1. Sitagliptin (DPP-4 Inhibitor):
   • Inhibits the enzyme DPP-4, which degrades incretin hormones (GLP-1 and GIP). By prolonging incretin activity, it:
     • Enhances Glucose-Dependent Insulin Secretion: Stimulates pancreatic β-cells to release insulin in response to elevated blood glucose.
     • Suppresses Hepatic Glucose Production: Reduces glucagon secretion from α-cells (Lippincott).
   • Unlike sulfonylureas, it carries a low risk of hypoglycemia when used alone (Lange).
2. Metformin (Biguanide):
   • Reduces Hepatic Gluconeogenesis: Activates AMP-activated protein kinase (AMPK), decreasing glucose production.
   • Improves Insulin Sensitivity: Enhances glucose uptake in peripheral tissues (BNF).

Synergy: The combination targets both insulin deficiency (via Sitagliptin) and insulin resistance (via Metformin), offering comprehensive glycemic control.

1. BNF-Approved Indications:
   • Sitagliptin Monotherapy: For T2DM when metformin is contraindicated or poorly tolerated.
   • Sitagliptin/Metformin Combination:
     • First-line therapy for patients requiring dual-pathway intervention.
     • Adjunct to diet/exercise or other agents (e.g., insulin, sulfonylureas) (BNF).
2. Contraindications:
   • Sitagliptin: Hypersensitivity to DPP-4 inhibitors.
   • Metformin: Severe renal impairment (eGFR <30 mL/min/1.73m²), acidosis, hepatic failure (BNF).

1. Sitagliptin Monotherapy:
   • Adults: 100 mg once daily, with or without food.
   • Renal Adjustment:
     • eGFR 30–50 mL/min: 50 mg daily.
     • eGFR <30 mL/min: 25 mg daily (BNF).
2. Sitagliptin/Metformin Combination:
   • Available Strengths: 50/500 mg, 50/850 mg, 50/1000 mg.
   • Dosing:
     • Initial: 50/500 mg twice daily, titrated to glycemic response.
     • Max Daily Dose: 100 mg Sitagliptin + 2000 mg Metformin (BNF).
   • Renal Adjustment: Avoid if eGFR <45 mL/min (Metformin contraindicated <30 mL/min).

1. Sitagliptin:
   • Common: Nasopharyngitis, headache, dizziness.
   • Rare: Acute pancreatitis, hypersensitivity reactions (e.g., angioedema) (BNF).
2. Metformin:
   • Common: Gastrointestinal disturbances (nausea, diarrhea, abdominal pain).
   • Serious: Lactic acidosis (rare; risk factors include renal impairment, dehydration) (Lippincott).

Combination Therapy: Side effects reflect both components, with GI issues predominating.

• Renal Function:
  • Monitor eGFR before and during treatment. Discontinue Metformin if eGFR <30 mL/min.
• Hepatic Impairment: Avoid in severe liver disease (Metformin risk).
• Pancreatitis: Discontinue Sitagliptin if severe abdominal pain occurs.
• Pregnancy:
  • Sitagliptin: Limited data; insulin preferred.
  • Metformin: BNF advises against use in pregnancy (Lange).

1. Sitagliptin:
   • ACE Inhibitors: Increased risk of angioedema.
   • CYP3A4/5 Inducers (e.g., rifampicin): May reduce efficacy (Lippincott).
2. Metformin:
   • Cimetidine: Increases Metformin levels via renal tubular competition.
   • Iodinated Contrast Media: Temporarily discontinue to prevent lactic acidosis (BNF).
   • Alcohol: Potentiates lactic acidosis risk.

Combination: Monitor glucose levels with concomitant insulin/sulfonylureas.

• Sitagliptin:
  • Generic: Sitagliptin.
  • Brand Names:
    • UK (BNF): Januvia®, Tesavel®.
    • US: Januvia®.
• Sitagliptin/Metformin:
  • Generic: Sitagliptin + Metformin.
  • Brand Names:
    • UK (BNF): Janumet®, Velmetia®.
    • US: Janumet®.