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

• ClinicalTrials.gov Identifier: NCT06054035
• Recruitment Status: Recruiting
• First Posted: September 26, 2023
• Last Update Posted: May 14, 2024
• Sponsor: University Hospital Tuebingen
• Collaborators: German Federal Ministry of Education and Research; German Center for Diabetes Research; AstraZeneca
• Information provided by (Responsible Party): University Hospital Tuebingen

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Type2diabetes; PreDiabetes; Renal Failure	Drug: Dapagliflozin (Forxiga®); Drug: Placebo matching Dapaglifolzin; Behavioral: Lifestyle Intervention	Phase 4

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 182 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Randomization will be performed stratified by prediabetes cluster and by intake of antihypertensive medication (yes/no).
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: October 26, 2023
• Estimated Primary Completion Date: March 31, 2026
• Estimated Study Completion Date: December 31, 2026

Arms and Interventions

Arm	Intervention/treatment
Experimental: Dapagliflozin (Forxiga®) and lifestyle counselling	Drug: Dapagliflozin (Forxiga®); Dapagliflozin 10 mg once daily for 2 years. Route of administration: oral.; Behavioral: Lifestyle Intervention; 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).
Placebo Comparator: Placebo matching Dapaglifolzin and lifestyle lifestyle counselling	Drug: Placebo matching Dapaglifolzin; Placebo matching Dapaglifolzin once daily for 2 years. Route of administration: oral.; Behavioral: Lifestyle Intervention; 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).

Outcome Measures

Primary Outcome Measures :

1. Change in albuminuria [ Time Frame: 24 months ]
   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.

Secondary Outcome Measures :

1. Change in estimated glomerular filtration rate (eGFR) [ Time Frame: 24 and 25 months ]
   To test differences between the two treatment arms for reduction in estimated glomerular filtration rate (eGFR).
2. Change in measured glomerular filtration rate (mGFR) [ Time Frame: 25 months ]
   To test differences between the two treatment arms for reduction in measured glomerular filtration rate (mGFR).
3. Slopes over time of estimated glomerular filtration rate (eGFR). [ Time Frame: 4 weeks, 25 months and 22 months. ]
   To test differences between the two treatment arms for slopes over time of estimated glomerular filtration rate (eGFR).
4. Slopes over time of measured glomerular filtration rate (mGFR) [ Time Frame: 25 months ]
   To test differences between the two treatment arms for slopes over time of measured glomerular filtration rate (mGFR).
5. Numbers of patients showing resolution of chronic kidney disease (CKD) [ Time Frame: 19 months ]
   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

Other Outcome Measures:

1. Numbers of patients showing a resolution of Prediabetes [ Time Frame: 24 months ]
   Effects of 2 years treatment with dapagliflozin 10 mg and lifestyle counseling compared to placebo and lifestyle intervention on 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
2. Interaction between diabetes risk cluster and intervention for numbers of patients showing a resolution of Prediabetes [ Time Frame: 24 months ]
   To test interaction between diabetes risk clusters and intervention for effects of 2 years treatment with dapagliflozin 10 mg and lifestyle counseling compared to placebo and lifestyle intervention on 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.
3. Insulin sensitivity [ Time Frame: 24 months ]
   Baseline-adjusted insulin sensitivity at EoT using Insulin sensitivity: ISI-Matsuda/Oral glucose insulin sensitivity index.
4. Interaction between diabetes risk cluster and intervention for insulin sensitivity. [ Time Frame: 24 months ]
   To test interaction between diabetes risk clusters and intervention for baseline-adjusted insulin sensitivity at EoT using Insulin sensitivity: ISI-Matsuda/Oral glucose insulin sensitivity index.
5. Number of patients progressing to Type 2 Diabetes [ Time Frame: 24 months ]
   Effects of 2 years treatment with dapagliflozin 10 mg and lifestyle counseling compared to placebo and lifestyle intervention on the progression to T2DM as defined as a HbA1c ≥ 6.5
6. Interaction between diabetes risk cluster and intervention for number of patients progressing to Type 2 Diabetes [ Time Frame: 24 months ]
   To test interaction between diabetes risk clusters and intervention for effects of 2 years treatment with dapagliflozin 10 mg and lifestyle counseling compared to placebo and lifestyle intervention on the progression to T2DM as defined as a HbA1c ≥ 6.5
7. Change in body weight [ Time Frame: 24 months ]
   Effects of 2 years treatment with dapagliflozin 10 mg and lifestyle counseling compared to placebo and lifestyle intervention on change in body weight.
8. Arterial blood pressure [ Time Frame: 24 months ]
   Baseline-adjusted arterial blood pressure at EoT
9. New onset or progress of neuropathy [ Time Frame: 24 months ]
   Effects of 2 years treatment with dapagliflozin 10 mg and lifestyle counseling compared to placebo and lifestyle intervention on new onset or progress of and neuropathy assessed by using the Rydel-Seiffer tuning fork and a 10 g monofilament
10. Quality of life using the Short Form Health Survey (SF)-36 questionnaire [ Time Frame: 24 months ]
    Effects of 2 years treatment with dapagliflozin 10 mg and lifestyle counseling compared to placebo and lifestyle intervention on quality of life using the SF-36 questionnaire (scored on a 0 to 100 range; the higher the score, the higher quality of life)
11. Small vessel density [ Time Frame: 24 months ]
    Change in small vessel density and junction-to-endpoint branches between baseline and EoT in the dapagliflozin versus placebo group as assessed by optoacustic imagingMyocardial function
12. Interaction between diabetes risk cluster and intervention on small vessel density [ Time Frame: 24 months ]
    To test interaction between diabetes risk clusters and intervention for change in small vessel density and junction-to-endpoint branches between baseline and EoT in the dapagliflozin versus placebo group as assessed by optoacustic imagingMyocardial function
13. New onset or progress of diabetic retinopathy [ Time Frame: 24 months ]
    New onset or progress of retinopathy between baseline and EoT in the dapagliflozin versus placebo group. This will be assessed by a grading algorithm using the iCare DRSplus camera. Since macula edema at early stages cannot adequately be assessed with fundus pictures, we will assess maculopathies using optical coherence tomography
14. Composition of the gut microbiome [ Time Frame: 24 months ]
    Change in gut microbial community and gene abundances within and between intervention and placebo groups over time using next generation sequencing data and machine learning algorithms
15. Interaction between diabetes risk cluster and intervention for composition of the gut microbiome [ Time Frame: 24 months ]
    To test interaction between diabetes risk clusters and intervention change in gut microbial community and gene abundances within and between intervention and placebo groups over time using next generation sequencing data and machine learning algorithms
16. Urinary metabolite signature of SGLT2 inhibitors [ Time Frame: 24 months ]
    Changes in urinary metabolites within and between intervention and placebo groups over time using MS-based metabolomics and machine learning algorithms
17. Interaction between diabetes risk cluster and intervention for urinary metabolite signature of SGLT2 inhibitors [ Time Frame: 24 months ]
    To test interaction between diabetes risk clusters and intervention changes in urinary metabolites within and between intervention and placebo groups over time using MS-based metabolomics and machine learning algorithms
18. Myocardial function shown by left ventricular mass index [ Time Frame: 24 months ]
    Effects of dapagliflozin 10 mg and lifestyle counseling compared to placebo and lifestyle intervention on left ventricular mass index assessed via cardiac magnetic resonance imaging
19. Myocardial function shown by systolic myocardial function [ Time Frame: 24 months ]
    Effects of dapagliflozin 10 mg and lifestyle counseling compared to placebo and lifestyle intervention on systolic myocardial function assessed via cardiac magnetic resonance imaging.
20. Myocardial function shown by diastolic myocardial function [ Time Frame: 24 months ]
    Effects of dapagliflozin 10 mg and lifestyle counseling compared to placebo and lifestyle intervention on diastolic myocardial function assessed via cardiac magnetic resonance imaging.
21. Interaction between diabetes risk cluster and intervention for insulin secretion [ Time Frame: 24 months ]
    To test interaction between diabetes risk clusters and intervention for baseline-adjusted insulin secretion at EoT using insulin secretion:C-peptide0-30AUC/glucose0-30AUC.
22. Change in BMI [ Time Frame: 24 months ]
    Effects of 2 years treatment with dapagliflozin 10 mg and lifestyle counseling compared to placebo and lifestyle intervention on BMI.
23. Change in whole body fat [ Time Frame: 24 months ]
    Effects of 2 years treatment with dapagliflozin 10 mg and lifestyle counseling compared to placebo and lifestyle intervention on whole body fat measures by magnetic resonance imaging.
24. Interaction between diabetes risk cluster and intervention for change in whole body fat [ Time Frame: 24 months ]
    To test interaction between diabetes risk clusters and intervention for effects of 2 years treatment with dapagliflozin 10 mg and lifestyle counseling compared to placebo and lifestyle intervention on whole body fat measures by magnetic resonance imaging.
25. Change in visceral fat [ Time Frame: 24 months ]
    Effects of 2 years treatment with dapagliflozin 10 mg and lifestyle counseling compared to placebo and lifestyle intervention on visceral fat measures by magnetic resonance imaging.
26. Interaction between diabetes risk cluster and intervention for change in visceral fat [ Time Frame: 24 months ]
    To test interaction between diabetes risk clusters and intervention for effects of 2 years treatment with dapagliflozin 10 mg and lifestyle counseling compared to placebo and lifestyle intervention on visceral fat measures by magnetic resonance imaging.
27. Change in subcutaneous fat [ Time Frame: 24 months ]
    Effects of 2 years treatment with dapagliflozin 10 mg and lifestyle counseling compared to placebo and lifestyle intervention on subcutaneous fat measures by magnetic resonance imaging.
28. Interaction between diabetes risk cluster and intervention for change in subcutaneous fat [ Time Frame: 24 months ]
    To test interaction between diabetes risk clusters and intervention for effects effects of 2 years treatment with dapagliflozin 10 mg and lifestyle counseling compared to placebo and lifestyle intervention on subcutaneous fat measures by magnetic resonance imaging.
29. Change in liver fat [ Time Frame: 24 months ]
    Effects of 2 years treatment with dapagliflozin 10 mg and lifestyle counseling compared to placebo and lifestyle intervention on liver fat measures by magnetic resonance spectroscopy.
30. Interaction between diabetes risk cluster and intervention for change in liver fat [ Time Frame: 24 months ]
    To test interaction between diabetes risk clusters and intervention for effects effects of 2 years treatment with dapagliflozin 10 mg and lifestyle counseling compared to placebo and lifestyle intervention on liver fat measures by magnetic resonance spectroscopy.
31. Interaction between diabetes risk cluster and intervention for changes of estimated glomerular filtration rate (eGFR) [ Time Frame: 24 and 25 months ]
    To test interaction between diabetes risk clusters and intervention on changes of reduction in estimated glomerular filtration rate (eGFR).
32. Interaction between diabetes risk cluster and intervention for changes of measured glomerular filtration rate (mGFR). [ Time Frame: 24 months ]
    To test interaction between diabetes risk clusters and intervention on changes of reduction in measured glomerular filtration rate (mGFR).
33. Interaction between diabetes risk cluster and intervention for slopes over time of estimated glomerular filtration rate (eGFR). [ Time Frame: 4 weeks, 25 months and 22 months. ]
    To test interaction between diabetes risk clusters and intervention on slopes over time of estimated glomerular filtration rate (eGFR).
34. Interaction between diabetes risk cluster and intervention for slopes over time of measured glomerular filtration rate (mGFR) [ Time Frame: 25 months ]
    To test interaction between diabetes risk clusters and intervention on slopes over time of measured glomerular filtration rate (mGFR).
35. Interaction between diabetes risk cluster and intervention for numbers of patients showing resolution of chronic kidney disease (CKD) [ Time Frame: 19 months ]
    To test interaction between diabetes risk clusters and intervention for resolution of chronic kidney disease (CKD) for at least 3 months continuously: Urine Albumin Creatinin Ratio (uACR) < 30mg/g
36. Interaction between diabetes risk cluster and intervention for change in albuminuria [ Time Frame: 24 months ]
    To test interaction between diabetes risk clusters and intervention for 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.

Eligibility Criteria

• Ages Eligible for Study: 35 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Contacts

Contact: Andreas Birkenfeld, Prof. Dr.; 0049707129 ext 83670; andreas.birkenfeld@med.uni-tuebingen.de

Contact: Andreas Fritsche, Prof. Dr.; 0049707129 ext 80590; andreas.fritsche@med.uni-tuebingen.de

Locations

Germany

German Diabetes Center, Leibniz-Center for Diabetes Research at the Heinrich-Heine-University Duesseldorf; Not yet recruiting

Duesseldorf, Germany, 40225

Contact: Robert Wagner, Prof. Dr. med.

Heidelberg University Hospital - Department of Endocrinology and Metabolism; Not yet recruiting

Heidelberg, Germany, 69120

Contact: Julia Szendrödi, Prof. Dr. med.

University Hospital Tuebingen, Otfried-Mueller Str. 10; Recruiting

Tuebingen, Germany, 72076

Contact: Andreas Birkenfeld, Prof. Dr. +49 (0)7071 29 80662 andreas.birkenfeld@med.uni-tuebingen.de

Sponsors and Collaborators

University Hospital Tuebingen

German Federal Ministry of Education and Research

German Center for Diabetes Research

AstraZeneca

More Information

• Responsible Party: University Hospital Tuebingen
• ClinicalTrials.gov Identifier: NCT06054035
• Other Study ID Numbers: LIFETIME
• First Posted: September 26, 2023
• Last Update Posted: May 14, 2024
• Last Verified: September 2023

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Prediabetic State; Glucose Intolerance; Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Hyperglycemia; Dapagliflozin; Sodium-Glucose Transporter 2 Inhibitors; Molecular Mechanisms of Pharmacological Action; Hypoglycemic Agents; Physiological Effects of Drugs