What are the classes of antidiabetic medications?

Classes of Antidiabetic Medications

Antidiabetic medications are organized into several distinct classes based on their mechanisms of action: biguanides, sulfonylureas, thiazolidinediones (TZDs), glinides (meglitinides), α-glucosidase inhibitors, DPP-4 inhibitors, GLP-1 receptor agonists, SGLT2 inhibitors, and insulin. 1

Biguanides

• Metformin is the only biguanide currently recommended for clinical use and serves as the preferred initial pharmacologic agent for type 2 diabetes. 1
• Metformin reduces blood glucose primarily by decreasing hepatic glucose production and increasing peripheral tissue insulin sensitivity without stimulating pancreatic insulin secretion. 1, 2
• The medication reduces HbA1c by approximately 1.0-1.5% and does not cause hypoglycemia when used alone. 1
• Common adverse effects include mild, transient gastrointestinal symptoms (abdominal distension, flatulence) that can be minimized by starting with low doses and gradual titration. 1
• Metformin is inexpensive, has long-established efficacy and safety data, and may reduce cardiovascular events and death. 1
• The drug can be continued in patients with declining renal function down to a GFR of 30-45 mL/min, though dose reduction is required. 1

Sulfonylureas (Insulin Secretagogues)

• Sulfonylureas stimulate insulin secretion from pancreatic β-cells and are effective in reducing HbA1c by 0.7-1.0%. 1
• Available agents in various markets include gliburide (glibenclamide), glimepiride, gliclazide, glipizide, and gliquidone. 1
• The primary risk is hypoglycemia, particularly in elderly patients and those with liver or kidney dysfunction. 1
• Sulfonylureas commonly cause weight gain. 1
• Patients with mild renal insufficiency should use gliquidone, which has safer renal clearance. 1

Thiazolidinediones (TZDs)

• TZDs decrease blood glucose by increasing target cell sensitivity to insulin action. 1
• Available agents include rosiglitazone and pioglitazone, which reduce HbA1c by 0.7-1.0%. 1
• TZDs do not cause hypoglycemia when used alone but increase hypoglycemia risk when combined with insulin or insulin secretagogues. 1
• Common adverse effects include weight gain and edema, which are more pronounced when combined with insulin. 1
• TZD use correlates with increased risk of bone fractures and heart failure. 1
• Contraindications include heart failure (NYHA class II and above), active liver disease, transaminase elevations exceeding 2.5 times the upper limit of normal, and severe osteoporosis. 1

Glinides (Meglitinides/Non-Sulfonylurea Insulin Secretagogues)

• Available agents include repaglinide, nateglinide, and mitiglinide. 1
• Glinides reduce postprandial blood glucose by stimulating early-phase insulin secretion and lower HbA1c by 0.5-1.5%. 1
• These medications must be taken immediately before meals and can be used separately or in combination with other antidiabetic agents. 1
• The risk and degree of hypoglycemia are lower with glinides than with sulfonylureas. 1
• Glinides can be safely used in patients with renal insufficiency. 1
• Common adverse effects include hypoglycemia and weight gain. 1

α-Glucosidase Inhibitors

• α-Glucosidase inhibitors reduce postprandial blood glucose by inhibiting carbohydrate absorption in the upper small intestine. 1
• Available agents include acarbose, voglibose, and miglitol. 1
• These medications are particularly suitable for patients who consume carbohydrates as their main food ingredient and experience postprandial hyperglycemia. 1
• Acarbose 300 mg/day demonstrates hypoglycemic effects similar to metformin 1500 mg/day in newly diagnosed patients. 1
• Common adverse reactions are gastrointestinal (abdominal distension, flatulence), which can be reduced by starting with small doses and gradually increasing. 1
• The risk of hypoglycemia is very low when used alone. 1
• When hypoglycemia occurs in patients using α-glucosidase inhibitors, glucose or honey must be used for treatment—dietary sucrose and starchy foods have poor ability to correct hypoglycemia. 1

DPP-4 Inhibitors (Dipeptidyl Peptidase-4 Inhibitors)

• DPP-4 inhibitors increase endogenous GLP-1 levels by reducing GLP-1 deactivation through DPP-4 inhibition. 1, 3
• GLP-1 enhances insulin secretion and inhibits glucagon secretion in a glucose-dependent manner. 1
• Available agents include sitagliptin, saxagliptin, vildagliptin, linagliptin, and alogliptin. 1
• These medications reduce HbA1c by 0.4-0.9%. 1, 3
• DPP-4 inhibitors have minimal hypoglycemia risk when used as monotherapy due to their glucose-dependent mechanism. 4, 3
• The medications are generally weight-neutral. 3
• Saxagliptin and alogliptin have been associated with increased heart failure hospitalization risk and should be avoided in patients with heart failure. 3
• Most DPP-4 inhibitors require dose adjustment in renal impairment, except linagliptin. 3

GLP-1 Receptor Agonists (Glucagon-Like Peptide-1 Receptor Agonists)

• GLP-1 receptor agonists stimulate insulin secretion and inhibit glucagon secretion in a glucose-dependent manner. 4
• These medications have minimal hypoglycemia risk when used as monotherapy due to their glucose-dependent action on both insulin and glucagon. 4
• In the LEADER trial, liraglutide produced a 20% reduction in confirmed hypoglycemia and 31% reduction in severe hypoglycemia compared to placebo. 4
• GLP-1 receptor agonists reduce severe hypoglycemia compared with sulfonylureas and insulin. 4
• When combined with insulin or insulin secretagogues (particularly sulfonylureas), the risk of hypoglycemia increases significantly. 4
• Short-acting agents (exenatide twice-daily, lixisenatide) have greater effects on postprandial glucose, while long-acting agents (dulaglutide, semaglutide, exenatide extended-release) have more pronounced effects on fasting glucose. 4

SGLT2 Inhibitors (Sodium-Glucose Cotransporter-2 Inhibitors)

• SGLT2 inhibitors are recommended as combination therapy options with metformin for type 2 diabetes. 1
• These medications work through an insulin-independent mechanism. 5
• SGLT2 inhibitors offer additional benefits of weight loss and reduced cardiovascular risk in patients with established cardiovascular disease. 5
• SGLT2 inhibitors provide minimal glycemic effect when eGFR falls below 30 mL/min/1.73 m² and are contraindicated in dialysis patients. 3

Insulin

• Insulin therapy is eventually indicated for many patients with type 2 diabetes due to the progressive nature of the disease. 1
• For type 1 diabetes, patients should use insulin analogues to reduce hypoglycemia risk. 1
• Initial insulin therapy should be considered when blood glucose levels are ≥300-350 mg/dL and/or HbA1c levels are 10-12%, especially if symptomatic or catabolic features are present. 1
• Basal insulin options include neutral protamine Hagedorn (NPH), glargine, detemir, and degludec. 1
• Rapid-acting insulin analogs can be administered immediately before, during, or after meals, providing flexibility compared to regular insulin which requires 30-45 minute pre-meal administration. 1