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 research compound and the first-in-class dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist. Marketed as Mounjaro for type 2 diabetes and Zepbound for chronic weight management, tirzepatide represents a new approach to incretin-based research. Its simultaneous activation of two incretin receptors has yielded some of the most impressive clinical trial results in metabolic research to date.

Dual GIP/GLP-1 Mechanism of Action

Tirzepatide is a synthetic linear peptide of 39 amino acids with a C20 fatty diacid chain that enables albumin binding and extends its circulating half-life to approximately five days. This supports once-weekly subcutaneous dosing.

The compound’s defining feature is its dual receptor activity. Tirzepatide binds to both the GIP receptor and the GLP-1 receptor, though with distinct pharmacological characteristics:

  • GIP receptor: Tirzepatide acts as a potent agonist at the GIP receptor, with activity comparable to native GIP. Researchers have observed that 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 its affinity and signalling profile differ from selective GLP-1 RAs. At the GLP-1 receptor, tirzepatide shows reduced β-arrestin recruitment relative to native GLP-1, which researchers have hypothesised may influence receptor desensitisation and tolerability.

The 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 independently.

SURPASS Trial Programme (Type 2 Diabetes)

The SURPASS clinical trial programme evaluated tirzepatide across a broad range of adults with type 2 diabetes:

  • SURPASS-1 (monotherapy, n=478): Researchers observed 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): Head-to-head against semaglutide 1.0 mg, 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.
  • SURPASS-3 (n=1,444): Compared to insulin degludec, tirzepatide showed superior HbA1c reductions (2.37% for 15 mg vs 1.34%) with significantly less hypoglycaemia.
  • SURPASS-4 (n=2,002): In adults with cardiovascular risk, tirzepatide demonstrated non-inferiority to insulin glargine for MACE, with superior HbA1c and weight outcomes.
  • SURPASS-5: In combination with basal insulin, tirzepatide provided additional HbA1c reductions of up to 2.59%.

Across the SURPASS programme, the most commonly reported adverse events were gastrointestinal (nausea, diarrhoea, decreased appetite, vomiting), generally mild to moderate in severity and most frequent 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): Researchers observed mean body weight reductions of 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 ≥20% weight loss — a threshold that had been historically associated with bariatric surgery outcomes.
  • SURMOUNT-2 (n=938): In adults with type 2 diabetes, tirzepatide 15 mg achieved 14.7% weight reduction versus 3.2% with placebo.
  • SURMOUNT-3: Combined with intensive behavioural intervention, tirzepatide produced 24.3% weight loss (tirzepatide) versus 9.8% (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 observed in the SURMOUNT programme has positioned tirzepatide as a benchmark compound in obesity research.

Regulatory Status in Australia

In Australia, tirzepatide is classified as a Schedule 4 (Prescription Only) compound:

  • Mounjaro (tirzepatide injection) was approved by the Therapeutic Goods Administration (TGA) 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.

Supply considerations have been relevant in the Australian context, with demand-driven shortages periodically affecting availability.

Research Context and Ongoing Studies

Tirzepatide continues to be evaluated in several research 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 opened investigation into tirzepatide’s role in weight-dependent conditions.
  • Heart failure: Ongoing trials assessing tirzepatide in heart failure with preserved ejection fraction (HFpEF) in people with obesity.
  • Combination approaches: Researchers are exploring tirzepatide alongside other metabolic agents to understand potential additive effects.

The dual GIP/GLP-1 mechanism has spurred broader interest in multi-agonist approaches, with the next generation of compounds exploring triple agonism (see retatrutide).

Researchers studying tirzepatide may also be interested in:

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.