Both are from Eli Lilly. One is approved and on shelves today. The other may redefine what weight loss medicine can do. Here's how they compare.
This is a fascinating comparison because both drugs come from the same company — Eli Lilly. Tirzepatide (brand names Mounjaro for diabetes, Zepbound for obesity) was Lilly's landmark dual agonist that took the weight loss world by storm. Retatrutide is essentially its successor — adding a third receptor target to push metabolic outcomes even further.
Understanding how they differ helps illustrate exactly what the glucagon receptor adds to the equation, and whether that addition is worth waiting for.
| Category | Tirzepatide (Mounjaro/Zepbound) | Retatrutide (LY3437943) |
|---|---|---|
| Developer | Eli Lilly | Eli Lilly |
| Receptor Targets | GLP-1 + GIP (dual) | GLP-1 + GIP + Glucagon (triple) |
| Avg. Weight Loss | ~20–22% (72 weeks, SURMOUNT-1) | ~24% (48 weeks, Phase 2) |
| Administration | Once weekly injection | Once weekly injection |
| FDA Approved | ✓ Yes — Diabetes (2022), Obesity (2023) | ✗ Not yet — Phase 3 ongoing |
| Available Now? | ✓ Yes | ✗ Trials only |
| Sleep Apnea Approved | ✓ Yes (2024) | Under investigation |
| Liver Disease (MASH) | Under investigation | Under investigation (TRIUMPH-4) |
| Cardiovascular Data | SURPASS-CVOT completed | TRIUMPH-3 ongoing |
| Energy Expenditure | Limited direct effect | Increased via glucagon pathway |
| Est. List Price | ~$1,060–$1,400/month | Unknown (not approved) |
Tirzepatide proved that adding GIP to GLP-1 produced meaningfully better weight loss than GLP-1 alone — its SURMOUNT-1 trial showed approximately 20–22% weight loss versus ~15% for semaglutide. This validated the dual-agonist concept and set a new benchmark.
Retatrutide then adds glucagon receptor agonism on top of that GLP-1/GIP foundation. The glucagon pathway does something neither of the other two receptors can: it increases the body's resting energy expenditure — essentially raising the metabolic rate. This means the body is not just eating less, it is also burning more. The liver is also directly targeted, with glucagon activation promoting fat oxidation in hepatocytes.
The Phase 2 data suggests this third mechanism adds roughly 2–4 percentage points of additional weight loss beyond what tirzepatide achieves. Whether that holds in the larger, longer Phase 3 trials is the critical unanswered question.
Key distinction: Tirzepatide's weight loss curves showed signs of plateauing by 72 weeks. Retatrutide's Phase 2 curves had not plateaued at 48 weeks — suggesting treatment duration may matter more with the triple agonist, and final weight loss may exceed what Phase 2 captured.
Both drugs share the core GLP-1/GIP side effect signature — nausea, vomiting, diarrhea, and constipation being the most common, predominantly during dose escalation. Both use gradual titration protocols to manage this.
The key difference in tolerability relates to the glucagon component in retatrutide. Glucagon receptor activation can cause a modest additional increase in heart rate and may contribute to slightly higher rates of nausea at the highest doses. Discontinuation rates due to adverse events were somewhat higher for retatrutide at 12 mg (~16%) compared to tirzepatide at its highest approved dose in trials.
That said, the commercial dose of retatrutide — if approved — will be chosen partly based on optimising the tolerability/efficacy balance, so direct Phase 2-to-approval comparisons are imperfect.
You need treatment now. It's FDA approved, widely available, covered by some insurance plans, and has a strong real-world safety track record. At 20–22% weight loss, it already exceeds what most patients need. It's also approved for sleep apnea — a significant added benefit for many patients with obesity.
You need very substantial weight loss, have significant liver fat accumulation, or are someone who hasn't responded adequately to dual agonists. If Phase 3 confirms Phase 2 results, retatrutide could become the preferred option for the highest-need patients — particularly those approaching bariatric surgery territory.
Probably not entirely — and Eli Lilly likely doesn't want it to. Tirzepatide is an enormous commercial success and will continue to serve the large population of patients who respond well to dual agonism. Retatrutide, if approved, is more likely to be positioned as a step-up therapy for patients who need more aggressive intervention, or as a first-line option for specific indications like MASH where the glucagon mechanism adds unique value.
The two drugs could also end up competing head-to-head in the obesity market if retatrutide earns broad approval — at which point the weight loss differential, side effect profile, and price will all factor into prescribing decisions.