Type 2 Diabetes
Conditions
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)
Interventions
DRUGMetformin
Active comparator
DRUGDapagliflozin 10 MG
Experimental treatment
Sponsors
Uppsala University
Uppsala University Hospital
Swedish Healthcare Regions
National Board of Health and Welfare, Sweden
The Swedish National Diabetes Register
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
Treatment is blinded to outcome analysis team, until after database lock
Intervention model description
Prospective randomized, open label, blinded endpoint design (PROBE). Multicenter study.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to first occurence of a confirmed composite endpoint of death, myocardial infarction, stroke, heart failure, diabetic nephropathy, retinopathy or foot ulcer. | 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) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Ordinal analysis of components of primary endpoint (see above) | 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 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 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 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 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 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 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 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 | Change during study period, at 12, 24, 36 and 48 months | HbA1c level (mmol/mol) |
| Change in LDL-cholesterol | 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 | 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 | Change during study period; assessment at baseline, 12, 24, 36 and 48 months | Change in total cholesterol from baseline (mmol/L) |
| Change in triglycerides | Change during study period; assessment at baseline, 12, 24, 36 and 48 months | Change in triglycerides from baseline (mmol/L) |
| Change in albuminuria | 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 | 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 | Change during study period; assessment at baseline, 12, 24, 36 and 48 months | Change in body weight (kg) |
| Change in BMI | Change during study period; assessment at baseline, 12, 24, 36 and 48 months | Change in BMI (kg/m2) |
| Health care costs | 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 | 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. | 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. |
Countries
Sweden
Contacts
PRINCIPAL_INVESTIGATORJan Eriksson, MD
Uppsala University
Outcome results
None listed