Problem Is the problem a priority?
Judgment	Research evidence	Additional considerations
Yes	Specific recommendations for patients with prior cardiovascular events are provided by some guidelines23−26. The absolute risk of cardiovascular events and all-cause mortality is particularly increased in patients with type 2 diabetes and established cardiovascular disease. The risk reduction observed with some classes of drugs for diabetes could therefore produce very relevant benefits in this subset of patients with diabetes
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 MACE28.: Metformina: − 40%; GLP-1 RA: − 11%; SGLT-2i: − 15% Pioglitazone: − 15% SU/insulin secretagogues: + 19% Overall effects of different classes on hospitalization for heart failure 28 SGLT-2i: − 10% Pioglitazoine: + 30% Overall effects of different classes on all-cause mortality 28 : GLP-1 RA: − 12%; SGLT-2i: − 15%; Sulfonylureas: + 12% Quality of life GLP-1RA is associated with improved quality of life in comparison with DPP-4 inhibitors or insulin28	MACE: no trial was found for alpha-glucosidase inhibitors
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 (pioglitazone and sulfonylureas); 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
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 favors 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 drug used; comprehensive network meta-analysis exploring the economic implication of the different approaches are lacking, if we consider the large availability of options
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 guidelines23−26
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 prescribed, despite being less frequently than in the last years