Journal — Deep dives
Semaglutide, tirzepatide, retatrutide — where the GLP-1 class is heading
Three molecules. Two FDA approvals. One late-stage triple agonist that may rewrite the market. A field guide.
On this page · Where the class started
Three years ago the GLP-1 conversation was a niche endocrinology beat. Today it's the loudest molecule story in metabolic medicine, and the next wave — triple agonists like retatrutide — is already in late-stage trials. This piece traces the line from semaglutide to what comes after.
Where the class started
Semaglutide is a long-acting GLP-1 receptor agonist, dosed weekly, that came out of Novo Nordisk's incretin program. Its first approval was for type 2 diabetes; the body-composition data fell out of the same trials and reframed it as a weight-loss molecule.
The mechanism is unromantic — slowed gastric emptying, blunted appetite signal, modulated reward circuitry — and the trial outcomes were the kind that move a market. Weekly injection, 0.25mg ramping to 2.4mg over 16 weeks, ~15% body-weight loss at one year in the published cohort.
Why tirzepatide moved the goalposts
Tirzepatide is a dual GIP/GLP-1 agonist. The GIP arm adds an upstream insulinotropic signal that, in the SURMOUNT trials, produced weight loss outcomes meaningfully larger than semaglutide head-to-head. Meaningfully larger in this context is roughly 20% versus 15% at the same time horizon. That gap is the entire reason Eli Lilly's market cap re-rated.
- Weekly subcutaneous injection.
- Dose ladder 2.5mg → 15mg over 20 weeks.
- GI tolerability the limiting factor, especially on faster ramps.
The dual-agonist data wasn't a refinement — it was an inflection. Everyone with a triple-agonist candidate suddenly looked credible.
Retatrutide — the next inflection
Retatrutide adds a glucagon-receptor arm on top of GIP and GLP-1. The Phase II readout in 2023 was the most aggressive weight-loss outcome ever reported for a peptide in this category — figures that, if they hold in Phase III, will reset the ceiling on what clinically meaningful means for this class.
Caveats apply. Phase II is not Phase III. Cardiovascular and hepatic safety signals at the highest doses warrant patience. But the direction of travel is now clear: more receptors, more selectivity, more outcome.
What this means for the research market
Three things, in order of confidence. One, demand for the research-grade versions of all three molecules will continue to climb — vendors who can hold supply through Lilly's and Novo's branded-product shortages have a multi-year window. Two, the protocol literature lags the molecule by 12–18 months; expect the conversation to catch up to tirzepatide's tolerability tricks well before retatrutide gets its own. Three, the regulator's posture will tighten. Treat that as a when, not an if.
The reading list
The papers that matter for this trajectory are the STEP, SURPASS, SURMOUNT, and the early retatrutide Phase II series. Read the supplementary tables, not just the abstracts — that's where the dose-finding texture lives. [1]
Footnotes
- 1.The supplementary tables of SURPASS-2 in particular separate weight-loss curves by ramp speed in a way the main figures gloss over. Worth the click-through. ↩