Weight loss drugs!

14 Oct, 2025

1. What is the chemical compound in the drug?

• Tirzepatide is a dual incretin mimetic (incretins are hormones released after we eat that control blood sugar levels), it mimics two natural hormones called glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). (Ozempic only acts on GLP-1)
• Tirzepatide exhibits an agonist behavior, meaning that it activates GIP and GLP-1 receptors, that when activated, lead to the release of insulin.
• You can think of its chemical structure as a backbone that resembles that of both GIP and GLP-1 inducing hormones, with an added fatty acid chain that makes it less prone to breakdown by enzymes so that it lasts longer in the bloodstream.
• It contains a portion that binds to GIP and one that binds to GLP-1.

1. A biochemistry basic: what is insulin and how does it work?

• Insulin is a hormone released by pancreatic beta cells.
• Insulin release is triggered when pancreatic cells intake glucose, which leads to a cascade of events:
  • ATP production → closes potassium channels → Depolarization opens calcium channels → triggers fusion of insulin-containing vesicles to fuse with cell membrane (exocytosis).
• Insulin signals the cells in the body to uptake more glucose from the blood to control blood glucose levels.

1. What are the GIP and GLP-1 receptors?

GLP-1 receptor:

• Located mostly in the pancreas on Beta cells, but also in the brain and heart tissue.
• It stimulates insulin secretion when blood glucose is high and suppresses glucagon secretion in pancreatic alpha cells.
• It also slows down gastric emptying, which also blunts post-meal spikes in blood sugar.
• Increases satiety by acting in the brain to reduce apetite.
• Cardiovascular effects: improves endothelial function and can lower blood pressure.

GIP receptor:

• Located mostly in the pancreas on Beta cells, but also in the brain.
• It potently stimulates insulin secretion after meals and enhances signaling for fat storage.
• It also acts on the brain to amplify the signals induced on the GLP-1 receptor, boosting GLP-1's appetite-suppressing effects.
• Weaker effects in type 2 diabetes patients when activated.

1. Combined effects of activating GIP and GLP-1 receptors:

• GLP-1 alone: lowers blood glucose, reduces appetite and has positive cardiovascular effects
• GIP alone: strong insulin secretagogue, but less effective in diabetes when used by itself
• Together (tirzepatide):
  • Greater insulin release after meals
  • More robust appetite suppression
  • Lower side effects (like nausea) compared to GLP-1 alone

1. How does more insulin secretion play into type 2 diabetes control?

• Type 2 diabetes develops as a result of cells becoming insulin resistant, causing pancreatic beta cells to produce more insulin to compensate. Eventually, beta cells become overworked and eventually can no longer produce insulin.
• Therefore, Mounjaro and Ozempic can be used to treat T2D by:
  • GLP-1 and GIP mimetics help beta cells secrete insulin more efficiently and may protect them from burnout.
  • They also decrease glucagon secretion, preventing the unecessary release of glucose by the liver.
  • Even though cells in T2D are insulin resistant, the combined effects of the drugs like weight loss and lower glucagon can essentially reduce insulin resistance and bring glucose back under control.

1. Why does the insulin release caused by these drugs not increase the risk of type 2 diabetes, since this is caused by insulin resistance?

• In T2D, beta cells are already stressed because they're compensating for insulin resistance. So yes, in theory, constantly stimulating beta cells could worsen things. But incretin mimetics like tirzepatide don't act in that blunt way.
• Both GLP-1 and GIP receptors only trigger insulin release when glucose is elevated. So incretin mimetics won't push insulin out when glucose is normal or low.
  • So you avoid the problem of constant hyperinsulinemia, which can drive fat storage.
  • Without tirzepatide, a big carb meal → huge glucose spike → body has to dump a large, uncontrolled burst of insulin to bring sugar down.
• Incretins actually seem to preserve beta cell function.
• The systemic effects of lowering weight, improving insulin sensitivity and reducing glucagon reduces the overall demand on beta cells over time.

1. Mounjaro vs. Ozempic

• Ozempic (semaglutide): only activates GLP-1 receptors → increases insulin release, suppresses glucagon, slows gastric emptying, suppresses appetite.
  • 10-15% body weight loss
• Mounjaro (tirzepatide): timulates both GLP-1 and GIP receptors → added GIP effects may boost insulin release, improve insulin sensitivity and enhance GLP-1 satiety effects
  • Up to 20% body weight loss (more than semaglutide)

Are these drugs safe?

• The popularity of Ozempic and Mounjaro has exploded so fast that it feels a bit sus… But what does the evidence tell us?
• GLP-1 receptor agonists (like semaglutide/Ozempic) have been studied for over 15 years in large randomized controlled trials (RCTs).
• Tirzepatide/Mounjaro is newer (FDA-approved in 2022) but its clinical trials showed even stronger glucose and weight reductions than semaglutide.
• What are the risks?
  • Common side effects include GI issues like nausea, vomiting, diarrhea and constipation
  • Serious but rare risks include pancreatitis and possible increased risk of certain thyroid tumors (seen in rodents but unclear in humans).
• Both drugs were initially only tested in T2D patients but have now been tested in people that don't have T2D and have shown to be safe.