Peptides

Tirzepatide (Mounjaro/Zepbound) Research Overview

Research overview of tirzepatide, the dual GIP/GLP-1 receptor agonist. Clinical trial data from SURPASS and SURMOUNT programmes, mechanism of action, and Australian context.

Tirzepatide (Mounjaro/Zepbound) Research Overview

Tirzepatide is a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist - the first compound of this class to reach Phase 3 trials. Marketed as Mounjaro for type 2 diabetes and Zepbound for chronic weight management, tirzepatide activates two incretin receptors simultaneously. Clinical data from the SURPASS and SURMOUNT programmes have produced some of the largest glycaemic and weight loss effects reported in metabolic research.

Dual GIP/GLP-1 Mechanism of Action

A synthetic linear peptide of 39 amino acids, tirzepatide carries a C20 fatty diacid chain that enables albumin binding and extends its circulating half-life to approximately five days. Once-weekly subcutaneous dosing is supported by this pharmacokinetic profile.

The compound’s defining characteristic is its dual receptor activity:

  • GIP receptor: Tirzepatide acts as a potent agonist at the GIP receptor, with activity comparable to native GIP. GIP receptor activation enhances insulin secretion in response to oral nutrient intake and may improve lipid metabolism and adipose tissue function.
  • GLP-1 receptor: Tirzepatide also activates the GLP-1 receptor, though with a different signalling profile than selective GLP-1 RAs. At the GLP-1 receptor, tirzepatide shows reduced beta-arrestin recruitment relative to native GLP-1, which may influence receptor desensitisation and gastrointestinal tolerability.

Combined GIP and GLP-1 receptor engagement is thought to produce additive or synergistic effects on glycaemic control, appetite regulation, and energy expenditure beyond what either pathway achieves alone.

SURPASS Trial Programme (Type 2 Diabetes)

The SURPASS programme evaluated tirzepatide across multiple populations of adults with type 2 diabetes:

  • SURPASS-1 (monotherapy, n=478): HbA1c reductions of 1.87% (5 mg), 1.89% (10 mg), and 2.07% (15 mg) versus 0.04% with placebo at 40 weeks. Mean body weight decreased by 7.6 kg, 9.3 kg, and 11.2 kg respectively.
  • SURPASS-2 (n=1,879): Published in July 2021, this head-to-head trial against semaglutide 1.0 mg showed tirzepatide 15 mg achieved superior HbA1c reduction (2.46% vs 1.86%) and weight loss (12.4 kg vs 6.2 kg) at 40 weeks (Frías et al. (2021)). The trial is registered at ClinicalTrials.gov.
  • SURPASS-3 (n=1,444): Compared to insulin degludec, tirzepatide 15 mg produced superior HbA1c reductions (2.37% vs 1.34%) with significantly less hypoglycaemia.
  • SURPASS-4 (n=2,002): Published in November 2021, this trial enrolled adults with type 2 diabetes and cardiovascular risk. Tirzepatide demonstrated non-inferiority to insulin glargine for MACE, with superior HbA1c and weight outcomes (Del Prato et al. (2021)).
  • SURPASS-5: In combination with basal insulin, tirzepatide provided additional HbA1c reductions of up to 2.59%.

Gastrointestinal adverse events (nausea, diarrhoea, decreased appetite, vomiting) were the most commonly reported across the SURPASS programme. These were generally mild to moderate in severity and occurred most frequently during dose titration.

SURMOUNT Trial Programme (Weight Management)

The SURMOUNT trials evaluated tirzepatide for chronic weight management in adults with obesity or overweight:

  • SURMOUNT-1 (n=2,539): Published in July 2022, mean body weight reductions were 15.0% (5 mg), 19.5% (10 mg), and 20.9% (15 mg) versus 3.1% with placebo at 72 weeks. Approximately 57% of participants on the highest dose achieved at least 20% weight loss - a threshold historically associated with bariatric surgery outcomes (Jastreboff et al. (2022)). The trial is registered at ClinicalTrials.gov.
  • SURMOUNT-2 (n=938): Published in June 2023, adults with type 2 diabetes receiving tirzepatide 15 mg lost 14.7% of body weight versus 3.2% with placebo (Garvey et al. (2023)).
  • SURMOUNT-3: Combined with intensive behavioural intervention, tirzepatide produced 24.3% weight loss versus 9.8% during a placebo lead-in period.
  • SURMOUNT-4: Demonstrated sustained weight loss maintenance over 88 weeks, with participants maintaining approximately 25% total body weight reduction.
  • SURMOUNT-OSA: Investigated tirzepatide in adults with obesity and obstructive sleep apnoea, showing significant reductions in apnoea-hypopnoea index alongside weight loss.

The magnitude of weight loss in the SURMOUNT programme has positioned tirzepatide as a benchmark compound in obesity research.

Regulatory Status in Australia

Tirzepatide is classified as Schedule 4 (Prescription Only) by the Therapeutic Goods Administration (TGA):

  • Mounjaro (tirzepatide injection) is TGA-approved for type 2 diabetes in adults, as an adjunct to diet and exercise. It is available in multiple dose strengths (2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg) in single-dose pre-filled pens.
  • The TGA has also approved tirzepatide for weight management indications, reflecting the SURMOUNT trial outcomes.
  • PBS listing for tirzepatide in Australia has been subject to ongoing government review, with access expanding as listing criteria are finalised.

Demand-driven shortages have periodically affected availability in Australia.

Ongoing Research

Tirzepatide continues to be evaluated across several therapeutic areas:

  • SURPASS-CVOT: A dedicated cardiovascular outcomes trial designed to assess MACE endpoints in adults with type 2 diabetes.
  • SYNERGY-NASH: Investigating tirzepatide in metabolic dysfunction-associated steatohepatitis (MASH/NASH), based on evidence of hepatic fat reduction.
  • Obstructive sleep apnoea: SURMOUNT-OSA results have prompted further investigation into tirzepatide’s role in weight-dependent conditions.
  • Heart failure: Ongoing trials are assessing tirzepatide in heart failure with preserved ejection fraction (HFpEF) in people with obesity.

The dual GIP/GLP-1 mechanism has accelerated interest in multi-agonist approaches. The next generation of compounds explores triple agonism (see retatrutide).

Disclaimer: This page is for research and educational purposes only. No therapeutic claims are made. Tirzepatide is a Schedule 4 (Prescription Only) compound in Australia. This information does not constitute medical advice. Consult a qualified healthcare professional for any health-related decisions. All data referenced is drawn from published peer-reviewed clinical trials.