Clinical trial NCT06054035: SGLT2 Inhibition in Addition to Lifestyle Intervention and Risk for Complications in Subtypes of Patients With Prediabetes
Official title: SGLT2 Inhibition in Addition to Lifestyle Intervention and Risk for Complications in Subtypes of Patients With Prediabetes - a Randomized, Placebo Controlled, Multi-center Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Type2diabetes
PreDiabetes
Renal Failure
Lead sponsor: University Hospital Tuebingen
Sponsor class: OTHER
Collaborators: name: German Federal Ministry of Education and Research
name: German Center for Diabetes Research
name: AstraZeneca
First posted: 2023-09-26
Enrollment: 182
Sex: ALL
Minimum age (years): 35
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomization will be performed stratified by prediabetes cluster and by intake of antihypertensive medication (yes/no).
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: Inclusion Criteria:

1. Male, female or diverse patients aged between 35 and 75 years (including)
2. 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)
3. Prediabetes (defined by one of the following: FG \> 100 mg/dL, HbA1c \> 5,6 or 2h OGTT glucose \> 140 mg/dL)
4. BMI ≥20 kg/m2
5. TSH within normal range
6. Ability to understand and follow study-related instructions
7. Negative pregnancy test for premenopausal women (blood or urine)
8. 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)
9. 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)
10. 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
11. Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures.
12. 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:

1. Manifest diabetes mellitus
2. eGFR (as calculated by the CKD-EPI equation) \< 60 ml/min/1.73 m2
3. all glucose altering medications (including current therapy with dapagliflozin or empagliflozin or any other SGLT2-Inhibitor)
4. Symptomatic chronic congestive heart disease
5. New diuretic or antihypertensive medication or dosing changes within the last 2 weeks, for aldosterone antagonists within the last 6 weeks
6. known or suspected orthostatic proteinuria
7. 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
8. history of or current therapy for congestive heart failure (NYHA III and IV), pacemaker or aortic stenosis \> II°
9. acute pancreatic disease (i.e. elevated lipase 3x ULN)
10. rapidly progressing renal disease or anuria
11. known HIV infection or positive HIV test at screening
12. history of or planned organ transplantation
13. 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
14. 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).
15. treatment with glucocorticoids
16. antibiotic treatment within the last 4 weeks
17. History of ketoacidosis
18. history of repeated urogenital infection
19. hemoglobinopathies, haemolytic anaemia, or chronic anaemia (haemoglobin concentration \< 12.0 g/dL)
20. presence of psychiatric disorder or intake of antidepressant or antipsychotic agents
21. Positive Screening for a moderate/severe depression (BDI ≥29)
22. history of hypersensitivity to the study drug or its ingredients
23. allergy to iodine contrast dye
24. more than 5% weight loss in the last 3 months
25. Pregnant or breastfeeding women
26. 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).
27. 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.
28. Current participation in other interventional clinical trials or treatment with other IMPs within five times the half-life of the drug
29. Previous therapy with dapagliflozin or other drugs that can potentially lead to overlapping toxicities within five times the half-life of the drug
30. Patients who do not want to be informed about accidental findings
31. Any other clinical condition that would jeopardize subjects' safety or well-being while participating in this clinical trial
32. 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

Primary outcomes:
measure: Change in albuminuria
timeFrame: 24 months
Secondary outcomes:
measure: Change in estimated glomerular filtration rate (eGFR)
timeFrame: 24 and 25 months
measure: Change in measured glomerular filtration rate (mGFR)
timeFrame: 25 months
measure: Slopes over time of estimated glomerular filtration rate (eGFR).
timeFrame: 4 weeks, 25 months and 22 months.
measure: Slopes over time of measured glomerular filtration rate (mGFR)
timeFrame: 25 months
measure: Numbers of patients showing resolution of chronic kidney disease (CKD)
timeFrame: 19 months
Other outcomes:
measure: Numbers of patients showing a resolution of Prediabetes
timeFrame: 24 months
measure: Interaction between diabetes risk cluster and intervention for numbers of patients showing a resolution of Prediabetes
timeFrame: 24 months
measure: Insulin sensitivity
timeFrame: 24 months
measure: Interaction between diabetes risk cluster and intervention for insulin sensitivity.
timeFrame: 24 months
measure: Number of patients progressing to Type 2 Diabetes
timeFrame: 24 months
measure: Interaction between diabetes risk cluster and intervention for number of patients progressing to Type 2 Diabetes
timeFrame: 24 months
measure: Change in body weight
timeFrame: 24 months
measure: Arterial blood pressure
timeFrame: 24 months
measure: New onset or progress of neuropathy
timeFrame: 24 months
measure: Quality of life using the Short Form Health Survey (SF)-36 questionnaire
timeFrame: 24 months
measure: Small vessel density
timeFrame: 24 months
measure: Interaction between diabetes risk cluster and intervention on small vessel density
timeFrame: 24 months
measure: New onset or progress of diabetic retinopathy
timeFrame: 24 months
measure: Composition of the gut microbiome
timeFrame: 24 months
measure: Interaction between diabetes risk cluster and intervention for composition of the gut microbiome
timeFrame: 24 months
measure: Urinary metabolite signature of SGLT2 inhibitors
timeFrame: 24 months
measure: Interaction between diabetes risk cluster and intervention for urinary metabolite signature of SGLT2 inhibitors
timeFrame: 24 months
measure: Myocardial function shown by left ventricular mass index
timeFrame: 24 months
measure: Myocardial function shown by systolic myocardial function
timeFrame: 24 months
measure: Myocardial function shown by diastolic myocardial function
timeFrame: 24 months
measure: Interaction between diabetes risk cluster and intervention for insulin secretion
timeFrame: 24 months
measure: Change in BMI
timeFrame: 24 months
measure: Change in whole body fat
timeFrame: 24 months
measure: Interaction between diabetes risk cluster and intervention for change in whole body fat
timeFrame: 24 months
measure: Change in visceral fat
timeFrame: 24 months
measure: Interaction between diabetes risk cluster and intervention for change in visceral fat
timeFrame: 24 months
measure: Change in subcutaneous fat
timeFrame: 24 months
measure: Interaction between diabetes risk cluster and intervention for change in subcutaneous fat
timeFrame: 24 months
measure: Change in liver fat
timeFrame: 24 months
measure: Interaction between diabetes risk cluster and intervention for change in liver fat
timeFrame: 24 months
measure: Interaction between diabetes risk cluster and intervention for changes of estimated glomerular filtration rate (eGFR)
timeFrame: 24 and 25 months
measure: Interaction between diabetes risk cluster and intervention for changes of measured glomerular filtration rate (mGFR).
timeFrame: 24 months
measure: Interaction between diabetes risk cluster and intervention for slopes over time of estimated glomerular filtration rate (eGFR).
timeFrame: 4 weeks, 25 months and 22 months.
measure: Interaction between diabetes risk cluster and intervention for slopes over time of measured glomerular filtration rate (mGFR)
timeFrame: 25 months
measure: Interaction between diabetes risk cluster and intervention for numbers of patients showing resolution of chronic kidney disease (CKD)
timeFrame: 19 months
measure: Interaction between diabetes risk cluster and intervention for change in albuminuria
timeFrame: 24 months
Locations:
city: Duesseldorf
country: Germany
facility: German Diabetes Center, Leibniz-Center for Diabetes Research at the Heinrich-Heine-University Duesseldorf
city: Heidelberg
country: Germany
facility: Heidelberg University Hospital - Department of Endocrinology and Metabolism
city: Tuebingen
country: Germany
facility: University Hospital Tuebingen, Otfried-Mueller Str. 10
Study officials:
References: