SGLT2 Inhibitor or Metformin as Standard Treatment of Early Stage Type 2 Diabetes (SMARTEST)

A Multicenter, Register-based, Randomized, Controlled Trial Comparing Dapagliflozin With Metformin Treatment in Early Stage Type 2 Diabetes Patients by Assessing Mortality and Macro- and Microvascular Complications

A real-world, nationwide, register-based, randomised trial (RRCT) comparing SGLT2 inhibitors with metformin as standard treatment in early typ 2 diabetes. An open-label trial addressing efficacy with respect to clinically important macro- and microvascular events.

Study Overview

• Status: Active, not recruiting
• Conditions: Type 2 Diabetes
• Intervention / Treatment: Drug: Metformin; Drug: Dapagliflozin 10 MG

Detailed Description

2067 type 2 diabetes (T2D) patients on monotherapy or drug naive. Randomization 1:1, metformin, dosing according to treatment guidelines or SGLT2 inhibitor, dapagliflozin 10 mg od.

844 events estimated for study completion (90% power to detect hazard ratio (HR) <0.8 for dapagliflozin vs metformin ) Endpoint collection during study duration (about 4 years) from national health care registers: Patient, Prescribed drugs, Cause of death and Population registers; National diabetes register (NDR) Primary analysis according to insulin tolerance test (ITT)

• Study Type: Interventional
• Enrollment (Actual): 2067
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Jan Eriksson, MD; Phone Number: +46 738 681133; Email: jan.eriksson@medsci.uu.se
• Study Contact Backup: Name: Sofia Löfving, RN; Phone Number: +46 18 6113571; Email: sofia.lofving@medsci.uu.se

Study Locations

• Sweden
  • Uppsala, Sweden, 75185
    • Uppsala University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Men and women ≥18 years old
• T2D (according to World Health Organization (WHO) criteria) of less than 4 years duration
• BMI 18.5-45 kg/m2
• Drug naïve or oral monotherapy with glucose-lowering drug.
• Accepting NDR participation and other register data collection.

Exclusion Criteria:

• Known or suspected other form of diabetes than type 2
• Ongoing or more than >4 weeks in total of any previous treatment with: insulin, GLP-1 receptor agonists, SGLT2 inhibitors or combination of any diabetes medications
• Medical need to start or intensify any specific GLD treatment, e.g. insulin due to marked hyperglycemia
• HbA1c >70 mmol/mol for patients on monotherapy, >80 in drug naïve
• Contraindication to either metformin or dapagliflozin, or any unacceptable risk with either treatment as assessed by the investigator
• History or signs of established cardiovascular disease: diagnosis of myocardial infarction, angina pectoris, heart failure, stroke, lower extremity arterial disease, any limb amputation (except due to trauma or malignancy)
• Any serious illness or other condition with short life expectancy (<4 yr)
• Renal impairment (eGFR <60 ml/min/1,73m2)
• Any condition, as judged by the investigator, that suggests that the patient will be non-compliant or otherwise unsuitable to study medication or study participation
• Pregnancy or breastfeeding, women of childbearing potential (WOCBP; including perimenopausal women who have had a menstrual period within 1 year) without adequate anticonception during any part of the study period
• Involvement in the planning and/or conduct of the study
• Ongoing participation in another clinical trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Metformin; Metformin 1000-3000 mg per day according to clinical guidelines. Split into 2-3 doses per day.	Drug: Metformin; Active comparator
Experimental: Dapagliflozin; Dapagliflozin 10 mg once daily	Drug: Dapagliflozin 10 MG; Experimental treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to first occurence of a confirmed composite endpoint of death, myocardial infarction, stroke, heart failure, diabetic nephropathy, retinopathy or foot ulcer.	A confirmed composite endpoint includes death, myocardial infarction, stroke, heart failure, diabetic nephropathy, retinopathy or foot ulcer (ICD10 diagnosis codes)	Time to first event during study period (for each patient 24-48 months, mean 36 months )

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ordinal analysis of components of primary endpoint (see above)	Death, major adverse cardiovascular event or microvascular event at 2 years follow-up (ICD10 diagnosis codes), scored according to severity as specified in statistical analysis plan.	Events of any of above having occurred during 48 months following randomization.
Time to first occurence of a confirmed composite endpoint of death, myocardial infarction, stroke, heart failure, diabetic nephropathy, retinopathy or foot ulcer (ICD10 diagnosis codes) or initiation of insulin treatment.	A confirmed composite endpoint includes death, myocardial infarction, stroke, heart failure, diabetic nephropathy, retinopathy or foot ulcer (ICD10 diagnosis codes) or initiation of insulin treatment (filled prescription according to Swedish Prescribed Drug Register)	Time to first event during study period (for each patient 24-48 months, mean 36 months )
Time to first occurence of a confirmed composite endpoint of non-fatal myocardial infarction, stroke, heart failure, unstable angina or cardiovascular death.	A confirmed composite endpoint includes non-fatal myocardial infarction, stroke, heart failure, unstable angina or cardiovascular death (ICD10 diagnosis codes).	Time to first event during study period (for each patient 24-48 months, mean 36 months )
Time to first occurence of a confirmed composite endpoint of heart failure or cardiovascular death.	A confirmed composite endpoint includes heart failure or cardiovascular death (ICD10 diagnosis codes)	Time to first event during study period (for each patient 24-48 months, mean 36 months )
Death	Time to death (Population Register data)	Time to event during study period (for each patient 24-48 months, mean 36 months)
Microvascular events, first of; occurrence or progression of retinopathy, nephropathy, diabetic foot lesions	Time to first event of: occurrence or progression of retinopathy, nephropathy, diabetic foot ulcers (ICD10 diagnosis codes)	Time to first event during study period (for each patient 24-48 months, mean 36 months )
Need for insulin treatment	Time to initiation of insulin treatment (filled prescription according to Swedish Prescribed Drug Register)	Time to first event during study period (for each patient 24-48 months, mean 36 months )
Treatment failure, defined as add-on or switch to another glucose-lowering drug	Time to event of: add-on or switch to another glucose-lowering drug (filled prescription according to Swedish Prescribed Drug Register)	Time to first event during study period (for each patient 24-48 months, mean 36 months )
Change in glycemic control	HbA1c level (mmol/mol)	Change during study period, at 12, 24, 36 and 48 months
Change in LDL-cholesterol	Change in LDL cholesterol from baseline (mmol/L)	Change during study period; assessment at baseline, 12, 24, 36 and 48 months
Change in HDL-cholesterol	Change in HDL cholesterol from baseline (mmol/L)	Change during study period; assessment at baseline, 12, 24, 36 and 48 months
Change in total cholesterol	Change in total cholesterol from baseline (mmol/L)	Change during study period; assessment at baseline, 12, 24, 36 and 48 months
Change in triglycerides	Change in triglycerides from baseline (mmol/L)	Change during study period; assessment at baseline, 12, 24, 36 and 48 months
Change in albuminuria	Change in urinary albumin/creatinine ratio (mg/mol)	Change during study period; assessment at baseline, 12, 24, 36 and 48 months
Change in blood pressure	Change in systolic and diastolic blood pressure (mm Hg)	Change during study period; assessment at baseline, 12, 24, 36 and 48 months
Change in body weight	Change in body weight (kg)	Change during study period; assessment at baseline, 12, 24, 36 and 48 months
Change in BMI	Change in BMI (kg/m2)	Change during study period; assessment at baseline, 12, 24, 36 and 48 months
Health care costs	Diagnosis-based (IDG) costs for all health care during study period plus medication cost	Accumulated health care costs during study period (for each patient 24-48 months, mean 36 months )
Health-related quality of life	The Short Form 36-Item Survey version 1.0 (SF-36) is used for patient-reported health and consists of 36 questions. The weighted sums of scores in each of eight defined domains (relating to experience of different aspects of general health, symptoms and functions) are compiled into different scales according to a standardized algorithm. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability, i.e. a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability. We use the public domain version, called the the RAND-36 Item Health Survey.	Assessment at baseline, 12, 24 months
Health-related quality of life with respect to diabetes treatment satisfaction.	The Diabetes Treatment Satisfaction Questionnaire (DTSQ) is used. It has been developed to assess patient satisfaction with diabetes treatment. The questionnaire is composed of two different factors. The first factor assesses treatment satisfaction and consists of six questions and the second factor consists of two questions, which assess the burden from hyper- and hypoglycemia. Treatment satisfaction is assessed as the sum of the scores of the six questions on the first factor (total score 36), with a higher score indicating higher treatment satisfaction.	Assessment at baseline, 12, 24 months

Collaborators and Investigators

• Sponsor: Uppsala University
• Collaborators: Uppsala University Hospital; Swedish Healthcare Regions; Swedish National Board of Health and Welfare; The Swedish National Diabetes Register
• Investigators: Principal Investigator: Jan Eriksson, MD, Uppsala University

Publications and helpful links

General Publications

• Gnesin F, Thuesen ACB, Kahler LKA, Madsbad S, Hemmingsen B. Metformin monotherapy for adults with type 2 diabetes mellitus. Cochrane Database Syst Rev. 2020 Jun 5;6(6):CD012906. doi: 10.1002/14651858.CD012906.pub2.
• Sundstrom J, Kristofi R, Ostlund O, Bennet L, Eliasson B, Jansson S, Leksell J, Almby K, Lundqvist M, Eriksson JW; SMARTEST study group (see list in Appendix). A registry-based randomised trial comparing an SGLT2 inhibitor and metformin as standard treatment of early stage type 2 diabetes (SMARTEST): Rationale, design and protocol. J Diabetes Complications. 2021 Oct;35(10):107996. doi: 10.1016/j.jdiacomp.2021.107996. Epub 2021 Jul 21.

Study record dates

Study Major Dates

• Study Start (Actual): September 5, 2019
• Primary Completion (Estimated): October 15, 2025
• Study Completion (Estimated): October 15, 2025

Study Registration Dates

• First Submitted: May 27, 2019
• First Submitted That Met QC Criteria: June 10, 2019
• First Posted (Actual): June 11, 2019

Study Record Updates

• Last Update Posted (Actual): November 22, 2023
• Last Update Submitted That Met QC Criteria: November 17, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin; Metformin
• Other Study ID Numbers: SMART-2019; 2019-001046-17 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: IPD will be available to all scientific collaborators

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No