Obesity treatment before GLP-1s

For decades, obesity treatment was defined by failure. Lifestyle interventions produced modest results that rarely lasted. The few FDA-approved medications available offered single-digit percentage weight loss. Bariatric surgery remained the only intervention capable of producing dramatic, sustained weight loss, but it carried surgical risks and was accessible to only a fraction of those who needed it.

By 2020, more than 650 million adults worldwide were living with obesity. The field was waiting for a breakthrough, and it arrived from an unlikely source: the gut.

What is GLP-1 and how does it work

Glucagon-like peptide-1 (GLP-1) is a 30-amino-acid hormone produced by L-cells in the small intestine. When you eat, these cells release GLP-1 into the bloodstream, where it stimulates insulin secretion, suppresses glucagon release, slows gastric emptying, and signals satiety to the brain.

Natural GLP-1 has a half-life of roughly two minutes. The enzyme DPP-4 rapidly degrades it. The key insight behind GLP-1 receptor agonist drugs was engineering synthetic versions that resist enzymatic breakdown, extending their activity from minutes to days or weeks.

Key mechanism: GLP-1 receptor agonists work on multiple pathways simultaneously: they reduce appetite through brain signaling, slow stomach emptying to increase fullness, improve insulin sensitivity, and reduce food reward behavior. This multi-target approach is why they outperform older single-mechanism weight-loss drugs.

From Gila monster to FDA approval

In 1992, endocrinologist John Eng discovered exendin-4 in the saliva of the Gila monster, a peptide that mimicked GLP-1 but resisted DPP-4 degradation. This led to exenatide (Byetta), approved by the FDA in 2005 as the first GLP-1 receptor agonist for type 2 diabetes.

Liraglutide (Victoza) followed in 2010 for diabetes. Novo Nordisk developed a higher-dose formulation approved in 2014 as Saxenda, the first GLP-1 receptor agonist specifically indicated for weight management, producing approximately 5-8% body weight loss beyond placebo.

The bigger change came with semaglutide. By modifying the GLP-1 peptide backbone and attaching a fatty acid chain that binds to albumin, Novo Nordisk created a molecule with a half-life of roughly one week. Ozempic was approved in December 2017. Then came the STEP trials.

The STEP trials: semaglutide clinical results

  • STEP 1 (2021): 1,961 adults without diabetes lost an average of 14.9% of body weight over 68 weeks vs. 2.4% with placebo.
  • STEP 2 (2021): In adults with type 2 diabetes, semaglutide produced 9.6% weight loss vs. 3.4% with placebo.
  • STEP 3 (2021): Combined with intensive behavioral therapy, participants achieved 16.0% weight loss vs. 5.7% with placebo.
  • STEP 5 (2022): Over two years, participants maintained 15.2% weight loss, demonstrating durability.

The FDA approved semaglutide 2.4 mg as Wegovy for chronic weight management in June 2021. A third of participants in STEP 1 lost 20% or more of their body weight, results previously achievable only through bariatric surgery.

Tirzepatide: dual agonist results

Tirzepatide is a dual GIP/GLP-1 receptor agonist that activates receptors for both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). In SURMOUNT-1, at the highest dose (15 mg), participants lost an average of 22.5% of body weight over 72 weeks. More than one-third lost at least 25%, numbers approaching what gastric bypass surgery typically achieves.

Tirzepatide was approved for type 2 diabetes as Mounjaro in May 2022 and for weight management as Zepbound in November 2023.

Cardiovascular and kidney benefits

The SELECT trial, published in November 2023, enrolled 17,604 adults with cardiovascular disease and overweight/obesity. Semaglutide 2.4 mg reduced the risk of major adverse cardiovascular events by 20% compared to placebo. In March 2024, the FDA expanded Wegovy's label to include cardiovascular risk reduction.

The FLOW trial demonstrated that semaglutide also slowed progression of chronic kidney disease in people with type 2 diabetes, reducing clinically significant kidney events by 24%.

SELECT trial significance: The SELECT trial was the first to demonstrate that a weight-loss medication could reduce cardiovascular events independently of diabetes status. GLP-1 receptor agonists are no longer just weight-loss drugs; they are cardiovascular risk-reduction tools.

Retatrutide and the next generation

Retatrutide is a triple agonist that activates GLP-1, GIP, and glucagon receptors simultaneously. Phase 2 trial results showed an average of 24.2% body weight loss at 48 weeks at the highest dose, with weight loss still trending downward. Nearly 26% of participants lost more than 30% of their body weight.

Other next-generation candidates include Amgen's MariTide (potentially monthly dosing) and survodutide, a dual GLP-1/glucagon agonist being developed for both weight loss and fatty liver disease.

Oral vs. injectable formulations

Higher-dose oral semaglutide (50 mg) showed 15.1% weight loss over 68 weeks in the OASIS 1 trial, comparable to Wegovy's injectable results. Eli Lilly is also developing orforglipron, a small-molecule oral GLP-1 receptor agonist with Phase 2 results showing up to 14.7% weight loss over 36 weeks.

Access and cost challenges

At list prices exceeding ,000 per month in the United States, these medications are out of reach for many patients. Insurance coverage remains inconsistent, and supply shortages plagued both Wegovy and Mounjaro through 2023-2024. Competition is beginning to exert downward pressure on prices as more medications enter the market.

The future

The next five years will likely bring triple agonists to market, oral formulations with injectable-level efficacy, and longer-acting compounds. Beyond obesity, GLP-1 receptor agonists are being studied for MASH (fatty liver disease), obstructive sleep apnea, osteoarthritis, addiction, and even Alzheimer's disease. What began with venom from a desert lizard now spans dozens of clinical programs across multiple disease areas.

Sources

  1. Wilding JPH, et al. Once-weekly semaglutide in adults with overweight or obesity (STEP 1). N Engl J Med. 2021;384(11):989-1002.
  2. Jastreboff AM, et al. Tirzepatide once weekly for the treatment of obesity (SURMOUNT-1). N Engl J Med. 2022;387(3):205-216.
  3. Lincoff AM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes (SELECT). N Engl J Med. 2023;389(24):2221-2232.
  4. Perkovic V, et al. Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes (FLOW). N Engl J Med. 2024;391(2):109-121.
  5. Jastreboff AM, et al. Triple-hormone-receptor agonist retatrutide for obesity, a phase 2 trial. N Engl J Med. 2023;389(6):514-526.
  6. Knop FK, et al. Oral semaglutide 50 mg taken once daily in adults with overweight or obesity (OASIS 1). Lancet. 2023;402(10403):705-719.
  7. Drucker DJ. The GLP-1 journey: from discovery science to therapeutic impact. J Clin Invest. 2024;134(2):e175634.
  8. Müller TD, et al. Anti-obesity drug discovery: advances and challenges. Nat Rev Drug Discov. 2022;21(3):201-223.