The landscape of peptides for body weight management is dominated by three molecules representing three successive generations of innovation: semaglutide, tirzepatide, and retatrutide. Retatrutide — which we call TRIPLE-G on this blog for its three G’s (GLP-1, GIP, Glucagon) — is the first triple agonist in advanced clinical development, and it promises to change the rules of the game.
If semaglutide was the wheel, tirzepatide was the engine, TRIPLE-G is the complete car.
In this comparison, we analyze the fundamental differences between the three compounds, drawing on data from clinical studies published in peer-reviewed journals, to give you a clear and up-to-date picture.
Mechanism of Action: From Single to Triple Agonism
The most significant difference between the three molecules lies in the number and type of receptors they activate.
Semaglutide — Single GLP-1 Agonist
Semaglutide acts exclusively on the GLP-1 receptor (Glucagon-Like Peptide-1). Developed by Novo Nordisk, it is a 31-amino-acid peptide modified with a C18 fatty acid that extends its half-life to approximately 7 days, enabling once-weekly administration. It is marketed as Ozempic (type 2 diabetes) and Wegovy (weight management).
Its mechanism rests on three main pillars:
- Appetite reduction through action on hypothalamic satiety centers
- Delayed gastric emptying, prolonging the feeling of fullness
- Improved insulin secretion in a glucose-dependent manner
Tirzepatide — Dual GIP/GLP-1 Agonist
Tirzepatide, developed by Eli Lilly, represents the second generation. It is a dual agonist that simultaneously activates GIP (Glucose-dependent Insulinotropic Polypeptide) and GLP-1 receptors. It is marketed as Mounjaro (diabetes) and Zepbound (obesity).
The peptide consists of 39 amino acids with a C20 diacid fatty acid linker. The addition of the GIP receptor confers:
- Enhanced insulinotropic effect with improved glycemic control
- Action on lipid metabolism with direct effects on adipocytes
- Receptor synergy: combined GIP/GLP-1 activation produces effects greater than the sum of each individual agonism
Retatrutide (TRIPLE-G) — Triple GIP/GLP-1/Glucagon Agonist
Retatrutide (LY3437943), also developed by Eli Lilly, is the first triple receptor agonist in advanced clinical development. To the GIP and GLP-1 receptors, it adds glucagon receptor agonism — and it is precisely this third “G” that inspired the name TRIPLE-G.
This third component introduces mechanisms absent in its predecessors:
- Stimulation of hepatic lipolysis: glucagon activates the breakdown of triglycerides stored in the liver
- Increased energy expenditure: glucagon-induced thermogenesis raises basal metabolic rate
- Effect on brown adipose tissue: promotion of energy dissipation as heat
The result is an approach that does not merely reduce caloric intake but actively increases energy expenditure — an entirely new paradigm in peptide research for obesity.
Clinical Efficacy: Data Compared
Weight Loss
The data come from randomized, placebo-controlled clinical trials conducted in populations with obesity or overweight with comorbidities.
| Compound | Trial | Maximum dose | Duration | Weight loss (%) |
|---|---|---|---|---|
| Semaglutide | STEP 1 | 2.4 mg/wk | 68 weeks | -15.3% |
| Semaglutide | STEP 5 | 2.4 mg/wk | 104 weeks | -15.2% |
| Tirzepatide | SURMOUNT-1 | 15 mg/wk | 72 weeks | -22.5% |
| Tirzepatide | SURMOUNT-2 | 15 mg/wk | 72 weeks | -14.7% (with T2D) |
| Retatrutide | Phase 2 | 12 mg/wk | 48 weeks | -24.2% |
The retatrutide figure is particularly significant for two reasons: first, it was achieved at only 48 weeks (versus 68-72 for the other studies), with a weight loss curve that had not yet plateaued; second, the maximum dose has not yet been optimized in Phase 3 trials.
Percentage of Participants Achieving Loss Thresholds
| Threshold | Semaglutide (STEP 1) | Tirzepatide (SURMOUNT-1) | Retatrutide (Phase 2, 12 mg) |
|---|---|---|---|
| greater than or equal to 5% | 86% | 96% | 100% |
| greater than or equal to 10% | 69% | 89% | 93% |
| greater than or equal to 15% | 51% | 78% | 83% |
| greater than or equal to 20% | 32% | 63% | 63% |
These data indicate that tirzepatide and retatrutide offer a more consistent response, with higher percentages of people reaching clinically significant weight loss thresholds.
Adaptation Signals and Tolerability
Initial Gastrointestinal Responses
All three compounds share a response profile dominated by gastrointestinal symptoms, a direct consequence of GLP-1 agonism and delayed gastric emptying. These are adaptation signals that in most cases diminish over time.
| Response | Semaglutide 2.4 mg | Tirzepatide 15 mg | Retatrutide 12 mg |
|---|---|---|---|
| Nausea | 44% | 31% | 35% |
| Diarrhea | 30% | 23% | 22% |
| Vomiting | 24% | 13% | 18% |
| Constipation | 24% | 12% | 12% |
| Dyspepsia | 9% | 9% | 8% |
Semaglutide tends to show slightly higher rates of nausea and vomiting, likely due to the absence of the modulatory effect of GIP, which in tirzepatide and the triple agonist appears to mitigate nausea. The glucagon component of TRIPLE-G does not add significant gastrointestinal responses.
Non-Gastrointestinal Responses
- Heart rate: all three cause a mild increase (1-4 bpm), typical of GLP-1 agonists.
- Pancreatitis: a rare but monitored risk in all studies; no significant differences between compounds are observed.
- Gallstones: the risk increases with rapid weight loss, regardless of the specific compound.
- Thyroid responses: in preclinical studies, thyroid C-cell tumors were observed in rodents exposed to GLP-1 receptor agonists. Not confirmed in humans, but remains a label warning.
Discontinuation Rates
| Compound | Discontinuation rate |
|---|---|
| Semaglutide 2.4 mg | 7.0% |
| Tirzepatide 15 mg | 6.2% |
| Retatrutide 12 mg | 5.6% |
TRIPLE-G shows the lowest discontinuation rate, suggesting overall tolerability at least comparable to its predecessors, despite the addition of a third receptor agonism.
Development Status and Approvals
Semaglutide — Approved and Established
- FDA: approved as Ozempic (2017, T2D) and Wegovy (2021, obesity)
- EMA: approved for both indications
- Post-marketing experience: millions of people treated, well-characterized safety profile
- Oral formulation: Rybelsus (oral semaglutide for T2D) already available
Tirzepatide — Approved and Expanding
- FDA: approved as Mounjaro (2022, T2D) and Zepbound (2023, obesity)
- EMA: approved as Mounjaro (T2D); Zepbound in European rollout phase
- Ongoing studies: additional indications for NASH/MASLD, obstructive sleep apnea, heart failure
Retatrutide — Phase 3
- Status: Phase 3 trials (TRIUMPH program) ongoing
- Availability: already accessible in Europe as a research-grade compound for scientific research
- Ongoing studies: TRIUMPH-1 (obesity), TRIUMPH-2 (T2D), TRIUMPH-3 (long-term maintenance), TRIUMPH-4 (cardiovascular outcomes)
Dosing Schedules and Titration
All three compounds require gradual titration to minimize the initial gastrointestinal responses.
Semaglutide
- Start: 0.25 mg/week for 4 weeks
- Escalation: 0.5 mg, then 1.0 mg, then 1.7 mg, then 2.4 mg (target dose)
- Total titration period: approximately 16-20 weeks
Tirzepatide
- Start: 2.5 mg/week for 4 weeks
- Escalation: 5 mg, then 7.5 mg, then 10 mg, then 12.5 mg, then 15 mg (target dose)
- Total titration period: approximately 20-28 weeks
Retatrutide
- Start: 0.5 mg/week for 4 weeks (in the Phase 2 study)
- Escalation: the protocol includes gradual increases to the target dose of 12 mg
- Final titration protocol details will be defined by the Phase 3 studies
Effects on Body Composition
One of the most debated aspects of GLP-1 receptor agonist research is the ratio of fat mass to lean mass lost during use of these peptides.
The “25% Rule”
With most weight loss approaches — diet, exercise, or peptides — approximately 25% of weight lost consists of lean mass (muscle, body water, bone mass), with the remaining 75% being fat mass. This ratio has also been observed with semaglutide in the STEP 1 trial.
Tirzepatide and the Improved Ratio
SURMOUNT-1 data with DEXA analysis suggest that tirzepatide may preserve lean mass slightly better, with a fat-to-lean loss ratio of approximately 80:20 at the highest doses.
Retatrutide: The Role of Glucagon
The glucagon component of retatrutide is particularly interesting for body composition. Glucagon:
- Stimulates lipolysis preferentially in visceral adipose tissue
- Promotes beta-oxidation of fatty acids in the liver
- May favor lean mass preservation through increased energy expenditure (the body burns more fat and has less need to catabolize muscle protein)
While Phase 2 data are promising, definitive confirmation of a more favorable fat-to-lean ratio with retatrutide requires the complete DEXA analyses from the TRIUMPH studies.
Metabolic Benefits Beyond Weight Loss
Hepatic Steatosis (MASLD/NASH)
| Compound | Liver fat reduction | Notes |
|---|---|---|
| Semaglutide | -30-40% (STEP/SELECT) | Histological NASH improvement |
| Tirzepatide | -50-55% (SYNERGY-NASH) | NASH resolution in 74% of cases |
| Retatrutide | -up to 86% (Phase 2 MASLD) | The highest result ever recorded |
The retatrutide data on hepatic steatosis are extraordinary and likely linked to the direct effect of glucagon on hepatic fatty acid beta-oxidation. If confirmed in Phase 3, it could represent the first truly effective approach for MASLD/NASH.
Lipid Profile
All three compounds improve the lipid profile, but with different patterns:
- Semaglutide: triglyceride reduction (-15-20%), modest LDL reduction
- Tirzepatide: triglyceride reduction (-25-30%), HDL improvement
- Retatrutide: triglyceride reduction (-30-35%), more pronounced effect due to the glucagon component
Cardiovascular Protection
The SELECT trial demonstrated that semaglutide 2.4 mg reduces major adverse cardiovascular events (MACE) by 20% in people with obesity without diabetes. Tirzepatide has ongoing CV studies (SURPASS-CVOT). For retatrutide, the TRIUMPH-4 study will investigate cardiovascular outcomes, but results will not be available for several years.
Availability and Format: Pen vs Lyophilized
Semaglutide and Tirzepatide
As approved molecules, semaglutide and tirzepatide are available by prescription in Europe. However, global supply shortages, high costs, and insurance restrictions limit accessibility. They are distributed in pre-filled pens that, while convenient, contain preservatives and have transport/storage conditions that are not always transparent.
Retatrutide (TRIPLE-G) — Lyophilized
The triple agonist is available as a lyophilized peptide (powder) for research. And the lyophilized format has important advantages over pre-filled pens:
- Storable at room temperature before reconstitution
- You reconstitute it yourself with bacteriostatic water — you know it is fresh
- No preservatives — pure product
- Total quality control, lower cost
Think of it like the difference between supermarket sushi and sushi made fresh right in front of you.
For those looking to learn more about the TRIPLE-G protocol, aurapep.eu publishes detailed guides, including a free dosage calculator.
Summary Table: Three Generations Compared
| Parameter | 1st gen: Semaglutide (Ozempic) | 2nd gen: Tirzepatide (Mounjaro) | 3rd gen: Retatrutide (TRIPLE-G) |
|---|---|---|---|
| Target receptors | GLP-1 | GLP-1 + GIP | GLP-1 + GIP + Glucagon |
| Developer | Novo Nordisk | Eli Lilly | Eli Lilly |
| Max weight loss | ~15-17% | ~22-26% | ~24-26%+ |
| Clinical stage | Approved | Approved | Phase 3 |
| Administration | SC weekly | SC weekly | SC weekly |
| Liver fat reduction | 30-40% | 50-55% | Up to 86% |
| Format | Pre-filled pen | Pre-filled pen | Lyophilized (powder) |
| MACE reduction | -20% (SELECT) | Under study | Under study |
Conclusions
The comparison of semaglutide, tirzepatide, and retatrutide illustrates a clear evolutionary trajectory: each generation adds receptor complexity and, with it, efficacy. Semaglutide remains the molecule with the largest body of clinical and post-marketing data; tirzepatide offers the best balance between efficacy and current availability; TRIPLE-G promises to redefine the limits of what a single peptide can do, with potentially unique benefits for body composition and hepatic steatosis.
For those following this field, the question is no longer “if” triple agonism works, but “how much better” it will perform once the TRIUMPH study data become available.
References
- Jastreboff AM, et al. “Tirzepatide Once Weekly for the Treatment of Obesity.” N Engl J Med. 2022;387(3):205-216.
- Wilding JPH, et al. “Once-Weekly Semaglutide in Adults with Overweight or Obesity.” N Engl J Med. 2021;384(11):989-1002.
- Jastreboff AM, et al. “Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial.” N Engl J Med. 2023;389(6):514-526.
- Lincoff AM, et al. “Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes.” N Engl J Med. 2023;389(24):2221-2232.
- Coskun T, et al. “LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist.” J Clin Invest. 2022.
- Sanyal AJ, et al. “Tirzepatide for Treatment of NASH.” N Engl J Med. 2024.
- Rosenstock J, et al. “Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes.” Lancet. 2023;402(10401):529-544.
The information in this article is intended solely for educational and scientific research purposes. It does not constitute medical advice, diagnosis, or treatment. Always consult a qualified healthcare professional.
Frequently Asked Questions
Which GLP-1 peptide produces the most weight loss?
Based on published clinical trial data, retatrutide (triple GIP/GLP-1/glucagon agonist) achieved the highest weight loss at 24.2% in 48 weeks at the 12 mg dose, with the curve still trending downward. Tirzepatide achieved 22.5% in 72 weeks, while semaglutide reached 15.3% in 68 weeks. However, direct head-to-head comparisons between these compounds have not been conducted.
Is tirzepatide better than semaglutide for weight loss?
Tirzepatide produces greater weight loss than semaglutide in clinical trials (22.5% vs 15.3%), likely due to its dual GIP/GLP-1 agonism providing synergistic appetite reduction and enhanced insulin sensitivity. Tirzepatide also shows lower rates of nausea than semaglutide. However, semaglutide has the advantage of proven cardiovascular protection from the SELECT trial and an oral formulation option. Read more about the incretin system behind both compounds.
What is the main advantage of retatrutide over tirzepatide?
Retatrutide’s key advantage is its third receptor target: glucagon. This adds active energy expenditure through thermogenesis and lipolysis, meaning the body burns more fat rather than relying solely on appetite reduction. Retatrutide also showed an unprecedented 86% liver fat reduction versus tirzepatide’s 50-55%, making it particularly promising for MASLD/NASH research. See the clinical trial data for details.
How do the side effects compare between semaglutide, tirzepatide, and retatrutide?
All three share gastrointestinal side effects as the most common responses. Semaglutide shows the highest nausea rates (44%), followed by retatrutide (35%) and tirzepatide (31%). Discontinuation rates are lowest for retatrutide (5.6%), followed by tirzepatide (6.2%) and semaglutide (7.0%). The GIP component in tirzepatide and retatrutide appears to mitigate some nausea.
Where can I find research-grade retatrutide in Europe?
As retatrutide is not yet approved, it is available in Europe only as a research-grade lyophilized peptide. When sourcing it, verify HPLC purity of 98% or higher, request a Certificate of Analysis with mass spectrometry, and ensure proper lyophilization for stability. Aura Peptides is a verified European supplier offering research-grade retatrutide with HPLC purity of 98% or above, COA included, and free EU shipping.
