To Örebro University

AIMS: Metformin has hitherto not been proven superior to other type 2 diabetes (T2D) medications for the prevention of organ complications. The aim of this study is to report baseline data and blinded interim analyses in the register-based randomised clinical trial (RRCT) SMARTEST, which compares metformin and the SGLT2 inhibitor dapagliflozin in early T2D. We also present learnings from the novel decentralised methodology of this first RRCT in diabetes care.

MATERIALS AND METHODS: Participants with T2D since <4 years and without major cardiovascular or renal disease were included at 36 centres across Sweden between 2019 and 2023 at on-site visits or via remote inclusion using digital informed consent. Participants were randomised 1:1 to open-label dapagliflozin 10 mg/day or metformin at an individualised dose, and they are followed for 2-6 years, with blinding of researchers to endpoints per treatment arm. The composite primary endpoint is time to first event of: myocardial infarction, stroke, heart failure (MACE), appearance or progression of microvascular complications or all-cause death. These events are collected from the Swedish National Diabetes Register and the National Patient Register using automated extraction.

RESULTS: A total of 2072 patients, mean age 61.2 years, 39% women, entered randomised treatment. Signs of nephropathy, retinopathy and foot-at-risk were found in 6.1%, 13.2%, and 5.7%, respectively. Hypertension was present in 64.4%, and dyslipidaemia in 57.1%. In blinded interim analyses at a mean follow-up time of 19.0 months, the preliminary event rate of the primary composite endpoint was 11.7/100 patient-years (py) in the whole study population, mainly driven by microvascular complications. In contrast, rates of cardiovascular events and all-cause death were 0.6 and 0.3/100 py, respectively.

CONCLUSIONS: This decentralised RRCT in newly onset T2D demonstrates a highly feasible option for large-scale trials in the primary care setting, enabling representative participant recruitment. Blinded interim analyses showed a low risk of MACE or death, but unexpectedly high rates of microvascular complications. Study completion is event-driven and is expected by January 2026. The study will challenge or reinforce the current metformin paradigm in early T2D. (EUDRA-CT number 2019-001046-17; EU number 2024-516228-33-00; ClinicalTrials.gov Identifier: NCT03982381).