SGLT2 inhibition in addition to lifestyle intervention and risk for complications in subtypes of patients with prediabetes - a randomized, placebo controlled, multi-center trial

INTERVENTION: Trade Name: Forxiga Product Name: Forxiga Pharmaceutical Form: Film‐coated tablet INN or Proposed INN: Dapagliflozin CAS Number: 461432‐26‐8 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 10‐ Pharmaceutical form of the placebo: Film‐coated tablet Route of administration of the placebo: Oral use CONDITION: The study will include adult male and female patients with an early stage of chronic kidney disease (CKD stage G1A2/G2A2) and prediabetes Therapeutic area: Diseases [C] ‐ Nutritional and Metabolic Diseases [C18] PRIMARY OUTCOME: Main Objective: The primary objective is to test if kidney damage can be improved Primary end point(s): mean of baseline‐adjusted uACR measurements (V2‐V6) with dapagliflozin in comparison to treatment with placebo Secondary Objective: •Reduction in estimated glomerular filtration rate (eGFR) and measured GFR (mGFR) as well as slopes over time of eGFR and mGFR ; •insulin secretion and insulin sensitivity; •progress to T2DM as defined as a HbA1c = 6.5; •remission of prediabetes as defined by HbA1c <5.7 % and in the oGTT a fasting glucose <100 mg/dl and 2 h glucose <140 mg/dl; •body weight, body mass index (BMI) and body composition; •resolution of CKD; •arterial blood pressure; •left ventricular mass index and systolic and diastolic myocardial function; Timepoint(s) of evaluation of this end point: mean of baseline‐adjusted uACR measurements (V2‐V6) with dapagliflozin in comparison to treatment with placebo SECONDARY OUTCOME: Secondary end point(s): mean of baseline‐adjusted uACR measurements (V2‐V6) with dapagliflozin in comparison to treatment with placebo Timepoint(s) of evaluation of this end point: mean of baseline‐adjusted uACR measurements (V2‐V6) with dapagliflozin in comparison to treatment with placebo INCLUSION CRITERIA: • • Male, female or diverse patients aged 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/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 (i.e. TSH within normal range) 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 (i.e. no hospital admission due to excessive hyperte