How does it work?
The body itself makes two gut hormones, GIP and GLP-1, which are released when we eat and help regulate blood sugar and appetite. Tirzepatide is designed to mimic both of these hormones at once – which is why it is called a "dual-acting" molecule. Research has seen that it affects how the body releases insulin, how quickly the stomach empties and the feeling of being full.
Technical mechanism
Dual agonist at the GIP and GLP-1 receptors. Mimics two gut hormones at the same time; affects insulin secretion, gastric emptying and satiety.
What is being researched?
- Blood sugar regulation in adults with type 2 diabetes (the SURPASS studies)
- Body weight and overweight (the SURMOUNT studies)
- Maintenance of weight loss when treatment is continued over time
- Obstructive sleep apnoea in people with overweight
- Fatty liver/liver inflammation linked to metabolism (MASH)
- Insulin sensitivity and pancreatic function
About the evidence: The evidence base for tirzepatide rests on large, randomised phase 3 studies in humans (the SURPASS and SURMOUNT programmes) with thousands of participants, published in journals such as the New England Journal of Medicine and The Lancet. Much of the liver research (MASH) is so far at phase 2 level, and the very longest-term effects are still being explored. The studies are largely funded by the manufacturer. All research here is presented for informational purposes and says nothing about use outside research.
Research profile
Studies and sources
The links go to independent research databases (PubMed, PubMed Central, ClinicalTrials.gov). The studies are in English and open in a new tab.
Blood sugar and type 2 diabetes (the SURPASS programme)
SURPASS is a series of large phase 3 studies in which researchers have compared tirzepatide with placebo, with the medicine semaglutide and with insulin in adults with type 2 diabetes.
- Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial Clinical (human)PubMed· 2021
In this phase 3 study (SURPASS-1) of 478 adults with type 2 diabetes that was not adequately controlled with diet and exercise, participants received tirzepatide at three different doses or placebo as a weekly injection for 40 weeks. All tirzepatide doses lowered long-term blood sugar (HbA1c) clearly more than placebo, and most reached their blood sugar targets. Participants also lost weight.
- Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes Clinical (human)PubMed· 2021
In this study of 1,879 patients with type 2 diabetes, tirzepatide was compared with semaglutide, both as a weekly injection for 40 weeks. Tirzepatide lowered long-term blood sugar (HbA1c) at least as much as, and at higher doses more than, semaglutide. Weight loss was also greater with tirzepatide. The most common side effects were mild to moderate gastrointestinal complaints in both groups, such as nausea, diarrhoea and vomiting.
- Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial Clinical (human)PubMed· 2021
In this study (SURPASS-4) of adults with type 2 diabetes and high cardiovascular risk, tirzepatide was compared with insulin (glargine), both for at least 52 weeks. Tirzepatide lowered long-term blood sugar (HbA1c) more than insulin. Gastrointestinal complaints such as nausea, diarrhoea, decreased appetite and vomiting were more common with tirzepatide, and were mostly mild to moderate. The study was specifically designed to assess cardiovascular safety.
Body weight and overweight (the SURMOUNT programme)
The SURMOUNT studies have explored how tirzepatide affects body weight in adults with overweight, both with and without diabetes, and what happens to weight when treatment is continued or stopped.
- Tirzepatide Once Weekly for the Treatment of Obesity Clinical (human)PubMed· 2022
In this 72-week phase 3 study (SURMOUNT-1), 2,539 adults with obesity but without diabetes received tirzepatide at three doses or placebo as a weekly injection. Participants lost substantial weight – on average 15 to 21 per cent depending on dose, compared with around 3 per cent with placebo. Most achieved at least 5 per cent weight loss, and many over 20 per cent. The most common side effects were mild to moderate gastrointestinal complaints, mostly during dose escalation.
- Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial Clinical (human)PubMed· 2023
In this 72-week study (SURMOUNT-2), 938 adults with both obesity and type 2 diabetes received tirzepatide (10 or 15 mg) or placebo as a weekly injection. Participants on tirzepatide lost on average around 13 to 15 per cent of their weight, compared with about 3 per cent with placebo. Far more on tirzepatide achieved at least 5 per cent weight loss. The most common side effects were mild to moderate gastrointestinal complaints such as nausea, diarrhoea and vomiting.
- Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial Clinical (human)PubMed· 2024
In this study (SURMOUNT-4), adults with obesity first received tirzepatide for 36 weeks, losing around 21 per cent of their weight. Half then continued with tirzepatide, while the others switched to placebo for 52 weeks. Those who continued lost a little more weight, while those who switched to placebo regained much of the weight. The study thus observed that continued treatment was needed to maintain the weight loss. Side effects were mostly mild to moderate gastrointestinal complaints.
Other metabolic outcomes: sleep apnoea and liver
Researchers have also investigated tirzepatide in obstructive sleep apnoea in people with overweight, and in metabolism-related fatty liver disease with liver fibrosis (MASH).
- Tirzepatide for the Treatment of Obstructive Sleep Apnea and Obesity Clinical (human)PubMed· 2024
In these two phase 3 studies, adults with moderate to severe obstructive sleep apnoea and obesity received tirzepatide or placebo for 52 weeks – some used a breathing machine (PAP), others did not. Tirzepatide reduced the number of breathing pauses per hour (AHI) clearly more than placebo in both studies. Participants also lost weight, and several other measures improved, such as blood pressure and an inflammatory marker (CRP). The most common side effects were mild to moderate gastrointestinal complaints.
- Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis Clinical (human)PubMed· 2024
In this phase 2 study, 190 participants with the liver disease MASH and moderate to severe scarring (fibrosis) of the liver received tirzepatide at three doses or placebo for 52 weeks. Far more on tirzepatide had resolution of MASH without worsening of fibrosis – up to around 62 per cent, compared with 10 per cent with placebo. The most common side effects were mild to moderate gastrointestinal complaints. The authors point out that larger and longer studies are needed.
Mechanism of action, cardiovascular safety and reviews
These papers look more closely at how the molecule affects insulin and the pancreas, pool cardiovascular data across studies, and give an overall overview of the research field.
- Dual GIP and GLP-1 Receptor Agonist Tirzepatide Improves Beta-cell Function and Insulin Sensitivity in Type 2 Diabetes Clinical (human)PubMed· 2021
In this post-hoc analysis of a study of 316 people with type 2 diabetes, the researchers investigated how tirzepatide affects the pancreas's insulin production and the body's insulin sensitivity, compared with dulaglutide and placebo. Tirzepatide improved markers of both insulin sensitivity and cell function more than dulaglutide. Only a small part of the improvement in insulin sensitivity could be explained by weight loss alone. The researchers therefore suggest that action on two receptors provides separate mechanisms for blood sugar control.
- Tirzepatide cardiovascular event risk assessment: a pre-specified meta-analysis ReviewPubMed· 2022
This pre-planned analysis pooled all seven SURPASS studies of tirzepatide in type 2 diabetes, with data from over 7,000 participants. The aim was to see whether tirzepatide affected the risk of serious cardiovascular events (such as heart attack, stroke and cardiac death). Compared with the control groups, tirzepatide did not increase this risk. The authors conclude that tirzepatide did not lead to a higher risk of serious cardiovascular events in people with type 2 diabetes.
- Tirzepatide, a dual GIP/GLP-1 receptor co-agonist for the treatment of type 2 diabetes with unmatched effectiveness regrading glycaemic control and body weight reduction ReviewPubMed· 2022
This review summarises tirzepatide, the first approved medicine that acts on two receptors (GIP and GLP-1) at the same time, for type 2 diabetes. The authors refer to five studies (SURPASS 1–5) in which tirzepatide lowered long-term blood sugar and body weight more than earlier single-agent medicines, and more than semaglutide and insulin. The most common side effects were gastrointestinal complaints. Analyses did not indicate an increased risk of cardiovascular events. The authors point out that the mechanism of action is still not fully understood.