For Amy

Page 1

Introduction to GLP-1

  • GLP-1 (Glucagon-Like Peptide-1)

  • Vital in the management of Type 2 Diabetes (T2D)

Page 2: The GLP-1 Journey

Overview of GLP-1

  • Emerged from discovery science to therapeutic applications

  • Impact on T2D management and obesity treatments

Mechanisms of Action

  • GLP-1 Functionality:

    • Increases insulin secretion

    • Inhibits glucagon secretion

  • Cardiovascular safety of GLP-1 RA (Receptor Agonists)

  • Includes phase 3 trials involving:

    • Heart Failure with Preserved Ejection Fraction (HFpEF)

    • Peripheral Artery Disease (PAD)

    • Diabetic Kidney Disease (DKD)

    • Nonalcoholic Steatohepatitis (NASH)

    • Alzheimer’s Disease (AD)

    • Parkinson’s Disease (PD)

Page 3: Modified GLP-1

Advancements in Treatment

  • Modern therapeutics modify GLP-1 to enhance efficacy

  • Key focuses include:

    • Exploiting multiple receptors

    • Avoiding short half-lives through enzymatic degradation modifications

Page 4: Physiological Effects of GLP-1

Impact on Various Body Systems

  • Appetite regulation and Satiety

  • Effects on:

    • Muscle metabolism

    • Blood pressure control

    • Cardiac functions (myocardial contractility, diastolic function)

    • Kidney function (natriuresis)

    • Gastrointestinal activity (gastric emptying and acid secretion)

Page 5: Triple-Hormone-Receptor Agonist

Retatrutide Overview

  • Retatrutide: A phase 2 trial focusing on obesity

  • Key Investigators:

    • Daniel J. Drucker et al.

  • Published in The New England Journal of Medicine

Page 6: Weight-Loss Drug Analysis

Clinical Trial Results

  • Summary of selected drugs and their mean weight loss percentages

  • Drugs include:

    • Eli Lilly (retatrutide, tirzepatide)

    • Novo Nordisk (semaglutide)

    • Emerging candidates like pemvidutide and mazutide

Page 7: LY3437943

Triple Agonist Activity

  • Effectiveness of LY3437943 at GLP-1, GIP, and glucagon receptors

  • Superior body weight loss in obese mice compared to tirzepatide

  • Similar safety profile to existing incretin-based drugs

Page 8: Retatrutide Chemical Information

Retatrutide Structure and Activity

  • Detailed composition:

    • Contains modified amino acids to prevent proteolysis

    • EC50 values for receptors indicating biological activity

Page 9: Energy Expenditure Discussion

Evaluating Energy Expenditure

  • TDEE (Total Daily Energy Expenditure):

    • Essential metric for understanding metabolic functions

  • Impact of GCGR agonism on energy expenditure yet to be clearly substantiated

Page 10: Weight Reduction Efficacy

Outcome Measurements from Clinical Trials

  • Comparative results indicating weight reduction targets over time

  • Different dosages of retatrutide showing variability in weight loss outcomes

Page 11: Peptide Therapeutics

Summary of Peptides vs Small Molecules

  • Advantages of peptides:

    • Target specificity

    • Superior safety profile

    • Long-term potential in pharmaceutical development

  • Disadvantages include injection dependency and higher manufacturing costs

  • Future perspectives on peptide-based pharmaceuticals seem promising.