The era of single-mechanism obesity pharmacotherapy is ending. Every major manufacturer is developing — or already testing — combination approaches that pair GLP-1 receptor agonism with one or more additional mechanisms: GIP agonism, glucagon agonism, amylin agonism, or entirely novel targets. The pipeline is deep, and the weight loss numbers keep rising.
The pipeline by mechanism
| Compound | Sponsor | Mechanism | Phase | Key Data |
|---|---|---|---|---|
| CagriSema | Novo Nordisk | GLP-1 + Amylin | Phase 3 (REDEFINE) | ~22-25% weight loss at 68wk |
| Retatrutide (LY3437943) | Eli Lilly | GLP-1 + GIP + Glucagon | Phase 3 (TRIUMPH) | ~24% at 48wk (Phase 2) |
| Survodutide (BI 456906) | Boehringer / Zealand | GLP-1 + Glucagon | Phase 3 | ~19% at 46wk (Phase 2) |
| Amycretin | Novo Nordisk | GLP-1 + Amylin (oral) | Phase 2 | ~13% at 12wk (early signal) |
| Pemvidutide | Altimmune | GLP-1 + Glucagon | Phase 2 | ~10-15% at 48wk |
| Mazdutide (LY3305677) | Innovent / Lilly | GLP-1 + Glucagon | Phase 3 (China) | ~15-18% at 48wk |
| CT-388 | Carmot / Roche | GLP-1 + GIP | Phase 2 | Ongoing |
| VK2735 | Viking Therapeutics | GLP-1 + GIP | Phase 2 | ~14.7% at 13wk |
| Ecnoglutide | Sciwind / MSD | GLP-1 (long-acting) | Phase 2/3 | Biweekly dosing option |
Triple agonists: the frontier
Retatrutide is the only triple agonist (GLP-1 + GIP + glucagon) in Phase 3 development. The addition of glucagon receptor agonism to the GLP-1/GIP dual mechanism adds a thermogenic component — glucagon increases energy expenditure. Phase 2 data showed ~24% weight loss at 48 weeks at the highest dose, the most impressive early-stage data in the class.
The risk of triple agonism is the glucagon component's effect on hepatic glucose output. Glucagon raises blood sugar — a manageable issue when balanced by GLP-1's glucose-lowering effect, but one that requires careful dose optimization. The TRIUMPH Phase 3 program will determine whether the Phase 2 efficacy translates to a confirmatory trial at a dose that balances weight loss, glucose control, and tolerability.
Amylin combinations: CagriSema and amycretin
Novo Nordisk is pursuing amylin agonism through two approaches: CagriSema (injectable cagrilintide + semaglutide, Phase 3) and amycretin (oral GLP-1/amylin co-agonist, Phase 2). Amycretin is particularly noteworthy — if the early Phase 2 signal holds, it could be the first oral combination peptide for obesity, combining the convenience of a pill with multi-mechanism efficacy.
GLP-1 + glucagon dual agonists
Survodutide and pemvidutide represent the GLP-1 + glucagon dual-agonist approach. The glucagon component provides hepatic fat reduction benefits that pure GLP-1 agonists achieve indirectly. This positions GLP-1/glucagon duals as potentially superior for patients with both obesity and metabolic-associated steatotic liver disease (MASLD/NASH) — a massive overlap population.
The pipeline is shifting from 'how much weight can a single mechanism produce' to 'which combination of mechanisms optimizes efficacy, tolerability, and organ-specific benefits.' By 2028-2030, physicians may choose between GLP-1/amylin (CagriSema), GLP-1/GIP/glucagon (retatrutide), GLP-1/glucagon (survodutide), and oral combinations (amycretin) — each tailored to different patient profiles.