To Örebro University

Background: Metformin is generally recommended as 1 st line medication in T2D. However, there is no compelling evidence of its superiority in preventing diabetes complications. SGLT2 inhibitors prevent cardiovascular mortality, heart failure and renal impairment in T2D patients at high cardiovascular risk.

Aim: To assess whether an SGLT2 inhibitor is superior to metformin in preventing organ complications and premature death in early-stage T2D.

Method: The SMARTEST study (SGLT2 inhibitor or Metformin As standaRd Treatment of Early Stage Type 2 diabetes) is a registry-based trial in primary care. Participants are included via on-site or video visits at 31 centers across Sweden; T2D <4 yr; drugnaïve (currently 31%) or montherapy; no cardiorenal diseases. Randomizaton 1:1, open label metformin (individualized dose) or dapagliflozin 10 mg/day. Diet, exercise and other medications are stipulated according to national guidelines. Patients are followed 2–6 yrs.

Endpoints are collected using NDR and the national Patient Registry. The study will close when 844 primary endpoint events have occurred, giving 90% power to detect a HR of 0.8 for dapagliflozin vs metformin. Primary composite endpoint: time to death, myocardial infarction, stroke, heart failure or appearance/progression of microvascular complications (retinopathy, nephropathy, diabetic foot lesions). Other endpoints include: need for insulin therapy; blood pressure, BMI, HbA1c, PROM and health economy.

Results: From late 2019 until May 2022 1100 patients are included. 38% are females, mean age is 60 years and HbA1c 46.5 mmol/mol (6.4%). So far, the primary endpoint event rate is 11/100 patient years (PY), whereas 7/100 PY was estimated from previous data. Nephropathy and foot-at-risk had high rates (6 and 3/100 PY) but MACE was rare (1/100 PY). The recruitment target is 2700 participants, expected by end 2023.

Conclusion: Final results are expected in 2025 and can challenge or, equally important, reinforce the current metformin paradigm in early T2D. Event rates are higher than previously recognized for nephropathy and diabetic foot problems but lower for MACE.