Aims To investigate the effects of glucose‐lowering agents on all‐cause mortality, and cardiovascular and renal outcomes in adults with type 2 diabetes. Methods A MEDLINE and EMBASE search was performed to identify randomized controlled trials, published up to 28 February 2022, with a follow‐up ≥52 weeks, in which glucose‐lowering drugs were compared with either placebo or active comparators. We included only trials reporting formal external adjudication of events. All‐cause mortality, 3‐point MACE (major cardiovascular events), and hospitalization for heart failure (HHF) were considered as principal outcomes. Doubling of serum creatinine, worsening albuminuria, and renal death were considered as secondary endpoints. Results We included randomized controlled trials performed on metformin (n = 17), pioglitazone (n = 20), alpha‐glucosidase inhibitors (n = 9), insulin secretagogues (n = 42), dipeptidyl‐peptidase‐4 inhibitors (n = 67), glucagon‐like peptide‐1 receptor agonists (n = 45) or sodium‐glucose co‐transporter‐2 inhibitors (SGLT‐2i; n = 42) and insulin (n = 18). Glucagon‐like peptide‐1 receptor agonist and SGLT‐2i were associated with a significant reduction in all‐cause mortality [Mantel‐Haenszel odds ratio (MH‐OR), 95% confidence interval: 0.88 (0.83; 0.95) and 0.85 (0.79; 0.91), respectively] and MACE [MH‐OR, 95% confidence interval: 0.89 (0.84; 0.94) and 0.90 (0.84; 0.96), respectively]. SGLT‐2i was associated with a reduced risk of HHF [MH‐OR 0.68 (0.62; 0.75)], worsening albuminuria [MH‐OR 0.67 (0.55; 0.80)] and doubling of serum creatinine [MH‐OR 0.58 (0.44; 0.79)]. Metformin and pioglitazone were associated with a significantly lower risk of MACE [MH‐OR 0.60 (0.47; 0.80) and 0.85 (0.74; 0.97), respectively] and pioglitazone with a higher risk of HHF [MH‐OR 1.30 (1.04; 1.62)]. Insulin secretagogues were associated with increased risk of all‐cause mortality [MH‐OR 1.12 (1.01; 1.24)] and MACE [MH‐OR 1.19 (1.02; 1.39)]. Conclusions The results of this updated meta‐analysis need to be considered in the choice of drug treatment for type 2 diabetes mellitus, which cannot be merely based on the effect of glucose‐lowering drugs on long‐term glycaemic control.

Aim: This guideline is aimed at providing a reference for the pharmacological and non-pharmacological treatment of type 2 diabetes in adults.Methods: These recommendations apply to outpatients, either in primary care or at specialist referral. Prior cardiovascular events, heart failure, renal disease, hypoglycemic risk and other conditions affecting life expectancy have been considered as factors capable of modifying treatment strategies. The following areas have been assessed: therapeutic goals, nutritional therapy, physical exercise, educational programs, pharmacological treatment, glucose monitoring. This guideline has been developed following the methods described in the Manual of the National Guideline System (http:// www. snlg-iss. it). For each question, the panel nominated by the Società Italiana di Diabetologia (SID) and Associazione Medici Diabetologi (AMD) identified potentially relevant outcomes, which were then rated for their impact on therapeutic choices. Only outcomes classified as "critical" were considered in the systematic review of evidence and in the formulation of recommendations. Results:The present guideline contains recommendations on the following clinical aspects of type 2 diabetes: 1) treatment targets; 2) nutritional therapy; 3) physical exercise; 4) educational therapy; 5) pharmacological treatment (for patients with and without previous cardiovascular disease); and 6) glycemic monitoring. Conclusions:The present guideline is directed to physicians, nurses, dietitians and educators working in Diabetes specialist clinics; general practitioners; nurses and dietitian working in territorial services or private offices; and patients with diabetes.

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