Oral polychemotherapy to induce remission in newly diagnosed type 2 diabetes: a pragmatic, multicenter, randomized controlled trial

Objectiveto assess the incremental efficacy of a four-drug (POLYCHEM: metformin/pioglitazone/sitagliptin/empagliflozin) regimen vs standard diabetes care (SDC) in inducing remission in patients with newly diagnosed type 2 diabetes. Research Design and MethodsA multicenter, open-label, pragmatic, phase III, randomized clinical trial was conducted in 6 Italian Diabetes Outpatient Clinics. Major inclusion criteria were age 35-75 years, HbA1c <10% (97 mmol/mol), fasting C-peptide >0.3 nmol/l, GAD-antibody negative. Patients were randomized (visit 1) to receive POLYCHEM or SDC for 16 weeks, after which, if there was regression of diabetic hyperglycemia (visit 2), drug therapy was suspended. The primary endpoint was remission (HbA1c < 6.5 %; 48 mmol/mol) assessed at least 12 weeks (visit 3) after ceasing any glucose-lowering pharmacotherapy. Results108 patients (80% males, age: 58{+/-}9 yrs), were enrolled in the study, of whom 60 were randomized to POLYCHEM and 48 to SDC treatment. After 16 weeks, 54 (90.0%) and 37 (77.1%) patients achieved regression of diabetic hyperglycemia in the POLYCHEM and SDC arm, respectively (p=0.002). At visit 3, 23 (38.3%) and 21 (43.8%) patients achieved diabetes remission in the POLYCHEM and SDC arm, respectively (p=0.59). The difference between the upper 95% CI in POLYCHEM (50.9%) and the lower 95% CI in SDC (30.4%) of diabetes remission was 20.5%. ConclusionA four-drug regimen with minimal to null weight-lowering effect is not superior to current SDC in achieving remission in patients with newly diagnosed type 2 diabetes. If a superiority of POLYCHEM over SDC exists, it is expected to be less than 21%. Trial registrationClinicalTrials.gov number: NCT04271189