Clinical trial NCT03982381: SGLT2 Inhibitor or Metformin As Standard Treatment of Early Stage Type 2 Diabetes
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
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE4
Conditions: Type 2 Diabetes
Lead sponsor: Uppsala University
Sponsor class: OTHER
Collaborators: name: Uppsala University Hospital
name: Swedish Healthcare Regions
name: Swedish National Board of Health and Welfare
name: The Swedish National Diabetes Register
First posted: 2019-06-11
Enrollment: 2067
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Prospective randomized, open label, blinded endpoint design (PROBE). Multicenter study.
Primary purpose: TREATMENT

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: 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)

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.

Primary outcomes:
measure: Time to first occurence of a confirmed composite endpoint of death, myocardial infarction, stroke, heart failure, diabetic nephropathy, retinopathy or foot ulcer.
timeFrame: Time to first event during study period (for each patient 24-48 months, mean 36 months )
Secondary outcomes:
measure: Ordinal analysis of components of primary endpoint (see above)
timeFrame: Events of any of above having occurred during 48 months following randomization.
measure: 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.
timeFrame: Time to first event during study period (for each patient 24-48 months, mean 36 months )
measure: Time to first occurence of a confirmed composite endpoint of non-fatal myocardial infarction, stroke, heart failure, unstable angina or cardiovascular death.
timeFrame: Time to first event during study period (for each patient 24-48 months, mean 36 months )
measure: Time to first occurence of a confirmed composite endpoint of heart failure or cardiovascular death.
timeFrame: Time to first event during study period (for each patient 24-48 months, mean 36 months )
measure: Death
timeFrame: Time to event during study period (for each patient 24-48 months, mean 36 months)
measure: Microvascular events, first of; occurrence or progression of retinopathy, nephropathy, diabetic foot lesions
timeFrame: Time to first event during study period (for each patient 24-48 months, mean 36 months )
measure: Need for insulin treatment
timeFrame: Time to first event during study period (for each patient 24-48 months, mean 36 months )
measure: Treatment failure, defined as add-on or switch to another glucose-lowering drug
timeFrame: Time to first event during study period (for each patient 24-48 months, mean 36 months )
measure: Change in glycemic control
timeFrame: Change during study period, at 12, 24, 36 and 48 months
measure: Change in LDL-cholesterol
timeFrame: Change during study period; assessment at baseline, 12, 24, 36 and 48 months
measure: Change in HDL-cholesterol
timeFrame: Change during study period; assessment at baseline, 12, 24, 36 and 48 months
measure: Change in total cholesterol
timeFrame: Change during study period; assessment at baseline, 12, 24, 36 and 48 months
measure: Change in triglycerides
timeFrame: Change during study period; assessment at baseline, 12, 24, 36 and 48 months
measure: Change in albuminuria
timeFrame: Change during study period; assessment at baseline, 12, 24, 36 and 48 months
measure: Change in blood pressure
timeFrame: Change during study period; assessment at baseline, 12, 24, 36 and 48 months
measure: Change in body weight
timeFrame: Change during study period; assessment at baseline, 12, 24, 36 and 48 months
measure: Change in BMI
timeFrame: Change during study period; assessment at baseline, 12, 24, 36 and 48 months
measure: Health care costs
timeFrame: Accumulated health care costs during study period (for each patient 24-48 months, mean 36 months )
measure: Health-related quality of life
timeFrame: Assessment at baseline, 12, 24 months
measure: Health-related quality of life with respect to diabetes treatment satisfaction.
timeFrame: Assessment at baseline, 12, 24 months
Other outcomes:
Locations:
city: Uppsala
country: Sweden
facility: Uppsala University Hospital
Study officials:
affiliation: Uppsala University
name: Jan Eriksson, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.