Semaglutide's Effect on Renal Hemodynamics and Function in Patients With Type 2 Diabetes Mellitus and Nephropathy

NCT ID: NCT06555146

Last Updated: 2024-08-15

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: NA
• Total Enrollment: 15 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-08-31
• Study Completion Date: 2025-03-31

Brief Summary

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

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.

Conditions

Diabetes Mellitus, Type 2; Kidney Disease, Chronic

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: DOUBLE

Study Groups

Randomized to start with Semaglutide intervention in study period 1

Placebo will be given in study period 2

Group Type: OTHER

Semaglutide, 0.5 mg/mL

Intervention Type: DRUG

1 subcutaneous injection on baseline day

Placebo, Saline

Intervention Type: DRUG

1 subcutaneous injection on baseline day

Randomized to start with Placebo intervention in study period 1

Semaglutide will be given in study period 2

Group Type: OTHER

Semaglutide, 0.5 mg/mL

Intervention Type: DRUG

1 subcutaneous injection on baseline day

Placebo, Saline

Intervention Type: DRUG

1 subcutaneous injection on baseline day

Interventions

Semaglutide, 0.5 mg/mL

1 subcutaneous injection on baseline day

Intervention Type: DRUG

Placebo, Saline

1 subcutaneous injection on baseline day

Intervention Type: DRUG

Eligibility Criteria

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.

• Minimum Eligible Age: 20 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

Bispebjerg Hospital

OTHER

Sponsor Role: lead

Responsible Party

Ali Asmar

Chief Physician, Associate Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Ali Asmar, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Bispebjerg Hospital, Department of Clinical Physiology & Nuclear Medicine

Locations

Bispebjerg Hospital, Department of Clinical Physiology & Nuclear Medicine

Copenhagen, Capital Region, Denmark

Countries

Denmark

Central Contacts

Peter Sørensen, MD

Role: CONTACT

peter.soerensen@regionh.dk

+4530516279

Ali Asmar, MD, PhD

Role: CONTACT

ali.asmar@regionh.dk

Facility Contacts

Peter Sørensen, MD

Role: primary

peter.soerensen@regionh.dk

+4530516279

Ali Asmar, MD, PhD

Role: backup

ali.asmar@regionh.dk

References

Natale P, Green SC, Tunnicliffe DJ, Pellegrino G, Toyama T, Strippoli GF. Glucagon-like peptide 1 (GLP-1) receptor agonists for people with chronic kidney disease and diabetes. Cochrane Database Syst Rev. 2025 Feb 18;2(2):CD015849. doi: 10.1002/14651858.CD015849.pub2.

Reference Type: DERIVED

PMID: 39963952 (View on PubMed)

Other Identifiers

H-20036378

Identifier Type: -

Identifier Source: org_study_id