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SGLT2 inhibitor or metformin as standard treatment in early-stage type 2 diabetes? : Baseline data in SMARTEST, a novel, decentralised, register-based randomised trial on prevention of diabetic complications

Eriksson, Jan W ; Fanni, Giovanni ; Lundqvist, Martin H ; Jansson, Stefan ; Rådholm, Karin ; Sofizadeh, Sheyda ; Patsoukaki, Vagia ; Nilsson, Albert ; Lindholm, Daniel and Rolandsson, Olov , et al. (2025) In Diabetes, obesity & metabolism
Abstract

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... (More)

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).

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publication status
epub
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Diabetes, obesity & metabolism
publisher
John Wiley & Sons Inc.
external identifiers
  • scopus:105023285930
  • pmid:41311237
ISSN
1462-8902
DOI
10.1111/dom.70320
language
English
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yes
additional info
© 2025 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.
id
dcb737c7-990d-4636-9ac9-dd84d81dfd72
date added to LUP
2025-12-03 10:59:15
date last changed
2025-12-09 04:00:55
@article{dcb737c7-990d-4636-9ac9-dd84d81dfd72,
  abstract     = {{<p>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.</p><p>MATERIALS AND METHODS: Participants with T2D since &lt;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.</p><p>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.</p><p>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).</p>}},
  author       = {{Eriksson, Jan W and Fanni, Giovanni and Lundqvist, Martin H and Jansson, Stefan and Rådholm, Karin and Sofizadeh, Sheyda and Patsoukaki, Vagia and Nilsson, Albert and Lindholm, Daniel and Rolandsson, Olov and Norhammar, Anna and Granstam, Elisabet and Eliasson, Björn and Bennet, Louise and Sundström, Johan}},
  issn         = {{1462-8902}},
  language     = {{eng}},
  month        = {{11}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Diabetes, obesity & metabolism}},
  title        = {{SGLT2 inhibitor or metformin as standard treatment in early-stage type 2 diabetes? : Baseline data in SMARTEST, a novel, decentralised, register-based randomised trial on prevention of diabetic complications}},
  url          = {{http://dx.doi.org/10.1111/dom.70320}},
  doi          = {{10.1111/dom.70320}},
  year         = {{2025}},
}