Correspondence
Fresenius, Gilead, and Merck. JC reports grants
from NFK and the US National Institutes of Health
(NIH). LAI reports grants from NIH and NKF;
funding from NIH, NKF, Retrophin, Omeros, and
Reata Pharmaceuticals (research and contracts
[Tufts Medical Center]); and consulting
agreements with Tricida and Omeros. LAI also
reports a provisional patent (filed Aug 15, 2014;
precise estimation of glomerular filtration rate
from multiple biomarkers, patent no PCT/
US2015/044567), and Tufts Medical Center, John
Hopkins University, and Metabolon have a
collaboration agreement to develop a product to
estimate glomerular filtration rate from a panel of
markers. RTG reports no competing interests.
Hiddo J L Heerspink, Josef Coresh,
Ron T Gansevoort, *Lesley A Inker
linker@tuftsmedicalcenter.org
Department of Clinical Pharmacy and Pharmacology
(HJLH) and Department of Nephrology (RTG),
University of Groningen, University Medical Center
Groningen, Groningen, Netherlands; Department of
Epidemiology, Johns Hopkins Bloomberg School of
Public Health, Baltimore, MD, USA (JC); and Division
of Nephrology, Tufts Medical Center, Boston,
MA 02111, USA (LAI)
1 Heerspink HJL, Greene T, Tighiouart H, et al.
Change in albuminuria as a surrogate endpoint
for progression of kidney disease: a meta-
analysis of treatment effects in randomised
clinical trials. Lancet Diabetes Endocrinol 2019;
7: 128–39.
2 Coresh J, Heerspink HJL, Sang Y, et al. Change
in albuminuria and subsequent risk of end-
stage kidney disease: an individual participant-
level consortium meta-analysis of
observational studies.
Lancet Diabetes Endocrinol 2019; 7: 115–27.
3 Mann JF, Schmieder RE, McQueen M, 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: 547–53.
4 Fried LF, Emanuele N, Zhang JH, et al.
Combined angiotensin inhibition for the
treatment of diabetic nephropathy.
N Engl J Med 2013; 369: 1892–903.
5 Heerspink HJ, Kropelin TF, Hoekman J, de
Zeeuw D. Drug-induced reduction in
albuminuria Is associated with subsequent
renoprotection: a meta-analysis.
J Am Soc Nephrol 2015; 26: 2055–64.
GLP-1 and the renin–
angiotensin–
aldosterone system
We read with interest Muskiet
and colleagues’ Review 1 on new
pharmacological strategies for
protecting kidney function in type 2
diabetes. In the Review—and specifically
in figure 2—it is taken for granted
www.thelancet.com/diabetes-endocrinology Vol 7 May 2019
that glucagon-like peptide-1 (GLP-1)
receptor agonists inhibit both
angiotensin II and renin. We agree
with the authors about the activation
of the renin–angiotensin–aldosterone
system (RAAS) by sodium-glucose
co-transporter-2 inhibitors through
volume depletion, shown in figure 2.
However, although it has been shown
that GLP-1 receptor agonists inhibit the
formation of angiotensin II,2,3 inhibition
of renin by these drugs is not supported
by clear evidence.
GLP-1 receptor agonists inhibit
angiotensin II through two possible
mechanisms. First, angiotensin
inhibition could be a result of a
decrease in renin secretion through
the macula densa after activation
of tubuloglomerular feedback,
because of the natriuresis produced
by inhibiting sodium–hydrogen
exchanger 3 in the proximal tubule.
However, this theoretical mechanism
has not been adequately clarified.
The second mechanism is mediated
by direct inhibition of angiotensin II
production in tissues.2,3
Several examples show the effect of
GLP-1 receptor agonists on angiotensin
II and a null effect on renin. In a
12-week trial done with sitagliptin and
liraglutide in overweight patients, no
change in plasma renin concentration
was seen at the end of the study with
either dug, when both were compared
with placebo.4 In a trial in healthy men
given a 2 h infusion of GLP-1, although
there was a significant decrease in
angiotensin II (19%), there were no
changes in renin, aldosterone, or
urinary angiotensinogen excretion.5
In another trial,2 done in 11 men with
type 2 diabetes, assessing a single
dose of liraglutide compared with
placebo, a decrease in angiotensin II
(21%) was seen with liraglutide, but
no changes in the concentrations of
other components of the RAAS were
observed (although plasma renin
activity was not measured).
Although studies show evidence
of a decrease in angiotensin II caused
by GLP-1 receptor agonists via the
mechanisms described above, it is
possible that this effect is amplified
by the local effect on the production
of angiotensin II that is generated by
the activation of the tubuloglomerular
feedback. However, the full mechanism
has not been clearly shown in studies
because there are variations in renin
concentration and activity. More
studies are needed to investigate
the effect of GLP-1 on the RAAS that
differentiate the activity of plasma
renin from plasma renin concentration.
We declare no competing interests.
*David León Jiménez,
Miguel Camafort Babkowski,
José Pablo Miramontes González
davidleonj@yahoo.es
Vascular Risk Unit, Internal Medicine Department,
Virgen Rocio University Hospital, Sevilla 41013,
Spain (DLJ); Internal Medicine Department, School
of Medicine, University of Barcelona, Barcelona,
Spain (MCB); and Internal Medicine Department,
Clinic University Hospital, Valladolid, IBSAL:
Instituto de investigaciones biomédicas
de Salamanca, Spain (JPMG)
1 Muskiet MHA, Wheeler DC, Heerspink HJL.
New pharmacological strategies for protecting
kidney function in type 2 diabetes.
Lancet Diabetes Endocrinol 2018; published
online Dec 19. https://doi.org/10·1016/S2213–
8587(18)30263–8.
2 Skov J, Pedersen M, Holst JJ, et al. Short-term
effects of liraglutide on kidney function and
vasoactive hormones in type 2 diabetes:
a randomized clinical trial. Diabetes Obes Metab
2016; 18: 581–89.
3 Skov J, Persson F, Frøkiær J, Christiansen JS.
Tissue renin–angiotensin systems: a unifying
hypothesis of metabolic disease.
Front Endocrinol (Lausanne) 2014; 5: 23.
4 Tonneijck L, Smits MM, Muskiet MHA, et al.
Renal effects of DPP-4 inhibitor sitagliptin
or GLP-1 receptor agonist liraglutide in
overweight patients with type 2 diabetes:
a 12-week, randomized, double-blind,
placebo-controlled trial. Diabetes Care 2016;
39: 2042–50.
5 Skov J, Dejgaard A, Frøkiær J, et al. Glucagon-
like peptide-1 (GLP-1): effect on kidney
hemodynamics and renin–angiotensin–
aldosterone system in healthy men.
J Clin Endocrinol Metab 2013; 98: E664–71.
Published Online
March 7, 2019
http://dx.doi.org/10.1016/
S2213-8587(19)30065-8
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