Version July 2025
| Intervention | Expected decrease in A1C with monotherapy (%) | Advantages | Disadvantages |
| Initial therapy | |||
| Lifestyle change to decrease weight and increase activity | 1 to 2 | Broad benefits | May be insufficient for most within first year due to limited adherence, inadequate weight loss, and/or weight regain |
| Metformin | 1 to 2 | Weight loss to weight neutral, low cost, low risk of hypoglycemia, generally well tolerated, well-studied in combination with other agents | GI side effects, contraindicated with impaired kidney function (eGFR <30 mL/min/1.73 m2)* |
| Additional therapy¶ | |||
| Insulin (usually with a single daily injection of intermediate- or long-acting insulin initially) | 1.5 to 3.5 | No dose limit, rapidly effective, improved lipid profile | Hypoglycemia, may require more than 1 daily injection, requires home glucose monitoring, weight gain, analogs are expensive |
| Dual GLP-1 and GIP receptor agonist (once-weekly injections) | 2 to 2.5 | Weight loss | Requires injection, frequent GI side effects, very expensive |
| GLP-1 receptor agonist (oral or daily to weekly injections) | 0.5 to 2 | Weight loss, reduction in major adverse cardiovascular events (liraglutide, subcutaneous semaglutide, dulaglutide) in patients with established CVD and at high risk for CVD | Most agents require injection, frequent GI side effects, very expensive |
| SGLT2 inhibitor | 0.5 to 0.7 | Weight loss, reduction in systolic blood pressure, reduced heart failure and cardiovascular mortality, improved kidney outcomes in patients with nephropathy | Mycotic genital infection, DKA; SGLT2 inhibitors have also been associated with urinary tract infections, bone fractures, and lower limb amputations |
| Sulfonylurea (shorter-acting agents preferred) | 1 to 2 | Rapidly effective | Hypoglycemia (especially with glyburide/glibenclamide or chlorpropamide), weight gain |
| Glinide | 0.5 to 1.5Δ | Rapidly effective | Hypoglycemia, weight gain, may require 3 times daily dosing |
| Pioglitazone | 0.5 to 1.4 | Improved lipid profile, potential decrease in MI and stroke | Fluid retention, HF, weight gain, bone fractures, and bladder cancer; side effects minimized at doses of 15 to 30 mg |
| DPP-4 inhibitor | 0.5 to 0.8 | Weight neutral | Possible increased risk of HF with saxagliptin, expensive |
| Alpha-glucosidase inhibitor | 0.5 to 0.8 | Weight neutral | Frequent GI side effects limit use, 3 times daily dosing |
A1C: glycated hemoglobin; CVD: cardiovascular disease; DKA: diabetic ketoacidosis; DPP-4: dipeptidyl peptidase 4; eGFR: estimated glomerular filtration rate; GI: gastrointestinal; GIP: glucose-dependent insulinotropic polypeptide; GLP-1: glucagon-like peptide 1; HF: heart failure; MI: myocardial infarction; SGLT2: sodium-glucose cotransporter 2.
* Initiation is contraindicated with eGFR <30 mL/min/1.73 m2 and not recommended with eGFR 30 to 45 mL/min/1.73 m2.
¶ The order of listing of additional therapies does not indicate a preferred order of selection. The choice of additional therapy should be based on criteria discussed in the UpToDate topics on the management of hyperglycemia in diabetes mellitus.
Δ Repaglinide is more effective in lowering A1C than nateglinide.With additional data from:
