Obesity
~100 million Americans; ~2 billion globally. Fewer than 1 in 10 eligible Americans currently using modern obesity medicines. Discussed extensively by Jay Bradner (Amgen) and Kenneth Custer (Lilly) at Session VII.
The Incretin Evolution
Each generation outmodes the last by efficacy (technological obsolescence, not patent cliff):
| Generation | Drug | Weight Loss | Dosing |
|---|---|---|---|
| GLP-1 mono-agonist | Semaglutide | ~15% | Weekly SC or oral |
| GIP/GLP-1 dual agonist | Tirzepatide | ~21-22% | Weekly SC |
| Oral GLP-1R agonist | Orforglipron | ~15% (maintenance) | Daily oral |
| GIPR antagonist + GLP-1 | Maritide | Profound, no plateau at 52 wk | Monthly SC |
| GIP/GLP-1/glucagon triple | Retatrutide | 28.7% | Weekly SC |
| Amylin agonist | (Lilly, Phase 2) | ~20% | TBD |
See also: tirzepatide, orforglipron, maritide, retatrutide
Key Data
- Retatrutide TRIUMPH-4: 28.7% weight loss at 68 weeks; ~75% WOMAC pain reduction
- Orforglipron: manufacturable “like a blood pressure pill” — the scale argument for reaching 2 billion patients
- Amylin: GI vomiting rate ~1 in 52 (vs ~21% semaglutide) — orthogonal tolerability for GLP-1 intolerant patients
The Scale Imperative
Injectable pens require sterile fill-finish facilities serving single-digit millions. Oral tablets arrive by train car. To reach 2 billion people, the drug must be manufactured at that scale.
Beyond Cardiometabolic
Lilly has Phase 3 trials in substance use disorder, MDD, schizophrenia, bipolar, alcohol/tobacco/opioid use disorder — incretin signaling being reconceived as general-purpose neuromodulation.
Muscle Loss Debate
- Lean mass loss during major weight loss is physiologically normal (~80/20 fat-to-lean split regardless of mechanism)
- BELIEVE study (semaglutide + bimagrumab): clear bias toward fat loss over lean mass loss
- Key question is functional preservation, not absolute lean mass
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