Clinician Article

Antihypertensive agents for preventing diabetic kidney disease.

  • Lv J
  • Perkovic V
  • Foote CV
  • Craig ME
  • Craig JC
  • Strippoli GF
Cochrane Database Syst Rev. 2012 Dec 12;12:CD004136. doi: 10.1002/14651858.CD004136.pub3. (Review)
PMID: 23235603
Read abstract Read evidence summary
  • Nephrology
    Relevance - 7/7
    Newsworthiness - 6/7
  • Endocrine
    Relevance - 7/7
    Newsworthiness - 5/7
  • Family Medicine (FM)/General Practice (GP)
    Relevance - 7/7
    Newsworthiness - 5/7
  • General Internal Medicine-Primary Care(US)
    Relevance - 7/7
    Newsworthiness - 5/7
  • Cardiology
    Relevance - 6/7
    Newsworthiness - 5/7
  • Internal Medicine
    Relevance - 6/7
    Newsworthiness - 4/7


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.

Clinical Comments


Given the prior lack of clarity in the literature regarding this area, this review offers some definitive information regarding a practical evidence based approach to prevention of diabetic renal disease. Death-Ace-I is the winner and should be the first choice in caring for the diabetic patient at risk. ARB's come in second but are equal in high risk patients [I'm not quite sure I understand that]. This is one of the few reviews of studies looking at hard end points to provide direction to the practicing physician. For the time being, at least until a better or more definitive analysis is done, this looks like the gold standard of care. It is nice to see information with outcomes of clinical importance presented,instead of the usual surrogate markers. Good job, Cochrane Collaboration!!

Family Medicine (FM)/General Practice (GP)

What's really useful is that, in the words of Will Rogers, it's what we know that ain't so that gives us trouble. That ACEI's reduce diabetic kidney injury is confirmed. That ARBs do NOT is news to me. It is important to know and probably not what most clinicians think/believe. The numbers suggest that the ARB data is reasonably solid - over 7,000 patients included in the RCTs of ARBs. I also strongly suspect that there is likely a lot of: "absence of evidence does not equal evidence of absence." That is, we lack any useful data as to whether other antihypertensives work as well as ACEI's (outside of ARB's). I think some type of research should examine this question - perhaps beginning with epidemiologic research progressing to RCT's if preliminary data suggests efficacy.


The robust meta-analysis highlights the benefits of ACEi for diabetic patients without proteinuria. This finding has been challenged recently by results from single epidemiological and/or observational studies. In addition, the findings regarding ARB's is interesting and should re-enforce the notion amongst practitioners that not all RAAS blockade is equivalent. The finding of a trend towards a potential benefit from combined ACEi/ARB therapy indicates that the question about the benefits of combined therapy might not be entirely settled. The findings reported in this meta-analysis challenge current conventional wisdom.


This is unexpected as ARB are touted as having better side effects profile than ACE inhibitors. ONTARGET study enrolled about 38% diabetics with no kidney disease and showed ARB is better in terms of tolerability but with similar reduction of end points.


A very comprehensive systematic review on the prevention of diabetic kidney disease by antihypertensive agents. The important fact, which is not really known by most physicians, is the differential effect between ACEis and ARBs, in favour of the use of ACEis as first line treatment in diabetic patients without microalbuminuria, despite the incidence of cough. The lack of effect of calcium channel blockers is well known and is confirmed by the review. There were only 2 studies comparing directly ACEIs and ARBs for prevention of microalbuminuria. The review emphasizes the need for further studies, in order: first, to explore more precisely the preventive potential of ARBs probably in high risk patients (the risk of cardiovascular events would also be a relevant endpoint); second, to confirm or not the possible superiority of a combination of ACEis and ARBs for the prevention of diabetic kidney disease. These studies should pay attention to the blood pressure status of included patients.

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