Background and aims: Drastic weight lowering strategies (metabolic surgery, very low calorie diet) can achieve remission of type 2 diabetes (T2DM). Oral anti-T2DM drugs featuring glucose-, but modest or no weight-lowering action have provided mixed results. However, none of them entailed the simultaneous use of four agents, targeting different facets of T2DM pathophysiology. Our aim was to assess the incremental efficacy of a four-drug (POLYCHEM: metformin 2000 mg/day + pioglitazone 30 mg/day + sitagliptin 100 mg/day + empagliflozin 10 mg/day) regimen vs standard diabetes care (SDC) in inducing remission in patients with newly diagnosed T2DM. Materials and methods: A multicenter, open label, pragmatic, phase III, randomized clinical trial (NCT04271189) was performed in 6 Diabetes Outpatient Clinics. Major inclusion criteria were age 35-75 years, HbA1c<11.0% (97 mmol/mol), fasting C-peptide>0.3 nmol/l, GAD-antibody negative. Patients with newly diagnosed T2DM were randomized (visit 1) to receive POLYCHEM or SDC for 16 weeks, after which, if there was regression of diabetes hyperglycemia (visit 2), drug therapy was suspended. Primary end-point was T2DM remission (HbA1c<48 mmol/mol) assessed at least 12 weeks (visit 3) after ceasing any glucose-lowering pharmacotherapy. Secondary outcomes are not included in this report. Continuous variables are presented as mean±SEM. Results: Between October 2020 and July 2023, 108 patients (80% males, age: 58±0.99 y/o, HbA1c 49.8±1.3) were enrolled in the study, of whom 60 were randomized to POLYCHEM and 48 to SDC treatment. Five participants were lost to follow-up. Body weight was 89.5±2.2 vs 90.0±2.0, 87.7±2.2 vs 87.0±1.9, and 89.6±2.5 vs 87.6±2.2 kg in POLYCHEM vs SDC at visit 1, 2, and 3, respectively (p<0.06 POLYCHEM vs SDC at visit 3). In the SDC arm, 2 (4.2%), 19 (39.6%), 21 (43.8%) and 6 (12.5%) patients were put on no, 1, 2, and 3 drug regimens, respectively. After 16 weeks, 33 (55.0%) and 25 (52.1%) patients achieved regression of diabetic hyperglycemia in the POLYCHEM and SDC arm, respectively. At visit 3, 23 (38.3%) and 21 (43.8%) patients achieved T2DM remission in the POLYCHEM and SDC arm, respectively (p=0.57). Conclusion: A four-drug regimen with modest weight-lowering effect is not superior to current SDC in achieving remission in patients with newly diagnosed T2DM. Current SDC by diabetes specialists may achieve higher rates of T2DM remissions than previously reported, possibly due to early use of multidrug regimens.