SGLT2 Inhibition in Addition to Lifestyle Intervention and Risk for Complications in Subtypes of Patients With Prediabetes

Study Overview
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Brief Summary
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More than 50% of patients with type 2 diabetes develop micro- and/or macrovascular complications during the course of the disease. Additionally, many patients at risk for diabetes develop metabolically driven complications including kidney and heart disease. Novel sub-phenotyping analysis identified clusters of risk for diabetes associated with different complications, mainly affecting the kidneys, opening opportunities to new therapeutic approaches, despite and in addition to lifestyle changes. So far, pharmacological therapy is not indicated for patients with prediabetes. SGLT2 inhibitors reduce progression of diabetic nephropathy and ischemic heart disease in patients with diabetes and high cardiovascular risk, in patients with heart failure with reduced ejection fraction and in individuals with advanced CKD. Yet, no prospective data are available in patients with prediabetes and beginning chronic kidney disease, reflected by normal or modestly reduced GFR and increased uACR (> 30mg/g, KDIGO G1A2 - G2A2). Subphenotyping of patients with newly onset diabetes suggests that for some individuals, it would be too late to start interventions against deteriorating renal function at the time of diagnosis of type 2 diabetes. Therefore, individuals at the highest risk to develop T2D and renal failure should receive preventive measures well before the diagnosis of T2D. This study will provide evidence whether such an early intervention contributes to the preservation of renal function in high-risk individuals who already have microalbuminuria. The studied population will comprise individuals who are likely to develop T2D and nephropathy but in clinical practice do not receive medical treatment due to the early stage of the disease. Thereese subjects will receive Dapagliflozin 10 mg or Placebo for two years. The placebo treatment arm reflects current practice. In order guarantee a benefit the patients in the placebo arm will receive a lifestyle intervention.

Official Title
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SGLT2 Inhibition in Addition to Lifestyle Intervention and Risk for Complications in Subtypes of Patients With Prediabetes - a Randomized, Placebo Controlled, Multi-center Trial

Conditions
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Type2diabetes, PreDiabetes, Renal Failure

Intervention / Treatment
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* Drug: Dapagliflozin (Forxiga®)
* Drug: Placebo matching Dapaglifolzin
* Behavioral: Lifestyle Intervention


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male, female or diverse patients aged between 35 and 75 years (including) Patients assigned to high risk for diabetes clusters 3, 5 and 6 according to (Wagner et al., 2021) who have signs of early kidney disease (urinary albumin-to-creatinine ratio (uACR) 30mg/g - 300 mg/g, CKD stage G1A2 or G2A2) Prediabetes (defined by one of the following: FG > 100 mg/dL, HbA1c > 5,6 or 2h OGTT glucose > 140 mg/dL) BMI ≥20 kg/m2 TSH within normal range Ability to understand and follow study-related instructions Negative pregnancy test for premenopausal women (blood or urine) Patients who are receiving thyroid replacement therapy must be on a stable treatment regimen for at least 3 months prior to the screening visit (V0) Patients who are receiving antihypertensive medication such as mineralocorticoid receptor antagonists must be on a stable treatment regimen for at least 6 weeks prior to the screening visit (V0) Patients who are treated antihypertensive medication such as ACE inhibitors and AT1 receptor antagonists, thiazides as well as loop diuretics must be on stable treatment for at least 2 weeks Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures. Patients will not be included in the study if, in the opinion of the investigator, participation will lead to an unacceptable risk to the subjects' safety or well-being Exclusion Criteria: Manifest diabetes mellitus eGFR (as calculated by the CKD-EPI equation) < 60 ml/min/1.73 m2 all glucose altering medications (including current therapy with dapagliflozin or empagliflozin or any other SGLT2-Inhibitor) Symptomatic chronic congestive heart disease New diuretic or antihypertensive medication or dosing changes within the last 2 weeks, for aldosterone antagonists within the last 6 weeks known or suspected orthostatic proteinuria any acute severe or chronic severe illness, including the following: malignant disease ongoing or < 5 years ago, unstable cardiovascular disease or procedure within 3 months prior to enrolment or expected to require coronary revascularisation procedure history of or current therapy for congestive heart failure (NYHA III and IV), pacemaker or aortic stenosis > II° acute pancreatic disease (i.e. elevated lipase 3x ULN) rapidly progressing renal disease or anuria known HIV infection or positive HIV test at screening history of or planned organ transplantation history or presence of inflammatory bowel disease or other severe gastrointestinal diseases, particularly those which may impact gastric emptying, such as gastroparesis or pyloric stenosis relevant hepatic disease, including, but not limited to, acute hepatitis, chronic active hepatitis, or severe hepatic insufficiency, including patients with alanine aminotransferase and/or aspartate aminotransferase > 3 x upper limit of normal and/or total bilirubin (TB) > 2 mg/dL (> 34.2 μmol/L) (patients with TB > 2 mg/dL [> 34.2 μmol/L] and documented Gilbert's syndrome will be allowed to participate). treatment with glucocorticoids antibiotic treatment within the last 4 weeks History of ketoacidosis history of repeated urogenital infection hemoglobinopathies, haemolytic anaemia, or chronic anaemia (haemoglobin concentration < 12.0 g/dL) presence of psychiatric disorder or intake of antidepressant or antipsychotic agents Positive Screening for a moderate/severe depression (BDI ≥29) history of hypersensitivity to the study drug or its ingredients allergy to iodine contrast dye more than 5% weight loss in the last 3 months Pregnant or breastfeeding women Subject (male, female or diverse) is not willing to use highly effective contraceptive methods during treatment and for 14 days (male or female) after the end of treatment (highly effective methods are defined as: combined hormonal contraception associated with inhibition of ovulation, progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized partner, sexual abstinence). Vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner of the trial participant and that the vasectomized partner has received medical assessment of the surgical success. Current participation in other interventional clinical trials or treatment with other IMPs within five times the half-life of the drug Previous therapy with dapagliflozin or other drugs that can potentially lead to overlapping toxicities within five times the half-life of the drug Patients who do not want to be informed about accidental findings Any other clinical condition that would jeopardize subjects' safety or well-being while participating in this clinical trial Patients will not be included in the study if, in the opinion of the investigator, participation leads to an unacceptable risk to their safety and well-being

Ages Eligible for Study
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Minimum Age: 35 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomization will be performed stratified by prediabetes cluster and by intake of antihypertensive medication (yes/no).
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dapagliflozin (Forxiga®) and lifestyle counselling<br> | Drug: Dapagliflozin (Forxiga®)<br>* Dapagliflozin 10 mg once daily for 2 years. Route of administration: oral.<br>Behavioral: Lifestyle Intervention<br>* Patients receive a conventional lifestyle intervention (one in depth individual session at the beginning and standard care information on a healthy lifestyle at every visit thereafter).<br>|
| Placebo Comparator: Placebo matching Dapaglifolzin and lifestyle lifestyle counselling<br> | Drug: Placebo matching Dapaglifolzin<br>* Placebo matching Dapaglifolzin once daily for 2 years. Route of administration: oral.<br>Behavioral: Lifestyle Intervention<br>* Patients receive a conventional lifestyle intervention (one in depth individual session at the beginning and standard care information on a healthy lifestyle at every visit thereafter).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in albuminuria | The primary objective is to test if kidney damage as shown by albuminuria in patients with CKD stage G1A2/G2A2 and prediabetes can be improved by a treatment with the SGLT2 inhibitor dapagliflozin (10mg/day) and lifestyle counselling compared to placebo and lifestyle counselling for two years calculated as mean of baseline-adjusted uACR measurements with dapagliflozin in comparison to treatment with placebo. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in estimated glomerular filtration rate (eGFR) | To test differences between the two treatment arms for reduction in estimated glomerular filtration rate (eGFR). | 24 and 25 months | 
| Change in measured glomerular filtration rate (mGFR) | To test differences between the two treatment arms for reduction in measured glomerular filtration rate (mGFR). | 25 months | 
| Slopes over time of estimated glomerular filtration rate (eGFR). | To test differences between the two treatment arms for slopes over time of estimated glomerular filtration rate (eGFR). | 4 weeks, 25 months and 22 months. | 
| Slopes over time of measured glomerular filtration rate (mGFR) | To test differences between the two treatment arms for slopes over time of measured glomerular filtration rate (mGFR). | 25 months | 
| Numbers of patients showing resolution of chronic kidney disease (CKD) | To test differences between the two treatment arms for resolution of chronic kidney disease (CKD) for at least 3 months continuously: Urine Albumin Creatinin Ratio (uACR) < 30mg/g | 19 months |