Prevention of Chronic Kidney Disease(CDK) Progression in Type 1 Diabetes With Long Term Use of Sodium-Glucose-coTransporter Inhibitors Avoiding Kidney hypOxia

Study Overview
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Brief Summary
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Background: Sodium-glucose-cotransporter (SGLT) inhibition has been observed to reduce risk of cardiovascular events and kidney failure in persons with type 2 diabetes. People with type 1 diabetes also have increased risk of cardiovascular and kidney disease, and may benefit from SGLT-inhibition. The exact mechanism of how SGLT-inhibition benefits the kidneys are yet unknown. Change in renal hypoxia may be a factor. Objective: The primary aim of this study is to assess the effects of 12 weeks SGLT-1 and 2 inhibition on renal oxygenation in persons with type 1 diabetes and chronic kidney disease. Further aims are to study if renal oxygen consumption and response to SGLT-inhibition differs between people of African-Caribbean or Northern European decent. Additionally effects on left ventricular ejection fraction, kidney function and biomarkers in blood and urine will be explored. Method: 12 weeks treatment with oral sotagliflozin or matching placebo as intervention. Kidney oxygenation and perfusion parameters and left ventricular ejection fraction will be assessed by functional magnetic resonance imaging. Kidney function and biomarkers will be assessed according to local hospital laboratory guidelines. Design: Randomized, double-blinded, placebo-controlled, cross over intervention study. Study population: 69 persons with type 1 diabetes and diabetic kidney disease with albuminuria will be included, 39 at Steno Diabetes Center Copenhagen, 30 at King's College London. Endpoints: Primary end-point: Change from 0 to 12 weeks in dynamic R2*-weighted signal after treatment with sotagliflozin compared to placebo. Secondary endpoints: Change from 0 to 12 weeks with sotagliflozin compared with placebo on renal perfusion, renal artery flow, renal oxygen consumption, renal parenchymal triglyceride fraction, renal fibrosis, left ventricular ejection fraction, urinary albumin-creatinin ratio, ketone bodies, erythropoietin, pro brain natriuretic peptide, and plasma- and urine inflammation- and fibrosis biomarkers as well as difference after 12 weeks treatment in glomerular filtration rate. Timeframe: Inclusion of patients from february 2024. Last visit september 2025. Presentation spring 2026, publication fall 2026.

Official Title
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Prevention of CKD Progression in Type 1 Diabetes With Long Term Use of SGLTi Avoiding Kidney hypOxia(PLUTO)

Conditions
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Nephropathy, Diabetic Nephropathies, Diabetes Mellitus, Type 1, Albuminuria, Diabetic Complications Renal, Diabetic Complications Cardiovascular, Hypoxia

Intervention / Treatment
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* Drug: Sotagliflozin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Persons ≥ 18 years of age with a diagnosis of type 1 diabetes (age at onset <40 years; permanent insulin treatment initiated within 1 year of diagnosis) Albuminuria: UACR > 100 mg/g (in ≥2 out 3 morning spot urine collections prior to randomization) estimated Glomerular Filtration Rate(eGFR) ≥20 and < 75 ml/min/1.73m2 Participants must be on stable renin-angiotensin system blocking treatment 4 weeks before start of study drug and throughout study duration. Able to understand the written participant information and give informed consent Exclusion Criteria: Non-diabetic kidney disease indicated by medical history and/or laboratory findings. eGFR< 20 ml/min/1.73m2, dialysis or kidney transplantation. Previous diabetic ketoacidosis, except at debut. Dysregulated diabetes (HbA1c > 85 mmol/mol) Decreased awareness or unawareness Pregnancy, lactating or with a wish of pregnancy within the next year Low carbohydrate diet Receiving therapy with an SGLT inhibitor within 8 weeks prior to enrolment or previous intolerance of an SGLT inhibitor. New York Heart Association (NYHA) class IV Congestive Heart Failure at the time of enrolment Myocardial infarction, unstable angina, stroke or transient ischemic attack within 12 weeks prior to enrolment The receipt of any investigational product 90 days prior to this trial Unable to participate in study procedures Any clinically significant disorder, except for conditions associated with type 1 diabetes, which in the Investigators opinion could interfere with the results of the trial Participation in another intervention study Exclusion criteria for MRI: known claustrophobia, known chronic lung disease, surgery within past 6 weeks or having foreign bodies of metal in the body (e.g. pacemaker, metal plates, metal screws) Recurrent urogenital infections.

Ages Eligible for Study
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Minimum Age: 18 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: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: randomized, double-blinded, placebo-controlled, cross-over intervention study
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Sotagliflozin<br>In the active arm, participants will be treated with Sotagliflozin 200mg as an oral tablet once daily for 12 weeks. | Drug: Sotagliflozin<br>* Sodium-glucose-co-transporter 1 and 2 inhibitor<br>* Other names: Inpefa (TM);|
| Placebo Comparator: Placebo<br>In the placebo arm, participants will be treated with a matched placebo as an oral tablet once daily for 12 weeks. | Drug: Placebo<br>* Placebo tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in dynamic R2*-weighted signal (BOLD) as an indirect measure of renal blood oxygenation | difference between change from 0 to 12 weeks after treatment with sotagliflozin compared to treatment with placebo | 0 to 12 weeks in both treatment arms, last measure 30 weeks after randomization. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in renal perfusion (medullary and cortical) | Measured with MRI by arterial spin labelling in mL/g/min | From 0 to 12 weeks in each treatment arm. Last measure 30 weeks after randomization | 
| Change in renal artery flow | Renal artery flow measured by using phase contrast (PC) MRI. It is measured in mL/min. | From 0 to 12 weeks in each treatment arm. Last measure 30 weeks after randomization | 
| Change in renal oxygen consumption | Renal oxygen consumption measured by MRI with T2-relaxation-under-spin-tagging. | From 0 to 12 weeks in each treatment arm. Last measure 30 weeks after randomization | 
| Change in renal parenchymal triglyceride fraction | Renal parenchymal triglyceride fraction is measured by MRI spectroscopy | From 0 to 12 weeks in each treatment arm. Last measure 30 weeks after randomization | 
| Change in renal fibrosis | Renal fibrosis is measured by MRI-derived apparent diffusion coefficient | From 0 to 12 weeks in each treatment arm. Last measure 30 weeks after randomization | 
| Change in left ventricular ejection fraction | Left ventricular ejection fraction is assessed by MRI | From 0 to 12 weeks in each treatment arm. Last measure 30 weeks after randomization | 
| Change in albuminuria | Urinary albumin-creatinine ratio (UACR) - morning void spot urine samples collected at home by participants. | From 0 to 12 weeks in each treatment arm. Last measure 30 weeks after randomization. | 
| Change in levels of ketone bodies | Capillary blood ketones, possibly measured by continous ketone monitoring device | From 0 to 12 weeks in each treatment arm. Last measure 30 weeks after randomization. | 
| Change in plasma and urine inflammation- and fibrosis biomarkers | Measured from blood and urine samples using a commercially available panel from the company Olink. Includes 92 biomarkers. | From 0 to 12 weeks in each treatment arm. Last measure 30 weeks after randomization. | 
| Change in endogenous erythropoietin | Analysis on blood samples at regional hospital laboratory. | From 0 to 12 weeks in each treatment arm. Last measure 30 weeks after randomization. | 
| Change in pro brain natriuretic peptide | Analysis on blood samples at regional hospital laboratory. | From 0 to 12 weeks in each treatment arm. Last measure 30 weeks after randomization. | 
| Difference in Kidney Function after 12 weeks treatment with sotagliflozin vs placebo | Glomerular filtration rate. At Steno Diabetes Center Copenhagen this will be measured by plasma clearance of Tc-99m diethylene-triamine-pentaacetate. | From 12 to 30 weeks after randomization |