Dual GLP-1/glucagon agonists: review

A September 2026 systematic review found that dual GLP-1/glucagon receptor agonists produced more weight loss than control treatments across 19 randomized trials in adults with overweight or obesity. The review assessed mazdutide, survodutide, cotadutide, and efinopegdutide. It did not pool retatrutide, because retatrutide also activates GIP, a third receptor.^[1]

What the review found

The authors searched five databases and ClinicalTrials.gov through 20 July 2026, then combined results from 19 randomized controlled trials. Compared with controls, the dual agonists reduced absolute body weight by a mean 6.65 kg and relative weight by 7.15%. Participants were also more likely to reach at least 5% weight loss, although the certainty for that outcome was rated low.^[1]

A systematic review is useful here because the individual programs are easy to blur together. A GLP-1 receptor agonist mimics a gut hormone that affects appetite and glucose handling. Adding glucagon receptor activity may alter energy expenditure and metabolism, but it also creates a safety question that has to be judged across trials, not from a single headline result. The review found improvements in HbA1c and body-mass index. It also reported changes in waist circumference. Systolic blood pressure and triglycerides improved.^[1]

Confidence behind the findings was not identical for every outcome. The authors rated the evidence for the 6.65 kg absolute-weight result as moderate certainty and the serious-adverse-event result as high certainty. For at least 5% weight loss, the evidence was low certainty. Each result therefore carries a different evidentiary weight.^[1]

Which medicines were included

This is a class-specific review, not a verdict on every medicine discussed alongside GLP-1 drugs. Its eligibility criteria covered mazdutide, survodutide, cotadutide, and efinopegdutide in adults with overweight or obesity. The authors said earlier meta-analyses often mixed this group with GIP-containing agents such as tirzepatide and retatrutide, which makes it harder to tell what belongs to the dual GLP-1/glucagon class itself.^[1]

That distinction matters for readers following retatrutide. Retatrutide is a triple agonist: it acts at GIP, GLP-1, and glucagon receptors. In its 48-week phase 2 obesity trial, the 12 mg arm had a least-squares mean body-weight change of minus 24.2%, versus minus 2.1% with placebo. That result is notable, but it cannot be used to infer the effect of a two-receptor class without separating the role of GIP and the differences in trial design.^[2]

Safety is not a footnote

The meta-analysis found any adverse event was more frequent with the dual agonists than with controls, with a risk ratio of 1.16. Serious adverse events did not differ statistically from controls, with a risk ratio of 0.90 and high-certainty evidence. Those findings describe the short-term trial record in the included studies. They do not establish long-term cardiovascular safety or settle how adverse effects compare between individual medicines.^[1]

The retatrutide phase 2 trial also reported a dose-related gastrointestinal pattern, including nausea, diarrhoea, vomiting, and constipation. The paper reported dose-dependent heart-rate increases that peaked at week 24 and declined later in the study. The trial administered several dose-escalation schedules; those schedules are research methods, not instructions for readers.^[2]

What this review does not answer

The review's authors called for longer head-to-head trials to test durability and cardiovascular safety. Its results therefore do not tell a patient which investigational dual agonist is preferable, whether a given result will persist for years, or how a medicine should be used outside a trial. The pooled estimates are an early map of a developing class, not a treatment recommendation.^[1]

The included trials also do not remove the usual limits of pooled research. Drugs, doses, participant populations, and follow-up periods differed across the programs. A mean effect can describe the group of trials while still leaving uncertainty about a particular medicine. The review's subgroup work identified mazdutide and survodutide as the medicines with the largest effects, but that observation is not a substitute for direct comparisons designed around the same population and endpoint.^[1]

The review also used sensitivity, subgroup, GRADE, and publication-bias analyses. Those methods test how stable a pooled finding is when the evidence is examined from different angles, but they cannot manufacture longer follow-up than the trials supplied. For readers comparing the available research with retatrutide coverage, the useful question is which receptor profile and study population each estimate actually represents.^[1]

For retatrutide specifically, the registered TRIUMPH-1 study enrolled 2,335 participants with obesity or overweight and reached its actual primary completion date on 30 April 2026. Trial completion is not the same as regulatory approval or a published full dataset. Readers tracking the molecule can check retatrutide's regulation status separately from research updates.^[3]

Why the class label matters

The cleanest takeaway is narrower than the marketing around newer obesity drugs. The evidence reviewed supports meaningful short-term weight and metabolic changes for four dual GLP-1/glucagon agonists, while adverse events were more common overall and long-horizon questions remain open. Retatrutide belongs in the wider discussion because it includes glucagon activity, but its three-receptor mechanism means its results should be read on their own terms.^[1]