Abstract

Introduction Type 2 diabetes (T2D) is associated with severe complications, including chronic kidney disease (CKD), cardiovascular disease, heart failure and premature death. By the time T2D is diagnosed, many patients already have emerging complications. Therefore, early treatment has the potential for prevention or even early reversal of serious complications. However, until recently, it was not well-defined which patients were most at risk of developing complications in the stage of prediabetes. By establishing the Tübingen Prediabetes Clusters, we have categorized patients with prediabetes according to their geno- and phenotype and predicted their risk for T2D and future complications. To date, no effective drug therapy has been tested in the Tübingen Prediabetes Clusters, which are at high risk of developing complications. Sodium-dependent glucose co-transporter-2 inhibitors (SGLT2) are effective in lowering blood glucose and preventing renal and cardiovascular complications in patients with T2D, heart failure or chronic higher stage renal disease. Therefore, the aim of this study is to investigate whether SGLT2 inhibition with dapagliflozin compared to placebo is effective in reducing the risk of CKD progression and other complications in patients with prediabetes from the high-risk Tübingen Prediabetes Clusters.

Methods LIFETIME (NCT06054035) is a randomized, placebo-controlled, double-blind phase IV trial of 24 months duration in 182 adults within the Tübingen Prediabetes Clusters with high risk for developing complications, with prediabetes according to ADA criteria and an urinary albumin ratio (uACR) of ≥ 30mg/g. Main exclusion criteria include T2D and treatment with any glucose lowering medication.

Results The primary endpoint is the mean of baseline-adjusted uACR over 24 months. Secondary outcomes include the resolution of microalbuminuria (uACR < 30mg/g), as well as changes in measured and estimated glomerular filtration rate (mGFR and eGFR). Other outcomes include the interaction between Tübingen Prediabetes Clusters and intervention, remission of prediabetes and prevention of T2D, changes in body fat distribution, small vessel integrity, myocardial function, the composition of the gut microbiome, quality of life, markers for glucose regulation as well as costs and incremental cost-effectiveness ratios, and changes of risk and time preferences. With these measures, we aim to establish the feasibility and efficacy as well as health economic aspects of an early precision treatment for patients from Tübingen Prediabetes Clusters at high risk for development of complications.

Ethics and dissemination The study protocol has been reviewed and approved by all local ethics committees. The results will be disseminated through conference presentations and peer-reviewed publications.

Strengths and limitations of this study

The study is the first to test the feasibility and efficacy of an early precision treatment of complications in patients in Tübingen Prediabetes Clusters with high risk for the development of complications (high-risk Tübingen Prediabetes Clusters) and moderately increased albuminuria.

The study design allows to explore the efficacy of SGLT2 inhibition on the interaction of treatment between the different high-risk Tübingen Prediabetes Clusters with moderately increased albuminuria.

The two-year drug administration allows to determine the rate of decline in measured GFR in patients of these high-risk Tübingen Prediabetes Clusters to estimate needed patient numbers in future cardiorenal outcome trials in a precision treatment approach.

The study uses highly validated and broadly accepted bridging biomarker of kidney damage and function, namely the uACR and slope of measured and estimated GFR.

Competing Interest Statement

NS is Senior Associate Editor of Diabetes and has received speaking honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer and Sanofi for scientific talks over which he had full control of content. RW reports lecture fees from Boehringer − Ingelheim, Novo Nordisk, Sanofi and Eli Lilly and served on an advisory board for Akcea Therapeutics, Daiichi Sankyo, Sanofi, Eli Lilly, and NovoNordisk. MG reports lecture fees and advisory board membership from AstraZeneca, Bayer, Boehringer Ingelheim, and Eli Lilly. MB received honoraria as a consultant and speaker from Amgen, AstraZeneca, Bayer, Boehringer − Ingelheim, Lilly, Novo Nordisk, Novartis, and Sanofi. MR received fees for lectures and/or advisory boards from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Target RWE and investigator − initiated research support from Boehringer Ingelheim, Nutricia/Danone, and Sanofi. CW reports consultancy for Bayer, Boehringer Ingelheim, GSK, MSD, NovoNordisk, Sanofi and CSL − Vifor; Sanofi grant to institution and Idorsia grant to institution; honoraria for lecturing from Amgen, Astellas, AstraZeneca, Amicus, Bayer, Boehringer Ingelheim, Chiesi, Eli Lilly, FMC, Novartis, Sanofi, and Takeda. HJLH has served as a consultant for AstraZeneca, Bayer, Boehringer Ingelheim, CSL Behring, Gilead, Janssen, Novartis, NovoNordisk, Mitsubishi Tanabe, and Travere Therapeutics; and has received grant support from AbbVie, AstraZeneca, Boehringer Ingelheim, and Janssen. AF reports lecture fees and/or advisory board membership from Sanofi, Novo Nordisk, Eli Lilly, Stada and AstraZeneca. ALB reports lecture fees and advisory board membership from Boehringer Ingelheim, Novo Nordisk, and AstraZeneca − paid to the University Clinic Tübingen. None of the other authors report a conflict of interest directly related to the content of this work.

Clinical Trial

Clinical Trial ID # NCT06054035

Funding Statement

The LIFETIME study is funded by a grant from the Federal Ministry of Education and Research (BMBF) (01KG2306) and by AstraZeneca.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study protocol has been reviewed and approved by the ethics committee of the University Hospital Tübingen (protocol numbers 061/2023AMG1) as well as from all other sites.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Data Availability Statement

The datasets generated during the study are not available publicly because they are subject to national data protection laws and restrictions imposed by the ethics committee to ensure privacy of study participants. However, they can be requested after the primary publication through an individual project agreement with the corresponding author. The request will be reviewed by the data steering committee. A data access agreement will have to be reached after request approval.

AbbreviationsAEsAdverse eventsCDMSClinical Trial Data Management System(e)CRF(Electronic) Case Report FormCKDChronic kidney diseasee/mGFREstimated/measured Glomerular filtration rateEoTEnd of TreatmentKDIGOKidney Disease: Improving Global OutcomesMRIMagnetic resonance imagingMRSMagnetic resonance spectroscopyOGTTOral glucose tolerance testSAEsSerious adverse eventsSGLT2Sodium-dependent glucose co-transporter-2SUSARSuspected Unexpected Serious Adverse ReactionT2DType 2 diabetesuACRUrinary albumin-creatinine ratio