GLP-1 medicines changed obesity care in under a decade. The next generation is already in late-stage trials, and it works differently: instead of mimicking one gut hormone, the new candidates hit two or three hormone pathways at once, or add a different hormone family entirely. For health systems planning budgets, workforce and access policies, understanding these mechanisms is becoming as important as understanding GLP-1 itself.
From one hormone to three
The first wave mimicked glucagon-like peptide-1 (GLP-1), which boosts insulin release, slows stomach emptying and reduces appetite. The second wave, led by tirzepatide, added a second gut hormone, glucose-dependent insulinotropic polypeptide (GIP), and produced larger weight losses.
The third wave goes further. Retatrutide, developed by Eli Lilly, activates three receptors: GIP, GLP-1 and glucagon. Adding glucagon is counterintuitive, because glucagon raises blood sugar. But it also increases energy expenditure and fat burning in the liver, and when balanced against GLP-1 and GIP the net effect appears strongly favourable.
What the 2026 data show
Retatrutide’s phase 2 trial, published in the New England Journal of Medicine in 2023, reported mean weight loss of 24.2% at 48 weeks on the highest dose. The phase 3 TRIUMPH programme has since reported:
- TRIUMPH-1 (May 2026): in 2,339 adults with obesity or overweight and no diabetes, mean weight loss at 80 weeks was 17.6%, 23.7% and 25.0% at the 4, 9 and 12 mg doses, versus 3.9% on placebo. Nausea, diarrhoea, constipation and vomiting were the most common side effects.
- TRIUMPH-2 and TRIUMPH-3 (July 2026): positive results in people with type 2 diabetes and in people with severe obesity and established cardiovascular disease, with reductions in triglycerides, blood pressure and inflammatory markers.
Lilly has said it plans to file for FDA approval in the first quarter of 2027. Until then, retatrutide is an investigational molecule; the company has stated it is legally available only in clinical trials.
Amylin: the other satiety hormone
A parallel track targets amylin, a hormone released alongside insulin by pancreatic beta cells. Amylin slows stomach emptying, reduces after-meal glucagon and signals fullness through the brainstem. A short-acting analogue, pramlintide, has been used in diabetes since 2005.
Cagrilintide, developed by Novo Nordisk, is a long-acting amylin analogue suited to once-weekly dosing. Combined with semaglutide in a single weekly injection known as CagriSema, it produced mean weight loss of about 20% at 68 weeks in the phase 3 REDEFINE 1 trial. Because amylin works through different brain circuits from GLP-1, combinations may reach larger losses at lower doses of each.
Why preclinical research still matters
Large trials answer whether a drug works. They do not answer every question about how it works, which tissues respond, or how these hormones interact with muscle, bone and the liver over time. That work happens in cell cultures and animal models.
Laboratories studying these pathways use research-grade compounds such as retatrutide (GLP-RT) and cagrilintide, supplied strictly for in vitro and animal research with batch-specific certificates of analysis. These are not medicines, and their use in people outside a clinical trial is neither legal nor safe.
Implications for health systems
- Demand will keep rising. Each generation has produced larger weight losses, which widens the group of patients for whom treatment makes clinical sense.
- Muscle preservation is the next question. Rapid weight loss includes lean mass. Systems may need protein and resistance-training support built into obesity pathways.
- The grey market is a public health risk. Demand for unapproved compounds sold online as “research chemicals” for personal use is already a concern for regulators. Clear public messaging about the difference between approved medicines and research compounds will matter.
- Access and cost will dominate policy. Combination and triple-agonist therapies will force new decisions on coverage, prioritisation and long-term budgets.
The science of metabolic disease is moving faster than at any point in modern medicine. The systems that understand the mechanisms early will be better placed to use the new medicines well.
