Weight Loss Drugs Overview

Introduction to Weight Loss Drugs

  • Categories of Weight Loss Drugs:
    • Appetite Suppressors: Anorectic that affect neurotransmission.
    • Hormones: Influence metabolism and thermogenesis.
    • Metabolism Targeting: Directly target specific genes.
    • Lower Food Absorption: Impact on signaling pathways.

Historical Context: Rainbow Diet Pills (1940s-1960s)

  • Characteristics:
    • Multi-colored pills designed to curb appetite and promote weight loss.
    • Contents included substances like amphetamines, laxatives, and thyroid hormones.

Leptin and Obesity

  • Discovery:
    • Jeffrey Friedman identified leptin as a protein-signaling molecule in 1994 from adipose tissue.
    • Functions include regulating metabolism.
    • Absence in mice linked with severe obesity due to defects in leptin or its receptor.
  • Mechanism:
    • Crosses blood-brain barrier, reduces food intake, stimulates long-term energy expenditure.
  • Clinical Trials:
    • First trials in 1999; effectiveness remained limited but used for lipodystrophy treatment with recombinant methionyl human leptin (r-metHuLeptin).

Cannabinoids and Weight Control

  • Cannabinoids:
    • THC is known to stimulate appetite; has 2 receptors.
  • CB-1 Antagonists:
    • Reduce weight in animal models; notable case Rimonabant (2005-2007) was linked to reduced BMI and diabetic benefits but caused severe psychiatric side effects.

Opioids and Weight Management

  • Opioids:
    • Generally stimulate food intake.
  • Antagonists (e.g., Naltrexone):
    • block opioid receptors to reduce appetite; effective in clinical trials but raised concerns over liver toxicity.

Naltrexone/Bupropion (Contrave)

  • Approved: 2014.
  • Components:
    • Naltrexone: Opioid receptor blocker.
    • Bupropion: Atypical antidepressant affecting mood and appetite.
  • Formulation:
    • Extended-release hydrocholoride (8 mg naltrexone / 90 mg bupropion).

Orlistat: A Unique Approach

  • Timing: Developed in 1999, based on Lipstatin.
  • Mechanism:
    • Targets lipases, prevents triglyceride absorption, inhibits Fatty Acid Synthase (FASN).
  • Market Availability:
    • Sold as Alli (OTC in the US) and Xenical (prescription in Canada).

Topiramate

  • Usage: Approved since 1996.
  • Roles: Appetite suppressor for binge eating, mood enhancer, and anticonvulsant.
  • Target: Works on GABA receptors and neurotransmission functions.

Setmelanotide (Imcivree)

  • Mechanism: Targets Leptin-Melanocortin pathway as an agonist for MC4R in the brain.
  • Impacts: Regulates hunger and satiety; FDA approved in 2020 for specific genetic obesity disorders.

Diabetes Overview

  • Types:
    • Group of diseases associated with misregulated blood sugar (hyperglycemia), linked to insulin levels.
    • Symptoms include fatigue, mood changes, and slow healing.

Insulin Discovery

  • Key Figures: Banting and Best isolated insulin in 1921, with the first human injection in 1922 leading to a Nobel prize in 1923.
  • Function: Produced by pancreatic beta cells; crucial for glucose metabolism, signaling, and energy regulation.

Insulin Mechanism and Signaling

  • Insulin Release:
    • High blood glucose stimulates insulin release, which promotes glucose uptake in fat cells and liver regulation.
  • Signaling Pathway:
    • Insulin binds to its receptor, activates signaling pathways for glucose metabolism, and regulates various tissue functions.

Diabetes Types and Management

  • Type 1 Diabetes:
    • Autoimmune failure of insulin production (5-10% of cases); requires insulin injections or pumps for management.
  • Type 2 Diabetes:
    • Insulin resistance (90% of cases); can be managed through diet and lifestyle changes.

Diabetes Medications

  • Classes for Type 2:
    • Metformin, Sulfonylureas, DPP-4 inhibitors, SGLT2 inhibitors, Thiazolidinediones, Meglitinides, GLP-1 receptor agonists (e.g., Liraglutide, Semaglutide).

Current Anti-Obesity Drugs (Approved by FDA)

  • List of Approved Medications:
    • Bupropion-naltrexone (Contrave)
    • Liraglutide (Saxenda)
    • Orlistat (Xenical, Alli)
    • Phentermine-topiramate (Qsymia)
    • Semaglutide (Wegovy)
    • Setmelanotide (Imcivree).
  • Canada's Approved Drugs:
    • Same as above, with explanations on how each drug works to assist obesity management and related conditions.