Weight Loss Drug Pipeline Overview
The pipeline for weight loss medications is extremely exciting. In 2014, the first GLP-1 agonist, Saxenda (liraglutide), was approved for weight loss. An agonist is a medication that switches a receptor on — in this case, the receptor for GLP-1. Average weight loss was about 8%, which seemed revolutionary at the time. In 2021, Wegovy (semaglutide), another GLP-1 agonist, was approved with an average weight loss of about 15%. In 2023, Zepbound (tirzepatide), a single medication that activates both the GLP-1 and GIP receptors, was approved with an average weight loss of about 21% at the highest dose. Since then, the first weight loss pills have arrived: oral Wegovy in late 2025 and Foundayo (orforglipron) in 2026.
These medications are based on incretins — hormones made in the intestine that help regulate blood sugar and appetite. GLP-1 is one of the two main incretins. It helps keep us full, boosts insulin release from the pancreas when blood sugar rises, and slows how fast food moves through the digestive tract. The problem is that our natural GLP-1 breaks down within minutes. Synthetic GLP-1 medications are designed to resist that breakdown, so they keep working for days instead of minutes.
The other main incretin is GIP, which stands for glucose-dependent insulinotropic polypeptide. It’s also made in the small intestine, and it acts on the pancreas (increasing insulin release), fat cells (helping them store fat safely), and the brain. Interestingly, GIP appears to reduce nausea. That’s key: researchers believe one reason GIP boosts weight loss is that it offsets the nausea GLP-1 medications cause, letting patients tolerate higher doses. Unlike GLP-1, GIP doesn’t slow digestion. On its own, it produces little weight loss — so far only one small early study has shown a modest effect. But when combined with GLP-1, the two work better together than either alone. That’s likely where much of Zepbound’s extra weight loss over Wegovy comes from.
The future of anti-obesity medications is full of hormone-based treatments that go beyond GLP-1 and GIP, along with some promising options that work in completely different ways. Below is a table I made of seven new medications currently in trials. New approaches include GIP antagonists (which turn a receptor OFF), amylin agonists, and glucagon agonists. The most exciting to me is an entirely new class: activin type 2 receptor antagonists, which help build and preserve muscle during weight loss. I’ll cover each of these seven drugs in detail over the coming weeks, so stay tuned for a deep dive into retatrutide.
Seth Jarrell, MD