Effects of GLP1-RA on Ectopic Fat Deposition in Chronic Kidney Disease

Study Overview
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Brief Summary
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Chronic kidney disease (CKD) is a burden of morbidity and mortality. Increased protein breakdown in skeletal muscle (wasting) and ectopic fat deposition are important determinants of poor clinical outcome in patient with CKD. Insulin resistance plays a critical role in skeletal muscle wasting and ectopic fat deposition. Glucagon-like peptide-1 receptor agonists (GLP-1RA) decrease ectopic fat deposition in patients with type 2 diabetes, prediabetes, obese and overweight subjects. The influence of GLP-1RA on ectopic fat deposition in CKD patients in unknown. The investigators' will test the hypothesis that GLP-1RA decreases intermuscular (ectopic) fat deposition in patients with stage 3-4 CKD. The investigators' will do so by addressing the following specific aims: Specific Aim 1: To test the hypothesis that GLP-1RA decreases intermuscular fat deposition in patients with stage 3-4 CKD. Specific Aim 2: To test the hypothesis that GLP-1RA improves skeletal muscle mitochondrial function in patients with stage 3-4 CKD. Specific Aim 3: To test the hypothesis that GLP-1RA improves physical performance in patients with stage 3-4 CKD. Specific Aim 4: To test the safety and feasibility of 12 weeks of dulaglutide 1.5 mg/wk administration as an adjunct therapy to the standard care of patients with stage 3-4 CKD.

Official Title
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Effects of Glucagon-Like Peptide-1 Agonists on Metabolism and Ectopic Fat Deposition in Chronic Kidney Disease: A Pilot and Feasibility Study

Conditions
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Chronic Kidney Diseases

Intervention / Treatment
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* Drug: dulaglutide injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with stage 3-4 CKD (eGFR 15-59 ml/min/1/73 m2) Age ≥ 18 years and ≤75 years Exclusion Criteria: Patients with type 1 diabetes mellitus Patients with T2D who are on insulin therapy or who started a new antidiabetic medication within 1 month prior to study or who received incretin-based therapy within 3 months prior to study BMI <25 kg/m2, BMI >40 kg/m2 HbA1c>8% measured within 1 month prior to study, or a history of hypoglycemic episode within 1 year prior to study, or a history of diabetic ketoacidosis Uncontrolled hypertension (>200/100 mmHg) despite optimal antihypertensive therapy Arrythmia, heart failure (NYHA class III-IV), valve disease or heart diseases other than coronary artery disease History of major gastrointestinal surgery, inflammatory bowel disease, pancreatitis or cholelithiasis Personal or family history of medullary thyroid cancer, or personal history of Multiple Endocrine Neoplasia (MEN)-2 Pregnancy, breast feeding or intention to become pregnant Previous renal transplantation Acute or chronic infectious diseases Cancer or chemotherapy within 3 years prior to study Treatment with systemic corticosteroids within 3 months prior to study Known or suspected allergy to dulaglutide Claustrophobia or other contraindications for magnetic resonance imaging

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: dulagutide arm<br>Patient will receive 1.5 mg injections per week for 12 weeks. | Drug: dulaglutide injection<br>* All participants will undergo a 4-week run-in phase followed by 12 weeks of treatment (dulaglutide 1.5 mg/wk), followed by 4 weeks of follow up after discontinuing the study medication<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in intermuscular fat deposition as assessed by magnetic resonance imaging (MRI). | Sequential MRI will be performed during the run-in phase, at the beginning and end of the dulaglutide treatment and at the end of the observational follow up period. Intermuscular fat will be calculated as the ratio between intermuscular fat and muscle volumes in the mid-thigh region. Changes in intermuscular fat deposition will be calculated. | 16 weeks | 
| Changes in skeletal muscle mitochondrial function as assessed by phosphocreatine recovery time constant by 31P magnetic resonance spectroscopy (31P-MRS). | Sequential 31P-MRS, a gold standard technique for muscle mitochondrial function assessment, will be performed during the run-in phase, at the beginning and end of the dulaglutide treatment and at the end of the observational follow up period. Changes in phosphocreatine recovery time constant will be assessed. | 16 weeks | 
| Changes in physical performance as assessed by six-minute walk test. | Sequential six-minute walk test will be performed during the run-in phase, at the beginning and end of the dulaglutide treatment and at the end of the observational follow up period. Changes in the distance walked by the patients in a self-determined pace within six minutes will be assessed. | 16 weeks | 
| Safety and feasibility of dulaglutide treatment as evaluated by subject interview, continuous glucose monitoring, adverse events (AE), laboratory tests, vital signs, ECG & allergic/hypersensitivity reactions. | An AE will be defined as any undesirable medical event occurring to a subject in a clinical trial, whether it is related to the study agent. All adverse events will be graded as follows: 0 = No adverse events or within normal limits; 1 = Mild-did not require treatment; 2 = Moderate resolved with treatment; 3 = Severe-required professional medical attention; 4 = Life-threatening or disabling; 5 = Death. | 16 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Kidney Disease, Intermuscular fat deposition, Glucagon-like peptide-1 agonist, Insulin resistance, Mitochondrial function