GLP1 Agonists and DPP4 Inhibitors How do they

GLP-1 Agonists and DPP-4 Inhibitors How do they work? Part 6

Exenatide Continued to Reduce Weight in 3 -Year Completers (n=217)

GLP-1 and Central Nervous System • Induces the differentiation of neuronal cells in culture, similar to nerve growth factor • Protects against neuronal death, via a mechanism involving increased c. AMP • Protects against beta-amyloid–induced neurotoxicity (Alzheimer’s disease) and suppresses neurodegenerative cascades

Actions of DPP-4 Inhibitors and GLP-1 R Agonists in Regulating Glucose Homeostasis

Summary of Pharmacologic Incretin Actions on Different Target Tissues Neuroprotection Heart Brain Appetite Stomach Gastric Emptying Cardioprotection Cardiac Output GLP-1 _ Liver GI Tract Insulin Secretion β-Cell Neogenesis Glucose Production Drucker DJ, Cell Metab. 2006; 3: 153 -165. Muscle + β-Cell Apoptosis Glucose Uptake Glucagon Secretion

Cardiac Actions of GLP-1 • ↑ Cardiac output, ↓ LV end diastolic pressure, and ↑ myocardial glucose uptake in animal (rodent and dog) models of CHF and myocardial injury • ↓ Infarct size in ischemic animal models • ↑ LVEF and ↑ wall motion in humans with MI and EF <40% • GLP-1 (9 -36)amide ↑ myocardial contractility (dp/dt) and glucose uptake in dogs with cardiomyopathy

Emerging Roles of Bioactive GLP-1 Metabolites

DPP-4 Degrades Multiple Peptide Substrates

GLP-1 R Agonists vs DPP-4 Inhibitors

GLP-1 vs DPP-4 Inhibitors: Understanding the Antidiabetic Actions of Incretin-Based Therapies