Back to resultsSGLT2 Inhibitor or Metformin as Standard Treatment of Early Stage Type 2 Diabetes (SMARTEST)
Primary Purpose
Type 2 Diabetes
Status
Recruiting
Phase
Phase 4
Locations
Sweden
Study Type
Interventional
Intervention
Metformin
Dapagliflozin 10 MG
Sponsored by
About this trial
This is an interventional treatment trial for Type 2 Diabetes
Eligibility Criteria
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.
Sites / Locations
- Uppsala University HospitalRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Experimental
Arm Label
Metformin
Dapagliflozin
Arm Description
Metformin 1000-3000 mg per day according to clinical guidelines. Split into 2-3 doses per day.
Dapagliflozin 10 mg once daily
Outcomes
Primary Outcome Measures
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)
Secondary Outcome Measures
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.
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 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 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)
Death
Time to death (Population Register data)
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)
Need for insulin treatment
Time to initiation of insulin treatment (filled prescription according to Swedish Prescribed Drug Register)
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)
Change in glycemic control
HbA1c level (mmol/mol)
Change in LDL-cholesterol
Change in LDL cholesterol from baseline (mmol/L)
Change in HDL-cholesterol
Change in HDL cholesterol from baseline (mmol/L)
Change in total cholesterol
Change in total cholesterol from baseline (mmol/L)
Change in triglycerides
Change in triglycerides from baseline (mmol/L)
Change in albuminuria
Change in urinary albumin/creatinine ratio (mg/mol)
Change in blood pressure
Change in systolic and diastolic blood pressure (mm Hg)
Change in body weight
Change in body weight (kg)
Change in BMI
Change in BMI (kg/m2)
Health care costs
Diagnosis-based (IDG) costs for all health care during study period plus medication cost
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.
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.
Full Information
NCT ID
NCT03982381
First Posted
May 27, 2019
Last Updated
May 8, 2023
Sponsor
Uppsala University
Collaborators
Uppsala University Hospital, Swedish Healthcare Regions, Swedish National Board of Health and Welfare, The Swedish National Diabetes Register
1. Study Identification
Unique Protocol Identification Number
NCT03982381
Brief Title
SGLT2 Inhibitor or Metformin as Standard Treatment of Early Stage Type 2 Diabetes
Acronym
SMARTEST
Official Title
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
Study Type
Interventional
2. Study Status
Record Verification Date
May 2023
Overall Recruitment Status
Recruiting
Study Start Date
September 5, 2019 (Actual)
Primary Completion Date
November 30, 2025 (Anticipated)
Study Completion Date
September 20, 2026 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Uppsala University
Collaborators
Uppsala University Hospital, Swedish Healthcare Regions, Swedish National Board of Health and Welfare, The Swedish National Diabetes Register
4. Oversight
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
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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.
Detailed Description
4300 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)
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Type 2 Diabetes
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Model Description
Prospective randomized, open label, blinded endpoint design (PROBE). Multicenter study.
Masking
Outcomes Assessor
Masking Description
Treatment is blinded to outcome analysis team, until after database lock
Allocation
Randomized
Enrollment
4300 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Metformin
Arm Type
Active Comparator
Arm Description
Metformin 1000-3000 mg per day according to clinical guidelines. Split into 2-3 doses per day.
Arm Title
Dapagliflozin
Arm Type
Experimental
Arm Description
Dapagliflozin 10 mg once daily
Intervention Type
Drug
Intervention Name(s)
Metformin
Intervention Description
Active comparator
Intervention Type
Drug
Intervention Name(s)
Dapagliflozin 10 MG
Intervention Description
Experimental treatment
Primary Outcome Measure Information:
Title
Time to first occurence of a confirmed composite endpoint of death, myocardial infarction, stroke, heart failure, diabetic nephropathy, retinopathy or foot ulcer.
Description
A confirmed composite endpoint includes death, myocardial infarction, stroke, heart failure, diabetic nephropathy, retinopathy or foot ulcer (ICD10 diagnosis codes)
Time Frame
Time to first event during study period (for each patient 24-48 months, mean 36 months )
Secondary Outcome Measure Information:
Title
Ordinal analysis of components of primary endpoint (see above)
Description
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.
Time Frame
Events of any of above having occurred during 48 months following randomization.
Title
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.
Description
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 Frame
Time to first event during study period (for each patient 24-48 months, mean 36 months )
Title
Time to first occurence of a confirmed composite endpoint of non-fatal myocardial infarction, stroke, heart failure, unstable angina or cardiovascular death.
Description
A confirmed composite endpoint includes non-fatal myocardial infarction, stroke, heart failure, unstable angina or cardiovascular death (ICD10 diagnosis codes).
Time Frame
Time to first event during study period (for each patient 24-48 months, mean 36 months )
Title
Time to first occurence of a confirmed composite endpoint of heart failure or cardiovascular death.
Description
A confirmed composite endpoint includes heart failure or cardiovascular death (ICD10 diagnosis codes)
Time Frame
Time to first event during study period (for each patient 24-48 months, mean 36 months )
Title
Death
Description
Time to death (Population Register data)
Time Frame
Time to event during study period (for each patient 24-48 months, mean 36 months)
Title
Microvascular events, first of; occurrence or progression of retinopathy, nephropathy, diabetic foot lesions
Description
Time to first event of: occurrence or progression of retinopathy, nephropathy, diabetic foot ulcers (ICD10 diagnosis codes)
Time Frame
Time to first event during study period (for each patient 24-48 months, mean 36 months )
Title
Need for insulin treatment
Description
Time to initiation of insulin treatment (filled prescription according to Swedish Prescribed Drug Register)
Time Frame
Time to first event during study period (for each patient 24-48 months, mean 36 months )
Title
Treatment failure, defined as add-on or switch to another glucose-lowering drug
Description
Time to event of: add-on or switch to another glucose-lowering drug (filled prescription according to Swedish Prescribed Drug Register)
Time Frame
Time to first event during study period (for each patient 24-48 months, mean 36 months )
Title
Change in glycemic control
Description
HbA1c level (mmol/mol)
Time Frame
Change during study period, at 12, 24, 36 and 48 months
Title
Change in LDL-cholesterol
Description
Change in LDL cholesterol from baseline (mmol/L)
Time Frame
Change during study period; assessment at baseline, 12, 24, 36 and 48 months
Title
Change in HDL-cholesterol
Description
Change in HDL cholesterol from baseline (mmol/L)
Time Frame
Change during study period; assessment at baseline, 12, 24, 36 and 48 months
Title
Change in total cholesterol
Description
Change in total cholesterol from baseline (mmol/L)
Time Frame
Change during study period; assessment at baseline, 12, 24, 36 and 48 months
Title
Change in triglycerides
Description
Change in triglycerides from baseline (mmol/L)
Time Frame
Change during study period; assessment at baseline, 12, 24, 36 and 48 months
Title
Change in albuminuria
Description
Change in urinary albumin/creatinine ratio (mg/mol)
Time Frame
Change during study period; assessment at baseline, 12, 24, 36 and 48 months
Title
Change in blood pressure
Description
Change in systolic and diastolic blood pressure (mm Hg)
Time Frame
Change during study period; assessment at baseline, 12, 24, 36 and 48 months
Title
Change in body weight
Description
Change in body weight (kg)
Time Frame
Change during study period; assessment at baseline, 12, 24, 36 and 48 months
Title
Change in BMI
Description
Change in BMI (kg/m2)
Time Frame
Change during study period; assessment at baseline, 12, 24, 36 and 48 months
Title
Health care costs
Description
Diagnosis-based (IDG) costs for all health care during study period plus medication cost
Time Frame
Accumulated health care costs during study period (for each patient 24-48 months, mean 36 months )
Title
Health-related quality of life
Description
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.
Time Frame
Assessment at baseline, 12, 24 months
Title
Health-related quality of life with respect to diabetes treatment satisfaction.
Description
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.
Time Frame
Assessment at baseline, 12, 24 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Jan Eriksson, MD
Phone
+46 738 681133
Email
jan.eriksson@medsci.uu.se
First Name & Middle Initial & Last Name or Official Title & Degree
Sofia Löfving, RN
Phone
+46 18 6113571
Email
sofia.lofving@medsci.uu.se
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jan Eriksson, MD
Organizational Affiliation
Uppsala University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Uppsala University Hospital
City
Uppsala
ZIP/Postal Code
75185
Country
Sweden
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Martin Lundqvist, MD
Phone
+46 73 8115665
Email
martin.lundqvist@medsci.uu.se
First Name & Middle Initial & Last Name & Degree
Sofia Löfving, RN
Phone
+46 18 611 3571
Email
sofia.lofving@medsci.uu.se
12. IPD Sharing Statement
Plan to Share IPD
No
IPD Sharing Plan Description
IPD will be available to all scientific collaborators
Citations:
PubMed Identifier
34389234
Citation
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.
Results Reference
derived
PubMed Identifier
32501595
Citation
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.
Results Reference
derived
Learn more about this trial
SGLT2 Inhibitor or Metformin as Standard Treatment of Early Stage Type 2 Diabetes
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