Epidemiologic, social and economic burdens of type 2 diabetes mellitus (T2DM) keep rising worldwide. Implementation of T2DM preventive trategies is lagging behind. Metabolic surgery, very low calorie diet can induce T2DM remission, but so far for few patients. The investigators will assess the efficacy to cause T2DM remission (primary end point) and direct costs to the National Health System of a 4-month polychemotherapy (metformin+pioglitazone+sitagliptin+empagliflozin) regimen vs standard care in patients with newly diagnosed T2DM by an open label, pragmatic RCT. Mechanisms of action will be investigated in a sub-cohort by a prolonged OGTT plus dual tracer technique and modeling of beta cell function.

If proved efficacious in this proof-of-concept study and inducer of durable remission in the future, T2DM polychemotherapy will turn out to be a convenient, relatively unexpensive strategy to restrain prevalence of T2DM and its complications and to alleviate its personal, social and economic burden.

Hypothesis: at diagnosis of T2DM, a 4 month course of oral polychemotherapy (POLYCHEM), by engaging multiple glucose lowering mechanisms, results into euglycemia and, after suspension, in T2DM remission in a clinically significant higher number of patients when compared to standard diabetes care (SDC).

• Diabetes remission: simultaneous nondiabetic values of fasting glucose, 2-hour glucose (after OGTT) and HbA1c for at least 12 months with no pharmacologic/surgical treatment of diabetes.
• Complete remission: all values of fasting glucose, 2-hour glucose and HbA1c are within the limits of normal glucose regulation; otherwise, remission is partial.
• Hyperglycemia remission as in diabetes remission, but duration<12 months.

Based on the "Consensus Report: Definition and Interpretation of Remission in Type 2 Diabetes" published on Diabetes Care 2021;44(10):2438-2444, remission should be defined as a return of HbA1c to <6.5% (<48 mmol/mol) that occurs spontaneously or following an intervention and that persists for at least 3 months in the absence of usual glucose-lowering pharmacotherapy.

A POLYCHEM (metformin, pioglitazone, sitagliptin and empagliflozin) will be used to improve:

1. Insulin sensitivity of endogenous glucose output (EGO) and peripheral (muscle) glucose uptake (PGU);
2. Beta cell function;
3. GLP-1 and GIP bioavailability. To these effects, the direct glycosuric action of EMPA is added; EMPA effects on alpha cell and liver (increased glucagon secretion and EGO), may be, at least in part, counterbalanced by SITA and MET/PIO, respectively. Increased heart failure events with PIO may be, at least in part, counteracted by EMPA.

In many patients POLYCHEM should result in stable euglycemia, with negligible risk of hypoglycemia, and the number of patients in T2DM remission should be much higher than with MET+SU. The underpinning is that euglycemia reverses the detrimental effects of glucose toxicity and glucose regulation can be maintained in the nondiabetic range.

If the invesigators hypothesis is proved, POLYCHEM would be a convenient, simple and relatively unexpensive strategy to induce remission in a great number of patients with newly diagnosed T2DM. Novel, more efficacious goals of therapy could be introduced. Duration of remission is expected to delay the processes which result into the T2DM related risk of tissue damage. At the patient acceptance level, the trade off between the full T2DM burden (diabetes, its care and the risk of its complications) and the risk of T2DM relapse should favor the latter. At the society level, achieving a durable remission in a substantial number of these patients should attenuate, or even annull, the rises in prevalence, burden and tolls of "active" T2DM.

Patients with newly diagnosed (i.e. less than 6 months) T2DM will be recruited in the Diabetes Outpatient Clinics and will provide informed written consent before participation. After a screening visit (V0), patients will be randomized 1:1, with center stratification through web-based data collection (eCRF), to receive POLYCHEM or SDC with standard lifestyle intervention in both.

In both arms, patients will undergo planned visits at week 0 (V1), week 16 (V2), and week 28 (V3), after at least 3 days of drug washout. Patients will perform weekly a 6-point home blood glucose profile. Between week 17 and week 28, if a patient in hyperglycemia remission relapses, V3 will be anticipated (V3B), after which the patient will be treated as in SDC and will be re-evaluated at week 28 .

Visit procedures:

• V0: assessment of patient eligibility , including medical history, physical examination, and lab exams, if needed.
• V0S: between V0 and V1; signature of informed written consent and randomization.
• V1, V2, V3 and V3B: assessment of anthropometry, ambulatory blood pressure and heart rate, WBC, fasting glucose, HbA1c, lipids, AST, ALT, creatinine, lipase, urine analysis, microalbuminuria, insulin, C-peptide, glucagon, GLP-1, GIP, quality of life (QoL), and, only in V1, blood for DNA collection (the last for post hoc studies).

POLYCHEM-ARM: After V1, patients will start POLYCHEM (MET titrated to 1000 mg b.i.d., PIO 15 mg b.i.d., SITA 100 mg q.d., EMPA 10 mg q.d.) for 16 weeks, at the end of which (V2) patients in hyperglycemia remission stop drug therapy, the others are transferred to SDC. Patients with MET intolerance will be treated with PIO+SITA+EMPA only.

SDC-ARM: After V1, patients will continue their SDC for 16 weeks, at the end of which (V2) patients in hyperglycemia remission stop drug therapy, the others continue SDC.

Inclusion criteria:

• Age 35-75 years;
• HbA1c <= 10.0% (86 mmol/mol);
• T2DM diagnosis (< 6 months)
• BMI>=23 and <=40 kg/m2
• Fasting C-peptide > 0.3 nmol/l;
• GAD-antibody negative.

Exclusion criteria:

• Diagnosis of type 1 diabetes;
• History of cancer in the previous 5 years;
• Multiple daily insulin treatment;
• Acute cardiovascular event within the previous 6 months;
• Chronic heart failure;
• eGFR < 45 ml.min-1.1.73 m2 according to the MDRD formula;
• Women of child bearing potential with no use of acceptable contraception;
• Presence of diabetic retinopathy;
• Contraindications to the use of any drug of POLYCHEM.