GLP-1, GIP and glucagon: from single to dual to triple agonists

GLP-1 receptor agonism stimulates insulin and inhibits glucagon secretion, slows gastric emptying and is a physiological regulator of appetite ^1,2. The tirzepatide label adds that nonclinical studies suggest GIP receptor activity may further contribute to the regulation of food intake ³. Glucagon receptor activity is the least intuitive addition, because glucagon raises blood glucose; in obese mice, however, the triple agonist LY3437943 (retatrutide) was reported to add glucagon-receptor-mediated increases in energy expenditure to GIP- and GLP-1-receptor-driven reductions in calorie intake ⁴.

Single: GLP-1 alone

Semaglutide is a GLP-1 receptor agonist ⁵. In the STEP 1 trial, adults with overweight or obesity had a mean body-weight change of -14.9% at 68 weeks versus -2.4% with placebo ⁶.

Dual: GLP-1 plus GIP

A 2013 report described a unimolecular GLP-1/GIP co-agonist that outperformed selective GLP-1 agonists on glycaemic measures in rodents, monkeys and humans, while a selective GIP agonist showed negligible weight-lowering efficacy in obese rodents ⁷. Tirzepatide is the marketed example of a GIP and GLP-1 receptor agonist ³. In SURPASS-2, tirzepatide produced larger HbA1c and body-weight reductions than semaglutide over 40 weeks in an open-label trial in type 2 diabetes ⁸. In SURMOUNT-5, an open-label phase 3b trial, adults with obesity but without diabetes had a mean weight change of -20.2% with tirzepatide versus -13.7% with semaglutide at week 72 ⁹.

Dual: GLP-1 plus glucagon

Survodutide is an investigational glucagon receptor and GLP-1 receptor dual agonist ¹⁰. In a 46-week phase 2 trial in adults with overweight or obesity, mean body-weight change ranged from -6.2% to -14.9% across four doses versus -2.8% with placebo, and gastrointestinal adverse events occurred in 75% of survodutide recipients versus 42% of placebo recipients ¹¹. A phase 2 trial in MASH reported improvement without worsening of fibrosis in 43% to 62% of participants across survodutide groups versus 14% with placebo, with nausea, diarrhoea and vomiting more frequent than with placebo ¹². In the phase 3 SYNCHRONIZE-2 trial in adults with obesity and type 2 diabetes, mean weight change at week 76 was -8.2% and -9.8% in the two survodutide groups versus -3.9% with placebo ¹⁰.

Triple: GLP-1, GIP and glucagon

Retatrutide is an investigational agonist of all three receptors ^13,14. In a 48-week phase 2 trial in adults with obesity, mean body-weight change in the highest-dose group was -24.2% versus -2.1% with placebo, adverse events were mainly gastrointestinal and dose-related, and heart rate rose in a dose-dependent manner before declining after week 24 ¹³. In the phase 3 TRIUMPH-1 trial (80 weeks), the three retatrutide groups had mean weight changes of -17.6%, -23.7% and -25.0% versus -3.9% with placebo, and the trial also reported changes in knee-osteoarthritis pain scores and in apnoea-hypopnoea events in prespecified subgroups ¹⁵. In TRIUMPH-2, which enrolled adults with obesity and type 2 diabetes, weight change at week 80 ranged from -11.9% to -18.8% versus -5.1% with placebo ¹⁴.

Reading the numbers with care

Cross-trial comparison is unreliable: the trials differ in duration, population, comparator, blinding and statistical estimand ^9,14,15,16, and drug labels caution that adverse reaction rates from one programme cannot be directly compared with another ⁵. Only SURMOUNT-5 compared two of these drugs directly, and it was open-label ⁹. Retatrutide is also under investigation in comorbidities including knee osteoarthritis and obstructive sleep apnoea, and long-term outcome-trial reports for the glucagon-containing drugs were not among the sources reviewed here ^14,15.

Emerging safety signals

The Wegovy and Zepbound labels carry a boxed warning for thyroid C-cell tumours, based on rodent findings whose human relevance has not been determined ^3,5. Dysesthesia is one signal that has attracted attention: the Wegovy label lists it in 2% of treated adults versus 1% with placebo ⁵, and in TRIUMPH-2 it was reported in 4% to 7% of retatrutide recipients versus 1% with placebo, alongside more frequent hypotension and higher rates of discontinuation due to adverse events or death in the 9 mg and 12 mg groups than in the 4 mg and placebo groups ¹⁴. A 2026 pharmacovigilance analysis described dysesthesia as appearing dose-dependent and more frequent with more potent GLP-1 receptor agonists ¹⁷. That work was a disproportionality analysis of spontaneous reports, a design that cannot establish incidence ¹⁷. An observational study reported an association between semaglutide prescriptions and non-arteritic anterior ischemic optic neuropathy, with causality still to be assessed ¹⁸. A cross-sectional study has also examined self-reported adverse effects among social media users describing nonapproved retatrutide use, and self-reports of that kind cannot establish incidence ¹⁹.

Key points

• Adding GIP and then glucagon activity has been associated with larger weight changes in separate trials, but cross-trial comparison is unreliable ^6,15,16.
• SURMOUNT-5 is the main head-to-head obesity trial of tirzepatide and semaglutide and was open-label ⁹.
• Survodutide and retatrutide remain investigational, with phase 3 trial reports published in 2026 ^10,14.
• Gastrointestinal adverse events dominate across the class, and dysesthesia and heart rate changes are among the signals still being characterised ^11,13,14.