Beyond semaglutide: tirzepatide and retatrutide

Semaglutide showed that a long-acting peptide acting on one gut-hormone receptor could produce substantial weight loss. The next step in this field has been to build single molecules that act on two or three receptors at once. Tirzepatide adds activity at the glucose-dependent insulinotropic polypeptide (GIP) receptor. Retatrutide adds the glucagon receptor as well. This article compares how the three are designed, what their published human trials show, and how far the evidence for each has progressed.

Semaglutide and tirzepatide are licensed medicines, and retatrutide is investigational. This article summarises published research for scientific understanding. It is not a guide to treatment and does not compare the compounds as options for any individual.

Three generations of receptor targeting

One receptor: semaglutide

Glucagon-like peptide-1 (GLP-1) is released from the gut after eating. Through its receptor, it increases glucose-dependent insulin release, reduces glucagon secretion and slows gastric emptying. It also reduces food intake, acting through receptors in the brain and in the nerves linking gut and brain^[1]. Native GLP-1 is short-lived in the circulation. Semaglutide was engineered to resist degradation and to bind strongly to serum albumin, which prolongs its action^[2]. Its design and the STEP trials are covered in detail in our semaglutide review.

Two receptors: tirzepatide

Tirzepatide is a single fatty-acid-modified peptide that activates both the GIP and GLP-1 receptors. In mice, it reduced food intake and body weight more than a selective GLP-1 receptor agonist^[3]. Later pharmacology work showed that it engages the GIP receptor more than the GLP-1 receptor. At the GLP-1 receptor, it favours one intracellular signalling pathway over another. The developers proposed that this profile may contribute to its efficacy^[4]. Our tirzepatide review covers the SURPASS and SURMOUNT programmes.

Three receptors: retatrutide

Retatrutide, first known as LY3437943, is a single peptide that activates the glucagon, GIP and GLP-1 receptors. In cell assays, its activity at the glucagon and GLP-1 receptors was balanced, with greater activity at the GIP receptor^[5].

The rationale for adding glucagon is energy expenditure. In obese mice, the weight loss seen with retatrutide was explained by GIP and GLP-1 receptor-driven reductions in food intake plus glucagon receptor-driven increases in energy expenditure^[5]. A 2026 review of glucagon-based approaches noted that most mechanistic evidence for glucagon receptor agonism still comes from rodent studies, because clinical data remain very limited^[6].

Weight-related outcomes

The pivotal obesity trials of semaglutide and tirzepatide lasted 68 and 72 weeks. Both enrolled adults without diabetes who had obesity, or overweight with a weight-related condition.

• Semaglutide. In STEP 1, 1,961 adults lost a mean of 14.9% of body weight over 68 weeks, compared with 2.4% on placebo^[7].
• Tirzepatide. In SURMOUNT-1, 2,539 adults lost 15.0% to 20.9% over 72 weeks, depending on dose, compared with 3.1% on placebo^[8].
• Retatrutide. In a 48-week phase 2 trial of 338 adults, the highest dose group lost a mean of 24.2%, compared with 2.1% on placebo. Weight loss increased with dose. At that dose, 83% of participants lost at least 15% of their body weight^[9].

These figures come from different trials, with different durations, populations and phases of development. The retatrutide trial was a phase 2 dose-finding study, much smaller than the phase 3 trials. It was not designed to confirm efficacy.

Glycaemic outcomes in type 2 diabetes

All three compounds have been tested in people with type 2 diabetes, where the primary outcome is usually glycated haemoglobin (HbA1c).

• Tirzepatide. In SURPASS-2, tirzepatide lowered HbA1c by 2.01 to 2.30 percentage points, compared with 1.86 for semaglutide 1 mg, a head-to-head comparison^[10].
• Retatrutide, phase 2. In a 36-week trial of 281 participants, retatrutide at higher doses lowered HbA1c by about 2 percentage points at 24 weeks. In two of the higher-dose groups, the reduction was significantly greater than with the active comparator dulaglutide^[11].
• Retatrutide, phase 3. The first peer-reviewed phase 3 report was published in 2026. It covered 537 adults whose type 2 diabetes was inadequately controlled by diet and exercise alone. Over 40 weeks, HbA1c fell by 1.69 to 1.94 percentage points with retatrutide, against 0.81 with placebo. Body weight fell by 11.5% to 15.3%, against 2.6%^[12].

A phase 2 substudy also measured liver fat in people with metabolic dysfunction-associated steatotic liver disease. At 24 weeks, the higher doses of retatrutide reduced liver fat by more than 80% in relative terms. The reductions tracked changes in body weight and in metabolic measures^[13].

Adverse-event reporting

Across all three compounds, gastrointestinal effects were the most common adverse events. They were usually mild to moderate and occurred mainly during dose escalation.

• In SURMOUNT-1, adverse events led to discontinuation in 4.3% to 7.1% of participants on tirzepatide, compared with 2.6% on placebo^[8].
• In the retatrutide obesity trial, gastrointestinal events were dose-related and were partly reduced by a lower starting dose. Heart rate rose with dose, peaked at 24 weeks and then declined^[9].
• In the retatrutide phase 3 diabetes trial, 2% to 5% of participants on retatrutide stopped treatment because of adverse events, compared with none on placebo. No severe hypoglycaemia was reported^[12].
• The first multiple-dose study of retatrutide reported a half-life of about six days and gastrointestinal events as the most frequent adverse events^[14].

The heart-rate finding matters for a molecule that includes glucagon receptor activity. It is one reason longer and larger trials are needed before the safety profile of retatrutide can be considered established.

Phase of clinical development

The three compounds sit at very different points.

• Semaglutide has cardiovascular outcome evidence. In SUSTAIN-6, among 3,297 people with type 2 diabetes at high cardiovascular risk, major cardiovascular events were less frequent than with placebo (hazard ratio 0.74). Retinopathy complications were more frequent^[15]. SELECT extended the evidence to people with cardiovascular disease and overweight or obesity without diabetes^[16].
• Tirzepatide was compared with dulaglutide in SURPASS-CVOT, involving 13,299 people with type 2 diabetes and atherosclerotic cardiovascular disease. It was non-inferior for major cardiovascular events (hazard ratio 0.92), but superiority was not shown^[17].
• Retatrutide is in phase 3. The TRIUMPH programme comprises four trials with more than 5,800 participants, covering obesity, obstructive sleep apnoea, knee osteoarthritis and established cardiovascular disease^[18]. A mechanistic kidney study, TRANSCEND-CKD, is under way. Its authors describe a separate cardio-kidney outcome trial as ongoing^[19].

The limits of cross-trial comparison

It is tempting to rank the three compounds by their largest reported weight loss. That comparison is not valid:

• Different phases. A phase 2 dose-finding trial and a phase 3 confirmatory trial answer different questions. Smaller trials give less precise estimates.
• Different durations. A figure at 48 weeks cannot be compared directly with one at 68 or 72 weeks.
• Different populations. In the tirzepatide programme, people with type 2 diabetes lost less weight than people without diabetes over the same period^[20][8]. Baseline weight, age and background treatment also vary between trials.
• Different analyses. Trials handle discontinuation and rescue therapy differently, and this changes the headline estimate.
• Common sponsorship. The trials of tirzepatide and retatrutide were funded by the same manufacturer, and the semaglutide trials cited here involved its manufacturer^[12][17][16]. That does not invalidate them, but independent replication remains valuable.

Only head-to-head randomised trials support direct conclusions. For tirzepatide and semaglutide, these include SURPASS-2 in diabetes^[10] and SURMOUNT-5 in obesity^[21], both open-label. No head-to-head trial of retatrutide against either compound had been published at the time of writing.

Summary

The incretin field has moved from single-receptor agonists to molecules that act on two or three receptors. Semaglutide and tirzepatide are licensed medicines, supported by large phase 3 trials and cardiovascular outcome studies. Retatrutide adds glucagon receptor activity, intended to increase energy expenditure. It has produced large weight reductions in a phase 2 trial and glycaemic and weight benefits in a published phase 3 trial in type 2 diabetes. Its wider phase 3 programme has not yet been fully reported in peer-reviewed form. The compounds differ in mechanism, evidence and stage of development. Comparisons across separate trials should not be read as a ranking.