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

IntroductionType 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 Tubingen 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 Tubingen 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 Tubingen Prediabetes Clusters. MethodsLIFETIME (NCT06054035) is a randomized, placebo-controlled, double-blind phase IV trial of 24 months duration in 182 adults within the Tubingen Prediabetes Clusters with high risk for developing complications, with prediabetes according to ADA criteria and an urinary albumin ratio (uACR) of [&ge;] 30mg/g. Main exclusion criteria include T2D and treatment with any glucose lowering medication. ResultsThe 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 Tubingen 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 Tubingen Prediabetes Clusters at high risk for development of complications. Ethics and disseminationThe study protocol has been reviewed and approved by all local ethics committees. The results will be disseminated through conference presentations and peer-reviewed publications. RegistrationThe LIFETIME study was registered at clinicaltrials.gov (Identifier: NCT06054035) and EudraCT (EudraCT: 2021-005721-25). Strengths and limitations of this studyO_LIThe study is the first to test the feasibility and efficacy of an early precision treatment of complications in patients in Tubingen Prediabetes Clusters with high risk for the development of complications (high-risk Tubingen Prediabetes Clusters) and moderately increased albuminuria. C_LIO_LIThe study design allows to explore the efficacy of SGLT2 inhibition on the interaction of treatment between the different high-risk Tubingen Prediabetes Clusters with moderately increased albuminuria. C_LIO_LIThe two-year drug administration allows to determine the rate of decline in measured GFR in patients of these high-risk Tubingen Prediabetes Clusters to estimate needed patient numbers in future cardiorenal outcome trials in a precision treatment approach. C_LIO_LIThe study uses highly validated and broadly accepted bridging biomarker of kidney damage and function, namely the uACR and slope of measured and estimated GFR. C_LI