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

• ClinicalTrials.gov Identifier: NCT03982381
• Recruitment Status: Recruiting
• First Posted: June 11, 2019
• Last Update Posted: April 28, 2021
• Sponsor: Uppsala University
• Collaborators: Uppsala University Hospital; Swedish Healthcare Regions; Swedish National Board of Health and Welfare; The Swedish National Diabetes Register
• Information provided by (Responsible Party): Uppsala University

Tracking Information

• First Submitted Date: May 27, 2019
• First Posted Date: June 11, 2019
• Last Update Posted Date: April 28, 2021
• Actual Study Start Date: September 5, 2019
• Estimated Primary Completion Date: December 31, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 10, 2019)

Time to first occurence of a confirmed composite endpoint of death, myocardial infarction, stroke, heart failure, diabetic nephropathy, retinopathy or foot ulcer. [ Time Frame: Time to first event during study period (for each patient 24-48 months, mean 36 months ) ]

A confirmed composite endpoint includes death, myocardial infarction, stroke, heart failure, diabetic nephropathy, retinopathy or foot ulcer (ICD10 diagnosis codes)

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: June 10, 2019)

• Ordinal analysis of components of primary endpoint (see above) [ Time Frame: Events of any of above having occurred during 48 months following randomization. ]
  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. [ Time Frame: Time to first event during study period (for each patient 24-48 months, mean 36 months ) ]
  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. [ Time Frame: Time to first event during study period (for each patient 24-48 months, mean 36 months ) ]
  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. [ Time Frame: Time to first event during study period (for each patient 24-48 months, mean 36 months ) ]
  A confirmed composite endpoint includes heart failure or cardiovascular death (ICD10 diagnosis codes)
• Death [ Time Frame: Time to event during study period (for each patient 24-48 months, mean 36 months) ]
  Time to death (Population Register data)
• Microvascular events, first of; occurrence or progression of retinopathy, nephropathy, diabetic foot lesions [ Time Frame: Time to first event during study period (for each patient 24-48 months, mean 36 months ) ]
  Time to first event of: occurrence or progression of retinopathy, nephropathy, diabetic foot ulcers (ICD10 diagnosis codes)
• Need for insulin treatment [ Time Frame: Time to first event during study period (for each patient 24-48 months, mean 36 months ) ]
  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 Frame: Time to first event during study period (for each patient 24-48 months, mean 36 months ) ]
  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 [ Time Frame: Change during study period, at 12, 24, 36 and 48 months ]
  HbA1c level (mmol/mol)
• Change in LDL-cholesterol [ Time Frame: Change during study period; assessment at baseline, 12, 24, 36 and 48 months ]
  Change in LDL cholesterol from baseline (mmol/L)
• Change in HDL-cholesterol [ Time Frame: Change during study period; assessment at baseline, 12, 24, 36 and 48 months ]
  Change in HDL cholesterol from baseline (mmol/L)
• Change in total cholesterol [ Time Frame: Change during study period; assessment at baseline, 12, 24, 36 and 48 months ]
  Change in total cholesterol from baseline (mmol/L)
• Change in triglycerides [ Time Frame: Change during study period; assessment at baseline, 12, 24, 36 and 48 months ]
  Change in triglycerides from baseline (mmol/L)
• Change in albuminuria [ Time Frame: Change during study period; assessment at baseline, 12, 24, 36 and 48 months ]
  Change in urinary albumin/creatinine ratio (mg/mol)
• Change in blood pressure [ Time Frame: Change during study period; assessment at baseline, 12, 24, 36 and 48 months ]
  Change in systolic and diastolic blood pressure (mm Hg)
• Change in body weight [ Time Frame: Change during study period; assessment at baseline, 12, 24, 36 and 48 months ]
  Change in body weight (kg)
• Change in BMI [ Time Frame: Change during study period; assessment at baseline, 12, 24, 36 and 48 months ]
  Change in BMI (kg/m2)
• Health care costs [ Time Frame: Accumulated health care costs during study period (for each patient 24-48 months, mean 36 months ) ]
  Diagnosis-based (IDG) costs for all health care during study period plus medication cost
• Health-related quality of life [ Time Frame: Assessment at baseline, 12, 24 months ]
  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. [ Time Frame: Assessment at baseline, 12, 24 months ]
  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.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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)

• Study Type: Interventional
• Study Phase: Phase 4

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Prospective randomized, open label, blinded endpoint design (PROBE). Multicenter study.

Masking: Single (Outcomes Assessor)
Masking Description:

Treatment is blinded to outcome analysis team, until after database lock

Primary Purpose: Treatment

• Condition: Type 2 Diabetes

Intervention

• Drug: Metformin
  Active comparator
• Drug: Dapagliflozin 10 MG
  Experimental treatment

Study Arms

• Active Comparator: Metformin
  Metformin 1000-3000 mg per day according to clinical guidelines. Split into 2-3 doses per day.
  Intervention: Drug: Metformin
• Experimental: Dapagliflozin
  Dapagliflozin 10 mg once daily
  Intervention: Drug: Dapagliflozin 10 MG

Publications *

• 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.
• 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.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: June 10, 2019): 4300
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: September 20, 2025
• Estimated Primary Completion Date: December 31, 2024 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Jan Eriksson, MD; +46 738 681133; jan.eriksson@medsci.uu.se

Contact: Carola Almström, RN; +46 18 6114372; carola.almstrom@medsci.uu.se

• Listed Location Countries: Sweden

Administrative Information

• NCT Number: NCT03982381
• Other Study ID Numbers: SMART-2019; 2019-001046-17 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: No
• Plan Description: IPD will be available to all scientific collaborators

• Current Responsible Party: Uppsala University
• Original Responsible Party: Same as current
• Current Study Sponsor: Uppsala University
• Original Study Sponsor: Same as current

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

• PRS Account: Uppsala University
• Verification Date: April 2021