https://dom-pubs.onlinelibrary.wiley.com/doi/full/10.1111/dom.70320

 

Diabetes, obesity and metabolism

 

ORIGINAL ARTICLE

Open Access

 

 

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

 

Jan W. Eriksson PhD, Giovanni Fanni PhD, Martin H. Lundqvist PhD, Stefan Jansson PhD, Karin Rådholm PhD, Sheyda Sofizadeh RN, Vagia Patsoukaki MD, Albert Nilsson MSc, Daniel Lindholm PhD, Olov Rolandsson PhD, Anna Norhammar PhD, Elisabet Granstam PhD, Björn Eliasson PhD, Louise Bennet PhD, Johan Sundström PhD

First published: 28 November 2025

https://doi.org/10.1111/dom.70320

 

 

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 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)

 

 

 

From the article

INTRODUCTION

 

Type 2 diabetes (T2D) is a major public health concern affecting almost 10% of the global population, and its prevalence is still rising.1, 2 Its health burden is associated with long-term vascular complications: (1) macrovascular complications, that is, incident atherosclerotic cardiovascular disease (CVD), including coronary artery disease, cerebrovascular disease, and peripheral artery disease; and (2) microvascular complications, including diabetic retinopathy, nephropathy, and neuropathy.3-5

 

Other common diabetic complications, such as heart failure and diabetic foot lesions, involve vascular and metabolic mechanisms.4, 6 T2D also represents a remarkable economic burden, estimated to account for more than 2% of the global GDP by 2030.7 From the onset of diabetes onwards, it is thus important to reduce risk factors for long-term complications. Notably, there is no convincing evidence that metformin, the current first-line treatment for T2D, offers superior prevention of diabetes complications.8 Few head-to-head trials have directly compared antidiabetic agents with respect to macro- and/or microvascular complications in early T2D.

 

Superiority has typically not been demonstrated, for example in trials on DPP4 or SGLT2 inhibitors versus glimepiride.9, 10 Of note, sodium/glucose cotransporter 2 (SGLT2) inhibitors have repeatedly been shown to reduce mortality and cardiorenal morbidity in large clinical outcome trials enrolling patients with T2D and high cardiovascular risk, but also in patients with kidney or heart failure without diabetes.11-20 There were also similar findings in observational register studies.21, 22 It is possible that such beneficial effects also apply to patients with early-stage T2D without advanced complications, but this has hitherto not been studied.

 

In Sweden, T2D care is largely provided within primary care, which has been a challenging setting to perform controlled trials. In recent years, however, the register-based randomised controlled trial (RRCT) design has emerged as a cost-effective alternative to traditional RCTs and has been previously successfully employed in several fields of medicine, including cardiology, orthopaedic surgery, and gynaecology.23-26 Endpoint data collection from health care registers enables large-scale clinical trials in real-world clinical care with limited research resources.27

 

The ongoing SMARTEST study (SGLT2 inhibitor or Metformin As standaRd Treatment of Early-Stage Type 2 diabetes) is the first RRCT within the diabetes field.

 

The study is largely performed in primary care and aims to assess whether the SGLT2 inhibitor dapagliflozin is superior to metformin in preventing diabetes micro- and macrovascular complications, as well as premature death in individuals with early-stage T2D.28

 

Outcomes are captured in Swedish health care registers including the national Swedish Diabetes Register (NDR) and the Swedish National Patient Register (NPR).29-31

 

In this article, we present the baseline clinical characteristics of the study participants with early-stage T2D who entered the SMARTEST study. We highlight the benefits of the RRCT in T2D care and also present novel options for remote participant recruitment.

 

 

From the article

DISCUSSION

We have designed and launched a register-based decentralised clinical trial (RRCT) largely run in primary care. This is, to the best of our knowledge, the first RRCT conducted in the diabetes field.

 

With the help of digital tools and mobile study staff for remote recruitment, enrolment, and randomisation, we could include patients with early-stage T2D across the entire Sweden, including participants from scarcely populated areas with long distances to health care facilities.

 

Based on blinded interim data, we found that the overall rates of major cardiovascular events and mortality were lower than previously reported for similar populations.21, 22, 37 In contrast, the incidence of microvascular complications was higher than expected.35

 

 

 

From the article.

CONCLUSIONS

The decentralised procedure for inclusion in the SMARTEST trial enables efficient trials in primary care patients with T2D, allowing study sites of different capacities to participate. The study conduct was simplified, and follow-up was largely handled in routine primary health care thanks to the collection of study endpoints from national registers.

 

The SMARTEST study provides positive learnings on nationwide research networks, automated endpoint capture, and digital tools for remote participant recruitment. This facilitated the enrolment of a socioeconomically and geographically representative study population. The study can serve as a model to perform pragmatic and cost-effective real-world clinical trials in the diabetes field, as well as in other diseases areas, within the primary care setting.

 

The important research question on the choice of first-line glucose-lowering agent in T2D is currently unresolved, and the main results of the SMARTEST trial will provide important guidance in the near future. They may either reinforce the metformin paradigm or argue for an early introduction of SGLT2 inhibitors for better prevention of organ complications and premature death.

 

 

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