If orforglipron works as a pill, why would anyone choose injectable semaglutide or tirzepatide? Is there any advantage to injections?

A few reasons injections might remain preferable for some patients:

1. Efficacy ceiling: Tirzepatide (dual agonist) achieves ~21% weight loss. If orforglipron (single agonist) maxes out at ~15%, patients who need more weight loss will prefer the injectable.
2. Once-weekly vs. daily dosing: Some patients actually prefer a weekly injection over a daily pill. Adherence to daily medications is generally lower than weekly medications in chronic disease.
3. Drug interactions: Oral drugs are subject to food-drug interactions, CYP metabolism, and variable absorption. Injectable peptides bypass all of this. Orforglipron is CYP3A4-metabolized, which opens a whole world of potential drug-drug interactions that don't exist with injectable semaglutide.
4. GI effects on absorption: If a patient is vomiting from GLP-1 side effects, they may not absorb the next day's oral dose. Injectable bypasses this issue.

That said, for the majority of patients, an effective oral option is transformative. Most people prefer pills, and the expansion of treatment access could be enormous.

The access question is perhaps the most important one. Currently, ~40 million Americans would be eligible for GLP-1 RA therapy for obesity, but supply constraints and cost limit treatment to a small fraction. An oral small molecule that can be manufactured at scale and priced more aggressively could democratize access.

Lilly hasn't announced expected pricing, but analysts estimate orforglipron could be priced 30-50% below injectable GLP-1 RAs. If combined with insurance coverage expansion (driven by SELECT and FLOW outcome data), we could see a step-change in treatment uptake.

ATTAIN Phase 3 readouts in 2025-2026 will be pivotal. This thread will be worth revisiting when the data drop.

One more analytical note. The ATTAIN-4 CV outcome trial is particularly interesting. If orforglipron can replicate SELECT's MACE reduction with an oral formulation, it dramatically changes the cost-effectiveness equation. The per-year ARR might be similar, but if the drug cost is halved, the cost-per-QALY drops to potentially below the $100K/QALY threshold, making it cost-effective without even factoring in weight loss benefits.

ATTAIN-4 is event-driven and enrolling ~12,000 patients. Expected completion around 2028-2029. That's a long wait, but if positive, it would be the second GLP-1 RA with CV outcome benefit and the first oral one. The market and policy implications would be enormous.