1. Introduction: The Incretin Effect To understand GLP-1 agonists, one must first understand the "Incretin Effect." This physiological phenomenon describes the observation that oral glucose administration elicits a much higher insulin response than an isoglycemic intravenous (IV) glucose infusion. In Type 2 Diabetes Mellitus (T2DM), the incretin effect is significantly blunted, predominantly due to a reduction in GLP-1 secretion or responsiveness. This provides the rationale for pharmacological replacement. Figure 1. The Incretin Effect. The graph demonstrates the difference in plasma insulin levels following oral glucose intake versus intravenous infusion, despite identical plasma glucose levels. This difference is attributed to the release of incretin hormones (GLP-1 and GIP). 2. Physiology of Endogenous GLP-1 Endogenous GLP-1 is rapidly degraded (half-life < 2 minutes) by the enzyme Dipeptidyl Peptidase-4 (DPP-4). This rapid degradation makes native GLP-1 unsuitable as a drug. Physiological Actions of GLP-1: 3. Classification of GLP-1 Receptor Agonists Pharmacological agents are structurally modified to resist degradation by DPP-4, prolonging their half-life. They are classified based on their structure and duration of action. 3.1 Based on Structure 3.2 Based on Duration of Action CategoryDrugsDosing FrequencyEffect on Fasting vs. Post-Prandial Glucose (PPG)Short-ActingExenatide (Standard), LixisenatideTwice Daily / DailyPredominantly lowers PPG (via delayed gastric emptying).Long-ActingLiraglutide, LixisenatideDailyLowers both Fasting and PPG.Ultra-Long ActingSemaglutide, Dulaglutide, Exenatide XROnce WeeklyStrong reduction in Fasting Glucose; sustained control. 4. Mechanism of Action GLP-1 agonists bind to the GLP-1 receptor, a G-protein coupled receptor (GPCR) on the surface of pancreatic beta-cells and other tissues. Intracellular Signaling: Figure 2. Molecular Mechanism. GLP-1 binds to its GPCR on the beta-cell, increasing cAMP. This pathway enhances glucose-dependent insulin secretion. Crucially, this pathway is only active when glucose enters the cell, minimizing the risk of hypoglycemia. Systemic Effects ( The "Pleiotropic" Effects): Figure 3. Systemic Effects of GLP-1 Agonists. Beyond the pancreas, these drugs act on the brain (satiety), stomach (delayed emptying), liver (reduced gluconeogenesis via lower glucagon), and heart (cardioprotection). 5. Individual Agents & Pharmacokinetics 5.1 Exenatide 5.2 Liraglutide 5.3 Semaglutide 5.4 Dulaglutide 5.5 Tirzepatide (The "Twincretin") 6. Clinical Uses & Guidelines 7. Adverse Effects 8. Contraindications 9. Comparison: GLP-1 Agonists vs. DPP-4 Inhibitors This comparison is a favorite topic for viva/board exams. FeatureGLP-1 Receptor AgonistsDPP-4 Inhibitors (Gliptins)ExamplesLiraglutide, SemaglutideSitagliptin, LinagliptinRouteSubcutaneous (mostly)OralMechanismPharmacological levels of GLP-1 activityIncreases endogenous GLP-1 (physiologic levels)HbA1c ReductionHigh (1.0 – 1.8%)Modest (0.5 – 0.8%)Weight EffectSignificant Weight LossWeight NeutralGastric EmptyingDelayed (causes nausea)No effectCV BenefitProven Benefit (Lira, Sema, Dula)Neutral (Saxagliptin risk of HF)Side EffectsNausea, VomitingWell tolerated (Rare joint pain)CostHighModerate 10. References
