Semaglutide vs Tirzepatide vs Retatrutide: Full GLP-1 Class Comparison (Australia)

GLP-1 receptor agonists are a class of peptide compounds that mimic glucagon-like peptide-1 (GLP-1), an incretin hormone secreted by intestinal L-cells in response to food intake. GLP-1 receptor activation produces multiple metabolic effects including enhanced glucose-stimulated insulin secretion, suppression of glucagon, delayed gastric emptying, and reduced appetite signalling in the hypothalamus.

Three compounds have emerged as the primary subjects of GLP-1-class metabolic research: Semaglutide (GLP-1 single agonist), Tirzepatide (GLP-1 / GIP dual agonist), and Retatrutide (GLP-1 / GIP / glucagon triple agonist). Each generation adds receptor targets that expand the mechanism and, in clinical data, improve weight-reduction outcomes.

The defining characteristic of each compound is its receptor target profile:

The addition of GIP receptor agonism (Tirzepatide, Retatrutide) potentiates insulin secretion and may reduce GLP-1-associated gastrointestinal side effects. The further addition of glucagon receptor agonism (Retatrutide) increases energy expenditure via thermogenesis and enhances hepatic fat mobilisation, mechanisms not present in Semaglutide or Tirzepatide.

Semaglutide is a GLP-1 receptor agonist with 94% sequence homology to native GLP-1, modified with a C18 fatty acid chain enabling albumin binding and extending its half-life to approximately 7 days (enabling once-weekly dosing). It was the first of the three compounds to reach Phase 3 clinical development at high doses for obesity.

The STEP 1 trial (Wilding et al., NEJM 2021) evaluated subcutaneous Semaglutide 2.4mg weekly over 68 weeks in adults with obesity (no diabetes). Mean body weight reduction: −14.9% versus −2.4% placebo. This established Semaglutide as the initial benchmark for GLP-1-class weight reduction research.

Additional STEP trials confirmed benefits in type 2 diabetes (STEP 2), cardiovascular risk reduction (SELECT trial: 20% reduction in MACE), and non-alcoholic steatohepatitis (NASH) resolution.

Tirzepatide (LY3298176) is a 39-amino-acid GIP/GLP-1 dual agonist with balanced agonism at both receptors and a C20 fatty diacid modification providing a ~5-day half-life (once-weekly dosing). Co-agonism at the GIP receptor appears to potentiate GLP-1-mediated effects, producing greater weight reduction than equivalent GLP-1 receptor engagement alone.

The SURMOUNT-1 trial (Jastreboff et al., NEJM 2022) evaluated Tirzepatide in adults with obesity over 72 weeks. At the 15mg dose, mean weight reduction was −20.9%, approximately 6 percentage points greater than the Semaglutide STEP benchmark despite comparable trial populations. SURPASS trials in type 2 diabetes also showed superior HbA1c and weight outcomes versus Semaglutide head-to-head.

Retatrutide (LY3437943) is a 39-amino-acid triple agonist at GLP-1, GIP, and glucagon receptors, adding GCGR agonism to the dual mechanism of Tirzepatide. Glucagon receptor activation increases thermogenesis and hepatic fat oxidation, theoretically enabling greater energy expenditure without proportionally increasing lean mass loss.

The Phase 2 trial (Jastreboff et al., NEJM 2023) evaluated Retatrutide over 48 weeks in adults with obesity. At 12mg weekly, mean body weight reduction was −24.2%, the highest reported weight reduction in any GLP-1-class compound as of the trial publication. Importantly, this trial was shorter (48 weeks vs 68–72 weeks for STEP/SURMOUNT), and Phase 3 data is required to fully characterise the efficacy and safety profile.

Additional research interests for Retatrutide include NAFLD/NASH (glucagon-driven hepatic fat reduction), cardiometabolic markers, and combination metabolic endpoints. Phase 3 trials (TRIUMPH programme) were ongoing as of 2025.

Note: Cross-trial comparisons have significant limitations, populations, endpoints, and trial design differ. No head-to-head RCT comparing all three compounds has been published.

Each compound has distinct strengths as a research tool depending on the hypothesis under investigation:

• Semaglutide, best-characterised safety and efficacy data; large Phase 3 cardiovascular dataset (SELECT); appropriate when GLP-1-only effects need isolation
• Tirzepatide, dual agonism with robust Phase 3 data; suitable for studies where GIP co-agonism is the independent variable of interest; superior HbA1c data in T2DM models
• Retatrutide, highest weight reduction signal in published Phase 2 data; glucagon receptor component adds thermogenic and hepatic fat research dimensions not available with the other two; Phase 3 data pending

OzPeps stocks research-grade Tirzepatide and Retatrutide for laboratory and in-vitro research use from Australian domestic stock. Semaglutide analogues are not currently stocked. All compounds are lyophilised powder requiring reconstitution with bacteriostatic water before use.

• Tirzepatide 30mg →
• Retatrutide 20mg →
• Retatrutide 30mg →

For individual compound deep-dives, see: Retatrutide guide → · Retatrutide vs Tirzepatide comparison →

All compounds discussed are supplied strictly for in-vitro laboratory and scientific research purposes. Not TGA-approved for human use. Not for human or animal consumption. Researchers are responsible for all applicable regulatory compliance in their jurisdiction.