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Tirzepatide represents a novel approach to type 2 diabetes management through its unique dual mechanism of action. As the first glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, tirzepatide offers distinct pharmacological advantages over existing incretin-based therapies. Marketed as Mounjaro in the UK, this once-weekly injectable medication mimics naturally occurring gut hormones to enhance glucose-dependent insulin secretion, suppress inappropriate glucagon release, slow gastric emptying, and promote satiety. Understanding tirzepatide's mechanism of action helps clinicians optimise treatment selection and patient counselling for adults with type 2 diabetes requiring treatment intensification.
Quick Answer: Tirzepatide works through dual agonism of GIP and GLP-1 receptors to stimulate glucose-dependent insulin secretion, suppress glucagon, slow gastric emptying, and reduce appetite in adults with type 2 diabetes.
Tirzepatide is a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist licensed for the treatment of type 2 diabetes mellitus in adults. Marketed under the brand name Mounjaro in the UK, it represents a new addition to incretin-based therapies, offering a dual mechanism that distinguishes it from existing GLP-1 receptor agonists such as semaglutide or dulaglutide.
The drug works by mimicking the action of two naturally occurring incretin hormones that are released from the gut in response to food intake. These hormones play crucial roles in glucose homeostasis by stimulating insulin secretion from pancreatic beta cells in a glucose-dependent manner, meaning insulin release occurs primarily when blood glucose levels are elevated. This glucose-dependent mechanism reduces the risk of hypoglycaemia compared to insulin secretagogues such as sulphonylureas, although the risk increases when tirzepatide is used in combination with insulin or sulphonylureas.
Beyond glycaemic control, tirzepatide influences multiple physiological pathways. It slows gastric emptying, which moderates the rate at which glucose enters the bloodstream after meals. The medication also acts on appetite-regulating centres in the hypothalamus, promoting satiety and reducing food intake. These combined effects contribute to weight loss alongside improvements in glycated haemoglobin (HbA1c) levels.
Tirzepatide is administered once weekly via subcutaneous injection, typically in the abdomen, thigh, or upper arm. The dosing schedule begins with an initiation dose of 2.5 mg weekly for 4 weeks (not intended for glycaemic control), which is then gradually increased every four weeks to minimise gastrointestinal side effects. Maintenance doses range from 5 mg to 15 mg weekly, depending on individual glycaemic response and tolerability. Due to delayed gastric emptying during initiation and dose escalation, women using oral contraceptives should consider using a non-oral contraceptive or add a barrier method for 4 weeks after each dose increase.
Patients should be counselled on proper injection technique and the importance of rotating injection sites to prevent injection-site reactions. If a dose is missed, it should be administered within 4 days of the scheduled dose; if more than 4 days have passed, the missed dose should be skipped and the next dose taken on the regularly scheduled day. Tirzepatide is not indicated for the treatment of type 1 diabetes or diabetic ketoacidosis.
The unique pharmacological profile of tirzepatide lies in its dual agonist activity at both GIP and GLP-1 receptors, making it the first medication in its class. Whilst GLP-1 receptor agonists have been available for over a decade, the addition of GIP receptor agonism represents a novel therapeutic approach that appears to enhance metabolic benefits beyond those achieved with GLP-1 agonism alone.
GLP-1 receptor activation produces several well-established effects. It stimulates glucose-dependent insulin secretion from pancreatic beta cells, suppresses inappropriate glucagon release from alpha cells (particularly in hyperglycaemic states), slows gastric emptying, and reduces appetite through central nervous system pathways. These mechanisms collectively improve glycaemic control whilst promoting weight loss. GLP-1 receptors are expressed in cardiovascular tissues, which may contribute to cardiovascular effects, though it should be noted that while some selective GLP-1 receptor agonists have demonstrated cardiovascular benefits in outcome trials, definitive cardiovascular outcome data for tirzepatide are still awaited.
GIP receptor activation was historically thought to have limited therapeutic potential in type 2 diabetes, as the insulinotropic response to GIP is often impaired in affected individuals. However, research suggests that tirzepatide's GIP agonism may help restore this response. Preclinical and early clinical studies indicate that GIP enhances insulin secretion in a glucose-dependent manner and may influence lipid metabolism, though these mechanisms require further clinical validation. The potential effects of GIP on insulin sensitivity and fat metabolism remain an area of active investigation.
The interaction between GIP and GLP-1 receptor pathways has been shown to result in improved glycaemic control and greater weight loss compared to semaglutide 1 mg in head-to-head clinical trials. Some preclinical studies suggest that GIP may modulate the gastrointestinal effects sometimes associated with GLP-1 agonism, though this hypothesis requires further clinical validation. The balanced dual agonism represents an approach to addressing multiple aspects of type 2 diabetes pathophysiology.
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The SURPASS clinical trial programme has provided robust evidence demonstrating tirzepatide's efficacy through its dual receptor mechanism. These phase 3 trials enrolled over 10,000 participants with type 2 diabetes across diverse clinical scenarios, including comparisons with placebo, insulin, and other incretin-based therapies.
SURPASS-2 directly compared tirzepatide with semaglutide 1 mg, a well-established GLP-1 receptor agonist. Results showed that all three tirzepatide doses (5 mg, 10 mg, and 15 mg) achieved superior HbA1c reductions compared to semaglutide at 40 weeks, with mean decreases of 2.01% (5 mg), 2.24% (10 mg), and 2.30% (15 mg) versus 1.86% with semaglutide. Weight loss was also significantly greater with tirzepatide, with participants losing 7.8 kg (5 mg), 10.3 kg (10 mg), and 12.4 kg (15 mg) compared to 6.2 kg with semaglutide. These findings suggest that the additional GIP receptor agonism provides clinical benefits beyond GLP-1 activation alone.
SURPASS-3 evaluated tirzepatide against titrated insulin degludec in patients inadequately controlled on metformin with or without an SGLT2 inhibitor. Tirzepatide demonstrated superior glycaemic control at 52 weeks, with 82% (5 mg), 86% (10 mg), and 88% (15 mg) of participants achieving HbA1c targets below 7.0% compared to 61% with insulin degludec. Notably, tirzepatide-treated patients experienced substantial weight loss (7.5 kg with 5 mg, 10.7 kg with 10 mg, and 12.9 kg with 15 mg), whilst those receiving insulin gained an average of 2.3 kg—a clinically important distinction for patients with type 2 diabetes who often struggle with weight management.
The cardiovascular outcomes trial SURPASS-CVOT is ongoing and will provide definitive evidence regarding tirzepatide's effects on major adverse cardiovascular events. Secondary analyses from the SURPASS programme suggest effects on cardiovascular risk markers, including blood pressure and lipid profiles, though these findings should be considered exploratory. Patients should be informed that whilst the mechanism suggests potential cardiovascular benefits, definitive outcome data are awaited. The MHRA-approved indication currently focuses on glycaemic control and does not include specific cardiovascular risk reduction claims.
Understanding how tirzepatide compares to other glucose-lowering therapies helps clinicians make evidence-based treatment decisions aligned with NICE guidance for type 2 diabetes management (NG28).
Versus GLP-1 receptor agonists: Tirzepatide has demonstrated superior HbA1c reduction and weight loss compared to semaglutide 1 mg in the SURPASS-2 trial. The magnitude of benefit—an additional 0.15% to 0.44% HbA1c reduction and approximately 1.6 kg to 6.2 kg greater weight loss—appears clinically meaningful for many patients. Gastrointestinal adverse effects (nausea, vomiting, diarrhoea) occur at similar frequencies to other GLP-1 receptor agonists, affecting approximately 12% to 24% of patients (nausea being most common), and are typically more frequent during dose escalation. These effects generally diminish over time with continued therapy.
Versus SGLT2 inhibitors: Whilst SGLT2 inhibitors (such as empagliflozin or dapagliflozin) offer proven cardiovascular and renal benefits, they typically produce more modest HbA1c reductions (0.5% to 0.8%) and weight loss (2 kg to 3 kg) compared to tirzepatide. SGLT2 inhibitors work through an insulin-independent mechanism—increasing urinary glucose excretion—making them mechanistically complementary to tirzepatide. Combination therapy may be appropriate for selected patients, though cost considerations should be evaluated.
Versus insulin therapy: Tirzepatide offers comparable or superior glycaemic control to basal insulin without the associated weight gain and with a different hypoglycaemia risk profile. This makes it an option for patients requiring treatment intensification beyond oral agents. However, insulin remains essential for patients with significant beta-cell dysfunction, those with type 1 diabetes, and during acute illness or perioperative periods. When tirzepatide is used with insulin or sulphonylureas, doses of these medications may need to be reduced to minimise hypoglycaemia risk.
Practical considerations include cost-effectiveness, patient preference regarding injectable therapy, and individual clinical circumstances. NICE guidance recommends considering GLP-1 receptor agonists for patients with type 2 diabetes who have inadequate glycaemic control despite optimal oral therapy and who have a BMI ≥35 kg/m² (or ≥32.5 kg/m² in certain ethnic groups), or for whom insulin therapy would have significant occupational implications or weight loss would benefit other obesity-related comorbidities.
Patients should be advised to seek prompt medical attention if they experience symptoms of acute pancreatitis (severe persistent abdominal pain, sometimes radiating to the back), signs of gallbladder disease, persistent vomiting or diarrhoea that could lead to dehydration, or changes in vision. Patients should also be encouraged to report any suspected adverse reactions via the MHRA Yellow Card scheme (yellowcard.mhra.gov.uk or via the Yellow Card app).
Tirzepatide is the first dual GIP and GLP-1 receptor agonist, whereas medications like semaglutide or dulaglutide activate only GLP-1 receptors. Clinical trials demonstrate that tirzepatide produces greater HbA1c reductions and weight loss compared to semaglutide 1 mg, suggesting the additional GIP receptor agonism provides enhanced metabolic benefits.
Tirzepatide stimulates insulin secretion in a glucose-dependent manner, which reduces hypoglycaemia risk when used alone. However, the risk increases when tirzepatide is combined with insulin or sulphonylureas, and dose reductions of these medications may be necessary.
Gastrointestinal adverse effects are most common, including nausea (affecting 12–24% of patients), vomiting, and diarrhoea. These effects typically occur during dose escalation and generally diminish over time with continued therapy.
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