Natriuretic Effect of GLP-1in Healthy Non Obese Subjects

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.

Conditions

• Sodium Excretion by Urination

Interventions

DRUG

Synthetic GLP-1 (1.5 pmol/kg/min) dissolved in 500 ml 0.9% saline

infusion of synthetic GLP-1 (1.5 pmol/kg/min) saline

OTHER

500 ml 0.9% saline

infusion of saline

Sponsors & Collaborators

• Merck Sharp & Dohme LLC

  collaborator INDUSTRY

• Clinical Hospital Centre Zagreb

  lead OTHER

Study Design

Allocation

NON_RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

SINGLE

Model

CROSSOVER

Eligibility

Min Age

18 Years

Max Age

70 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2014-04-30

Primary Completion

2015-10-31

Completion

2015-10-31

Countries

• Croatia

Study Locations