letter to the editor

ACE-I vs. ARB for blood pressure

control in diabetic kidney disease
To the Editor: With great interest we read the KDIGO
clinical update on diabetic kidney disease (DKD), which
addresses risk management in diabetes patients with chronic
kidney disease (CKD).1 In this position statement, the use of
renin-angiontensin-aldosterone system blockers is advocated
because of their renoprotective effects beyond blood pressure
lowering. The authors state that angiotensin-converting
enzyme inhibitors (ACE-I) and angiotensin receptor blockers
(ARB) are equally effective in providing cardiovascular (CV)
and renal protection, but that head-to-head studies in
diabetes are lacking.
First, we agree that most evidence supporting renoprotective effects for ACE-I is largely derived from studies in patients
with type 1 diabetes, whereas these actions of ARBs are based
on type 2 diabetes (T2DM) studies, showing comparable
effect sizes.2 However, we refer to the long-term DETAIL study,
not mentioned in the KDIGO update, which demonstrated
non-inferiority of the ARB telmisartan as compared with the
ACE-I enalapril on renal function in 250 T2DM patients with
hypertension and albuminuria. Unfortunately, the study was
hampered by large dropout rates.3
Second, in contrast to their renal effects, ACE-I and ARB
may differ in CV protection. A recent meta-analysis, which
included 35 ACE-I and 13 ARB trials in 56,694 diabetic
patients with and without CKD, reported that ACE-I reduced
all-cause mortality, CV mortality, myocardial infarction, and
heart failure, whereas ARB therapy only reduced heart failure.4
On the basis of these considerations, we feel that ACE-I
may be considered as first-line antihypertensive agent in DKD
management if tolerated. We stress the need for sufficiently
powered trials on renal and CV outcomes directly comparing
ACE-I and ARB therapy in diabetes patients.

The Authors Reply: In the KDIGO update on diabetic

kidney disease, we reaffirm that intervention in the
reninangiotensinaldosterone system is the backbone of
current kidney and cardioprotective therapy in diabetic kidney
disease.1 In response to Tonneijck et al.,2 we agree that the
DETAIL study showed no significant differences between an
angiotensin-converting enzyme inhibitor (ACE-I) and an
angiotensin receptor blocker (ARB) in delaying progression
of chronic kidney disease (CKD).3 The finding of better
cardiovascular (CV) outcomes in the recently published
meta-analysis of Cheng et al.4 (not available for the KDIGO
group to analyze) is not convincing for changing our
conclusions for at least three reasons: (a) the authors did
not study populations with diabetes and CKD, but
studied diabetic subjects with varying estimated glomerular
filtration rate and albuminuria levels; (2) the studies analyzed
did not make direct comparisons between ACE-I and ARB, but
only compared studies that have been published on ACE-I or
ARB effects and CV outcomes; and (3) the characteristics of
the ACE-I and ARB populations were markedly different,
which could well explain the purported difference in CV
outcomes. Thus, we conclude that we cannot recommend
an evidence-based choice between ACE-I or ARB for
antihypertensive treatment of diabetic patients with
nephropathy. The lack of evidence for ACE-I vs. ARB, for a
specific ACE-I or ARB within its class, or whether ACE-I or
ARB is specific for either renal or CV protection will haunt us
for a long time. We see no hard outcome comparator studies
on the horizon that address these clinically important
questions.

1.

2.
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2.

3.

4.

Molitch ME, Adler AI, Flyvbjerg A et al. Diabetic kidney disease: a

clinical update from Kidney Disease: Improving Global Outcomes. Kidney
Int 2014 (doi:10.1038/ki.2014.128).
KDIGO Blood Pressure Work Group. KDIGO clinical practice guideline for
the management of blood pressure in chronic kidney disease. Kidney Int
2012; 2(Suppl): 33714.
Barnett AH, Bain SC, Bouter P et al. Angiotensin-receptor blockade
versus converting-enzyme inhibition in type 2 diabetes and nephropathy.
N Engl J Med 2004; 351: 19521961.
Cheng J, Zhang W, Zhang X et al. Effect of angiotensin-converting enzyme
inhibitors and angiotensin II receptor blockers on all-cause mortality,
cardiovascular deaths, and cardiovascular events in patients with diabetes
mellitus: a meta-analysis. JAMA Intern Med 2014; 310003: 113.

3.

4.

Molitch ME, Adler AI, Flyvbjerg A et al. Diabetic kidney disease: a clinical
update from kidney disease: Improving Global Outcomes. Kidney Int 2014
(doi:10.1038/ki.2014.128).
Tonneijck L, Musket MHA, van Raalte DH. ACE-I vs. ARB for blood
pressure control in diabetic kidney disease. Kidney Int 2014;
86: 1270.
Barnett AH, Bain SC, Bouter P et al. Angiotensin-receptor blockade versus
converting-enzyme inhibition in type 2 diabetes and nephropathy. N Engl J
Med 2004; 351: 19521961.
Cheng J, Zhang W, Zhang X et al. Effect of angiotensin-converting
enzyme inhibitors and angiotensin ii receptor blockers on all-cause
mortality, cardiovascular deaths, and cardiovascular events in patients
with diabetes mellitus: a meta-analysis. JAMA Intern Med 2014; 175:
773785.

Dick de Zeeuw1 and Mark E. Molitch2

Diabetes Center, Department of Internal Medicine, VU University Medical

Center, Amsterdam, The Netherlands
Correspondence: Lennart Tonneijck, Diabetes Center, Department of
Internal Medicine, VU University Medical Center (VUMC), De Boelelaan
1117 (Room ZH 4A65), 1081 HV Amsterdam, The Netherlands.
E-mail: l.tonneijck@vumc.nl

1
Department of Clinical Pharmacy and Pharmacology, University Medical
Center Groningen, Groningen, The Netherlands and 2Division of
Endocrinology, Metabolism and Molecular Medicine, Department of
Medicine, Northwestern University Feinberg School of Medicine, Chicago,
Illinois, USA
Correspondence: Mark E. Molitch, Division of Endocrinology,
Metabolism and Molecular Medicine, Department of Medicine,
Northwestern University Feinberg School of Medicine, 645 N. Michigan
Avenue, Suite 530, Chicago, Illinois 60611, USA.
E-mail: molitch@northwestern.edu

Kidney International (2014) 86, 1270; doi:10.1038/ki.2014.262

Kidney International (2014) 86, 1270; doi:10.1038/ki.2014.263

Lennart Tonneijck1, Marcel H.A. Muskiet1 and

Daniel H. van Raalte1
1

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Kidney International (2014) 86, 12691272