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Meta-Analysis
. 2012 Dec 12;12(12):CD004136.
doi: 10.1002/14651858.CD004136.pub3.

Antihypertensive agents for preventing diabetic kidney disease

Jicheng Lv  1 , Vlado Perkovic, Celine V Foote, Maria E Craig, Jonathan C Craig, Giovanni F M Strippoli
Affiliations
Meta-Analysis

Antihypertensive agents for preventing diabetic kidney disease

Jicheng Lv et al. Cochrane Database Syst Rev. .

Abstract

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 normotensive 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 cardiovascular 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 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.

PubMed Disclaimer

Conflict of interest statement

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.

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1 ACEi versus placebo/no treatment, Outcome 1 Normo‐ to micro‐ or macroalbuminuria.
1.2
1.2. Analysis
Comparison 1 ACEi versus placebo/no treatment, Outcome 2 All‐cause mortality.
1.3
1.3. Analysis
Comparison 1 ACEi versus placebo/no treatment, Outcome 3 Doubling of SCr.
1.4
1.4. Analysis
Comparison 1 ACEi versus placebo/no treatment, Outcome 4 ESKD.
1.5
1.5. Analysis
Comparison 1 ACEi versus placebo/no treatment, Outcome 5 Adverse events.
1.6
1.6. Analysis
Comparison 1 ACEi versus placebo/no treatment, Outcome 6 Blood pressure.
2.1
2.1. Analysis
Comparison 2 ARB versus placebo/no treatment, Outcome 1 Normo‐ to micro‐ or macroalbuminuria.
2.2
2.2. Analysis
Comparison 2 ARB versus placebo/no treatment, Outcome 2 All‐cause mortality.
2.3
2.3. Analysis
Comparison 2 ARB versus placebo/no treatment, Outcome 3 Doubling of SCr.
2.4
2.4. Analysis
Comparison 2 ARB versus placebo/no treatment, Outcome 4 ESKD.
2.5
2.5. Analysis
Comparison 2 ARB versus placebo/no treatment, Outcome 5 Adverse events.
2.6
2.6. Analysis
Comparison 2 ARB versus placebo/no treatment, Outcome 6 Blood pressure.
3.1
3.1. Analysis
Comparison 3 ACEi versus ARB, Outcome 1 Normo‐ to micro‐ or macroalbuminuria.
3.2
3.2. Analysis
Comparison 3 ACEi versus ARB, Outcome 2 All‐cause mortality.
4.1
4.1. Analysis
Comparison 4 ACEi versus CCB, Outcome 1 Normo to micro or macroalbuminuria.
4.2
4.2. Analysis
Comparison 4 ACEi versus CCB, Outcome 2 All‐cause mortality.
4.3
4.3. Analysis
Comparison 4 ACEi versus CCB, Outcome 3 Doubling of SCr.
4.4
4.4. Analysis
Comparison 4 ACEi versus CCB, Outcome 4 ESKD.
4.5
4.5. Analysis
Comparison 4 ACEi versus CCB, Outcome 5 Blood pressure.
5.1
5.1. Analysis
Comparison 5 Prevention of kidney disease: other agents, Outcome 1 ACEi + ARB versus ACEi.
5.2
5.2. Analysis
Comparison 5 Prevention of kidney disease: other agents, Outcome 2 ACEi versus BB.
5.3
5.3. Analysis
Comparison 5 Prevention of kidney disease: other agents, Outcome 3 ACEi + CCB versus ACEi.
5.4
5.4. Analysis
Comparison 5 Prevention of kidney disease: other agents, Outcome 4 CCB versus placebo.
See this image and copyright information in PMC

Update of

References

References to studies included in this review

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    1. 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: ] - PubMed

References to studies excluded from this review

ALLHAT 2002 {published data only}
    1. 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: ] - PubMed
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CAPPP 1999 {published data only}
    1. 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: ] - PubMed
Hansson 1999 {published data only}
    1. 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: ] - PubMed
HOT 1998 {published data only}
    1. 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: ] - PubMed
INSIGHT 2000 {published data only}
    1. Brown MJ, Palmer CR, Castaigne A, 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: ] - PubMed
NORDIL 2000 {published data only}
    1. 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: ] - PubMed
Tuomilehto 1999 {published data only}
    1. 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: ] - PubMed

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References to other published versions of this review

Strippoli 2003
    1. 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] - DOI - PubMed
Strippoli 2005
    1. 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] - DOI - PubMed

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