ’envelope method was used’. Allocation

concealment was probably done


(performance bias)

All outcomes

High risk open-label



Baba 2001 (Continued)


bias)

All outcomes



All outcomes


Selective reporting (reporting bias) Low risk reported all the pre-specified outcomes

BENEDICT Study 2004




• Country: Italy

• Setting: multicentre (9 diabetic clinics)

• Diabetic subjects with normoalbuminuria; all type 2 diabetes; all hypertensive

• Number: treatment group (301); control group 1 (300); control group 2 (300);

control group 3 (300)

• Mean age ± SD (years): treatment group 1 (61.6 ± 8.1); treatment group 2 (62.5 ±

8.2); treatment group 3 (62.7 ± 7.7); control group (62.6 ± 8.2)

• Sex (M/F): treatment group 1 (157/144); treatment group 2 (164/139);

treatment group 3 (165/135); control group (149/151)

Exclusion criteria

• Concomitant non-DKD; concomitant diseases (heart failure, stroke, TIA, acute

myocardial infarction, unstable angina in the last 3 months, severe or secondary

hypertension, cancer, systemic disease, severe hematological or liver disorder,

malabsorption, and any major clinical condition that may jeopardize study

participation); specific contraindications to the study drugs; inability to provide

informed consent

Interventions Treatment group 1

• Trandolapril: 2 mg/d

Treatment group 2

• Verapamil SR: 240 mg/d

treatment group 3

• Trandolapril: 2 mg/d

• Verapamil: 180 mg/d

Control group

• Placebo

Outcomes • Onset of microalbuminuria

• All-cause mortality

• Cough



BENEDICT Study 2004 (Continued)

Notes • BP target equalization achieved in study by use of other antihypertensive co-

interventions


Risk of bias



bias)


Allocation concealment (selection bias) Unclear risk Not described


(performance bias)

All outcomes

Low risk ’a multicenter, double-blind, placebo-con-

trolled, randomised study’. Data analysts

were unblinded


bias)

All outcomes



All outcomes

Low risk 1204 (99.7%) were followed for a median

of 3.6 years. Only 0.3% of the patients with

lost during the follow-up

Selective reporting (reporting bias) Low risk Reported all outcomes described in the

methods

CALM II Study 2005




• Country: Denmark

• Setting: single centre

• Diabetic subjects with normoalbuminuria (45), microalbuminuria (36); type 1

diabetes (11); type 2 diabetes (63); all hypertensive




Exclusion criteria

• Age < 18 and > 75 years; nondiabetic cause of secondary hypertension or

malignant hypertension; cardiovascular events within 6 months before randomisation;

impaired renal function with a SCr 130 mol/L or plasma potassium outside normal

range; pregnancy or breast feeding



CALM II Study 2005 (Continued)


• Lisinopril: 40 mg/d

Control group

• Lisinopril: 20 mg/d

• Candesartan: 16 mg/d

Outcomes • BP

• Albuminuria



interventions

• End of treatment HbA1c: treatment group (8.6%); control group (8.0%)

Risk of bias



bias)




(performance bias)

All outcomes

Low risk ’double-blind, randomised, active-con-

trolled, parallel group study’, probably

done


bias)

All outcomes



All outcomes

Low risk All patients followed the treatment proto-

col and were available for follow-up

Selective reporting (reporting bias) High risk In the protocol the outcomes included

retinopathy and left ventricular mass, but

only albuminuria and BP were reported

here

Chan 1992




• Setting: single university centre

• Country: China

• All type 2 diabetes; all hypertensive; all treated with diet or oral agents, and none



Chan 1992 (Continued)

were receiving insulin treatment or lipid-lowering drugs at the time of recruitment


◦ Normoalbuminuria: treatment group (20); control group (24)

◦ Microalbuminuria: treatment group (21); control group (15)

• Mean age ± SD (years): treatment group (60 ± 9.3); control group (56.2 ± 9.9)


Exclusion criteria

• Receiving insulin; history of non-DKD; SCr ≥ 200 mol/L; plasma potassium

concentration ≥ 5 mmol/L; cardiac failure; any concurrent systemic disease; receiving

treatment for any concomitant disorder


• Enalapril: 10-40 mg/d

Control group

• Nifedipine SF: 40-80 mg/d

Outcomes • Death

• BP

• Albuminuria

Notes • BP target equalisation achieved in study by use of other antihypertensive co-

interventions


Risk of bias



bias)

Low risk ’according to a random allocation sched-

ule. A schedule of 102 allocation numbers

corresponding to similarly numbered drug

supplies was provided for this purpose.’ No

description of how random sequence was

produced

Allocation concealment (selection bias) Unclear risk No description of how allocation was per-

formed


(performance bias)

All outcomes

Unclear risk Patients blinded; blinding of investigators

not stated


bias)

All outcomes

Low risk “staff measuring BP and biochemical in-

dices were blinded to treatment.”


All outcomes

Low risk Detailed description of the reasons of the 9

patients (8.8%) who did not finish follow-

up



Chan 1992 (Continued)

Selective reporting (reporting bias) Low risk Reported all outcomes described in meth-

ods

Crepaldi 1995




• Country: Italy

• Setting: multicentre (12) anti-diabetic centres

• Men and women < 70 years with mild to moderate hypertension (phase V supine

DPB 90-115 mm Hg) and non-insulin-dependent diabetes (normoalbuminuria (55),

microalbuminuria (24)); all type 2 diabetes; all hypertensive

• Treatment group


• Mean age ± SD (years)

◦ Treatment group: males (54.7 ± 8.1); females (56.8 ± 7.9)

◦ Control group: males (56.3 ± 8.6); females (57.5 ± 9.0)


Exclusion criteria

• Secondary or malignant hypertension; a recent history of myocardial infarction;

unstable angina; heart failure or aortic; outflow obstruction; renal, hepatic, blood or

endocrine disorders other than diabetes; positive response to an Albustix test for

urinary protein; women capable of becoming pregnant or using oral contraceptives;

history of poor compliance with drug therapy; known hypersensitivity/

contraindication to ACEi or nifedipine.


• Lisinopril: 10-20 mg/d

Control group

• Nifedipine: 20-60 mg/d

Outcomes • Death

• ESKD

• BP

Notes • BP target equalization not achieved in study (no use of other antihypertensive co-

interventions)

• Change in end of treatment HbA1c: treatment group (-0.4%); control group (-0.

2%)

Risk of bias




Crepaldi 1995 (Continued)


bias)

Unclear risk “The randomization process was carried

out by the coordinating centre using stan-

dard randomization techniques.” No de-

scription of the generation of random se-

quence

Allocation concealment (selection bias) Unclear risk No description of allocation concealment


(performance bias)

All outcomes

Low risk ’double-blind, double-dummy,

randomised trial’


bias)

All outcomes



All outcomes

Low risk 171 patients qualified for admittance to

the study, of whom 9 withdrew during the

placebo, run-in phase

Selective reporting (reporting bias) High risk Described all the outcomes pre-specified in

the methods. Albuminuria change was not

reported in detail for the data to be included

in a meta-analysis

DIRECT Studies 2009


• Recruitment: commenced in August 2001, and the last patient was studied in

March 2008.


• Setting: international multicentre (309 centres)

• Countries: 30 countries

• DIRECT-Prevent 1

◦ Diabetic subjects with normoalbuminuria (1421); all type 1 diabetes; all

normotensive; no difference in end of treatment HbA1c values

◦ Number: treatment group (711); control group (710)

◦ Mean age ± SD (years): treatment group (29.6 ± 8.0); control group (29.9 ±

8.1)

◦ Sex (M/F): treatment group (413/298); control group (392/318)

• DIRECT-Protect 1

◦ Diabetic subjects with normoalbuminuria (1905); all type 1 diabetes; all

normotensive; no difference in end of treatment HbA1c values



8.5)




DIRECT Studies 2009 (Continued)

• DIRECT-Protect 2

◦ Diabetic subjects with normoalbuminuria (1905); all type 2 diabetes; 62%

with hypertensive; no difference in end of treatment HbA1c values



7.9)


Exclusion criteria

• Cataract or media opacity; angle closure glaucoma; history of retinopathy; history

or presence of clinical significant macular oedema; history or evidence of

photocoagulation of the retina; other retinal conditions which may mask assessment;

pregnant or lactating women or women of child bearing potential not practicing an

adequate method of contraception; need of treatment with ACEi; haemodynamically

significant aortic or mitral valve stenosis; known renal artery stenosis or kidney

transplantation; hypersensitivity to study drug; severe concomitant disease which may

interfere with the assessment of the patient; malignancy


• Candesartan: 16 mg/d increasing to 32 mg/d

Control group

• Placebo

Outcomes • Death

• New onset albuminuria

• BP

• headache

• hyperkalaemia

Notes • Supported By AstraZeneca and Takeda

• Statistical staff at AstraZeneca and Takeda did analyses according to the intention-

to-treat principle. The 2-sided P values were calculated without any adjustment for

multiple comparisons

Risk of bias



bias)

Unclear risk Randomisation into the three studies was

conducted based on primary grading of the

baseline photographs, using the ETDRS

severity scale.The patients are to be evalu-

ated in the correct study based on the final

grading of the photographs

No description of random sequence gener-

ation

Allocation concealment (selection bias) Low risk “randomly assigned eligible patients cen-

trally using an interactive voice-response

system”



DIRECT Studies 2009 (Continued)


(performance bias)

All outcomes

Low risk ’double-masked, placebo-controlled, paral-

lel design, randomised clinical trials’


bias)

All outcomes



All outcomes

High risk 286/1662 (17.2%) missing from interven-

tion group; 272/1664 (16.3%) missing

from control group

Selective reporting (reporting bias) Low risk Reporting all the outcomes of pre-specified

in the methods

EUCLID Study 1997




• Setting: multicentre (18 centres)

• Country: Europe

• Diabetic subjects normoalbuminuria (227), microalbuminuria (34),

macroalbuminuria (269); all type 1 diabetes; all normotensive


• Age, range (years): treatment group (33, 27-40); control group (33, 28-41)


Exclusion criteria

• History of renal-artery stenosis, cardiac-valve obstruction, or accelerated

hypertension; recent (previous 3 months) myocardial infarction, coronary bypass

surgery, stroke, or congestive cardiac failure; abnormal renal function (SCr > 150 mol/

L, > 1·8 mg/dL) in the previous 6 months, persistent proteinuria or persistent

haematuria on 3 occasions within the previous 12 months; postural hypotension,

medication that affects BP, a previous idiosyncratic reaction to ACEi; seropositivity for

hepatitis B or HIV



Control group

• Placebo

Outcomes • Death

• HbA1c

• AER

• BP

• Serious adverse events (hospital admission, hypoglycaemia, withdrawal due to

treatment)



EUCLID Study 1997 (Continued)

• Compliance

• Cough

Notes • End of treatment HbA1c not available

Risk of bias



bias)

Low risk FORTRAN computer program validated

against the SAS RANUNI random-num-

ber generator. Randomisation was stratified

by centre and albuminuric status

Allocation concealment (selection bias) Low risk Sealed envelopes were supplied to each cen-

tre


(performance bias)

All outcomes

Low risk ”This scheme was generated by Zeneca

Pharmaceuticals, so that both the coordi-

nating centre and the local investigators

were unaware of the allocation.“


bias)

All outcomes

Low risk Blood and urine samples were sent to the

laboratory of the Royal London Hospital,

UK. Laboratory investigators were given

the identification number only of the pa-

tient.”


All outcomes

High risk 42/365 (15.8%) missing from intervention

group; 40/265 (15.1%) missing from con-

trol group

Selective reporting (reporting bias) Low risk Reported outcomes specified in the meth-

ods (death not reported but there may not

have been any)

FACET Study 1998


• Recruitment: 1 January 1992 to 31 December 1992



• Setting: teaching hospital

• Country: Italy

• Diabetic subjects, microalbuminuria (380); type 1 and type 2 diabetes; all

hypertensive




FACET Study 1998 (Continued)

• Mean age ± SD (years): treatment group (10.7 ± 9.96); control group (63.3 ± 5.

52)


Exclusion criteria

• history of coronary heart disease, stroke, or any other morbid condition with poor

prognosis; SCr > 1.5 mg/dL; a microalbuminurialevel > 40 ug/min; use of lipid

lowering drugs, aspirin, or antihypertensive agents other than diuretics and beta-

blockers


• Fosinopril: 20 mg/d

Control group

• Amlodipine: 10 mg/d

Outcomes • Death

• Myocardial infarction

• BP

• Albuminuria

Notes • BP target equalization not achieved in study (despite use of other antihypertensive

co-interventions)


Risk of bias



bias)

Low risk Computer-generated random number se-

quence

Allocation concealment (selection bias) Low risk Adequate


(performance bias)

All outcomes

High risk Open-label design


bias)

All outcomes



All outcomes

High risk 17/189 (9.0%) missing from treatment

group; 23/191(12.0%) missing from con-

trol group

Selective reporting (reporting bias) Low risk Reported all outcomes specified in the

methods



HOPE Study 2000


• Recruitment: December 1993 to June 1995



• Setting: multicentre study (129 centres)

• Countries: 19 (Canada, USA, 14 European countries, Argentina, Brazil, Mexico)

• Type 1 and type 2 (3546) diabetic subjects, normoalbuminuria (2438),

microalbuminuria (1139); all hypertensive

• Treatment group



• Sex: M/F: treatment group (1112/696); control group (626/1143)

Exclusion criteria

• Dipstick-positive proteinuria or established DKD; other severe kidney disease;

hyperkalaemia; congestive heart failure; low ejection fraction (< 0.4); uncontrolled

hypertension; recent myocardial infarction or stroke (< 4 weeks); use of or

hypersensitivity to vitamin E or ACEi


• Ramipril: 10 mg/d

Control group

• Placebo

Outcomes • Death


• ESKD

• Doubling of SCr

• Onset of microalbuminuria

• Toxicity


• BP target equalization not achieved in study (despite use of other antihypertensive

co-interventions)


Risk of bias



bias)

Unclear risk Central randomisation (2 x 2 factorial de-

sign), no description of the random se-

quence generation



(performance bias)

All outcomes

Low risk ’Double-blind’



HOPE Study 2000 (Continued)


bias)

All outcomes



All outcomes



methods

Joglekar 1998




• Setting: multicentre (20)

• Country: India

• Proportion with normoalbuminuria, microalbuminuria or macroalbuminuria not

available; all type 2 diabetes; all hypertensive

• Treatment group


• Mean age ± SD (years): treatment group (54.7 ± 11.6); control group (53.4 ± 11.

6)


Exclusion criteria: not stated



Control group

• Prazosin GITS: 2.5-5 mg/d

Outcomes • Cough

• GFR

Notes • BP target equalization not achieved in study (no use of other antihypertensive co-

interventions)


Risk of bias



bias)

Unclear risk Random sequence generation not de-

scribed

Allocation concealment (selection bias) Unclear risk No description of allocation concealment



Joglekar 1998 (Continued)


(performance bias)

All outcomes



bias)

All outcomes



All outcomes

High risk 17/48 missing from intervention group;

12/41 missing from control group

Selective reporting (reporting bias) High risk Albuminuria change was not reported in

detail for the data to be included in a meta-

analysis

Kavgaci 2002





• Country: Turkey

• Diabetic subjects, normoalbuminuria (18), microalbuminuria (15); all type 2

diabetes; all hypertensive


• Median age, range (years): treatment group (49, 41-62); control group (59, 40-66)


Exclusion criteria

• Albuminuria level > 300 mg/d; CCr < 100 mL/min; patients taking ACEi and

ARB


• Fosinopril: 10 mg/d

Control group

• Losartan: 50 mg/d

Outcomes • changes in albuminuria

Notes • BP target equalization achieved in study by use of other antihypertensive co-

interventions

• End of treatment HbA1c 7.57 versus 6.58% in treatment and control group

Risk of bias




Kavgaci 2002 (Continued)


bias)




(performance bias)

All outcomes

High risk Open-label


bias)

All outcomes



All outcomes

Low risk All of the patients completed the 6 months

study period

Selective reporting (reporting bias) High risk Albuminuria change in the patients with

normoalbuminuria reported but with in-

adequate detail for the data to be included

in a meta-analysis

Kvetny 2001


• Follow-up duration: 36 months


• Setting: single hospital

• Country: Denmark

• Type 1 diabetic patients, no microalbuminuria, no hypertension



• Males (%): treatment group (55); control group (58)

Exclusion criteria

• Ongoing treatment with ACEi; know side-effects of ACEi; pregnancy or intended

pregnancy; known kidney disease; systolic BP < 100 mm Hg or diastolic BP < 50 mm

Hg


• Perindopril: 2 mg x 2/d

Control group

• Placebo

Outcomes • Changes in albuminuria


Risk of bias



Kvetny 2001 (Continued)



bias)




(performance bias)

All outcomes

Low risk ’double-blind’


bias)

All outcomes



All outcomes

High risk 11/89 patients drop out due to non-com-

pliance


methods

Lin 1995




• Setting: university

• Country: USA

• All type 2 diabetes, proportion with normoalbuminuria, microalbuminuria or

macroalbuminuria not available; all hypertensive

• Number: treatment group 1 (20); treatment group 2 (20); control group (20)

• Mean age ± SD (years): treatment group 1 (62 ± 7); treatment group 2 (63 ± 7);

control group (62 ± 8)

• Sex (M/F): only males



• Captopril: 25-150 mg/d

Treatment group 2


Control group

• Conventional treatment

Outcomes • BP

• Proteinuria



Lin 1995 (Continued)



interventions

• End of treatment HbA1c: treatment groups (7.0%); control group (7.6%)

Risk of bias



bias)

Low risk Randomisation order was arranged by

computer setting



(performance bias)

All outcomes



bias)

All outcomes



All outcomes


Selective reporting (reporting bias) High risk Albuminuria change was not reported in

detail for the data to be included in a meta-

analysis

ONTARGET Study 2008


• Recruitment: November 2001 to June 2004



• Setting: multicentre study (730 centres)

• Countries: 40 countries

• Type 1 and type 2 diabetes (37.5%); normoalbuminuria (4414); 86.2%

hypertensive

• Number: treatment group (8576); control group 1 (8542); control group 2 (8502)

• Mean age ± SD (years): treatment group (66.4 ± 7.2); control group 1 (66.4 ± 7.

1); control group 2 (66.5 ± 7.3)

• Sex (M/F): treatment group (6245/2331); control group 1 (6292/2250); control

group 2 (6252/2250)

Exclusion criteria

• Major renal artery stenosis; uncorrected volume or sodium depletion; a SCr > 265

µmol/L; uncontrolled hypertension (> 160 mm Hg systolic or > 100 mm Hg diastolic)



ONTARGET Study 2008 (Continued)


• Ramipril: 10 mg/d

Control group 1

• Telmisartan: 80 mg/d

Control group 2

• Combination of ramipril and telmisartan

Outcomes • Death


• ESKD

• Doubling of SCr


• Toxicity


Risk of bias



bias)

Low risk ’randomisation was stratified according to

site with the use of permuted blocks’

Allocation concealment (selection bias) Low risk ’randomised via a computerized voice-acti-

vated telephone call to a central office”


(performance bias)

All outcomes

Low risk Double-blind design


bias)

All outcomes



All outcomes

Low risk 0.2% of the participants were missing

Selective reporting (reporting bias) Low risk All outcomes described in the protocol were

reported

Perrin 2008





• Country: Sweden



Perrin 2008 (Continued)

• Diabetic subjects with normoalbuminuria; all type 1 diabetes; all normotensive


• Age (range): treatment group (23 years, 20-26); control group (24 years, 24-26)


Exclusion criteria

• Pregnancy or no reliable anti-conception treatment; microalbuminuria;

hypertension; severely reduced kidney or liver function; ongoing antihypertensive

treatment


• Candesartan: 16 mg/d

Control group

• Placebo

Outcomes • New onset albuminuria

• BP

• GFR

Notes • End of treatment HbA1c: treatment group (7.8%); control group (.7.7%)

• The study was sponsored by Astra Zeneca, and was also supported by a grant

from the Swedish Medical Research Council (no. 6864)

Risk of bias



bias)




(performance bias)

All outcomes

Low risk Double-blind design. The pills could not

be distinguished by patients or medical or

pharmacy personnel


bias)

All outcomes



All outcomes

High risk 3/13 patients missing from the study


methods



RASS Study 2002




• Country: Canada, USA

• Setting: multicentre (3)


• Number: treatment group (94); treatment group 2 (96); control group (95)

• Meand age ± SD (years): treatment group 1 (30.6 ± 10.0); treatment group 2 (29.

3 ± 10.2); control group (29.1 ± 9.1)

• Sex (M/F): treatment group 1 (48/46); treatment group 2 (46/50); control group

(45/50)

Exclusion criteria

• Hypertension or receipt of antihypertensive medications; albumin excretion rate >

20 µg/min; pregnancy; failure to take at least 85% of placebo pills during a 2-week

run-in period; GFR < 90 mL/min/1.73 m² (< 80 mL/min if the patient had a strictly

vegan diet)



Treatment group 2

• Losartan: 50-100 mg/d

Control group

• Placebo

Outcomes • Death

• ESKD

• Doubling of SCr

• New onset of microalbuminuria

• Toxicity



• ’Supported by research grants from the National Institutes of Health (NIH), the

National Institute of Diabetes and Digestive and Kidney Diseases (DK51975), Merck

(in the United States),Merck Frosst (in Canada), and the Canadian Institutes of Health

Research (CIHR) (DCT 14281). RASS was supported in part by a grant from the

National Center for Research Resources of the NIH, to the University of Minnesota

General Clinical Research Center (GCRC) (M01-RR00400)’

Risk of bias



bias)

Low risk Computer-generated blocks of six, stratifi-

cation by centre




RASS Study 2002 (Continued)


(performance bias)

All outcomes



bias)

All outcomes

Low risk All measurements were performed by one

observer, who was unaware of the study-

drug assignments


All outcomes

Low risk 256/285 (90%) had baseline and 5 year

biopsies; 223/285 (78%) had baseline and

5 year retinopathy

Selective reporting (reporting bias) Low risk Reported all outcomes described in the pro-

tocol

Ravid 1998




• Setting: multicentre (8 clinics)

• Country: Israel








Control group

• Placebo

Outcomes • Death


• Cough

• Hyperkalaemia

• Development of albuminuria

• Mean arterial pressure


• BP target equalisation achieved in study by use of other antihypertensive co-

interventions


Risk of bias



Ravid 1998 (Continued)



bias)

Low risk Random number table

Allocation concealment (selection bias) Low risk Randomisation was done centrally by tele-

phone


(performance bias)

All outcomes



bias)

All outcomes



All outcomes

High risk 16/97 missing from intervention group;

17/97 missing from control group

Selective reporting (reporting bias) Low risk Reported all outcomes described in the

methods

ROADMAP Study 2009


• Recruitment: October 2004 to May 2006

• Follow-up: 38.4 months



• Country: 19 European countries

• Diabetic subjects with normoalbuminuria; all type 2 diabetes; 90.3% hypertensive




Exclusion criteria

• ACEi or ARB during the 6 months before the start of the study


• Olmesartan: 40 mg/d

Control group

• Placebo

Outcomes • Death


• ESKD

• Doubling SCr

• Development of albuminuria



ROADMAP Study 2009 (Continued)

Notes • BP target equalisation achieved in study by use of other antihypertensive co-

interventions

• ’The sponsor (Daiichi Sankyo) had no role in the design or conduct of the study,

but representatives of the sponsor served as nonvoting members of the steering

committee’

Risk of bias



bias)

Low risk Randomisation list produced by PRA using

SAS software

Allocation concealment (selection bias) Low risk Sealed envelopes used in randomisation al-

location


(performance bias)

All outcomes



bias)

All outcomes



All outcomes

Low risk 51/2233 lost from intervention group; 57/

2216 lost from control group

Selective reporting (reporting bias) Unclear risk Reported all outcomes described in the pro-

tocol

Scognamiglio 1997


• Follow-up period: 36 weeks


• Setting: not described

• Country: Italy







• Captopril: 50-100 mg/d

Control group

• Nitrendipine: 20-40 mg/d



Scognamiglio 1997 (Continued)

Outcomes • Death

• ESKD

• BP

• Albuminuria

Notes • End of treatment HbA1c: treatment group (6.0%); control group (6.8%)

• BP target equalisation not achieved in study (no use of other antihypertensive co-

interventions)

Risk of bias



bias)




(performance bias)

All outcomes



bias)

All outcomes



All outcomes

Low risk 3/73 patients dropped out

Selective reporting (reporting bias) High risk Albuminuria was not reported in enough

detail for the data to be included in the

meta-analyses

TRANSCEND Study 2009


• Recruitment: November 2001 to May 2004




• Country: 40 countries

• Diabetic subjects with normoalbuminuria; type 1 and type 2 diabetes; 89%

hypertensive

• Treatment group






TRANSCEND Study 2009 (Continued)

Exclusion criteria

• Needed an ARB; hypersensitive or intolerant to ARB; heart failure, significant

valvular or cardiac outflow tract obstruction, constrictive pericarditis complex

congenital heart disease, unexplained syncope, planned cardiac surgery, cardiac

revascularization in the previous 3 months; systolic BP ≥ 160 mm Hg; heart

transplantation; subarachnoid haemorrhage; known significant renal artery stenosis;

SCr levels > 265 mol/L (3.0 mg/dL); hepatic dysfunction.


• Telmisartan: 80 mg/d

Control group

• Placebo

Outcomes • Death


• ESKD

• Doubling of SCr


• Toxicity


• ’Boehringer Ingelheim funded the study. The steering committee designed and

oversaw the study and had the final decision on the contents of the manuscript. All

data were received, checked, and analyzed independently at the coordinating center at

McMaster University.’

Risk of bias



bias)

Unclear risk ’randomisation was stratified according to

site with the use of permuted blocks’

Allocation concealment (selection bias) Low risk randomised via a computerized voice-acti-

vated telephone call


(performance bias)

All outcomes

Low risk Double-blind design ’All participants and

trial investigators were blinded to random-

ized treatment’

’Unblinded data were made available exclu-

sively to the independent data safety and

monitoring board by a statistician who was

independent of the trial’


bias)

All outcomes




TRANSCEND Study 2009 (Continued)


All outcomes

Low risk 10/2954 lost from intervention group; 8/

2972 lost from control group

Selective reporting (reporting bias) Low risk Reportes all outcomes in the protocol

Tuominen 1998


• Follow-up period: 24 months


• Setting: Teaching hospital

• Country: Finland



• Mean age ± SD (years): treatment group (34.0 ± 7.2); control group (36 ± 10)

• Sex (M/F): overall (14/12)




Control group

• Placebo

Outcomes • BP




• BP target equalisation not achieved in study (no use of other antihypertensive co-

interventions)

Risk of bias



bias)




(performance bias)

All outcomes



bias)

All outcomes




Tuominen 1998 (Continued)


All outcomes

Low risk Two patients discontinued the study (both

in the lisinopril group) because of preg-

nancy and a wish to become pregnant

Selective reporting (reporting bias) Unclear risk Reporting all outcomes described in the

methods

UKPDS Study 1998




• Setting: multicentre

• Country: UK

• Proportion with normoalbuminuria, microalbuminuria or macroalbuminuria not

available; all type 2 diabetes; all hypertensive


• Mean age SD (years): treatment group (56.3 ± 8.1); control group (56.0 ± 8.2)


Exclusion criteria

• Clinical requirement for strict BP control or beta blockade; severe vascular

disease; a severe concurrent illness or contraindications to beta blockers; pregnancy; or

unwillingness to join the study


• Captopril: 25-50 mg x 2/d

Control group

• Atenolol: 50-100 mg/d

Outcomes • Death

• Onset of micro or macroalbuminuria

• BP

Notes • BP target equalization achieved in study (use of other antihypertensive co-

interventions)

• End of treatment HbA1c: treatment group (8.3%); control group (8.%)

Risk of bias



bias)

Low risk ’Randomisation stratified for those with or

without previous treatment for hyperten-

sion was performed by the coordinating

centre’

Allocation concealment (selection bias) Low risk Sealed opaque envelopes were used



UKPDS Study 1998 (Continued)


(performance bias)

All outcomes

High risk Open label study


bias)

All outcomes

Low risk Copies of endpoint information, without

reference to the patient’s allocated or actual

treatment, were formally presented to two

independent physicians


All outcomes

Low risk 4% participants were lost follow-up

Selective reporting (reporting bias) Low risk Reported outcomes described in the proto-

col

Velussi 1996




• Setting: university

• Country: Italy

• Normoalbuminuria (29), microalbuminuria (21); all type 2 diabetes; all

hypertensive

• Number: overall (50)

• Age: unclear

• Sex (M/F): not stated



• Cilazapril: 2.5 mg/d

Control group

• Amlodipine: 5 mg/d

Outcomes • BP


• BP target equalisation achieved in study (use of other antihypertensive co-

interventions)


Risk of bias



bias)




Velussi 1996 (Continued)



(performance bias)

All outcomes

Low risk Double-blinded double-dummy design


bias)

All outcomes



All outcomes

High risk 6/50(12%) participants missing from the

study

Selective reporting (reporting bias) Unclear risk Reported all outcomes described in the

methods

ACEi - angiotensin-converting enzyme inhibitor; ARB - angiotensin receptor blockers; BP - blood pressure; DKD - diabetic kidney

disease; ESKD - end-stage kidney disease; SCr - serum creatinine

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

ALLHAT 2002 Baseline data on kidney disease were not available, so that we were not able to separate out the data of diabetic

patients with normoalbuminuria and could not include these data in our main analyses

CAPPP 1999 Baseline data on kidney disease were not available, so that we were not able to separate out the data of diabetic


Hansson 1999 Baseline data on kidney disease were not available, so that we were not able to separate out the data of diabetic


HOT 1998 Baseline data on kidney disease were not available, so that we were not able to separate out the data of diabetic


INSIGHT 2000 Baseline data on kidney disease were not available, so that we were not able to separate out the data of diabetic


NORDIL 2000 Baseline data on kidney disease were not available, so that we were not able to separate out the data of diabetic


Tuomilehto 1999 Baseline data on kidney disease were not available, so that we were not able to separate out the data of diabetic




D A T A A N D A N A L Y S E S

Comparison 1. ACEi versus placebo/no treatment

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Normo- to micro- or

macroalbuminuria

8 11906 Risk Ratio (M-H, Random, 95% CI) 0.71 [0.56, 0.89]

2 All-cause mortality 6 11350 Risk Ratio (M-H, Random, 95% CI) 0.84 [0.73, 0.97]

3 Doubling of SCr 5 10749 Risk Ratio (M-H, Random, 95% CI) 0.77 [0.39, 1.49]

4 ESKD 3 10504 Risk Ratio (M-H, Random, 95% CI) 1.94 [0.66, 5.70]

5 Adverse events 6 Risk Ratio (M-H, Random, 95% CI) Subtotals only

5.1 Cough 6 11791 Risk Ratio (M-H, Random, 95% CI) 1.84 [1.24, 2.72]

5.2 Headache 3 10504 Risk Ratio (M-H, Random, 95% CI) 1.19 [0.47, 3.02]

5.3 Hyperkalaemia 3 2783 Risk Ratio (M-H, Random, 95% CI) 2.98 [0.47, 18.78]

6 Blood pressure 2 Mean Difference (IV, Random, 95% CI) Subtotals only

6.1 Systolic BP 2 7526 Mean Difference (IV, Random, 95% CI) -5.37 [-7.12, -3.62]

6.2 Diastolic BP 2 7526 Mean Difference (IV, Random, 95% CI) -1.50 [-1.50, -1.50]

Comparison 2. ARB versus placebo/no treatment


studies

No. of



macroalbuminuria





5 Adverse events 3 Risk Ratio (M-H, Random, 95% CI) Subtotals only

5.1 Cough 2 1770 Risk Ratio (M-H, Random, 95% CI) 1.01 [0.42, 2.44]

5.2 Headache 3 3191 Risk Ratio (M-H, Random, 95% CI) 0.73 [0.52, 1.01]

5.3 Hyperkalaemia 3 3191 Risk Ratio (M-H, Random, 95% CI) 2.30 [0.69, 7.71]


6.1 Systolic BP 2 1770 Mean Difference (IV, Random, 95% CI) -3.28 [-5.29, -1.27]

6.2 Diastolic BP 2 1770 Mean Difference (IV, Random, 95% CI) -2.0 [-2.64, -1.36]



Comparison 3. ACEi versus ARB


studies

No. of



macroalbuminuria



Comparison 4. ACEi versus CCB


studies

No. of


1 Normo to micro or

macroalbuminuria






5.1 Systolic BP 2 430 Mean Difference (IV, Random, 95% CI) 4.0 [1.59, 6.41]

5.2 Diastolic BP 2 430 Mean Difference (IV, Random, 95% CI) 1.22 [-0.42, 2.85]

Comparison 5. Prevention of kidney disease: other agents


studies

No. of


1 ACEi + ARB versus ACEi 2 4171 Risk Ratio (M-H, Random, 95% CI) 0.88 [0.78, 1.00]

2 ACEi versus BB 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected

3 ACEi + CCB versus ACEi 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected

4 CCB versus placebo 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected



Analysis 1.1. Comparison 1 ACEi versus placebo/no treatment, Outcome 1 Normo- to micro- or

macroalbuminuria.

Review: Antihypertensive agents for preventing diabetic kidney disease

Comparison: 1 ACEi versus placebo/no treatment

Outcome: 1 Normo- to micro- or macroalbuminuria

Study or subgroup ACEiPlacebo/notreatment Risk Ratio Weight Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

ADVANCE Study 2009 1078/3931 1289/3946 45.5 % 0.84 [ 0.78, 0.90 ]

BENEDICT Study 2004 18/301 30/300 12.8 % 0.60 [ 0.34, 1.05 ]

EUCLID Study 1997 36/265 49/265 20.3 % 0.73 [ 0.49, 1.09 ]

HOPE Study 2000 18/1256 24/1182 11.4 % 0.71 [ 0.39, 1.29 ]

Kvetny 2001 0/43 10/46 0.7 % 0.05 [ 0.00, 0.84 ]

RASS Study 2002 4/94 6/95 3.4 % 0.67 [ 0.20, 2.31 ]

Ravid 1998 5/77 15/79 5.3 % 0.34 [ 0.13, 0.90 ]

Tuominen 1998 0/13 2/13 0.6 % 0.20 [ 0.01, 3.80 ]

Total (95% CI) 5980 5926 100.0 % 0.71 [ 0.56, 0.89 ]

Total events: 1159 (ACEi), 1425 (Placebo/no treatment)

Heterogeneity: Tau2 = 0.03; Chi2 = 10.20, df = 7 (P = 0.18); I2 =31%

Test for overall effect: Z = 2.91 (P = 0.0037)

Test for subgroup differences: Not applicable

0.002 0.1 1 10 500

ACEi Placebo/no treatment



Analysis 1.2. Comparison 1 ACEi versus placebo/no treatment, Outcome 2 All-cause mortality.



Outcome: 2 All-cause mortality

Study or subgroup ACEiPlacebo/notreatment Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

ADVANCE Study 2009 229/3931 267/3946 0.86 [ 0.73, 1.02 ]

BENEDICT Study 2004 2/301 1/300 1.99 [ 0.18, 21.87 ]

HOPE Study 2000 106/1256 126/1182 0.79 [ 0.62, 1.01 ]

Kvetny 2001 0/43 0/46 0.0 [ 0.0, 0.0 ]

RASS Study 2002 1/94 1/95 1.01 [ 0.06, 15.92 ]

Ravid 1998 3/77 2/79 1.54 [ 0.26, 8.96 ]

Total (95% CI) 5702 5648 0.84 [ 0.73, 0.97 ]


Heterogeneity: Tau2 = 0.0; Chi2 = 1.27, df = 4 (P = 0.87); I2 =0.0%



0.02 0.1 1 10 50




Analysis 1.3. Comparison 1 ACEi versus placebo/no treatment, Outcome 3 Doubling of SCr.



Outcome: 3 Doubling of SCr


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

ADVANCE Study 2009 16/3931 26/3946 0.62 [ 0.33, 1.15 ]

HOPE Study 2000 20/1256 14/1182 1.34 [ 0.68, 2.65 ]

Kvetny 2001 0/43 0/46 0.0 [ 0.0, 0.0 ]

RASS Study 2002 0/94 0/95 0.0 [ 0.0, 0.0 ]

Ravid 1998 3/77 8/79 0.38 [ 0.11, 1.40 ]

Total (95% CI) 5401 5348 0.77 [ 0.39, 1.49 ]





0.1 0.2 0.5 1 2 5 10




Analysis 1.4. Comparison 1 ACEi versus placebo/no treatment, Outcome 4 ESKD.



Outcome: 4 ESKD


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

ADVANCE Study 2009 0/94 0/95 0.0 [ 0.0, 0.0 ]

HOPE Study 2000 5/1256 2/1182 2.35 [ 0.46, 12.10 ]

RASS Study 2002 5/3931 3/3946 1.67 [ 0.40, 7.00 ]

Total (95% CI) 5281 5223 1.94 [ 0.66, 5.70 ]





0.05 0.2 1 5 20




Analysis 1.5. Comparison 1 ACEi versus placebo/no treatment, Outcome 5 Adverse events.



Outcome: 5 Adverse events


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 Cough

ADVANCE Study 2009 1/3931 3/3946 0.33 [ 0.03, 3.22 ]

BENEDICT Study 2004 4/301 2/300 1.99 [ 0.37, 10.80 ]

EUCLID Study 1997 21/265 7/265 3.00 [ 1.30, 6.94 ]

HOPE Study 2000 37/1256 24/1182 1.45 [ 0.87, 2.41 ]

RASS Study 2002 12/94 4/95 3.03 [ 1.01, 9.06 ]

Ravid 1998 4/77 2/79 2.05 [ 0.39, 10.88 ]

Subtotal (95% CI) 5924 5867 1.84 [ 1.24, 2.72 ]




2 Headache

ADVANCE Study 2009 2/3931 2/3946 1.00 [ 0.14, 7.12 ]

HOPE Study 2000 8/1256 6/1182 1.25 [ 0.44, 3.61 ]

RASS Study 2002 0/94 0/95 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 5281 5223 1.19 [ 0.47, 3.02 ]




3 Hyperkalaemia

HOPE Study 2000 1/1256 0/1182 2.82 [ 0.12, 69.24 ]

RASS Study 2002 1/94 0/95 3.03 [ 0.13, 73.49 ]

Ravid 1998 1/77 0/79 3.08 [ 0.13, 74.39 ]

Subtotal (95% CI) 1427 1356 2.98 [ 0.47, 18.78 ]




0.01 0.1 1 10 100




Analysis 1.6. Comparison 1 ACEi versus placebo/no treatment, Outcome 6 Blood pressure.



Outcome: 6 Blood pressure

Study or subgroup ACEiPlacebo/notreatment

MeanDifference Weight

MeanDifference

NMean(SD)[mm

Hg] NMean(SD)[mm

Hg] IV,Random,95% CI IV,Random,95% CI

1 Systolic BP

ADVANCE Study 2009 3391 133.53 (0.17) 3946 139.48 (0.17) 70.2 % -5.95 [ -5.96, -5.94 ]

RASS Study 2002 94 113 (9) 95 117 (8) 29.8 % -4.00 [ -6.43, -1.57 ]

Subtotal (95% CI) 3485 4041 100.0 % -5.37 [ -7.12, -3.62 ]


Test for overall effect: Z = 6.02 (P < 0.00001)

2 Diastolic BP

ADVANCE Study 2009 3391 75.5 (0.09) 3946 77 (0.09) 100.0 % -1.50 [ -1.50, -1.50 ]

RASS Study 2002 94 66 (6) 95 68 (5) 0.0 % -2.00 [ -3.58, -0.42 ]

Subtotal (95% CI) 3485 4041 100.0 % -1.50 [ -1.50, -1.50 ]



-10 -5 0 5 10




Analysis 2.1. Comparison 2 ARB versus placebo/no treatment, Outcome 1 Normo- to micro- or

macroalbuminuria.


Comparison: 2 ARB versus placebo/no treatment


Study or subgroup ARBPlacebo/notreatment Risk Ratio Weight Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

DIRECT Studies 2009 16/711 15/710 12.3 % 1.07 [ 0.53, 2.14 ]

Perrin 2008 0/7 2/6 1.0 % 0.18 [ 0.01, 3.06 ]

RASS Study 2002 16/96 6/95 8.3 % 2.64 [ 1.08, 6.45 ]

ROADMAP Study 2009 178/2233 210/2216 39.8 % 0.84 [ 0.70, 1.02 ]

TRANSCEND Study 2009 130/785 175/794 38.7 % 0.75 [ 0.61, 0.92 ]

Total (95% CI) 3832 3821 100.0 % 0.90 [ 0.68, 1.19 ]

Total events: 340 (ARB), 408 (Placebo/no treatment)




0.005 0.1 1 10 200

Favours ARB Favours placebo



Analysis 2.2. Comparison 2 ARB versus placebo/no treatment, Outcome 2 All-cause mortality.




Study or subgroup ARBPlacebo/notreatment Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

DIRECT Studies 2009 7/711 5/710 1.40 [ 0.45, 4.38 ]

Perrin 2008 0/7 0/6 0.0 [ 0.0, 0.0 ]

RASS Study 2002 1/96 1/95 0.99 [ 0.06, 15.59 ]

ROADMAP Study 2009 32/2233 19/2216 1.67 [ 0.95, 2.94 ]

TRANSCEND Study 2009 96/785 96/794 1.01 [ 0.78, 1.32 ]

Total (95% CI) 3832 3821 1.12 [ 0.88, 1.41 ]





0.05 0.2 1 5 20




Analysis 2.3. Comparison 2 ARB versus placebo/no treatment, Outcome 3 Doubling of SCr.





n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

RASS Study 2002 0/94 0/95 0.0 [ 0.0, 0.0 ]

ROADMAP Study 2009 15/785 7/794 2.17 [ 0.89, 5.29 ]

TRANSCEND Study 2009 23/2233 23/2216 0.99 [ 0.56, 1.76 ]

Total (95% CI) 3112 3105 1.36 [ 0.64, 2.88 ]





0.1 0.2 0.5 1 2 5 10




Analysis 2.4. Comparison 2 ARB versus placebo/no treatment, Outcome 4 ESKD.



Outcome: 4 ESKD


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

RASS Study 2002 0/94 0/95 0.0 [ 0.0, 0.0 ]

ROADMAP Study 2009 0/785 0/794 0.0 [ 0.0, 0.0 ]

TRANSCEND Study 2009 2/2233 4/2216 0.50 [ 0.09, 2.71 ]

Total (95% CI) 3112 3105 0.50 [ 0.09, 2.71 ]





0.05 0.2 1 5 20




Analysis 2.5. Comparison 2 ARB versus placebo/no treatment, Outcome 5 Adverse events.



Outcome: 5 Adverse events


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 Cough

RASS Study 2002 6/96 4/95 1.48 [ 0.43, 5.09 ]

TRANSCEND Study 2009 4/785 6/794 0.67 [ 0.19, 2.38 ]

Subtotal (95% CI) 881 889 1.01 [ 0.42, 2.44 ]




2 Headache

DIRECT Studies 2009 53/711 73/710 0.73 [ 0.52, 1.02 ]

RASS Study 2002 1/96 0/95 2.97 [ 0.12, 71.98 ]

TRANSCEND Study 2009 0/785 2/794 0.20 [ 0.01, 4.21 ]

Subtotal (95% CI) 1592 1599 0.73 [ 0.52, 1.01 ]




3 Hyperkalaemia

DIRECT Studies 2009 11/711 9/710 1.22 [ 0.51, 2.93 ]

RASS Study 2002 0/96 0/95 0.0 [ 0.0, 0.0 ]

TRANSCEND Study 2009 33/785 8/794 4.17 [ 1.94, 8.98 ]

Subtotal (95% CI) 1592 1599 2.30 [ 0.69, 7.71 ]




0.005 0.1 1 10 200




Analysis 2.6. Comparison 2 ARB versus placebo/no treatment, Outcome 6 Blood pressure.




Study or subgroup ARBPlacebo/notreatment

MeanDifference Weight

MeanDifference

NMean(SD)[mm

Hg] NMean(SD)[mm


1 Systolic BP

RASS Study 2002 96 115 (8) 95 117 (8) 39.0 % -2.00 [ -4.27, 0.27 ]

TRANSCEND Study 2009 785 135.5 (12.5) 794 139.6 (11.8) 61.0 % -4.10 [ -5.30, -2.90 ]

Subtotal (95% CI) 881 889 100.0 % -3.28 [ -5.29, -1.27 ]



2 Diastolic BP

RASS Study 2002 96 66 (6) 95 68 (5) 16.7 % -2.00 [ -3.57, -0.43 ]

TRANSCEND Study 2009 785 77 (7.1) 794 79 (7.1) 83.3 % -2.00 [ -2.70, -1.30 ]

Subtotal (95% CI) 881 889 100.0 % -2.00 [ -2.64, -1.36 ]



-10 -5 0 5 10




Analysis 3.1. Comparison 3 ACEi versus ARB, Outcome 1 Normo- to micro- or macroalbuminuria.


Comparison: 3 ACEi versus ARB


Study or subgroup ACEi ARB Risk Ratio Weight Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

ONTARGET Study 2008 407/2047 397/2067 57.2 % 1.04 [ 0.91, 1.17 ]

RASS Study 2002 4/94 16/95 42.8 % 0.25 [ 0.09, 0.73 ]

Total (95% CI) 2141 2162 100.0 % 0.57 [ 0.14, 2.23 ]

Total events: 411 (ACEi), 413 (ARB)




0.05 0.2 1 5 20

Favours ACEi Favours ARB

Analysis 3.2. Comparison 3 ACEi versus ARB, Outcome 2 All-cause mortality.


Comparison: 3 ACEi versus ARB


Study or subgroup ACEi ARB Risk Ratio Weight Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

ONTARGET Study 2008 1/94 1/95 0.4 % 1.01 [ 0.06, 15.92 ]

RASS Study 2002 212/2047 210/2067 99.6 % 1.02 [ 0.85, 1.22 ]

Total (95% CI) 2141 2162 100.0 % 1.02 [ 0.85, 1.22 ]

Total events: 213 (ACEi), 211 (ARB)




0.05 0.2 1 5 20

Favours ACEi Favours ARBs



Analysis 4.1. Comparison 4 ACEi versus CCB, Outcome 1 Normo to micro or macroalbuminuria.


Comparison: 4 ACEi versus CCB

Outcome: 1 Normo to micro or macroalbuminuria

Study or subgroup ACEi CCB Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Baba 2001 15/95 28/105 0.59 [ 0.34, 1.04 ]

BENEDICT Study 2004 18/301 36/303 0.50 [ 0.29, 0.87 ]

Chan 1992 4/18 7/25 0.79 [ 0.27, 2.31 ]

FACET Study 1998 5/189 5/191 1.01 [ 0.30, 3.43 ]

Velussi 1996 0/13 0/13 0.0 [ 0.0, 0.0 ]

Total (95% CI) 616 637 0.60 [ 0.42, 0.85 ]

Total events: 42 (ACEi), 76 (CCB)




0.2 0.5 1 2 5

Favours ACEi Favours CCB



Analysis 4.2. Comparison 4 ACEi versus CCB, Outcome 2 All-cause mortality.





n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Baba 2001 0/208 0/228 0.0 [ 0.0, 0.0 ]

BENEDICT Study 2004 1/301 1/303 1.01 [ 0.06, 16.02 ]

FACET Study 1998 4/189 5/191 0.81 [ 0.22, 2.96 ]

Scognamiglio 1997 0/36 0/37 0.0 [ 0.0, 0.0 ]

Velussi 1996 0/13 0/13 0.0 [ 0.0, 0.0 ]

Total (95% CI) 747 772 0.84 [ 0.26, 2.73 ]





0.05 0.2 1 5 20




Analysis 4.3. Comparison 4 ACEi versus CCB, Outcome 3 Doubling of SCr.





n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Baba 2001 0/95 0/106 0.0 [ 0.0, 0.0 ]

FACET Study 1998 0/189 0/191 0.0 [ 0.0, 0.0 ]

Velussi 1996 0/13 0/13 0.0 [ 0.0, 0.0 ]

Total (95% CI) 297 310 0.0 [ 0.0, 0.0 ]


Heterogeneity: Tau2 = ; Chi2 = 0.0, df = 0 (P<0.00001); I2 =0.0%



0.1 0.2 0.5 1 2 5 10




Analysis 4.4. Comparison 4 ACEi versus CCB, Outcome 4 ESKD.



Outcome: 4 ESKD


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Baba 2001 0/95 0/106 0.0 [ 0.0, 0.0 ]

FACET Study 1998 0/189 0/191 0.0 [ 0.0, 0.0 ]

Scognamiglio 1997 0/36 0/37 0.0 [ 0.0, 0.0 ]

Velussi 1996 0/13 0/13 0.0 [ 0.0, 0.0 ]

Total (95% CI) 333 347 0.0 [ 0.0, 0.0 ]


Heterogeneity: Tau2 = ; Chi2 = 0.0, df = 0 (P<0.00001); I2 =0.0%



0.1 0.2 0.5 1 2 5 10




Analysis 4.5. Comparison 4 ACEi versus CCB, Outcome 5 Blood pressure.




Study or subgroup ACEi CCBMean

Difference WeightMean

Difference

NMean(SD)[mm

Hg] NMean(SD)[mm


1 Systolic BP

FACET Study 1998 179 157 (13.37) 178 153 (13.34) 75.5 % 4.00 [ 1.23, 6.77 ]

Scognamiglio 1997 36 147 (11.8) 37 143 (9.2) 24.5 % 4.00 [ -0.86, 8.86 ]

Subtotal (95% CI) 215 215 100.0 % 4.00 [ 1.59, 6.41 ]



2 Diastolic BP

FACET Study 1998 179 88 (13.37) 178 86 (13.34) 34.8 % 2.00 [ -0.77, 4.77 ]

Scognamiglio 1997 36 87.5 (4) 37 86.7 (4.8) 65.2 % 0.80 [ -1.22, 2.82 ]

Subtotal (95% CI) 215 215 100.0 % 1.22 [ -0.42, 2.85 ]



-10 -5 0 5 10




Analysis 5.1. Comparison 5 Prevention of kidney disease: other agents, Outcome 1 ACEi + ARB versus

ACEi.


Comparison: 5 Prevention of kidney disease: other agents

Outcome: 1 ACEi + ARB versus ACEi

Study or subgroup ACEi + ARB ACEi Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

CALM II Study 2005 0/23 0/22 0.0 [ 0.0, 0.0 ]

ONTARGET Study 2008 364/2079 407/2047 0.88 [ 0.78, 1.00 ]

Total (95% CI) 2102 2069 0.88 [ 0.78, 1.00 ]

Total events: 364 (ACEi + ARB), 407 (ACEi)




0.5 0.7 1 1.5 2

Favours ACEi + ARB Favours ACEi

Analysis 5.2. Comparison 5 Prevention of kidney disease: other agents, Outcome 2 ACEi versus BB.



Outcome: 2 ACEi versus BB

Study or subgroup ACEi BB Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

UKPDS Study 1998 55/153 52/146 1.01 [ 0.74, 1.37 ]

0.5 0.7 1 1.5 2

ACEi BB



Analysis 5.3. Comparison 5 Prevention of kidney disease: other agents, Outcome 3 ACEi + CCB versus

ACEi.



Outcome: 3 ACEi + CCB versus ACEi

Study or subgroup ACEi + CCB ACEi Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

BENEDICT Study 2004 18/303 17/300 1.05 [ 0.55, 1.99 ]

0.2 0.5 1 2 5

Favours ACEi + CCB Favours ACEi

Analysis 5.4. Comparison 5 Prevention of kidney disease: other agents, Outcome 4 CCB versus placebo.



Outcome: 4 CCB versus placebo

Study or subgroup CCBs placebo Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

BENEDICT Study 2004 36/303 30/300 1.19 [ 0.75, 1.88 ]

0.2 0.5 1 2 5

Favours CCBs Favours placebo



A D D I T I O N A L T A B L E S

Table 1. Guidelines on pharmacological management of hypertension in diabetic patients

Guideline Indication ACEi ARB BB CCB Diuretics AB

Chobanian

2003a

USA

Hypertension Yes Yes Yes Yes Yes Yes

DKD (type 1

diabetes)

Yes Yes

DKD (type 2

diabetes)

Yes Yes

ADA 2010b

USA

Hypertension Yes Yes

DKD (type 1

diabetes)

Yes Yes

DKD (type 2

diabetes)

Yes Yes

KDOQI 2007c

USA

Hypertension

DKD (type 1

diabetes)

Yes Yes

DKD (type 2

diabetes)

Yes Yes

CDA 2008d

Canada

Hypertensionh

Yes Yes Yes Yes

DKD (type 1

diabetes)

Yes

DKD (type 2

diabetes)

Yes Yesj

ESH-ESC

2007e

Europe

Hypertensioni

Yes Yes Yes Yes

DKD (type 1

diabetes)

Yes Yes

DKD (type 2

diabetes)

Yes Yes

Williams

2004f

UK

Hypertension Yesl Yes



Table 1. Guidelines on pharmacological management of hypertension in diabetic patients (Continued)

DKD (type 1

diabetes)

Yes

DKD (type 2

diabetes)

Yes

Chadban

2010g

Australia

Hypertension

DKD (type 1

diabetes)

Yes

DKD (type 2

diabetes)

Yes Yes

a Joint National Committee on Prevention, Diagnosis and Management of Hypertension; b American Diabetes Association; c Kidney

Disease Outcome Quality Initiative; d Canadian Diabetes Association; e European Society of Hypertension; f British Hypertension

Society; g Caring for Australians with Renal Impairment; h With special consideration given to ACEi or ARB; i A blocker of the

renin-angiotensin system should be a regular component of combination treatment and the one preferred when monotherapy is

sufficient; j Consensus for ARB use in type 1 diabetes; kUse calcium antagonists for hypertension when can be managed with

monotherapy; use any agent for hypertension which requires combination treatment; lIf intolerant to other agents

AB - alpha-blocker; ACEi - angiotensin-converting enzyme inhibitors; ARB - angiotensin receptor blockers; BB - beta-blockers; CCB

- calcium channel blockers; DKD - diabetic kidney disease

Table 2. Subgroup analysis of ACEi and ARB for preventing diabetic kidney disease

Vari-

ables

ACEi versus placebo ARB versus placebo ACEi versus CCB

Sub-

group

Studies RR

(95%

CI)

Het-

ero-

geneity

(P)

Sub-

group

Studies RR

(95%

CI)

Het-

ero-

geneity

(P)

Sub-

group

Studies RR

(95%

CI)

Het-

ero-

geneity

(P)

Nor-

moal-

bumin-

uria

≥ 500 4 0.84 (0.

79,0.

90)

0.023 ≥ 1500 4 0.86 (0.

76,0.

97)

0.089 ≥ 300 2 0.57 (0.

34,0.

96)

0.756

< 500 4 0.36 (0.

17,0.

79)

< 1500 3 1.30 (0.

49,3.

45)

< 300 3 0.63 (0.

38,1.

04)

Event

rate/

100

person-

years

≥ 5 4 0.76 (0.

54,1.

07)

0.059 ≥ 2.8 4 0.83 (0.

73,0.

94)

0.035 ≥ 2.0 3 0.57 (0.

39,0.

82)

0.378



Table 2. Subgroup analysis of ACEi and ARB for preventing diabetic kidney disease (Continued)

< 5 4 0.59 (0.

41,0.

85)

< 2.8 3 1.27 (0.

79,2.

03)

< 2.0 2 1.01 (0.

30,3.

43)

Dura-

tion of

follow-

up

(years)

≥ 4 4 0.76 (0.

58,1.

00)

0.126 ≥ 4.8 4 1.27 (0.

52,3.

11)

0.062 ≥ 3 3 0.60 (0.

38,0.

94)

0.973

< 4 4 0.60 (0.

36,1.

00)

< 4.8 3 0.84 (0.

74,0.

94)

< 3 2 0.59 (0.

34,1.

04)

Dia-

betes

mellitusa

Type 1 4 0.54 (0.

24,1.

20)

0.526 Type 1 5 1.16 (0.

79,1.

70)

0.048 Type 1 0 Not es-

timated

Type 2 3 0.67 (0.

43,1.

04)

Type 2 3 0.83 (0.

73,0.

94)

Type 2 5 0.60 (0.

42, 0.

85)

mixed 1 0.71 (0.

39,1.

29)

Mixed 0 Mixed 0

Hyper-

tensionb

Yes 4 0.64 (0.

43,0.

96)

0.740 Yes 3 0.84 (0.

75,0.

95)

0.127 Yes 5 0.60 (0.

42, 0.

85)

Not es-

timated

No 5 0.82 (0.

73,0.

92)

No 5 1.06 (0.

67,1.

69)

No 0

Sys-

tolic BP

(mm

Hg)

(differ-

ence be-

tween

treat-

ment/

con-

trol)

≤ -3 4 0.84 (0.

79,0.

90)

0.075 ≤ -3.5 3 0.85 (0.

61, 1.

18)

0.259 > 0 3 0.68 (0.

43,1.

07)

0.420

> -3 3 0.41 (0.

15,1.

08)

> -3.5 3 1.21 (0.

72, 2.

05)

≤ 0 2 0.50 (0.

29,0.

87)

Dias-

tolic BP

(mm

Hg)

(differ-

≤ -2 4 0.68 (0.

50,0.

92)

0.175 ≤ -2 3 0.94 (0.

75, 1.

18)

0.828 > 0 2 0.65 (0.

39,1.

08)

0.651



Table 2. Subgroup analysis of ACEi and ARB for preventing diabetic kidney disease (Continued)

ence be-

tween

treat-

ment/

con-

trol)< -2 4 0.61 (0.

36,1.

05)

< -2 3 1.07 (0.

66, 1.

73)

≤ 0 3 0.55 (0.

34,0.

90)

Alloca-

tion

con-

ceal-

ment

Yes 3 0.84 (0.

79,0.

90)

0.019 Yes 5 0.86 (0.

77,0.

96)

0.047 Yes 1 1.01 (0.

30,3.

43)

0.378

Unclear 5 0.48 (0.

29,0.

79)

Unclear 2 0.96 (0.

07,12.

80)

Unclear 4 0.57 (0.

34,0.

82)

Inten-

tion-to-

treat

analysis

Yes 3 0.84 (0.

79,0.

90)

0.019 Yes 5 0.88 (0.

74,1.

05)

0.741 Yes 1 0.59 (0.

34,1.

04)

0.973

Un-

clear/

No

5 0.48 (0.

29,0.

79)

Un-

clear/

No

2 1.37 (0.

45,4.

14)

Un-

clear/

no

4 0.60 (0.

38,0.

94)

Lost to

follow-

up

< 1% 4 0.71 (0.

44,1.

16)

0.075 < 1% 3 0.77 (0.

63,0.

93)

0.119 < 1% 2 0.63 (0.

38,1.

04)

0.580

≤ 1% 4 0.64 (0.

48,0.

86)

≤ 1% 4 0.99 (0.

78,1.

24)

≤ 1% 3 0.57 (0.

34,0.

96)

a TRANSCEND was split as type 1 and type 2 diabetes mellitus; b ADVANCE was split as hypertension and normotension

ACEi - angiotensin-converting enzyme inhibitors; ARB - angiotensin receptor blockers; CCB - calcium channel blockers



A P P E N D I C E S

Appendix 1. Electronic search strategies

Database Search terms

CENTRAL 1. ANTIHYPERTENSIVE AGENTS explode all trees (MeSH)

2. chlorothiazide

3. chlorthalidone

4. hydralazine

5. hydrochlorothiazide

6. indapamide

7. minoxidil

8. (#1 or #2 or #3 or #4 or #5 or #6 or #7)

9. captopril

10. enalpril

11. cilazapril

12. enalaprilat

13. fosinopril

14. lisinopril

15. perindopril

16. ramipril

17. saralasin

18. teprotide

19. (#9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18)

20. LOSARTAN explode all trees (MeSH)

21. losartan

22. imidazole

23. irbesartan

24. candesartan

25. eprosartan

26. valsartan

27. olmesartan

28. telmisartan

29. (ace near inhibitor*)


31. CALCIUM CHANNEL BLOCKERS explode all trees (MeSH)

32. amlodipine

33. diltiazem

34. felodipine

35. nicardipine

36. nifedipine

37. nimodipine

38. nisoldipine

39. nitrendipine

40. verapamil


42. ADRENERGIC AGONISTS explode all trees (MeSH)

43. alprenolol



(Continued)

44. atenolol

45. metoprolol

46. nadolol

47. oxprenolol

48. pindolol

49. propranolol

50. labetalol

51. prazosin


53. DIURETICS explode all trees (MeSH)

54. spironolactone

55. triamterene

56. bumetanide

57. chlorthalidone

58. furosemide

59. indapamide

60. chlorothiazide

61. hydrochlorothiazide

62. #53 or #54 or #55 or #56 or #57 or #58 or #59 or #60 or #61

63. RECEPTORS ANGIOTENSIN [ai] single term (MeSH)

64. ANGIOTENSINS [ai] explode tree 1 (MeSH)

65. (angiotensin near inhibit*)

66. (angiotensin near antagonist*)

67. (angiotensin near blocker*)

68. antihypertensive*

69. #64 or #65 or #66 or #67 or #68

70. #8 or #19 or #30 or #41 or #52 or #62 or #69

71. DIABETES MELLITUS explode tree 1 (MeSH)

72. (diabetes next mellitus)

73. (iddm or niddm)

74. DIABETIC NEPHROPATHIES single term (MeSH)

75. (diabetic next nephrop*)

76. (diabetic next glomerul*)

77. (diabetic and (kidney next disease*))

78. (diabetic and (renal next disease*))

79. (diabetes and (renal next disease*))

80. (diabetes and (kidney next disease*))

81. (diabetes and nephro*)

82. (diabetes and nephri*)

83. (diabetes and glomerulo*)

84. (diabetic and glomerulo*)

85. (diabetic and nephrit*)

86. (diabetic and nephro*)

87. #71 or #72 or #73 or #74 or #75 or #76 or #77 or #78 or #79 or #80 or #81 or #82 or #83 or #84 or #85 or #86

MEDLINE 1. exp antihypertensive agents/

2. (antihypertensive$ adj (agent$ or drug)).tw.

3. chlorothiazide.tw.

4. chlorthalidone.tw.

5. hydralazine.tw.



(Continued)

6. hydrochlorothiazide.tw.

7. indapamide.tw.

8. minoxidil.tw.

9. exp angiotensin converting enzyme inhibitors/

10. captopril.tw.

11. enalapril.tw.

12. cilazapril.tw.

13. enalaprilat.tw.

14. fosinopril.tw.

15. lisinopril.tw.

16. perindopril.tw.

17. ramipril.tw.

18. saralasin.tw.

19. teprotide.tw.

20. exp losartan/

21. losartan.tw.

22. imidazole$.tw.

23. irbesartan.tw.

24. candesartan.tw.

25. eprosartan.tw.

26. valsartan.tw.

27. olmesartan.tw.

28. telmisartan.tw.

29. (ace adj2 inhibitor$).tw.

30. (angiotensin adj2 receptor antagonist$).tw.

31. exp calcium channel blockers/

32. amlodipine.tw.

33. diltiazem.tw.

34. felodipine.tw.

35. nicardipine.tw.

36. nifedipine.tw.

37. nimodipine.tw.

38. nisoldipine.tw.

39. nitrendipine.tw.

40. verapamil.tw.

41. exp adrenergic beta-antagonists/

42. alprenolol.tw.

43. atenolol.tw.

44. metoprolol.tw.

45. nadolol.tw.

46. oxprenolol.tw.

47. pindolol.tw.

48. propranolol.tw.

49. exp adrenergic alpha-antagonists/

50. labetalol.tw.

51. prazosin.tw.

52. beta block$.tw.

53. exp diuretics/



(Continued)

54. spironolactone.tw.

55. triamterene.tw.

56. bumetanide.tw.


58. furosemide.tw.

59. indapamide.tw.



62. or/1-61

63. exp diabetes mellitus/

64. diabetic nephropathies/

65. diabetic nephropath$.tw.

66. diabetic glomerulo$.tw.

67. ((diabetic or diabetes) and (kidney disease$ or renal disease$)).tw.

68. or/63-67

69. 62 and 68

EMBASE 1. exp antihypertensive agents/

2. (antihypertensive$ adj (agent$ or drug$)).tw.

3. (anti-hypertensive$ adj (agent$ or drug$)).tw.



6. hydralazine.tw.


8. indapamide.tw.

9. minoxidil.tw.

10. losartan.tw.

11. imidazole$.tw.

12. irbesartan.tw.

13. candesartan.tw.

14. eprosartan.tw.

15. valsartan.tw.

16. olmesartan.tw.

17. telmisartan.tw.

18. exp angiotensin converting enzyme inhibitors/

19. (ace adj2 inhibitor$).tw.

20. (acei or ace-i).tw.

21. captopril.tw.

22. enalapril.tw.

23. fosinopril.tw.

24. lisinopril.tw.

25. perindopril.tw.

26. ramipril.tw.

27. saralasin.tw.

28. teprotide.tw.

29. exp Angiotensin 2 Receptor Antagonist/

30. exp Angiotensin Receptor Antagonist/

31. Angiotensin II Antagonist/

32. angiotensin II receptor antagonist$.tw.



(Continued)

33. angiotensin 2 receptor antagonist$.tw.

34. angiotensin II receptor block$.tw.

35. angiotensin 2 receptor block$.tw.

36. AT 2 receptor block$.tw.

37. AT 2 receptor antagon$.tw.

38. angiotensin receptor antagonist$.tw.

39. exp Calcium Channel Blockers/

40. amlodipine.tw.

41. diltiazem.tw.

42. felodipine.tw.

43. nicardipine.tw.

44. nifedipine.tw.

45. nimodipine.tw.

46. nisoldipine.tw.

47. nitrendipine.tw.

48. verapamil.tw.

49. exp adrenergic beta-antagonists/

50. alprenolol.tw.

51. atenolol.tw.

52. metoprolol.tw.

53. nadolol.tw.

54. oxprenolol.tw.

55. pindolol.tw.

56. propranolol.tw.

57. exp adrenergic alpha-antagonists/

58. labetalol.tw.

59. prazosin.tw.

60. beta block$.tw.

61. exp diuretics/

62. spironolactone.tw.

63. triamterene.tw.

64. bumetanide.tw.

65. furosemide.tw.

66. indapamide.tw.

67. or/1-66

68. exp Diabetes Mellitus/

69. diabetes mellitus.tw.

70. (IDDM or NIDDM).tw.

71. Diabetic Nephropathies/

72. diabetic nephrop$.tw.

73. diabetic glomerulo$.tw.

74. ((diabetic or diabetes) and (kidney disease$ or renal disease$ or nephro$ or nephrit$ or glomerulo$)).tw.

75. or/68-74

76. and/67,75



Appendix 2. Risk of bias assessment tool

Potential source of bias Assessment criteria

Random sequence generation

Selection bias (biased allocation to interventions) due to inade-

quate generation of a randomised sequence

Low risk of bias: Random number table; computer random num-

ber generator; coin tossing; shuffling cards or envelopes; throwing

dice; drawing of lots; minimization (minimization may be imple-

mented without a random element, and this is considered to be

equivalent to being random)

High risk of bias: Sequence generated by odd or even date of birth;

date (or day) of admission; sequence generated by hospital or

clinic record number; allocation by judgement of the clinician; by

preference of the participant; based on the results of a laboratory

test or a series of tests; by availability of the intervention

Unclear: Insufficient information about the sequence generation

process to permit judgement

Allocation concealment

Selection bias (biased allocation to interventions) due to inade-

quate concealment of allocations prior to assignment

Low risk of bias: Randomisation method described that would not

allow investigator/participant to know or influence intervention

group before eligible participant entered in the study (e.g. central

allocation, including telephone, web-based, and pharmacy-con-

trolled, randomisation; sequentially numbered drug containers of

identical appearance; sequentially numbered, opaque, sealed en-

velopes)

High risk of bias: Using an open random allocation schedule (e.g. a

list of random numbers); assignment envelopes were used without

appropriate safeguards (e.g. if envelopes were unsealed or non-

opaque or not sequentially numbered); alternation or rotation;

date of birth; case record number; any other explicitly unconcealed

procedure

Unclear: Randomisation stated but no information on method

used is available


Performance bias due to knowledge of the allocated interventions

by participants and personnel during the study

Low risk of bias: No blinding or incomplete blinding, but the re-

view authors judge that the outcome is not likely to be influenced

by lack of blinding; blinding of participants and key study per-

sonnel ensured, and unlikely that the blinding could have been

broken

High risk of bias: No blinding or incomplete blinding, and the

outcome is likely to be influenced by lack of blinding; blinding

of key study participants and personnel attempted, but likely that

the blinding could have been broken, and the outcome is likely

to be influenced by lack of blinding

Unclear: Insufficient information to permit judgement



(Continued)

Blinding of outcome assessment

Detection bias due to knowledge of the allocated interventions by

outcome assessors

Low risk of bias: No blinding of outcome assessment, but the review

authors judge that the outcome measurement is not likely to be

influenced by lack of blinding; blinding of outcome assessment

ensured, and unlikely that the blinding could have been broken

High risk of bias: No blinding of outcome assessment, and the

outcome measurement is likely to be influenced by lack of blind-

ing; blinding of outcome assessment, but likely that the blinding

could have been broken, and the outcome measurement is likely

to be influenced by lack of blinding


Incomplete outcome data

Attrition bias due to amount, nature or handling of incomplete

outcome data

Low risk of bias: No missing outcome data; reasons for missing

outcome data unlikely to be related to true outcome (for survival

data, censoring unlikely to be introducing bias); missing outcome

data balanced in numbers across intervention groups, with similar

reasons for missing data across groups; for dichotomous outcome

data, the proportion of missing outcomes compared with observed

event risk not enough to have a clinically relevant impact on the

intervention effect estimate; for continuous outcome data, plau-

sible effect size (difference in means or standardized difference in

means) among missing outcomes not enough to have a clinically

relevant impact on observed effect size; missing data have been

imputed using appropriate methods

High risk of bias: Reason for missing outcome data likely to be

related to true outcome, with either imbalance in numbers or rea-

sons for missing data across intervention groups; for dichotomous

outcome data, the proportion of missing outcomes compared with

observed event risk enough to induce clinically relevant bias in

intervention effect estimate; for continuous outcome data, plau-

sible effect size (difference in means or standardized difference in

means) among missing outcomes enough to induce clinically rel-

evant bias in observed effect size; ‘as-treated’ analysis done with

substantial departure of the intervention received from that as-

signed at randomisation; potentially inappropriate application of

simple imputation


Selective reporting

Reporting bias due to selective outcome reporting

Low risk of bias: The study protocol is available and all of the

study’s pre-specified (primary and secondary) outcomes that are of

interest in the review have been reported in the pre-specified way;

the study protocol is not available but it is clear that the published

reports include all expected outcomes, including those that were

pre-specified (convincing text of this nature may be uncommon)



(Continued)

High risk of bias: Not all of the study’s pre-specified primary out-

comes have been reported; one or more primary outcomes is re-

ported using measurements, analysis methods or subsets of the

data (e.g. subscales) that were not pre-specified; one or more re-

ported primary outcomes were not pre-specified (unless clear jus-

tification for their reporting is provided, such as an unexpected

adverse effect); one or more outcomes of interest in the review are

reported incompletely so that they cannot be entered in a meta-

analysis; the study report fails to include results for a key outcome

that would be expected to have been reported for such a study


Other bias

Bias due to problems not covered elsewhere in the table

Low risk of bias: The study appears to be free of other sources of

bias.

High risk of bias: Had a potential source of bias related to the spe-

cific study design used; stopped early due to some data-dependent

process (including a formal-stopping rule); had extreme baseline

imbalance; has been claimed to have been fraudulent; had some

other problem

Unclear: Insufficient information to assess whether an important

risk of bias exists; insufficient rationale or evidence that an iden-

tified problem will introduce bias

F E E D B A C K

ACEi compared to calcium channel blockers

Summary

There may be an error in the results section on the bottom of page 2. Under Angiotensin Converting Enzyme inhibitors vs. CCBs

(comparison 2) it says, “There was no statistically significant difference in the risk of development of kidney disease (micro or

macroalbuminuria) outcome 04, four trials, 1210 patients: RR 0.58, 95% CI 0.40 to 0.84) with ACEi compared to calcium channel

blockers.”

This seems to contradict both the data and the last sentence in the abstract “Compared to CCBs, ACEi significantly reduced progression

to microalbuminuria (four trials, 1210 patients: RR 0.58, 95% CI 0.40 to 0.84).”

Reply

To Dr Kripke and Dr Dressler:

The statistics are all correct, although the text describing them in the results section is wrong. It should read: “There was a statistically

significant reduction in the risk of development of kidney disease (micro or macroalbuminuria)....”

Dr Giovanni Strippoli



Contributors

Dr Richard Dressler; Dr Clarissa Kripke

[email protected]; [email protected]

Family and General Preventive Medicine; Family Physician

W H A T ’ S N E W

Last assessed as up-to-date: 24 January 2011.

Date Event Description

8 November 2012 New search has been performed New studies and author team

1 August 2011 New citation required and conclusions have changed The updated review with more than 5 times of partic-

ipants has confirmed the effect with ACEi for the pri-

mary prevention of diabetic kidney disease and also re-

duction of all cause death, while no similar benefits of

angiotensin receptor blockers were observed

H I S T O R Y

Protocol first published: Issue 2, 2003

Review first published: Issue 4, 2005

Date Event Description

16 September 2008 Amended Converted to new review format.

C O N T R I B U T I O N S O F A U T H O R S

JL, VP, MC,CF, and GS were responsible for data collection, data analysis data interpretation, and preparation of the report. All authors

contributed to data interpretation and critical revision of the report.



D E C L A R A T I O N S O F I N T E R E S T

Vlado Perkovic is supported by a fellowship from the Heart Foundation of Australia and a various grants from the Australian National

Health and Medical Research Council. He has received speakers fees from Roche, Servier and Astra Zeneca, funding for a clinical trial

from Baxter, and serves on Steering Committees for trials funded by Johnson and Johnson, Boehringer Ingelheim, Vitae and Abbott.

His employer conducts clinical trials funded by Servier, Johnson and Johnson, Roche and Merck.

Celine Foote has been supported by general research grants from both Amgen and the NHMRC. Both Amgen and the NHMRC have

played no part in the design, conduct and reporting of this research project.

JL has received grant support from Pfizer for hypertension research, and also is a recipient of a Research Fellowship supported by

Amgen.

I N D E X T E R M SMedical Subject Headings (MeSH)

Albuminuria [prevention & control]; Angiotensin Receptor Antagonists [∗therapeutic use]; Angiotensin-Converting Enzyme Inhibitors

[∗therapeutic use]; Antihypertensive Agents [∗therapeutic use]; Calcium Channel Blockers [∗therapeutic use]; Diabetic Nephropathies

[∗prevention & control]; Hypertension [drug therapy]; Randomized Controlled Trials as Topic

MeSH check words

Humans



cochrane database of systematic reviews (reviews) || antihypertensive agents for preventing diabetic...

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