What are the mechanisms of action and typical dosing of the oral and injectable medications used to treat type 2 diabetes mellitus in adult patients after lifestyle therapy?

Mechanisms of Action of Diabetic Medications for Type 2 Diabetes

After lifestyle therapy fails, select pharmacologic agents based on their distinct mechanisms targeting insulin resistance, impaired insulin secretion, or excessive hepatic glucose production, with metformin as first-line and SGLT2 inhibitors or GLP-1 receptor agonists as preferred second agents when cardiovascular or renal disease is present. 1

Primary Mechanisms by Drug Class

Metformin (Biguanide)

• Reduces hepatic glucose production by decreasing gluconeogenesis in the liver, which addresses the primary defect causing fasting hyperglycemia in type 2 diabetes 2, 3, 4
• Improves insulin sensitivity in liver and muscle tissue without directly affecting pancreatic β-cell function 2
• Does not cause hypoglycemia when used alone and is weight-neutral with chronic use 3, 4
• Typical dosing: Start 500 mg once or twice daily with meals, titrate up by 500 mg weekly to maximum 2000-2550 mg daily in divided doses 3

SGLT2 Inhibitors (Sodium-Glucose Cotransporter-2 Inhibitors)

• Block glucose reabsorption in the proximal renal tubules, increasing urinary glucose excretion by 100 g/day through an insulin-independent mechanism 2, 5
• Lower the renal threshold for glucose from ~240 mg/dL to 70-90 mg/dL 5
• Increase sodium delivery to the distal tubule, reducing intraglomerular pressure and providing cardiovascular and renal protection 5
• Typical dosing: Empagliflozin 10-25 mg once daily, dapagliflozin 10 mg once daily, or canagliflozin 100-300 mg once daily before first meal 3, 5
• Reduce HbA1c by 0.5-0.7% 6

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

• Enhance glucose-dependent insulin secretion from pancreatic β-cells while simultaneously inhibiting glucagon secretion 1
• Delay gastric emptying and reduce food intake through central appetite suppression 1
• Typical dosing: Semaglutide 0.25 mg subcutaneously weekly, titrate to 0.5-1.0 mg weekly; liraglutide 0.6 mg subcutaneously daily, titrate to 1.2-1.8 mg daily; dulaglutide 0.75-1.5 mg subcutaneously weekly 1, 6
• Reduce HbA1c by 1.0-1.5% with significant weight loss benefits 6

Dual GIP/GLP-1 Receptor Agonists

• Activate both glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptors, providing enhanced glycemic control and weight loss compared to GLP-1 agonists alone 1, 7
• Typical dosing: Tirzepatide 2.5 mg subcutaneously weekly, titrate up to 5-15 mg weekly 1

DPP-4 Inhibitors (Dipeptidyl Peptidase-4 Inhibitors)

• Prolong the action of endogenous incretin hormones (GLP-1 and GIP) by inhibiting their degradation, thereby enhancing glucose-dependent insulin secretion 3
• Weight-neutral with minimal hypoglycemia risk 3, 6
• Typical dosing: Sitagliptin 100 mg once daily, linagliptin 5 mg once daily 3, 6
• Reduce HbA1c by 0.5-1.0% 3, 6

Sulfonylureas

• Close ATP-sensitive potassium channels on pancreatic β-cells, causing membrane depolarization and calcium influx that triggers insulin release 3
• Cause modest weight gain (2-3 kg) and carry significant hypoglycemia risk 3
• Typical dosing: Glimepiride 1-8 mg once daily, glipizide 5-40 mg daily in divided doses 3
• Maximal glucose-lowering effect achieved at ~50% of maximum recommended dose 8

Thiazolidinediones (TZDs)

• Activate peroxisome proliferator-activated receptor-gamma (PPAR-γ) in adipose tissue and muscle, improving peripheral insulin sensitivity 2, 3
• Reduce insulin resistance without affecting insulin secretion 2
• Typical dosing: Pioglitazone 15-45 mg once daily 3
• Cause weight gain and fluid retention; avoid in heart failure 3, 6

Alpha-Glucosidase Inhibitors

• Inhibit intestinal enzymes that break down complex carbohydrates, slowing carbohydrate absorption and reducing postprandial glucose spikes 2, 3
• Typical dosing: Acarbose 25 mg three times daily with meals, titrate to 50-100 mg three times daily 3
• Primary side effects are gastrointestinal (flatulence, diarrhea) 3

Insulin

• Directly replaces or supplements endogenous insulin, promoting glucose uptake in muscle and adipose tissue while suppressing hepatic glucose production 1
• Initiate immediately when HbA1c >10%, fasting glucose ≥300 mg/dL, or symptoms of catabolism (unexpected weight loss) are present 1
• Typical dosing: Basal insulin (glargine, detemir, degludec) 10 units or 0.1-0.2 units/kg once daily, titrate by 2-4 units every 3 days based on fasting glucose 1

Clinical Selection Algorithm Based on Comorbidities

Patients with Heart Failure (HFrEF or HFpEF)

• Use SGLT2 inhibitor as primary glucose-lowering agent to prevent heart failure hospitalizations and reduce cardiovascular events 1

Patients with CKD (eGFR 20-60 mL/min/1.73m² or Albuminuria)

• Use SGLT2 inhibitor to minimize CKD progression, reduce cardiovascular events, and prevent heart failure hospitalizations 1
• Note: Glycemic benefits diminish at eGFR <45 mL/min/1.73m² 1

Patients with Advanced CKD (eGFR <30 mL/min/1.73m²)

• Prefer GLP-1 receptor agonist over SGLT2 inhibitor for glycemic management due to lower hypoglycemia risk and cardiovascular event reduction 1

Patients with Established ASCVD or High Cardiovascular Risk

• Use GLP-1 receptor agonist or SGLT2 inhibitor as these reduce all-cause mortality and major adverse cardiovascular events by 12-26% over 2-5 years 1, 7

Patients Without Cardiovascular or Kidney Disease

• Address both glycemic and weight goals when selecting agents 1
• Metformin remains first-line; add SGLT2 inhibitor, GLP-1 RA, or DPP-4 inhibitor based on weight goals 1, 3

Critical Pitfalls to Avoid

• Do not delay combination therapy when HbA1c ≥9% at diagnosis; early combination therapy shortens time to glycemic goal attainment 1, 3
• Avoid sulfonylureas in older adults, those with irregular meal patterns, or high hypoglycemia risk due to significant risk of severe hypoglycemia 1, 3
• Do not use metformin when eGFR <30 mL/min/1.73m², in acute illness predisposing to lactic acidosis, or in patients with alcoholism 3
• Monitor vitamin B12 levels periodically in patients on long-term metformin therapy 3
• Assess renal function before starting metformin or SGLT2 inhibitors and monitor periodically 3
• Educate patients on SGLT2 inhibitors about adequate hydration and genital hygiene to prevent genitourinary infections 6
• Avoid thiazolidinediones in patients with heart failure or significant fluid retention risk 3, 6

Comparative Effectiveness on Mortality and Morbidity

• SGLT2 inhibitors and GLP-1 receptor agonists reduce all-cause mortality compared to usual care, insulin, and DPP-4 inhibitors (high certainty of evidence) 1
• SGLT2 inhibitors reduce major adverse cardiovascular events compared to DPP-4 inhibitors and sulfonylureas (moderate to high certainty) 1
• GLP-1 receptor agonists reduce stroke compared to usual care (high certainty) 1
• SGLT2 inhibitors reduce CKD progression and heart failure hospitalizations compared to usual care (high certainty) 1
• Insulin, tirzepatide, and DPP-4 inhibitors do not reduce all-cause mortality compared to usual care (low to high certainty) 1