Retatrutide vs tirzepatide vs semaglutide: what the research shows

Three molecules, three sets of receptors

Semaglutide, tirzepatide and retatrutide are synthetic peptides modelled on gut hormones. They differ mainly in how many hormone receptors they activate: one, two or three. [1] [4] [7]

Retatrutide adds activity at the glucagon receptor. In obese mice the developer attributed part of its effect on body weight to higher energy expenditure through that receptor, on top of the lower food intake driven by the GIP and GLP-1 receptors. [1]

What the main obesity trials reported

Each result in the table comes from a separate placebo-controlled trial funded by the developer of that molecule. The trials enrolled different people, lasted different lengths of time and used different dose schedules, so the numbers show the size of the effect in each programme but are not a direct comparison. [2] [3] [4] [7]

In STEP 1 both groups also followed a lifestyle intervention. The original papers give the full definitions of each endpoint and of the populations studied. [7]

Head-to-head trials

Tirzepatide has been compared directly with semaglutide in two published trials. In SURPASS-2, in 1,879 adults with type 2 diabetes, tirzepatide lowered HbA1c more than semaglutide at every dose tested, and body weight fell more as well. [5]

In SURMOUNT-5, an open-label phase 3b trial in 751 adults with obesity but without diabetes, the mean body-weight change after 72 weeks was -20.2% with tirzepatide and -13.7% with semaglutide, and waist circumference also fell more with tirzepatide. Both trials were funded by Eli Lilly. [5] [6]

We found no published randomised trial in people that compares retatrutide directly with either molecule. In a 21-day study in mice lacking the MC4R receptor, a model of genetic obesity, body weight fell by about 20% with semaglutide, 32% with tirzepatide and 24% with retatrutide. [8]

Safety findings they share

In all three programmes the most common adverse events were gastrointestinal, such as nausea, diarrhoea, vomiting and constipation, mostly mild to moderate and concentrated in the period when the dose was being increased. [2] [4] [6] [7]

The phase 2 retatrutide obesity trial also recorded dose-dependent increases in heart rate, which peaked at 24 weeks and declined afterwards. For the approved tirzepatide and semaglutide medicines the FDA notes a risk of thyroid C-cell tumours seen in rodents; whether such tumours occur in humans is unknown. [2] [9] [10]

Regulatory status (November 2026)

Semaglutide and tirzepatide are active ingredients of prescription medicines approved in the United States for weight management in certain adults; semaglutide is also approved to reduce the risk of cardiovascular death, heart attack and stroke in adults with cardiovascular disease and obesity or overweight. Retatrutide is not an approved medicine. [9] [10] [11]

The FDA has warned companies that sold semaglutide, tirzepatide or retatrutide directly to consumers for human use, with dosing instructions, while labelling the products ‘for research purposes’ or ‘not for human consumption’. Research material is not a medicine: it has not been reviewed for safety, effectiveness or quality in people and must not be used in people. We sell all three only for in vitro laboratory research, without instructions for use. [11]

Choosing one for a research model

In the laboratory the difference that matters is the receptor profile. Semaglutide isolates GLP-1 receptor signalling, tirzepatide adds the GIP receptor and retatrutide adds the glucagon receptor on top. A cell line or tissue that does not express a receptor cannot respond through it, so the receptors present in the model decide which comparison makes sense. [1] [8]