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

PreDiabetes Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06054035
• Other study ID #: LIFETIME
• Status: Recruiting
• Phase: Phase 4
• Start date: October 26, 2023
• Est. completion date: December 31, 2026

Study information

• Verified date: September 2023
• Source: University Hospital Tuebingen
• Contact: Andreas Birkenfeld, Prof. Dr.
• Phone: 0049707129
• Email: andreas.birkenfeld[@]med.uni-tuebingen.de
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 182
• Est. completion date: December 31, 2026
• Est. primary completion date: March 31, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 35 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Glucose Intolerance
• PreDiabetes
• Prediabetic State
• Renal Failure

Intervention

Drug:
• Dapagliflozin (Forxiga®)
Dapagliflozin 10 mg once daily for 2 years. Route of administration: oral.
• 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).

Locations

Country	Name	City	State
Germany	German Diabetes Center, Leibniz-Center for Diabetes Research at the Heinrich-Heine-University Duesseldorf	Duesseldorf
Germany	Heidelberg University Hospital - Department of Endocrinology and Metabolism	Heidelberg
Germany	University Hospital Tuebingen, Otfried-Mueller Str. 10	Tuebingen

Sponsors (4)

Lead Sponsor	Collaborator
University Hospital Tuebingen	AstraZeneca, German Center for Diabetes Research, German Federal Ministry of Education and Research

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Numbers of patients showing a resolution of Prediabetes	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	24 months
Other	Interaction between diabetes risk cluster and intervention for numbers of patients showing a resolution of Prediabetes	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.	24 months
Other	Insulin sensitivity	Baseline-adjusted insulin sensitivity at EoT using Insulin sensitivity: ISI-Matsuda/Oral glucose insulin sensitivity index.	24 months
Other	Interaction between diabetes risk cluster and intervention for insulin sensitivity.	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.	24 months
Other	Number of patients progressing to Type 2 Diabetes	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	24 months
Other	Interaction between diabetes risk cluster and intervention for number of patients progressing to Type 2 Diabetes	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	24 months
Other	Change in body weight	Effects of 2 years treatment with dapagliflozin 10 mg and lifestyle counseling compared to placebo and lifestyle intervention on change in body weight.	24 months
Other	Arterial blood pressure	Baseline-adjusted arterial blood pressure at EoT	24 months
Other	New onset or progress of neuropathy	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	24 months
Other	Quality of life using the Short Form Health Survey (SF)-36 questionnaire	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)	24 months
Other	Small vessel density	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	24 months
Other	Interaction between diabetes risk cluster and intervention on small vessel density	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	24 months
Other	New onset or progress of diabetic retinopathy	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	24 months
Other	Composition of the gut microbiome	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	24 months
Other	Interaction between diabetes risk cluster and intervention for composition of the gut microbiome	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	24 months
Other	Urinary metabolite signature of SGLT2 inhibitors	Changes in urinary metabolites within and between intervention and placebo groups over time using MS-based metabolomics and machine learning algorithms	24 months
Other	Interaction between diabetes risk cluster and intervention for urinary metabolite signature of SGLT2 inhibitors	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	24 months
Other	Myocardial function shown by left ventricular mass index	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	24 months
Other	Myocardial function shown by systolic myocardial function	Effects of dapagliflozin 10 mg and lifestyle counseling compared to placebo and lifestyle intervention on systolic myocardial function assessed via cardiac magnetic resonance imaging.	24 months
Other	Myocardial function shown by diastolic myocardial function	Effects of dapagliflozin 10 mg and lifestyle counseling compared to placebo and lifestyle intervention on diastolic myocardial function assessed via cardiac magnetic resonance imaging.	24 months
Other	Interaction between diabetes risk cluster and intervention for insulin secretion	To test interaction between diabetes risk clusters and intervention for baseline-adjusted insulin secretion at EoT using insulin secretion:C-peptide0-30AUC/glucose0-30AUC.	24 months
Other	Change in BMI	Effects of 2 years treatment with dapagliflozin 10 mg and lifestyle counseling compared to placebo and lifestyle intervention on BMI.	24 months
Other	Change in whole body fat	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 months
Other	Interaction between diabetes risk cluster and intervention for change in whole body fat	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.	24 months
Other	Change in visceral fat	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.	24 months
Other	Interaction between diabetes risk cluster and intervention for change in visceral fat	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.	24 months
Other	Change in subcutaneous fat	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.	24 months
Other	Interaction between diabetes risk cluster and intervention for change in subcutaneous fat	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.	24 months
Other	Change in liver fat	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.	24 months
Other	Interaction between diabetes risk cluster and intervention for change in liver fat	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.	24 months
Other	Interaction between diabetes risk cluster and intervention for changes of estimated glomerular filtration rate (eGFR)	To test interaction between diabetes risk clusters and intervention on changes of reduction in estimated glomerular filtration rate (eGFR).	24 and 25 months
Other	Interaction between diabetes risk cluster and intervention for changes of measured glomerular filtration rate (mGFR).	To test interaction between diabetes risk clusters and intervention on changes of reduction in measured glomerular filtration rate (mGFR).	24 months
Other	Interaction between diabetes risk cluster and intervention for slopes over time of estimated glomerular filtration rate (eGFR).	To test interaction between diabetes risk clusters and intervention on slopes over time of estimated glomerular filtration rate (eGFR).	4 weeks, 25 months and 22 months.
Other	Interaction between diabetes risk cluster and intervention for slopes over time of measured glomerular filtration rate (mGFR)	To test interaction between diabetes risk clusters and intervention on slopes over time of measured glomerular filtration rate (mGFR).	25 months
Other	Interaction between diabetes risk cluster and intervention for numbers of patients showing resolution of chronic kidney disease (CKD)	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	19 months
Other	Interaction between diabetes risk cluster and intervention for change in albuminuria	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.	24 months
Primary	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	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
Secondary	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
Secondary	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.
Secondary	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
Secondary	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