Semaglutide's Effect on Renal Hemodynamics and Function in Patients With Type 2 Diabetes Mellitus and Nephropathy (Sema-RMA)

Glucagon-like Peptide-1's Effect on Renal Regional Blood Flow and the Renal Function in Patients With Type 2 Diabetes Mellitus

The goal of this double-blinded, placebo-controlled, randomized, crossover study is to examine the effect of semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), on renal hemodynamics and function in patients with type 2 diabetes mellitus (T2DM) and moderate chronic kidney disease (CKD).

The study will determine the effects of semaglutide on:

• Renal arterial blood flow, regional renal perfusion, and oxygenation
• Activity of the renin-angiotensin-aldosterone system (RAAS)
• The glomerular filtration rate (GFR)
• Sodium excretion in urine
• Blood pressure and heart rate

Study Overview

• Status: Not yet recruiting
• Conditions: Diabetes Mellitus, Type 2; Kidney Disease, Chronic
• Intervention / Treatment: Drug: Semaglutide, 0.5 mg/mL; Drug: Placebo, Saline

Detailed Description

Mechanistic studies conducted in healthy humans demonstrate a Glucagon-like peptide-1 (GLP-1)-mediated gut-kidney crosstalk. The expansion of extracellular fluid volume uncovers a natriuretic action of GLP-1. This feed-forward natriuretic system is associated with high renal extraction of GLP-1, suppression in circulating angiotensin II levels, and increased renal medullary and cortical perfusion and oxygenation. Besides potent glucose-lowering actions, Glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve body weight, blood pressure, and dyslipidemia, and cardiovascular and renal outcome trials demonstrate beneficial actions of GLP-1RAs used in patients with type 2 diabetes mellitus (T2DM).

Thus the beneficial cardiovascular effects of GLP-1 may partly be related to renoprotection and might represent the restoration of the gut-kidney crosstalk.

The aim of the present study is to investigate possible mechanisms behind the renal effects of semaglutide in patients with type 2 diabetes mellitus and moderate chronic kidney disease.

This is a double-blinded, placebo-controlled, crossover study and patients will participate in two independent and randomized study periods with a washout period of around 4 weeks in between.

Fifteen male participants with type 2 diabetes mellitus in the age group 20-60 years are screened, randomized, and expected to complete the present study. Informed consent is obtained before the screening meeting followed by a 30-day run-in period prior to study days.

The two study periods each extend over 8 days, where all participants consume a controlled diet with fixed salt intake corresponding to a daily intake of 50-70 mmol + 2 mmol/kg sodium for 7 days. On the fourth day before each of the two baseline trials, 24-hour urine collection will be performed. Throughout the 7 days, water intake will be ad libitum and physical activity will not be allowed.

Each period consists of Baseline day (day 5) and Intervention day (day 8)

Renal flow, perfusion, and oxygenation are measured on both days, using multiparametric MRI.

Glomerular filtration rate (GFR) is measured, using Tc99m-Diethylenetriamine pentaacetic acid (DTPA) plasma clearance.

After conducting the baseline study, the participant is given a subcutaneous injection of either semaglutide or placebo.

During the intervention study, MRI is followed by catheterization of a renal vein via the femoral vein (the Seldinger technique) for blood sampling.

• Study Type: Interventional
• Enrollment (Estimated): 15
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Peter Sørensen, MD; Phone Number: +4530516279; Email: peter.soerensen@regionh.dk
• Study Contact Backup: Name: Ali Asmar, MD, PhD; Email: ali.asmar@regionh.dk

Study Locations

• Denmark
  • Capital Region
    • Copenhagen, Capital Region, Denmark, 2400
      • Bispebjerg Hospital, Department of Clinical Physiology & Nuclear Medicine
      • Contact: Peter Sørensen, MD; Phone Number: +4530516279; Email: peter.soerensen@regionh.dk
      • Contact: Ali Asmar, MD, PhD; Email: ali.asmar@regionh.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Type 2 diabetes mellitus diagnosed through either HbA1c ≥6,5% but ≤8,5%, or <6,5% combined with either fasting plasma glucose ≥7,0 mmol/L or plasma glucose ≥11,1 mmol/L two hours after an oral glucose tolerance test (OGTT).
• Estimated glomerular filtration rate (eGFR, CKD-EPI) between 30-60 mL/min/1.73m2
• Urine Albumin:Creatinine ratio (UACR) ≥30mg/g
• Stable RAAS blockade (ACE inhibitors or angiotensin II receptor blocker (ARB) with stable dosis for 4 weeks prior to screening)
• Discontinuation of treatment with selective sodium glucose transporter inhibitors (SGLT2i), dipeptidyl peptidase 4 inhibitors (DPP-4i), GLP-1R analogs, rapid-acting and mix insulin 30 days before screening.

Exclusion Criteria:

• Immunosuppressive therapy within 30 days of screening
• Alcohol abuse
• Medical treatment with glucocorticoids
• Kidney transplantation
• Treatment for renal failure with dialysis
• Myocardial infarction within 3 months of screening
• Heart failure (NYHA 3-4)
• Dysregulated arterial hypertension (systolic blood pressure ≥180 mm Hg or diastolic blood pressure ≥ 100 mm Hg)
• Liver disease (ALAT >2 x normal value)
• Conditions which may interfere with the glucose metabolism according to the PI
• Severe claustrophobia
• Elements incompatible with MRI
• Abnormal kidney size and/or position
• Venous and arterial anatomy hindering catheterization.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Randomized to start with Semaglutide intervention in study period 1; Placebo will be given in study period 2	Drug: Semaglutide, 0.5 mg/mL; 1 subcutaneous injection on baseline day; Drug: Placebo, Saline; 1 subcutaneous injection on baseline day
Other: Randomized to start with Placebo intervention in study period 1; Semaglutide will be given in study period 2	Drug: Semaglutide, 0.5 mg/mL; 1 subcutaneous injection on baseline day; Drug: Placebo, Saline; 1 subcutaneous injection on baseline day

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total blood flow	Volume of blood per unit time, ml/min	Measured during 30 minutes of MRI. One measurement will be done on each study day, a total of 4 measurements for each participant, over the span of the study (approximately 1 year).
Regional renal perfusion	volume of blood per unit time per unit tissue mass, ml/min/g	Measured during 30 minutes of MRI. One measurement will be done on each study day, a total of 4 measurements for each participant, over the span of the study (approximately 1 year)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glomerular filtration rate	Volume per unit time, ml/min	Measured with Tec99-DTPA clearance. One measurement will be done on each study day, a total of 4 measurements for each participant, over the span of the study (approximately 1 year)
Sodium excretion in urine	Concentration, mmol/l	One measurement will be done on each intervention day, a total of 2 measurements for each participant, over the span of the study (approximately 1 year)
Activation of the renin angiotensin aldosterone system	Concentration, mmol/l	Blood samples will be taken 3 times on each intervention day, a total of 6 measurements for each participant, over the span of the study (approximately 1 year)
Blood pressure	mmhg	Measured continuously during a 60 minute period on each intervention day, a total of 2 measurements for each participant, over the span of the study (approximately 1 year)
Heart Rate	Beats pr. minute	Measured continuously during a 60 minute period on each intervention day, a total of 2 measurements for each participant, over the span of the study (approximately 1 year)

Collaborators and Investigators

• Sponsor: Bispebjerg Hospital
• Investigators: Principal Investigator: Ali Asmar, MD, PhD, Bispebjerg Hospital, Department of Clinical Physiology & Nuclear Medicine

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2024
• Primary Completion (Estimated): March 1, 2025
• Study Completion (Estimated): March 1, 2025

Study Registration Dates

• First Submitted: August 7, 2024
• First Submitted That Met QC Criteria: August 12, 2024
• First Posted (Actual): August 15, 2024

Study Record Updates

• Last Update Posted (Actual): August 15, 2024
• Last Update Submitted That Met QC Criteria: August 12, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: Glomerular filtration rate; Renal flow; Regional renal perfusion; Sodium excretion in urine; Renin angiotensin aldosterone system
• Additional Relevant MeSH Terms: Pathologic Processes; Glucose Metabolism Disorders; Metabolic Diseases; Urologic Diseases; Endocrine System Diseases; Disease Attributes; Renal Insufficiency; Chronic Disease; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Kidney Diseases; Renal Insufficiency, Chronic; Hypoglycemic Agents; Physiological Effects of Drugs; Glucagon-Like Peptide-1 Receptor Agonists; Semaglutide
• Other Study ID Numbers: H-20036378

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No