A new trial reveals that once-weekly amycretin injections help adults shed more than 20% of their body weight, marking a major leap forward in obesity care and metabolic health.
Trial: Amycretin, a novel, unimolecular GLP-1 and amylin receptor agonist administered subcutaneously: results from a phase 1b/2a randomised controlled study. Image Credit: Gecko Studio / Shutterstock
In a recent study published in The Lancet, a group of researchers evaluated the safety, tolerability, pharmacokinetics, and weight-reducing effects of once-weekly subcutaneous amycretin in adults who are overweight or obese.
Background
Obesity affects more than one billion people worldwide. It drives serious conditions such as cardiovascular disease, type 2 diabetes, and sleep apnea. Yet, many individuals still fall short of their health goals despite using weight-loss medicines that mimic glucagon-like peptide 1 (GLP-1) or glucose-dependent insulinotropic polypeptide (GIP).
The gut hormone amylin, which suppresses appetite and slows gastric emptying, enhances the effects of GLP-1-based therapies when used in combination. Amycretin is a single peptide designed to activate GLP-1, amylin, and calcitonin receptors simultaneously, potentially delivering stronger and longer-lasting weight control.
The safety in regular use and efficacy of this multi-pathway approach in humans remain unclear, highlighting the need for further research.
About the Study
Investigators conducted a five-part, randomized, placebo-controlled Phase 1b/2a trial at a single site in the United States (San Antonio, Texas). Eligible adults (aged 18–55 years) had a body mass index (BMI) of 27.0–39.9 kg/m² and no major illnesses such as diabetes. Participants received either amycretin or placebo as a weekly subcutaneous injection.
Part A tested single ascending doses (0.3 mg, 0.6 mg, 1.0 mg). Parts B to E studied multiple doses in separate cohorts: Part B escalated doses up to 60 mg over 36 weeks; Part C escalated to a 20 mg maintenance dose for the last 12 weeks of 36 weeks; Part D escalated to a 5 mg maintenance dose for the last 12 weeks of 28 weeks; and Part E escalated to a 1.25 mg maintenance dose for the last 12 weeks of 20 weeks.
The primary endpoint was the incidence of treatment-emergent adverse events. Secondary endpoints included changes in body weight, pharmacokinetic metrics (maximum plasma concentration and area under the curve), and exploratory metabolic markers such as fasting plasma glucose and glycated hemoglobin (HbA1c).
Investigators monitored participants using laboratory tests, electrocardiograms, and safety visits, and analyzed outcomes with statistical models adjusted for baseline weight.
Study Results
Between September 2023 and April 2024, investigators enrolled 125 adults and randomly assigned 101 to amycretin and 24 to placebo at a single center in San Antonio, Texas. Participants were 18–55 years old, had baseline BMIs ranging from 30.0 to 33.1 kg/m² across groups (with an overall mean of 33.4 kg/m²), and weighed between 83.6 and 99.1 kg at baseline.
Part A evaluated single doses of 0.3 mg, 0.6 mg, and 1.0 mg and confirmed acceptable tolerability. Parts B through E then evaluated different dosing regimens: Part B escalated weekly doses to 60 mg over 36 weeks; Part C to a 20 mg maintenance dose; Part D to a 5 mg maintenance dose; and Part E to a 1.25 mg maintenance dose, each with a 12-week maintenance phase at the final dose.
Thirty-eight amycretin recipients (37%) and four placebo recipients (17%) discontinued participation, most frequently for non-safety reasons (e.g., withdrawal of consent, recreational drug use). Importantly, most discontinuations in the placebo group were unrelated to treatment, supporting a likely nocebo effect.
Treatment-emergent adverse events occurred in 92% of amycretin users compared with 100% of placebo participants in Parts B–E reporting at least one event. Gastrointestinal symptoms predominated and were generally mild or moderate in intensity.
Nausea affected 82%, vomiting 53%, and diarrhea 41% of treated participants, peaking during up-titration and diminishing thereafter. Dysaesthesia incidence varied by dose: 18% in Part B (60 mg), 29% in Part C (20 mg), and 6% in Part D (5 mg), resolving in all but one case. A single case of mild gallstone pancreatitis occurred in a Part C participant during dose escalation (2.5 mg); this later progressed to a serious recurrent event but resolved without sequelae by study end.
Weight reduction was rapid, dose-dependent, and sustained. At their respective end-of-treatment timepoints, estimated mean percentage losses from baseline were:
- 24.3% with 60 mg (week 36)
- 22.0% with 20 mg (week 36)
- 16.2% with 5 mg (week 28)
- 9.7% with 1.25 mg (week 20)
Placebo groups showed weight changes of -1.1% (Part B), +1.9% (Part C), +2.3% (Part D), and +2.0% (Part E). Superiority to placebo was evident by week 4 and widened through the study, with no weight-loss plateau observed during the 12-week maintenance phases in any cohort. Mixed-model repeated-measures analyses, adjusting for baseline weight, discontinuation, and missing data, yielded virtually identical estimates, reinforcing the accuracy.
Metabolic markers showed exploratory improvements in parallel with weight. Fasting plasma glucose levels declined by up to 0.8 mmol/L, and HbA1c levels decreased by 0.6 percentage points in the highest-dose cohort, although statistical significance versus placebo was inconsistent across doses. Lipid profiles and seated blood pressure remained neutral.
Continuous electrocardiography revealed no clinically relevant QT prolongation, and a transient increase in pulse of approximately 10 beats per minute after initial injections resolved spontaneously. Antidrug antibodies appeared in 29% (5/17) of Part B (60 mg) participants, 21%