Natriuretic Effect of GLP-1in Healthy Non Obese Subjects
Status:
Completed
Trial end date:
2015-10-01
Target enrollment:
Participant gender:
Summary
Adipose and diabetic patients have glomerular hyperfiltration and enhanced reabsorption of
sodium in the kidney leading to fluid retention and hypertension. It is already known that
obese mice (db/db) have salt retention and elevated intrarenal angiotensin II , and that the
mechanism of the salt retention is similar to the one described in human beings. In
experimental study from 2009 done by Hirata K and al., published in Biochemical and
Biophysical Research Communications to both obese type 2 diabetic db/db mice and non-diabetic
db/m mice hypertension was artificially induced (acute sodium-loading and angiotensin
II-infusion). Two groups of mice were treated with exendin-4 or vehicle for 12 weeks. Obese
type 2 diabetic db/db mice show high salt-sensitivity. Exendin-4 demonstrated
anti-hypertensive effect in db/db mice and angiotensin II-infused mice, related to
attenuation of high salt-sensitivity. That observation confirmed that exendin-4, a GLP-1
(Glucagon-like peptide-1) analogue, has extra-islet effect including the regulation of salt
handling. More then ten years before mentioned observations the presence of GLP 1 receptors
was confirmed all over the body, also in kidneys. In 2004 Gutzwiller published a study in
Journal of Clinical Endocrinology and Metabolism that examined 15 healthy subjects and 16
obese men (mean body mass index, 36 kg/m2) in a double-blind, placebo-controlled, crossover
study. After overnight fasting hypertonic saline was infuse followed by 3-h infusion of
GLP-1. Intravenous infusions of GLP-1 enhanced sodium excretion, reduced H+ secretion, and
reduced glomerular hyperfiltration in obese men. These findings suggest an action at the
proximal renal tubule and a potential renoprotective effect. Two years later same author with
colleagues published a new study in Digestion. In a part of new study he observed 8
volunteers. The protocol included intravenous salt load compared to the effect of an infusion
of GLP-to isotonic saline (placebo). Extracellular volume expansion induced by an intravenous
infusion of hypertonic saline was partially compensated by an increase in urinary sodium and
water excretion with GLP-1. He explained that volume expansion was associated with increased
renal perfusion, rise in glomerular filtration and the filtered sodium load. It was observed
that GLP-1 is able to increase renal sodium excretion by 69% and urine volume by 86%.
Considering all mentioned above it is obvious that GLP-1 have natriuretic effect, although
its exact mechanism and clinical usefulness remain unclear. Both GLP1 analogues and
inhibitors of DPP4 (dipeptidyl peptidase 4), elevate GLP1 level, and it would not be a
surprise to observe similar natriuretic effects in the body. Since GLP 1 is a peptide given
IV. or sc. there are on long-term studies that observe final possible effect no blood
pressure, but GLP1 analogues and DPP4 inhibitors enhancing the incretin action demonstrate
some antihypertensive properties. 2008 in a study done by Mistry GC and al., published in
Journal of Clinical Pharmacology antihypertensive effect of sitagliptin was observed. In
nineteen patients on stable treatment with antihypertensive agent(s) investigators found
small but statistically significant reductions of 24-hour ambulatory blood pressure. There
are no many definitive clues why the blood pressure should droop during any treatment that
elevates serum GLP1. At the end of 2009 an analysis was published in American Journal of
Hypertension, showing results from six trials including 2,171 subjects treated with exenatide
for at least 6. Again, a significantly greater reduction in systolic blood pressure was
confirmed, not giving an explanation why it happened so. Finally, Prof. Sjöholm from
Karolinska institute Sweden published in Diabetes, obesity and metabolism a review concerning
impact of GLP-1 on endothelial function. He mentioned again decreased blood pressure through
improvements in diuresis and natriuresis, but he also added a new element, improved
endothelial dysfunction through GLP-1 receptor-dependent pathway. Though there are many
speculations, exact antihypertensive effects and water homeostasis of both GLP-1 itself, also
of GLP1 analogues and DPP4 inhibitors is still unknown. Finally, recent review (Tanaka et
all) from 2011 confirms mentioned speculations regarding natriuretic effect of GLP1, quote …"
Incretin mimetics and DPP-IV inhibitors are a novel class of antihypertensive drugs with
natriuretic properties. They can be used in the treatment of salt-sensitive hypertension,
which is characterized by edema. The idea is to investigate the effect of GLP1 on
diuresis/natriuresis compared with placebo in healthy non-obese people and to compare
natriuresis with GLP-1, BNP (brain natriuretic peptide) and ADH (antidiuretic hormone) levels
in serum.