Problem Is the problem a priority?
Judgment	Research evidence	Additional considerations
Yes	Different guidelines propose different algorithms for the pharmacological treatment of type 2 diabetes. Many guidelines recommend metformin as first-line agents, but others prefer other agents in the majority of patients23−26. Recommendations on second- and third-line therapies are also heterogeneous23−26 The preference for a drug over another depends on its safety and tolerability, as well as its efficacy. Some side effects (e.g., weight gain, hypoglycemia, and gastrointestinal effects) are common with some glucose-lowering drugs. Those adverse effects, together with the complexity and potential burdens of therapy, may affect patients’ quality of life. In addition, several drugs have been shown renal and cardiovascular and/or nefro-protective effects. All those factors should be considered when selecting a drug, or a combination of drugs, for the treatment of an individual patient
Desirable Effects How substantial are the desirable anticipated effects?
Judgment	Research evidence	Additional considerations
Varies	Effects of different classes of drugs, as reported in direct comparisons27 (only statistical significant results are reported): 52-week HbA1c: compared to metformin GLP-1 RA: − 0.2% Acarbose: + 0.4% 104-week HbA1c: compared to metformin SGLT-2i: − 0.2% Sulfonylureas: + 0.1% Insulin: + 0.4% Overall effects of different classes on MACE 28 : Metformina: − 40%; GLP-1 RA: − 11%; SGLT-2i: − 10% Pioglitazone: − 15% Insulino-secretagogues/SU: + 19% Overall effects of different classes on all-cause mortality: GLP-1 RA: − 12%; SGLT-2i: − 15%; Sulfonylureas: + 11%. Despite the increased risk of mortality did not reach statistical significance in any of the trials considered, the overall mortality (combining all the trials using a meta-analytical approach) for sulfonylureas was higher in comparison with placebo/other classes Quality of life GLP-1RA are associated with improved quality of life in comparison with DPP-4 inhibitors or insulin	The effects on MACE and all-cause mortality derive from RCTs performed on patients with previous cardiovascular events
Undesirable Effects How substantial are the undesirable anticipated effects?
Judgment	Research evidence	Additional considerations
Varies	Severe hypoglycemia: Sulphonylureas increase the risk of hypoglycemia (OR: 2.7) in comparison with metformin27	Metformin: gastrointestinal side effects; rare cases of lactic acidosis Alpha-glucosidase inhibitors: gastrointestinal side effects Sulfonylureas: weight gain; hypoglycemia Pioglitazone: fluid retention; weight gain; heart failure; bone fracture DPP-4 inhibitors: suspected pancreatitis; rare cases of pemphigoid GLP-1RA: gastrointestinal side effects; cholelithiasis; pancreatitis SGLT-2 inhibitors: genito-urinary infections; rare keto-acidosis Insulin: hypoglycemia and weight gain
Certainty of evidence What is the overall certainty of the evidence of effects?
Judgment	Research evidence	Additional considerations
Moderate	High for MACE (with the exception of insulin: moderate); Moderate for all the other clinical outcomes
Values Is there important uncertainty about or variability in how much people value the main outcomes?
Judgment	Research evidence	Additional considerations
No important uncertainty or variability	No evidence of variability or uncertainty HbA1c, body weight, severe hypoglycemia, macrovascular complications, and mortality are already considered among critical outcomes of the treatment of type 2 diabetes by scientific societies23, 26, 29
Balance of effects Does the balance between desirable and undesirable effects favor the intervention or the comparison?
Judgment	Research evidence	Additional considerations
Varies	The balance of effects favor metformin, GLP-1 RA, and SGLT-2i over other classes of drugs, whereas it is unfavorable for sulfonylureas
Resources required How large are the resource requirements (costs)?
Judgment	Research evidence	Additional considerations
Varies	Low for metformin, pioglitazone, sulfonylureas, acarbose Moderate for other classes, higher for GLP-1RA and insulin	Some bioequivalent molecules could reduce direct costs for the most expensive approaches (i.e., insulin and GLP-1RA)
Certainty of evidence of required resources What is the certainty of the evidence of resource requirements (costs)?
Judgment	Research evidence	Additional considerations
High	Several good-quality studies explored this issue
Cost-effectiveness Does the cost-effectiveness of the intervention favor the intervention or the comparison?
Judgment	Research evidence	Additional considerations
Varies	The cost-effective evaluation depends on the form of the drug used
Equity What would be the impact on health equity?
Judgment	Research evidence	Additional considerations
Probably no impact	Drugs recommended in the present guideline are already considered as first- and second-line treatments for patients without previous cardiovascular events in the principal guidelines23, 24, 26, 29
Acceptability Is the intervention acceptable to key stakeholders?
Judgment	Research evidence	Additional considerations
Probably yes	No specific evidence is available on this issue
Feasibility Is the intervention feasible to implement?
Judgment	Research evidence	Additional considerations
Probably yes	A large part of patients with type 2 diabetes in Italy is already treated with metformin, whereas GLP-1 RA and SGLT-2i are still relatively underutilized and sulfonylureas still prescribed23, 26, 29