The GLP-1 receptor agonist revolution in the fight against obesity is only the beginning. While semaglutide, tirzepatide, and retatrutide are redefining efficacy standards, dozens of new molecules are in preclinical and clinical development with the ambition of surpassing even these results. The question is no longer “Is it possible to address obesity with peptides?” — the answer is unequivocally yes — but rather “How far can we go?”
Retatrutide — which we call TRIPLE-G on this blog for its three G’s (GLP-1, GIP, Glucagon) — represents the third generation of this revolution. Semaglutide opened the way as the first generation (single GLP-1 agonist), tirzepatide raised the bar as the second generation (dual GIP/GLP-1 agonist), and now TRIPLE-G takes the concept to the next level by activating three receptors simultaneously.
In this article, we explore the pipeline of next-generation molecules, emerging technologies, and the broader implications of a potential “solution” to the global obesity epidemic.
The State of the Art: Where We Stand Today
Before looking to the future, it is useful to take a snapshot of the present. The three compounds that define the current state of the art represent three successive generations:
| Generation | Compound | Mechanism | Max weight loss | Status |
|---|---|---|---|---|
| 1st gen | Semaglutide 2.4mg | Single GLP-1 agonist | ~15-17% | Approved (Wegovy) |
| 2nd gen | Tirzepatide 15mg | Dual GIP/GLP-1 agonist | ~22-26% | Approved (Zepbound) |
| 3rd gen | TRIPLE-G (retatrutide) 12mg | Triple GIP/GLP-1/Glucagon agonist | ~24-26% | Phase 3 (TRIUMPH) |
The pattern is clear: each generation adds a receptor target and increases efficacy. But this “additive” approach has a natural limit — there are only a finite number of relevant metabolic receptors. Future molecules explore both the refinement of multi-agonism and radically different approaches.
CagriSema: The Semaglutide + Amylin Combination
The Compound
CagriSema (Novo Nordisk) represents a different approach from multi-agonism: it is a fixed-dose combination of two distinct molecules administered together:
- Semaglutide 2.4mg: the already-approved GLP-1 agonist
- Cagrilintide 2.4mg: a long-acting amylin analog
Amylin: The Third Satiety Hormone
Amylin is a hormone co-secreted with insulin by pancreatic beta cells after meals. Its effects include:
- Slowing gastric emptying (complementary to GLP-1)
- Reducing post-prandial glucagon secretion
- Appetite suppression through the area postrema of the brainstem
- Reducing food intake mediated by neural pathways distinct from those of GLP-1
The crucial point is that amylin and GLP-1 act through complementary neural pathways: GLP-1 acts primarily on the hypothalamus (arcuate nucleus), while amylin acts on the area postrema and the nucleus of the solitary tract. Their combination produces a synergistic effect on satiety that is greater than the sum of the individual effects.
Clinical Results
The REDEFINE-1 study (Phase 3) showed remarkable results:
- Mean weight loss of 22.7% at 68 weeks with CagriSema
- Head-to-head comparison with semaglutide 2.4mg alone: 15.8%
- The 6.9% additional loss over semaglutide alone confirms the amylin-GLP-1 synergy
- Novo Nordisk’s stated goal is to achieve 25%+ weight loss with optimized formulations
Implications
CagriSema demonstrates a fundamental principle: combining peptides that act on different neural pathways can overcome the limitations of individual agonists. This opens the door to further unexplored combinations.
Survodutide: The Dual Agonist with a Hepatic Focus
The Compound
Survodutide (BI 456906, Boehringer Ingelheim/Zealand Pharma) is a dual GLP-1/glucagon agonist distinguished by a particularly favorable action profile on hepatic steatosis.
Mechanism of Action
Unlike TRIPLE-G (which is a triple agonist with a GIP component), survodutide combines only GLP-1 and glucagon, but with an optimized activity ratio:
- The GLP-1 component reduces appetite and improves glucose metabolism
- The glucagon component stimulates hepatic lipolysis, increases energy expenditure, and promotes fatty acid oxidation in the liver
This profile makes it particularly effective in reducing liver fat, a critical target in the management of metabolic dysfunction-associated steatotic liver disease (MASLD, formerly known as NAFLD/NASH).
Clinical Data on MASLD
The Phase 2b study results on MASLD were exceptional:
- Steatohepatitis resolution (MASH) in 83% of people treated with the highest dose
- Hepatic fibrosis improvement of at least one grade in 64% of participants
- Concurrent weight loss of 18-19% at 48 weeks
These data position survodutide as one of the most promising candidates not only for obesity but specifically for MASLD — a condition affecting approximately 30% of the global adult population and for which very few approved options exist.
Phase 3 Studies
The SYNCHRONIZE Phase 3 program includes studies on MASLD with fibrosis, obesity, and type 2 diabetes. Complete results are expected in 2026-2027.
Pemvidutide: Another Dual GLP-1/Glucagon Agonist
The Compound
Pemvidutide (ALT-801, Altimmune) is another dual GLP-1/glucagon agonist in development, with a profile similar to survodutide but some differences in pharmacokinetics and agonism ratio.
Preliminary Results
The MOMENTUM Phase 2 study showed:
- Weight loss of 15.6% at 48 weeks with the 2.4mg dose
- Significant liver fat reduction (more than 50% from baseline)
- Favorable safety profile with gastrointestinal response rates lower than some competitors
Pemvidutide is currently in Phase 2b for obesity and in dedicated studies for MASLD. Its competitive position will largely depend on the Phase 3 results of its competitors.
High-Dose Oral Semaglutide
The Oral Route Revolution
One of the practical limitations of GLP-1 peptides is the need for subcutaneous administration. Novo Nordisk has developed an oral formulation of semaglutide (Rybelsus) already approved for type 2 diabetes at 3, 7, and 14mg doses. However, its efficacy for weight loss at these doses is modest.
The REDEFINE program now includes oral semaglutide at much higher doses:
- 25mg and 50mg oral (compared to the currently approved 14mg)
- SNAC technology (sodium N-[8-(2-hydroxybenzoyl)amino]caprylate) for gastric absorption
How Oral Absorption Works
Peptides are normally destroyed by gastric acidity and intestinal proteases. SNAC technology overcomes this obstacle:
- SNAC creates a high-pH microenvironment around the tablet in the stomach
- This protects the peptide from acid degradation
- SNAC facilitates transepithelial absorption of semaglutide through the gastric mucosa
- Only a small percentage of the peptide is actually absorbed (~1%), but the high dose compensates
Clinical Results
The OASIS-1 study with oral semaglutide 50mg showed:
- Weight loss of 17.4% at 68 weeks
- Results comparable to the 2.4mg subcutaneous formulation
- Safety profile similar, with slightly higher nausea rates at the start
Implications
If confirmed in Phase 3, these results would represent a paradigm shift: people who prefer to avoid subcutaneous administration — a significant percentage — would have access to the same efficacy in a daily tablet. This could vastly expand the number of people who benefit.
Non-Peptide Oral GLP-1 Agonists
Small Molecules That Mimic Peptides
A particularly fascinating line of research is the development of non-peptide small molecules that activate the GLP-1 receptor. Unlike peptides, these molecules:
- Are chemically stable in the gastric environment
- Have high oral bioavailability without the need for SNAC technology
- Can be manufactured at significantly lower costs
- Are patentable with entirely new chemical structures
Key Candidates
Danuglipron (Pfizer): a non-peptide oral GLP-1 agonist in Phase 2. Initial results showed 6-8% weight loss at 32 weeks with an immediate-release formulation. A modified-release formulation (once daily) is being optimized.
Orforglipron (Eli Lilly): a non-peptide oral GLP-1 agonist in Phase 3. Phase 2 data (GZGI study) showed weight loss of up to 14.7% at 36 weeks — notable results for an oral non-peptide compound. The ATTAIN Phase 3 program is underway.
The Democratizing Potential
If oral non-peptide agonists achieve efficacy comparable to subcutaneous administration, the implications would be enormous:
- Manufacturing costs drastically lower (chemical synthesis vs peptide production)
- No cold chain required
- Greater compliance (tablet vs subcutaneous administration)
- Expanded global accessibility, including low- and middle-income countries
Gene Therapy Approaches
The Concept
A radically different approach is gene therapy for long-term expression of GLP-1 agonists. The idea is simple in concept but complex in execution: insert a gene encoding a GLP-1 analog into a person’s genome, obtaining continuous endogenous production of the peptide.
State of Research
Preclinical studies in mouse models have demonstrated the feasibility of the concept:
- Administration of AAV (adeno-associated virus) vectors encoding GLP-1 analogs
- Peptide expression for months or years after a single administration
- Significant and sustained weight loss in animal models
- Metabolic profile improvement comparable to chronic peptide administration
Challenges
The challenges remain formidable:
- Irreversible dosing: once the gene is inserted, it cannot be “turned off” if the person develops unwanted responses
- Immunogenicity: AAV vectors can trigger immune responses
- Expression variability: difficult to calibrate the exact level of peptide produced
- Regulation: gene therapies require even more complex regulatory pathways than traditional compounds
- Cost: current gene therapies cost hundreds of thousands of euros
Timeline Perspective
Gene therapy for obesity is realistically 10-15 years from clinical practice, if not more. However, the concept is scientifically sound and could represent the “definitive solution” for obesity in the distant future.
Combination Strategies
Beyond the Single Compound
An emerging trend is the use of molecular combinations with complementary mechanisms. The rationale is analogous to antiretroviral therapy for HIV or combination chemotherapy: attacking the condition from multiple angles simultaneously.
Combinations Under Study
GLP-1 + Amylin (CagriSema, discussed above)
GLP-1 + Activin/Myostatin
- Bimagrumab (anti-activin type II receptor antibody) + semaglutide
- Myostatin inhibition promotes muscle growth, compensating for the lean mass loss associated with rapid weight loss
- Promising preliminary results: greater fat loss with muscle mass preservation
GLP-1 + Melanocortin Receptor (MC4R) Agonists
- Setmelanotide (MC4R agonist approved for genetic obesity) in combination with GLP-1 agonists
- Potential synergy through the leptin-melanocortin pathway
GLP-1 + SGLT2 Inhibitors
- The combination of GLP-1 agonists with SGLT2 inhibitors (such as empagliflozin) is already used in clinical practice for diabetes and shows additive effects on weight loss and cardiometabolic protection.
Personalized Medicine and Pharmacogenomics
The Problem of Individual Variability
An often-overlooked aspect is the enormous variability in individual response to anti-obesity peptides. In the same clinical trial, with the same compound at the same dose, some people lose 30% of body weight while others lose less than 5%. Understanding why is one of the most important challenges for future research.
Predictive Biomarkers
Researchers are identifying genetic, epigenetic, and metabolomic biomarkers that predict response to different compounds:
- GLP-1 receptor polymorphisms: variants of the GLP1R gene that influence binding affinity
- Gut microbiome profile: the composition of gut flora influences peptide metabolism and response
- FTO gene variants: the primary obesity susceptibility gene, which modulates the response to different molecules
- Baseline endogenous GLP-1 levels: people with lower endogenous levels tend to respond better to exogenous agonists
Selection Algorithms
In the future, it is conceivable that a pharmacogenomic profile will guide the selection of the optimal compound for each person:
- Profile with GLP1R variant A —> semaglutide
- Profile with glucagon predominance —> TRIPLE-G (retatrutide)
- Profile with amylin deficit —> CagriSema
- Profile with predominant MASLD —> survodutide
For those looking to learn more about the TRIPLE-G protocol, aurapep.eu publishes detailed guides, including a free dosage calculator.
Will Obesity Become a “Solved Problem”?
Scientific Optimism
With peptides capable of producing 20-25% weight loss — comparable to bariatric surgery — and a pipeline rich with even more effective candidates, it is fair to ask: will obesity become a “solved” problem like many infectious diseases?
The arguments in favor are compelling:
- The efficacy of current molecules is already sufficient to bring the majority of people with obesity below the overweight threshold
- The future pipeline promises even greater efficacy
- Oral formulations and gene therapies will make access easier
- Benefits extend beyond weight: cardioprotective, hepatoprotective, metabolic
Persistent Challenges
However, several obstacles suggest caution:
Economic accessibility: GLP-1 peptides currently cost thousands of euros per year. Even with cheaper oral formulations, universal coverage remains a challenge.
Chronic nature: obesity is a chronic condition. Upon discontinuation, weight is regained in the majority of cases (on average, 60-70% of lost weight is regained within 12 months of stopping). This implies potentially lifelong use.
Unknown long-term body responses: no GLP-1 peptide has been studied for decades of continuous use. The body’s responses over 20-30 years remain unknown.
Muscle mass loss: rapid weight loss involves significant lean mass loss (up to 25-40% of total loss is muscle mass). Strategies to mitigate this (resistance exercise, anti-myostatin combinations) are still being optimized.
Social determinants: obesity is deeply rooted in socioeconomic determinants — access to healthy food, urban environment, stress, sleep, education level — that no molecule can modify.
Ethical and Social Considerations
The Medicalization of Body Weight
The advent of highly effective weight loss peptides raises significant ethical questions:
- Who should have access: only those with a BMI above 30? Those with a BMI above 25 as well? Anyone who wants to lose weight?
- Social pressure: the risk that the availability of “easy” compounds increases social pressure toward thinness
- Equity: in public health systems, does coverage of expensive obesity compounds divert resources from other conditions?
The Economic Impact
Obesity costs healthcare systems hundreds of billions per year in comorbidities (diabetes, cardiovascular disease, certain cancers). If anti-obesity peptides effectively reduce these comorbidities, the cost could be more than offset by long-term healthcare savings. Several pharmacoeconomic studies suggest a favorable cost-effectiveness ratio, especially for high-risk individuals.
The Role of the Food Industry
A provocative question: if obesity becomes treatable with peptides, will pressure on the food industry to produce healthier foods diminish? The risk of a “moral hazard” — “I can eat whatever I want because I take the peptide” — is a topic of active discussion among epidemiologists and health policymakers.
Anticipated Timeline
Here is a reasonable estimate of timelines for the major upcoming developments:
| Compound/Technology | Type | Estimated timeline |
|---|---|---|
| CagriSema | GLP-1 + Amylin combination | Approval 2026-2027 |
| Survodutide | Dual GLP-1/Glucagon | Approval 2027-2028 |
| Orforglipron | Oral non-peptide agonist | Approval 2027-2028 |
| TRIPLE-G (retatrutide) | Triple agonist | Approval 2027-2028 |
| Oral semaglutide 50mg | High-dose oral peptide | Approval 2026-2027 |
| Pemvidutide | Dual GLP-1/Glucagon | Phase 3 2026-2028 |
| Advanced combinations | Multi-peptide | Phases 2-3 2027-2030 |
| Personalized medicine | Pharmacogenomics | Gradual adoption 2028-2035 |
| Gene therapy | Gene therapy | Experimental 2030-2040 |
Conclusions
The future of anti-obesity peptide research is extraordinarily rich with promise. From the combination of amylin and GLP-1 to oral non-peptide agonists, from pharmacogenomics to gene therapy, each line of research addresses a different aspect of the complexity of obesity as a metabolic condition.
What makes this moment particularly exciting is the convergence of multiple innovative approaches: we are not simply optimizing a single class of compounds, but simultaneously exploring fundamentally different paradigms. The most likely outcome is that, within a decade, we will have a broad and diversified arsenal, capable of personalizing the approach based on each person’s individual profile.
If you want to stay up to date on the TRIPLE-G protocol and other next-generation molecules, aurapep.eu offers in-depth guides, practical resources, and a free dosage calculator.
References
- Novo Nordisk. “REDEFINE-1: CagriSema Phase 3 Results.” Press release and ADA presentation, 2025.
- Boehringer Ingelheim. “Survodutide Phase 2b Results in MASH.” Lancet. 2024.
- Altimmune. “MOMENTUM: Pemvidutide Phase 2 Obesity Results.” Press release, 2024.
- Knop FK, et al. “Oral semaglutide 50 mg taken once daily in adults with overweight or obesity (OASIS 1).” Lancet. 2023;402(10403):705-719.
- Eli Lilly. “Orforglipron Phase 2 Results (GZGI Study).” N Engl J Med. 2023.
- Jastreboff AM, et al. “Triple-Hormone-Receptor Agonist Retatrutide for Obesity.” N Engl J Med. 2023;389(6):514-526.
- Muller TD, et al. “Anti-obesity drug discovery: advances and challenges.” Nat Rev Drug Discov. 2022;21(3):201-223.
- Bluher M. “Obesity: global epidemiology and pathogenesis.” Nat Rev Endocrinol. 2019;15(5):288-298.
- Acosta A, et al. “Selection of Antiobesity Medications Based on Phenotypes.” Gastroenterology. 2021.
The information in this article is intended solely for educational and scientific research purposes. It does not constitute medical advice, diagnosis, or treatment. The approval timelines indicated are estimates based on publicly available information and may vary significantly. Always consult a qualified healthcare professional for health-related decisions.
Frequently Asked Questions
What comes after semaglutide and tirzepatide in anti-obesity research?
The next wave includes triple agonists like retatrutide (GLP-1/GIP/glucagon), the CagriSema combination (semaglutide plus amylin analog), dual GLP-1/glucagon agonists like survodutide for liver-focused approaches, and oral non-peptide GLP-1 agonists like orforglipron. Each targets different aspects of metabolic regulation for potentially greater efficacy.
What is a triple agonist peptide and why is it more effective?
A triple agonist activates three metabolic receptors simultaneously: GLP-1 (appetite suppression and glucose control), GIP (enhanced insulin response), and glucagon (increased energy expenditure and fat oxidation). By targeting three complementary pathways instead of one or two, triple agonists like retatrutide have shown weight loss of 24 to 26% in clinical trials, exceeding earlier single and dual agonists.
Will oral GLP-1 pills replace injectable peptides?
Oral formulations are advancing rapidly. High-dose oral semaglutide (50 mg) showed 17.4% weight loss comparable to the injectable version. Non-peptide oral agonists like orforglipron showed up to 14.7% in Phase 2. If Phase 3 confirms these results, oral options could dramatically expand access by eliminating the need for subcutaneous injections, though they may cost more per dose initially.
Why do people regain weight after stopping GLP-1 peptides?
Obesity is a chronic metabolic condition. When GLP-1 agonists are discontinued, the neurohormonal signals they were modulating return to their pre-treatment state. On average, 60 to 70% of lost weight is regained within 12 months of stopping treatment. This implies that long-term or lifelong use may be necessary, which is why researchers are exploring gene therapy approaches for sustained peptide expression.
Where can I source research-grade peptides in Europe?
For researchers interested in studying next-generation peptides like retatrutide, look for suppliers offering verified HPLC purity with independent testing, lot-specific COAs, and EU-based shipping. Aura Peptides is a verified European supplier offering HPLC purity of 98% or higher, Janoshik testing, free EU shipping, and cryptocurrency payment options.
