Table 1.
Mechanism of Action and Primary Effects of Different Glucose-Lowering Drugs Used in Patients Uncontrolled with Metformin8,42,60,61
| Drug class | Examples of drugs approved in the US | Administration and timing of dose | Primary MOA for glucose lowering | Primary effects for glucose lowering |
|---|---|---|---|---|
| Not sensitive to plasma glucose concentrations | ||||
| Sulfonylurea | Glibenclamide, glimepiride, glipizide, gliclazide | Oral; Once or twice daily | Increase insulin secretion | Target FPG, with resultant lowering of PPG |
| Thiazolidinedione | Pioglitazone, rosiglitazone | Once daily | Enhance insulin sensitivity; reduce free fatty acid release | Target FPG, with resultant lowering of PPG |
| Basal insulin and intermediate insulin | Insulin glargine, insulin detemir, insulin degludec, insulin NPH | SC injection; Once or twice daily | Exogenous insulin replacement | Target FPG, with resultant lowering of PPG |
| Rapid-acting insulin | Insulin aspart, insulin lispro, insulin glulisine | SC injection; Up to three times daily at mealtime | Exogenous insulin replacement | Target PPG, with resultant lowering of overall glucose |
| Glucose-dependent MOA | ||||
| α-Glucosidase inhibitors | Acarbose, miglitol | Oral; Up to three times daily at mealtime | Inhibit carbohydrate digestion in the small intestine and delay its absorption | Target PPG, with resultant lowering of overall glucose |
| SGLT-2 inhibitors | Dapagliflozin, canagliflozin, empagliflozin | Oral; Once daily | Increase urinary glucose secretion | Target FPG and PPG |
| DPP-4 inhibitors | Saxagliptin, sitagliptin, linagliptin, alogliptin | Oral; Once or twice daily | Increase circulating levels of incretins (e.g., GLP-1 and GIP) to increase insulin secretion and suppress glucagon secretion | Target PPG and lower overall glucose |
| Short-acting GLP-1RAs | Exenatide BID, lixisenatide QD | SC injection; Once or twice daily at mealtime | Stimulate GLP-1R to increase insulin secretion and suppress glucagon secretion | Target PPG and FPGa |
| Longer-acting GLP-1RAs | Liraglutide QD, exenatide QW, dulaglutide QW, albiglutide QW | SC injection; Once daily (liraglutide) or once weekly | Stimulate GLP-1R to increase insulin secretion and suppress glucagon secretion | Target FPG and PPGa |
a
Short-acting GLP-1RAs result in greater reductions in PPG versus longer-acting GLP-1RAs, whereas longer-acting GLP-1RAs result in greater reductions in FPG versus short-acting GLP-1RAs.
BID, twice daily; DPP-4, dipeptidyl peptidase-4; FPG, fasting plasma glucose; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1; GLP-1RA, glucagon-like peptide-1 receptor agonist; MOA, mechanism of action; NPH, neutral protamine Hagedorn; PPG, postprandial glucose; QD, once daily; QW, once weekly; SC, subcutaneous; SGLT-2, sodium–glucose cotransporter 2.