Type 2 diabetes: drug selection

ADA2026

Choose the glucose-lowering drug by the person's heart and kidney comorbidities and goals first, through shared decision-making (grade E). Without such considerations, metformin (effective, safe, inexpensive, and linked to fewer microvascular and cardiovascular events and deaths) is commonly used and has historically been first-line. The largest A1c reductions come with insulin, select GLP-1 receptor agonists (particularly semaglutide), and tirzepatide; DPP-4 inhibitors lower A1c the least.

ADA2026

With established or high-risk atherosclerotic cardiovascular disease, include a GLP-1 receptor agonist and/or an SGLT2 inhibitor that has proven cardiovascular benefit, chosen for cardiovascular risk reduction irrespective of A1c and with or without metformin (grade A). The two classes give additive cardiovascular and kidney benefit and can be combined.

ADA2026

Heart failure, reduced or preserved ejection fraction: an SGLT2 inhibitor is preferred, for glycemic control and fewer heart-failure hospitalizations, irrespective of A1c (grade A). Chronic kidney disease (eGFR at least 20 mL/min/1.73 m2, or albuminuria): an SGLT2 inhibitor or a GLP-1 receptor agonist with proven benefit slows CKD progression and cuts cardiovascular events. Below an eGFR of 30 a GLP-1 receptor agonist may be considered for its lower hypoglycemia risk, and most can still be used at low eGFR for cardiovascular protection. Add finerenone (a nonsteroidal MRA) for CKD with albuminuria when eGFR is at least 25.

ADA2026

Consider initial combination therapy to reach goal faster, especially when A1c is 1.5 to 2 percent above target (grade A). Prefer GLP-1-based therapy over insulin as the first injectable when there is no severe hyperglycemia (grade A); start insulin if the person is symptomatic or A1c is over 10 percent or glucose is at least 300 mg/dL. When adding a drug, reassess sulfonylureas, meglitinides, and insulin to limit hypoglycemia. Favor weight-friendly agents (tirzepatide and semaglutide have the highest glucose and weight effect), and use insulin, sulfonylureas, and thiazolidinediones judiciously since they add weight. Do not combine a DPP-4 inhibitor with a GLP-1 receptor agonist.

ACP2024Grade Strong recommendation, high-certainty evidence

When glycemic control is inadequate on metformin plus lifestyle, add an SGLT2 inhibitor or a GLP-1 agonist. Choose an SGLT2 inhibitor to lower all-cause mortality, major adverse cardiovascular events, CKD progression, and heart failure hospitalization; choose a GLP-1 agonist to lower all-cause mortality, major adverse cardiovascular events, and stroke. Do not add a DPP-4 inhibitor to reduce morbidity and all-cause mortality (strong against).