GLP-1 Side Effects: What the Retatrutide and Tirzepatide Trials Reported

The most common GLP-1 side effects reported in trials are gastrointestinal: nausea, diarrhoea, vomiting and constipation. In the SURMOUNT-1 tirzepatide trial, nausea was reported by 25% to 33% of participants depending on dose, against 9.5% on placebo; in the phase 2 retatrutide trial, nausea ranged from 14% at the lowest dose to 60% at the highest. Discontinuation because of adverse events ran from 4% to 7% for tirzepatide and 6% to 16% for retatrutide. Most events were mild to moderate and clustered in the early weeks of each study.

This article sets out what the pivotal trials actually reported for the three incretin compounds UK researchers ask about most (semaglutide, tirzepatide and retatrutide), what was seen beyond the gut, and how the amylin analogues compare. It is a summary of published data for research context. It is not medical advice, and research-grade peptides are not the trial products.

Why GLP-1 compounds cause gastrointestinal effects

GLP-1 is a gut hormone released after eating. Activating its receptor slows gastric emptying, reduces appetite through receptors in the hypothalamus and brainstem, and increases insulin release when glucose is high. The same slowing of the stomach that reduces food intake is the most likely reason nausea and a feeling of fullness are so consistent across every compound in the class. Tirzepatide adds GIP receptor activity and retatrutide adds glucagon receptor activity, but both keep the GLP-1 component, so the gastrointestinal profile carries across.

Two patterns recur in the trial reports. Adverse events are dose-related: higher doses produce more nausea. And they are time-related: rates are highest during the escalation phase of a trial and fall as participants remain on a stable dose. Both patterns are visible in every dataset discussed below.

Semaglutide: the STEP 1 baseline

Semaglutide 2.4mg is the reference point because it was the first weekly GLP-1 agonist licensed for weight management, and it is MHRA-licensed in the UK as Wegovy. In STEP 1 (Wilding and colleagues, New England Journal of Medicine, 2021), 1,961 adults with overweight or obesity were followed for 68 weeks. Nausea was reported by 44.2% of semaglutide participants versus 17.4% on placebo, diarrhoea by 31.5% versus 15.9%, vomiting by 24.8% versus 6.6% and constipation by 23.4% versus 9.5%. Discontinuation because of adverse events was 7.0% versus 3.1%. Gallbladder-related disorders were more frequent on semaglutide (2.6% versus 1.2%).

Tirzepatide: what SURMOUNT-1 reported

SURMOUNT-1 (Jastreboff and colleagues, New England Journal of Medicine, 2022) randomised 2,539 adults with obesity or overweight to tirzepatide 5mg, 10mg or 15mg weekly, or placebo, for 72 weeks. Mean weight loss was 15.0%, 19.5% and 20.9% respectively, against 3.1% on placebo. The adverse-event picture was dominated by gastrointestinal effects, which the authors described as mostly mild to moderate and occurring primarily during dose escalation.

Beyond the gut, SURMOUNT-1 reported alopecia (hair thinning) in roughly 5% of tirzepatide participants versus under 1% on placebo, injection-site reactions, and a small mean increase in resting heart rate. Serious adverse events were similar across arms. Tirzepatide is MHRA-licensed in the UK as Mounjaro, so the full adverse-event data is also set out in its UK product information; research-grade tirzepatide is a different material and is not that medicine.

Retatrutide: what the phase 2 trial reported

Retatrutide is a triple GIP, GLP-1 and glucagon receptor agonist developed by Eli Lilly. Its phase 2 obesity trial (Jastreboff and colleagues, New England Journal of Medicine, 2023) enrolled 338 adults and ran for 48 weeks, with weekly doses of 1mg, 4mg, 8mg and 12mg against placebo. Mean weight loss at 48 weeks reached 24.2% in the 12mg group, the largest figure reported for any single agent at that point.

Adverse events during treatment were reported by 70% of placebo participants and by 73% to 94% of retatrutide participants, with the highest rates in the 8mg and 12mg groups. Nausea ranged from 14% in the 1mg group to 60% in the 12mg group. Discontinuation because of adverse events was 6% to 16% across retatrutide groups and 0% on placebo, with gastrointestinal events the most common reason. The trial also reported an increase in heart rate that peaked at around 24 weeks and declined afterwards, and a small proportion of participants described altered skin sensation (dysaesthesia or hyperaesthesia), a finding that has been carried forward for monitoring in the phase 3 TRIUMPH programme.

The glucagon component is worth a separate note. Glucagon receptor activation raises energy expenditure and hepatic fat oxidation, which is part of the rationale for the triple agonist, but it also tends to raise heart rate and can affect glucose. The phase 2 trial did not report a safety signal that stopped development, and phase 3 trials with several thousand participants are now reading out, which will give a much clearer picture of these effects than 338 participants can.

Class effects beyond the gut

Regulators track a set of class-wide concerns for GLP-1 receptor agonists that go beyond the common gastrointestinal effects. These appear in the UK product information for the licensed medicines and are monitored through the MHRA Yellow Card scheme.

• Gallbladder disease: cholelithiasis and cholecystitis were more frequent on active treatment in STEP 1 and SURMOUNT-1, an effect often linked to rapid weight loss itself.
• Pancreatitis: rare in trials, but listed as a precaution for the whole class and actively monitored.
• Hypoglycaemia: uncommon with these compounds alone, but more frequent in trials where participants were also taking insulin or sulfonylureas.
• Thyroid C-cell tumours: observed in rodent studies of GLP-1 agonists; relevance to humans is unknown and the licensed medicines carry a warning.
• Delayed gastric emptying: the MHRA and anaesthesia bodies have highlighted a possible aspiration risk under general anaesthesia for people taking GLP-1 medicines.
• Mental health: the European Medicines Agency reviewed reports of suicidal thoughts in 2023 and 2024 and concluded that the evidence did not support a causal link.
• Lean mass: DXA substudies in STEP 1 and SURMOUNT-1 showed that a proportion of the weight lost was lean tissue, which has prompted research into combinations that preserve muscle.

How the amylin analogues compare

Cagrilintide and eloralintide act on amylin receptors rather than the GLP-1 receptor, but they also slow gastric emptying, so nausea is the leading adverse event for them too. In the 2021 Lancet phase 2 trial of cagrilintide, gastrointestinal events were reported in 41% to 63% of participants versus 32% on placebo, with nausea in 20% to 47% versus 18%. In the REDEFINE 1 phase 3 trial, the CagriSema combination of cagrilintide and semaglutide showed a gastrointestinal profile broadly similar to semaglutide alone. Eloralintide, a more selective amylin agonist, was reported in its 2025 phase 2 results to have a lower rate of nausea than is typical for the GLP-1 class, which is one reason it has attracted attention, though that is a single trial.

What this means for UK researchers

For a laboratory, the trial adverse-event data is useful mainly as a map of the pharmacology: it tells you that gastric emptying and appetite signalling are the dominant effects, that the glucagon component of retatrutide adds cardiovascular and sensory questions, and that receptor selectivity (as with eloralintide) may change the tolerability profile. Those are researchable questions in animal and cell models, and they are the reason these compounds are stocked as research chemicals.

It is also a reminder of what research-grade material is not. The percentages above come from pharmaceutical products manufactured under GMP, with defined impurity limits and clinical monitoring. A research peptide pen, however well tested, is a laboratory reagent. The relevant quality questions for a reagent are purity, identity and quantity, which is why Calibre publishes Janoshik Analytical certificates of analysis for tested batches (currently including Retatrutide 30mg and 40mg and Tirzepatide 60mg) on the COA page.

Summary

Across semaglutide, tirzepatide and retatrutide, the trials report the same core pattern of GLP-1 side effects: dose-related nausea, diarrhoea, vomiting and constipation that peak early and mostly resolve, with discontinuation rates in the mid single digits for the licensed medicines and up to 16% at the highest retatrutide dose. Retatrutide adds a heart-rate signal and reports of altered skin sensation that phase 3 will clarify. Class-wide concerns such as gallbladder disease and pancreatitis are monitored by the MHRA for the licensed products. Research-grade peptides are not those products and are supplied for laboratory use only.