GLP-1 Therapy: A Monster’s Weight-Loss Legacy

Half the internet discovered GLP-1s last year. The science community met them decades ago. This is the quick origin story, with one great creature cameo, and a practical nod to safety for people using these medicines for weight care.

The unlikely beginning

In the early 1990s, researchers studying a desert reptile—the Gila monster—isolated a peptide in its saliva called exendin-4. It acted like the human hormone GLP-1 but stuck around longer in the body. Chemists adapted that peptide into exenatide, and in 2005 the FDA approved it as the first GLP-1 receptor agonist for type 2 diabetes. The fact that someone thought to check Gila monster saliva isn’t just trivia. It’s a reminder that today’s weight-care tools sit on a long, iterative bench of biology and medicinal chemistry, and are not just whipped up overnight.

Twenty years of build, not a sudden boom

After exenatide, longer-acting analogs arrived and were tested at scale. The public's moment of recognition came later, when higher-dose formulations were studied in adults with overweight or obesity without diabetes. In STEP 1, once-weekly semaglutide plus lifestyle change drove large, sustained weight loss over 68 weeks. SURMOUNT-1 showed similar results for tirzepatide over 72 weeks. Those trials reframed GLP-1–based therapy as a metabolic reset tool, not just a glucose-lowering drug.

Clinically, this wasn’t a surprise. GLP-1 is an incretin hormone that helps the pancreas release insulin after meals, slows gastric emptying, and reduces appetite via central pathways. Decades of research mapped those levers. What changed was dose, duration, and the decision to study weight outcomes directly.

Why this history changes the conversation

When a therapy looks “new,” skepticism is rational. But GLP-1s have run a marathon already: discovery in the 1980s–90s, first approval in 2005, then large cardiovascular and weight-management trials across millions of patient-years. For patients, that means a clearer map of what to expect, how to dose, and how to pair the medicine with sleep, nutrition, and strength work for durable results—without fearing "unknown" outcomes or demonizing the drug.

Over two decades, GLP-1–based medicines have built a strong safety record across large randomized trials and long real-world use. Cardiovascular outcomes studies (e.g., LEADER 2016, SUSTAIN-6 2016, REWIND 2019) confirmed safety and, for several agents, reduced events. Obesity trials without diabetes (STEP 1, 2021; SURMOUNT-1, 2022) extended that profile at weight-care doses. Early worries about pancreatitis and thyroid cancer have not translated into clear human risk signals in randomized data, while gallbladder events show a modest increase, particularly with rapid weight loss. Most side effects are gastrointestinal and improve with slow titration. GLP-1s are not new, and suspected risks have generally diminished as evidence accumulated.

Takeaways

• GLP-1s are not new. First FDA approval was in 2005.

• Today’s weight-care use builds on decades of biology and large trials.

• Safety in non-diabetic use is mostly GI tolerance, gallbladder risk, rare pancreatitis, and preserving muscle with training and protein.

• Bottom line: established track record, not a trendy shortcut.

Kyndl perspective

We use GLP-1–based therapy as a primary tool among many. We have know GLP-1 are safe and effective from their long history. We pair dosing GLP-1 with nutrition, resistance training, and follow-up designed for tolerance and long-term maintenance.

This article is educational and not medical advice

Sources:

FDA Byetta approval package
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021773_byettatoc.cfm
Eng 1992: isolation of exendin-4 (Gila monster)
https://pubmed.ncbi.nlm.nih.gov/1313797/
Triplitt 2006: “Exenatide—From the Gila Monster to the Pharmacy”
https://pubmed.ncbi.nlm.nih.gov/16529340/
STEP 1 semaglutide RCT (NEJM, 2021)
https://www.nejm.org/doi/full/10.1056/NEJMoa2032183
SURMOUNT-1 tirzepatide RCT (NEJM, 2022)
https://www.nejm.org/doi/full/10.1056/NEJMoa2206038
Drucker 2024 review: “The GLP-1 journey” (JCI)
https://pubmed.ncbi.nlm.nih.gov/38226625/
GLP-1 RAs and gallbladder/biliary risk meta-analysis (JAMA Intern Med, 2022)
https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2790392
Wegovy (semaglutide) label PDF (2024 s011)
https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/215256s011lbl.pdf
FDA page: concerns with unapproved GLP-1 products
https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/fdas-concerns-unapproved-glp-1-drugs-used-weight-loss