GLP-1 Agonists for Weight Loss: Comprehensive Guide
What Are GLP-1s?
- Semaglutide (Ozempic, Wegovy, Rybelsus)
- Liraglutide (Saxenda, Victoza)
- Tirzepatide (Mounjaro — dual GLP-1/GIP agonist)
- Exenatide (Byetta, Bydureon)
- Dulaglutide (Trulicity)
How GLP-1s Work in the Body
- Brain: Reduces appetite via hypothalamic centers
- Stomach: Slows gastric emptying, reducing food intake
- Pancreas: Increases insulin and reduces glucagon
- Liver: Reduces hepatic glucose output
- Mitochondria: May enhance mitochondrial efficiency and biogenesis indirectly via insulin signaling and reduced oxidative stress
- Free energy: Creates a mild caloric deficit by reducing appetite and food intake, not by increasing basal metabolic rate directly
Emerging Surprising Positive Findings
- Alcohol and drug dependency: Shown to reduce addictive behavior via modulation of dopamine pathways
- Cardiovascular protection: Reduces risk of heart attack, stroke, and improves blood pressure
- Fertility: Improved ovulation and menstrual regulation in women with PCOS and obesity
- Cholesterol: Lowers LDL, improves lipid profiles
- Liver health: Reduces liver fat, helping NAFLD/NASH
- Neuroprotection: May reduce inflammation and support brain health
- Bulimia/Binge Eating: Reduces compulsive eating behavior, possibly affecting reward centers
Mental Health Effects
- Potentially beneficial for anxiety & depression - weight reduction improves insulin sensitivity, improving gut-brain axis
- Modulates reward circuits tied to food, addiction, and emotion
- Being studied for benefits in Alzheimer’s & Parkinson’s due to anti-inflammatory & insulin-mimetic properties
Testosterone and Hormonal Effects
- Testosterone: May indirectly improve testosterone by reducing visceral fat and insulin resistance
- No direct suppression of testosterone noted in trials
- Improvement in PCOS symptoms including androgen excess
Pros
- Sustainable weight loss
- Reduced cardiovascular and metabolic risks
- May reverse prediabetes/early type 2 diabetes
- Appetite and binge control
- May improve mental well-being
Cons
- GI side effects: nausea, vomiting, diarrhea, constipation
- Risk of pancreatitis
- Risk of gallstones, especially with rapid weight loss
- Can delay gastric emptying too much: gastroparesis
- Rare risk: thyroid C-cell tumors in rodent studies (not confirmed in humans)
- Possible hair loss due to rapid weight loss
Resistance to Treatment
- May occur over time if the dose is not escalated appropriately
- Plateau in weight loss may result from adaptive metabolic changes
- Possible solutions:
- Address leptin resistance
- Combine with strength training or thyroid optimization
- Microdosing strategies to reduce tolerance and side effects
- History of pancreatitis
- Personal/family history of medullary thyroid cancer
- Severe gastroparesis
- Pregnancy or breastfeeding (not approved)
- Electrolytes and hydration
- Gallbladder function
- HbA1c, glucose, insulin
- Thyroid nodules (if personal risk)
Fun Facts
- Originally developed for diabetes, but weight loss was so significant it became the primary use for some
- GLP-1 receptors are found in the brain—explains many of the cognitive/emotional benefits
- Tirzepatide (dual GIP/GLP-1 agonist) shows record-breaking weight loss in clinical trials
- Some GLP-1s are being studied for longevity and brain health beyond weight control
