Ignite Creation Date:
2024-05-06 @ 2:50 AM
Last Modification Date:
2024-10-26 @ 11:23 AM
Study NCT ID:
NCT02130778
Status:
COMPLETED
Last Update Posted:
2015-12-14
First Post:
2014-04-29
Brief Title:
Natriuretic Effect of GLP-1in Healthy Non Obese Subjects
Sponsor:
Clinical Hospital Centre Zagreb
Organization:
Clinical Hospital Centre Zagreb
Study Overview
Official Title:
Natriuretic Effect of GLP-1 in Healthy Non Obese Subjects Followed by Oral Sodium Load A Randomized Placebo-controlled Cross-over Study
Status:
COMPLETED
Status Verified Date:
2015-12
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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 dbdb 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 dbdb mice and non-diabetic dbm 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 dbdb mice show high salt-sensitivity Exendin-4 demonstrated anti-hypertensive effect in dbdb 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 kgm2 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 agents 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 2171 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 diuresisnatriuresis 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
Detailed Description:
This is a cross-over study Totally 15 participants will be randomized or other number later determined by power test The duration of the study is 9 days that will include 3 visits and screening visit before starting the study
Screening day -1 Inclusion criteria are fulfilled before approaching Visit 1 on screening Participants are instructed do come next day fasting and to collect 24h of urine sample
Visit 1 day 1 Participant voluntarily agrees to participate by giving informed written consent Baseline study assessment is going to be performed fasting blood count and differential blood chemistry liver enzymes sodium potassium calcium phosphorus magnesium chloride serum amorality urea and creatinine lipid panel including cholesterol triglycerides HDL and LDL cholesterol coagulation uric acid glucose and insulin renin activity aldosterone GLP1 level T4 TSH-thyroid stimulating hormone ADH BNP In the 24 h urine collection sodium chloride and calcium excretion osmolality creatinine are going to be measured glomerular filtration is going to be assessed by creatinine clearance urin analysis with microscopy is going to be preformed EKG kidney ultrasound together with 24-h blood pressure monitor HOMA2 The Homeostasis Model Assessment index is calculated and a total body water percentage determinated via Bioelectrical Impedance Analysis All samples of renin activity and aldosterone in a study are going to be taken while being in horizontal position at least for 3 hours Participants are going to be randomized regarding the glucose tolerance test First group it the one with fasting glucose 45 -57 mmolL and at 2 hour OGTT the amount of sodium in OGTT fluid used is 04 mg of sodium and 03 mg of chloride in 02 L of water glucose level below 78 mmoll The other group is the one with fasting glucose from 57 to 7 mmoll andor at 2 hour OGTT glucose level form 78 mmoll to 111 mmolL venous sample Patients are instructed to come on the next day fasting again
Visit 2 day 2 is a next study assessment 24-h blood pressure monitor is removed after the overnight fast oral saline load is going to be given in a form of a standardized meal soup in a amount of 12 g of NaCl average daily intake of salt in Croatia The soup is going to be consumed in 30 minutes Volunteers are going to be instructed to drink afterwards 12 L of water during next 1 h Placebo in a form iv infusion of hypertonic saline is going to be given at a rate of 006 mlkgin and infused during 3 hours from beginning of oral sodium load During 6 hours from oral sodium load urine is gong to be collected Finally blood samples are going to be drawn for glucose insulin sodium potassium serum osmolality serum creatinine renin activity and aldosterone BNP ADH and GLP1 level after 3 and 6 hours Sodium chloride and calcium excretion osmolality and creatinine are going to be measured in the urine after 3 hours Patients are instructed to come again after 7 days fasting
Visit 3 day 9 after the overnight fast again oral sodium load is going to be given in a form of a standardized meal soup in a same amount as previous day and again consumed in 30 minutes they are going to drink afterwards 12 L of water during next 1 h like pervious day Synthetic GLP-1 15 pmolkgmin dissolved in 500 ml 09 saline is going to be infused during 3 hours from beginning of oral sodium load During 6 hours from oral sodium load urine is gong to be collected blood samples are going to be drawn after 3 and 6 hours for the same analysis as in Visit 2 just like urine collection after 6 hours
Screening day -1 Inclusion criteria are fulfilled before approaching Visit 1 on screening Participants are instructed do come next day fasting and to collect 24h of urine sample
Visit 1 day 1 Participant voluntarily agrees to participate by giving informed written consent Baseline study assessment is going to be performed fasting blood count and differential blood chemistry liver enzymes sodium potassium calcium phosphorus magnesium chloride serum amorality urea and creatinine lipid panel including cholesterol triglycerides HDL and LDL cholesterol coagulation uric acid glucose and insulin renin activity aldosterone GLP1 level T4 TSH-thyroid stimulating hormone ADH BNP In the 24 h urine collection sodium chloride and calcium excretion osmolality creatinine are going to be measured glomerular filtration is going to be assessed by creatinine clearance urin analysis with microscopy is going to be preformed EKG kidney ultrasound together with 24-h blood pressure monitor HOMA2 The Homeostasis Model Assessment index is calculated and a total body water percentage determinated via Bioelectrical Impedance Analysis All samples of renin activity and aldosterone in a study are going to be taken while being in horizontal position at least for 3 hours Participants are going to be randomized regarding the glucose tolerance test First group it the one with fasting glucose 45 -57 mmolL and at 2 hour OGTT the amount of sodium in OGTT fluid used is 04 mg of sodium and 03 mg of chloride in 02 L of water glucose level below 78 mmoll The other group is the one with fasting glucose from 57 to 7 mmoll andor at 2 hour OGTT glucose level form 78 mmoll to 111 mmolL venous sample Patients are instructed to come on the next day fasting again
Visit 2 day 2 is a next study assessment 24-h blood pressure monitor is removed after the overnight fast oral saline load is going to be given in a form of a standardized meal soup in a amount of 12 g of NaCl average daily intake of salt in Croatia The soup is going to be consumed in 30 minutes Volunteers are going to be instructed to drink afterwards 12 L of water during next 1 h Placebo in a form iv infusion of hypertonic saline is going to be given at a rate of 006 mlkgin and infused during 3 hours from beginning of oral sodium load During 6 hours from oral sodium load urine is gong to be collected Finally blood samples are going to be drawn for glucose insulin sodium potassium serum osmolality serum creatinine renin activity and aldosterone BNP ADH and GLP1 level after 3 and 6 hours Sodium chloride and calcium excretion osmolality and creatinine are going to be measured in the urine after 3 hours Patients are instructed to come again after 7 days fasting
Visit 3 day 9 after the overnight fast again oral sodium load is going to be given in a form of a standardized meal soup in a same amount as previous day and again consumed in 30 minutes they are going to drink afterwards 12 L of water during next 1 h like pervious day Synthetic GLP-1 15 pmolkgmin dissolved in 500 ml 09 saline is going to be infused during 3 hours from beginning of oral sodium load During 6 hours from oral sodium load urine is gong to be collected blood samples are going to be drawn after 3 and 6 hours for the same analysis as in Visit 2 just like urine collection after 6 hours
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None