top of page
Search

How Gila Monsters and Gut Hormones Changed Modern Medicine

  • Writer: FibonacciMD
    FibonacciMD
  • 11 minutes ago
  • 5 min read

The History of GLP-1 Drugs


Today, glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are a medical and cultural phenomenon, now used by 12% of U.S. adults at an estimated cost of $132 billion per year.  The GLP-1 class of drugs has revolutionized the treatment of diabetes and obesity while also reducing cardiovascular adverse events.  Scientists are now investigating their ability to treat alcoholism and drug addiction, as these drugs appear to have a number of positive effects on both the body and the brain. 


History

The Discovery That the Gut Produced Hormones

  • In 1902, it was discovered that the small intestine (duodenum) secreted a hormone called secretin that stimulated pancreatic secretions and reduced acidity when food passed from the stomach into the duodenum.  

  • In 1930, another hormone secreted by the small intestine, called incretin, was discovered.  It causes the pancreas to release insulin following oral exposure to glucose.  By the 1960s, it was recognized that incretin hormones were responsible for 50-70% of the insulin response to oral glucose.  

  • In the 1970s, glucose-dependent insulinotropic polypeptide (GIP), an incretin hormone that stimulates the release of insulin after glucose ingestion, was isolated, synthesized and characterized. 



Discovery of GLP-1 and the Lizard Breakthrough 

  • In the 1980s, the incretin hormone GLP-1, which causes glucose-dependent glucagon suppression, delayed gastric emptying, appetite suppression, and increased insulin release from the pancreas, was discovered.  (Glucagon is a hormone produced by the pancreas that raises blood sugar levels by prompting the liver to release stored glucose).  Scientists were initially excited by this discovery as a potential treatment for diabetes, but human GLP-1 has a half-life of approximately two minutes in the bloodstream, making it unsuitable as a treatment.

  • However, in 1992, while investigating biologically active peptides in Gila monster venom, scientists identified the exendin-4 compound, a polypeptide that exhibited GLP-1-like properties.  Exendin-4 lacked the amino acid alanine at one position in the polypeptide chain, making it more resistant to breakdown than human GLP-1.  This markedly increased its half-life in the body, making it more suitable for clinical use than human GLP-1.  Amylin Pharmaceuticals initiated the development of a synthetic form of exendin-4, later named exenatide.  Preclinical studies demonstrated exenatide's sustained glucose-lowering effects and body weight reduction in animal models.  Human studies published in 2002 demonstrated weight loss and significant decreases in blood glucose levels without hypoglycemia.  The brand name for exenatide became Byetta, which was approved by the FDA in 2005 for the treatment of type 2 diabetes.


The Race to Produce Longer-Lasting Drugs   

  • Because Byetta had to be injected twice daily, drug companies began searching for longer-lasting GLP-1 medications.  In 2007, Novo Nordisk developed the once-daily drug liraglutide (Victoza for type 2 diabetes and Saxenda for weight management).  Victoza was approved by the FDA in 2010, while Saxenda followed in 2014.  Note that Victoza and Saxenda are the same drug, just given distinct brand names for different indications.  

  • In 2014, the FDA approved Eli Lilly’s drug dulaglutide (Trulicity), a once-weekly injection for the treatment of type 2 diabetes and for reducing the risk of major adverse cardiovascular events in patients with type 2 diabetes.  

  • In 2015, Novo Nordisk synthesized injectable semaglutide from liraglutide (Ozempic for type 2 diabetes and Wegovy for weight management), which gained FDA approval in 2017 as Ozempic and in 2021 as Wegovy.  In 2025, Wegovy was given additional FDA approval for treating a liver disease known as metabolic dysfunction-associated steatohepatitis (MASH), which causes inflammation, scarring, and fat deposits in the liver.  Wegovy and Ozempic are the same medication, but branded differently due to different FDA approved indications.


Oral, Dual-, and Triple-Action, and New Drug Formulations 

  • In 2019, Novo Nordisk introduced an oral semaglutide known as Rybelsus for type 2 diabetes and later oral Wegovy for weight management.  The FDA approved Rybelsus in 2019 and oral Wegovy in 2025 (Rybelsus was rebranded as oral Ozempic in 2026).  Clinical studies demonstrated both cardioprotective effects and substantial weight loss.  

  • In 2020, Eli Lilly developed the dual-action drug, injectable tirzepatide administered once weekly (Mounjaro for type 2 diabetes and Zepbound for weight management) that activates both GLP-1 and GIP receptors.  Clinical testing found this dual action more effective than some other GLP-1 receptor agonists.  FDA approval occurred in 2022 and 2023, respectively.  

  • In 2023, Eli Lilly synthesized injectable retatrutide, the first triple-action agonist targeting GLP-1, GIP, and glucagon receptors, which is currently undergoing Phase 3 clinical trials.  

  • In April 2026, the FDA approved the Eli Lilly drug orforglipron (Foundayo), the first non-peptide small-molecule, once-daily oral GLP-1 receptor agonist for weight management.  A non-peptide small molecule is a chemical compound not made of amino acids and therefore not broken down by stomach acid, allowing it to be taken orally.  These molecules are small enough to pass easily through cell membranes and work inside cells.  Studies are ongoing to obtain approval for type 2 diabetes treatment. 


Summary

What began as the study of gut hormones and lizard venom has evolved into one of the most important pharmaceutical advances in modern medicine.


That discovery has led to the development of some of the most widely prescribed drugs in use today, treating obesity, type 2 diabetes, cardiovascular complications, and certain forms of severe liver disease.  These medications have also been found to reduce cravings associated with substance abuse and alcoholism, and there is even a possibility that they may slow the progression of some cancers.  Scientists do not yet understand the full effects of these drugs, and it is possible that they, or related compounds, may be used to treat additional medical conditions in the future.


Editor’s Note- These drugs are generally well-tolerated, but they do have a number of potentially serious adverse effects. These risks should always be discussed with your clinician before starting treatment.

A few words of caution if starting a GLP-1 agonist

  • Titrate your dosage slowly and carefully. Be patient

  • Hold your medication at least two weeks before any scheduled future procedures under anesthesia

  • Make sure you drink water while taking GLP-1’s or GLP-1/GIP drugs. Dehydration is very common

  • Report any vomiting, light-headedness, upper abdominal pain, or upper or mid-back pain to your clinician

  • Consult with your ophthalmologist and let them know you are on a GLP-1 agonist

These are not all the risks or potential adverse effects


If you liked this article, you may also enjoy reading The History of Insulin and Type 1 Diabetes. 

You may also find these other FibonacciMedicine articles interesting:

References

bottom of page