Next-Generation GLP-1 Agonists and Triple Agonists for Weight Loss (2026 Update)

By Dr Frank Yap, MD -

1. Background: From GLP-1 to Multi-Agonists

GLP-1 receptor agonists (GLP-1 RAs) dramatically changed obesity care by reducing appetite, slowing gastric emptying, and improving glucose metabolism. Semaglutide (Wegovy/Ozempic) and liraglutide established the first wave of effective, widely used drugs.

Dual agonists (e.g., tirzepatide: GLP-1 + GIP) improved on those results, adding metabolic benefits via the glucose-dependent insulinotropic polypeptide (GIP) pathway and yielding higher average weight loss.

Now, multi-agonists — combining GLP-1 with additional receptors (GIP, glucagon, amylin) — aim to enhance weight loss further by synergistically increasing energy expenditure and reducing appetite beyond what single-target drugs achieve. (Endocrine Society)

Ozempic vs Wegovy vs Rybelsus
Credit: GoodRx Health

2. Next-Generation GLP-1-Based Therapies

✅ Oral GLP-1 Agonists

Recent advances include oral small-molecule GLP-1 agonists, which could significantly expand access and adherence:

  • Orforglipron — an oral GLP-1 receptor agonist from Eli Lilly, expected to be approved in 2026; promising convenience with competitive weight-loss efficacy and easier manufacturing logistics. (S&P Global)

  • Oral semaglutide (e.g., Wegovy pill) is now approved in the U.S. and demonstrates similar weight-loss results to injectables (~14-17% body weight reduction), with a stronger focus on accessibility and needle-free delivery. (The Washington Post)

Why it matters: Oral drugs could reduce barriers to treatment (no injections) and open obesity pharmacotherapy to broader patient populations.

🧬 3. Dual and Triple Agonists — The Power Players

🟢 Dual Agonists (GLP-1 + GIP or GLP-1 + Glucagon)

  • Tirzepatide (dual GLP-1/GIP): already approved and widely used (Mounjaro for diabetes; Zepbound for weight loss). It enhances insulin secretion and promotes up to ~22% average weight loss. (Medscape)

  • Mazdutide & Survodutide (GLP-1 + glucagon): experimental dual agonists targeting increased energy expenditure and fat oxidation. Mazdutide has been approved for obesity in China and shows clinically meaningful weight loss; survodutide shows promising trial results. (Wikipedia)

Mechanistic advantage: Dual agonists blend appetite suppression with enhanced metabolic effects like boosted energy use or improved glycemic handling. (PubMed)

🔥 Triple Agonists (GLP-1 + GIP + Glucagon)

These represent the most advanced next-generation class currently under investigation:

⭐ Retatrutide (Eli Lilly)

  • Mechanism: Activates GLP-1, GIP, and glucagon receptors simultaneously. (Wikipedia)

  • Efficacy: In Phase 2/3 data, average weight loss of ~24% after ~48 weeks — surpassing both semaglutide and tirzepatide in head-to-head comparisons. (Reta Weight Loss)

  • Clinical status: Phase 3 trials ongoing, with FDA submission anticipated in late 2025 to 2026 and potential approval in 2026-2027. (Reta Weight Loss)

Why triple agonism matters:

  • GLP-1 reduces appetite and slows gastric emptying.

  • GIP enhances metabolic effects and insulin sensitivity.

  • Glucagon increases energy expenditure and fat oxidation.

Together, these multi-pathway effects boost weight loss beyond dual/traditional drugs and improve broader cardiometabolic health parameters. (PubMed)

🧪 4. Other Innovative Multi-Receptor Strategies

Beyond GLP-1 + GIP/glucagon, alternative combinations are emerging:

  • GLP-1 + amylin agonists: Drugs like CagriSema (cagrilintide + semaglutide) leverage the satiety and glucose regulation benefits of amylin alongside GLP-1. (S&P Global)

  • GIP receptor antagonists with GLP-1 activation (e.g., maridebart cafraglutide): an innovative twist on incretin biology, potentially optimizing metabolic outcomes by modulating hormone balance. (Endocrine Society)

📊 5. Clinical & Industry Trends (2026)

Market shift and competition:

  • GLP-1 and multi-agonist drugs continue to drive a weight-loss drug boom — a trillion-dollar healthcare transformation. (FinancialContent)

  • The launch of oral GLP-1 pills (e.g., Wegovy) is triggering price competition and broadening treatment uptake. (The Guardian)

  • Pharmaceutical pipelines are crowded with next-gen candidates, spanning injectable peptides to orally bioavailable small molecules. (Medscape)

Evolving expectations:

  • Greater average weight loss, more durable effects, and multi-system metabolic benefits are realistic for future approved drugs.

  • Convenience and tolerability (e.g., oral dosing, fewer GI side effects) remain key innovation drivers.

📍 Summary: What’s New in 2026

GLP-1 agonists:

  • Oral formulations (Wegovy pill, orforglipron) gaining regulatory approval and clinical traction. (The Washington Post)

Dual agonists:

  • Tirzepatide is now a mainstream obesity medicine.

  • Novel GLP-1/glucagon dual agents show promise in trials. (Wikipedia)

Triple agonists:

  • Retatrutide leads the field with up to ~24% average weight loss — potentially setting a new benchmark. (Reta Weight Loss)

Future goals:

  • Better efficacy, improved side-effect profiles, and more patient-friendly delivery forms (especially oral) are the core of ongoing development. (Endocrine Society)


Related:

  1. Retatrutide vs Tirzepatide vs Semaglutide (Ozempic): What's the difference?

Comments

Post a Comment

Labels

Show more

Popular posts from this blog

Ivermectin and Fenbendazole in the Treatment of Psoriasis? A Case Series of 13 Patients (2026)

By Dr Frank Yap, MD -
Image
Abstract Psoriasis is a chronic autoimmune condition affecting approximately 7.5 million individuals in the United States, with significant economic, physical, and psychological burdens. This case series reports on 13 patients who experienced notable improvements in psoriasis symptoms following treatment with ivermectin and/or fenbendazole, antiparasitic agents repurposed for this indication. Cases were derived from self-reported testimonials shared on social media platforms. Treatment durations ranged from 3 days to 3 months, with dosages varying between 6 mg ivermectin twice daily and combinations with fenbendazole. Rapid resolution of skin lesions was observed in most cases, with some achieving near-complete clearance. While these anecdotal reports suggest potential therapeutic efficacy, controlled clinical trials are warranted to validate these findings and elucidate underlying mechanisms. Introduction Psoriasis is a chronic inflammatory disorder characterized by hyperproliferation...
Read more

Best Vitamin D3 + K2 Supplements in 2026: Doctor-Reviewed Picks for Bone, Heart & Immune Health

By Dr Frank Yap, MD -
Image
Vitamin D3 and Vitamin K2 are two of the most commonly deficient—and misunderstood—nutrients today. While Vitamin D improves calcium absorption, Vitamin K2 determines where that calcium actually goes . That’s why taking Vitamin D without K2 may be incomplete—and in some cases counterproductive. After reviewing ingredient quality, dosing accuracy, brand transparency, and real-world user feedback, the following are the best Vitamin D3 + K2 supplements available in 2026 . Most people in the United States consume less than recommended amounts of vitamin D . An analysis of data from the 2017–2018 National Health and Nutrition Examination Survey (NHANES) found that average daily vitamin D intakes from foods and beverages were 4.3 mcg in men, 3.8 mcg in women, and 5 mcg (200 IU) in children aged 2–19 years ( NHANES 2017 - 2018 ). Why Trust This Guide? This review prioritizes supplements that meet four non-negotiable criteria : Uses Vitamin D3 (cholecalciferol) — not D2 Includes Vitam...
Read more

7 Best Cetylpyridinium Chloride Mouthwash Brands 2025

By Dr Frank Yap, MD -
Image
A meta-analysis of 3 studies (C19early 2025) concluded that CPC (CetylPyridinium Chloride) may significantly lower risk with  viral clearance . One study shows significant benefit. Meta analysis using the most serious outcome reported shows 83% [6‑97%] lower risk . Results are consistent with early treatment being more effective than late treatment. A study, published in Nature ( Takeda 2022 ) concluded that CPC (CetylPyridinium Chloride) may inhibit SARS-CoV-2 infection even at lower concentrations. Another team of international scientists has also demonstrated the usefulness of cetylpyridinium chloride-containing mouthwashes in inhibiting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and reducing the risk of viral transmission. The study is published in the Journal of Medical Microbiology (2022). A scientific review, published in the  Journal of Formosan Medical Association  (2022) also concluded that mouthwash containing CPC shows potential fo...
Read more

Retatrutide vs Tirzepatide vs Semaglutide (Ozempic): GLP-1 Wars — Updated Review (2026)

By Dr Frank Yap, MD -
Image
The landscape of obesity treatment has evolved dramatically with the introduction of advanced medical therapeutics like retatrutide (RETA, LY3437943), tirzepatide (Mounjaro), and semaglutide (Ozempic). Glucagon-like peptide-1 receptor agonists and co-agonists, originally developed to manage type 2 diabetes, have shown remarkable efficacy in promoting weight loss, making them game-changers for obesity management. However, each drug has unique mechanisms, benefits, and potential applications, including emerging roles in cancer prevention. This article compares their mechanisms, clinical efficacy, broader health benefits, safety profiles, regulatory status, and practical considerations to help patients, clinicians, and informed readers understand how they stack up in 2026. Update: Are GLP-1s the first longevity drugs ? (Nature 2025) Credit: GoodRx Health Mechanism of Action Semaglutide : Semaglutide (Ozempic and Wegovy) is a glucagon-like peptide-1 receptor agonist (GLP-1 RA). It mimics ...
Read more

17 Best Natural Ozempic Alternatives 2026 (Resource Guide)

By Dr Frank Yap, MD -
Image
Some of the best natural alternatives to Ozempic include berberine, a supplement that has shown potential in managing blood sugar and promoting weight loss, often referred to as “nature’s Ozempic” in wellness communities. High-fiber foods also play a crucial role by helping to control appetite and improve metabolic health. Other natural options include psyllium husk, which provides soluble fiber supporting satiety and digestive health, and curcumin, known for its anti-inflammatory properties, which may aid metabolic balance. Additionally, green tea extract, magnesium, protein-rich foods, and lifestyle factors like adequate sleep and stress reduction contribute to weight management.  However, none of these natural alternatives are as potent or fast-acting as Ozempic itself, and their effects can vary widely among individuals. It is important to consult a healthcare provider before starting any supplement regimen, especially for managing blood sugar or weight loss. The 2023 rep...
Read more

7 Best Organic Vitamin D3 and K2 Supplements 2025

By Dr Frank Yap, MD -
Image
In recent weeks and months, several publications and studies have suggested that maintaining adequate levels of vitamin D would seem potentially beneficial in fighting the COVID-19 infection. How do you know that your vitamin D level is adequate? Most people in the United States consume less than recommended amounts of vitamin D. An analysis of data from the 2015–2016 National Health and Nutrition Examination Survey (NHANES) found that average daily vitamin D intakes from foods and beverages were 5.1 mcg (204 IU) in men, 4.2 mcg (168 IU) in women, and 4.9 mcg (196 IU) in children aged 2–19 years ( NHANES ). What Is Vitamin D? Vitamin D is a fat-soluble vitamin, meaning that it dissolves in fats and oils and can be stored in your body for a long time. Vitamin D is important to the body in many ways. It helps the body absorb calcium from food and supplements. Muscles need it to move, for example, nerves need it to carry messages between the brain and every body part, and the immune syste...
Read more

9 Best Vitamin D3, K2 and Magnesium Supplements 2025

By Dr Frank Yap, MD -
Image
Magnesium, vitamin D and Vitamin K2 are vitamin and minerals that are vital to several bodily processes. Though they occur naturally in a variety of foods, many people take supplements to help increase their intake. Magnesium, Vitamin D3 and Vitamin K Dosage The typical daily dosage recommendations for these nutrients are: Magnesium: 400–500 mg Vitamin D3: 800 IU (20 mcg)  Vitamin K : 120mcg Food With Magnesium, Vitamin D3 and Vitamin K Magnesium: dark chocolate, avocados, nuts, leafy vegetables, and legumes Vitamin D3: avocados, nuts, seeds, full-fat dairy products and eggs Vitamin K: turnips, spinach, kale, brocolli, soybeans, carrots, Chicken If you’re concerned you may be deficient in any of these nutrients, talk to a health professional who can test your levels and determine whether you should eat more of these foods or take a supplement. Benefits and uses 1. May support bone health Magnesium  plays a key role in converting vitamin D into its active form, which aids calci...
Read more

Hydroxychloroquine, Azithromycin and Zinc: Dosage, Z Pak and Zelenko Protocol for COVID-19 (2023)

By Dr Frank Yap, MD -
Image
As of January 2023, there are  more than 2,000 studies  published related to the treatment and prevention of COVID-19. As of January 2023, there are more than 350 published evidence of hydroxychloroquine for COVID-19 ( c19hcq.org ). As of January 2023, there are 38 published evidence of zinc for COVID-19 ( c19early.org/z ). In 2020, Hydroxychloroquine was touted as the most controversial drug in the world. Is there any new evidence to confirm or to disprove previous evidence? Hydroxychloroquine, Zinc and Azithromycin are among the handful of COVID-19 treatments that are being studied as potential candidates that might influence the outcome in the prevention and management of COVID-19.  Who makes hydroxychloroquine? Hydroxychloroquine (generic or scientific name) comes in various brand names. Plaquenil is a brand name of hydroxychloroquine from Sanofi.  Who makes azitromycin? Azithromycin (scientific name) comes in various brand names as well. Zithromax (from Pfizer),...
Read more

Gut Microbiome May Be a Game Changer for Cancer Prevention

By Dr Frank Yap, MD -
Image
In recent years, it's become increasingly apparent that the composition of microbes in your gut — which is as distinct to you as your fingerprint — plays an enormous role in health and disease prevention. Your gut flora influences the function of various internal organs, such as your skin, lungs, breasts and liver. 1 For example, 2018 research 2  by the National Institute of Health shows gut microbes control antitumor immune responses in the liver, and that antibiotics — by depleting your gut of valuable bacteria — can alter the composition of immune cells in your liver and trigger tumor growth. Aside from cancer, dozens of other health conditions have been traced back to the influence of gut microbes as well, including obesity, depression, chronic fatigue syndrome, Parkinson's and allergies, 3  just to name a few. One of the reasons for this is because your gut is the main residence of your immune system. 4 Disrupt your gut microbiome and you automatically...
Read more

9 Best Anti Aging Skincare Hong Kong 2025

By Dr Frank Yap, MD -
Image
It’s natural to have complex feelings about noticing signs of aging. You can embrace the beauty and privilege that it is to age, while also not love all of the physical changes that come along with it.  If you’d like to soften these signs but don’t want to go the injectables route, there are non-invasive products that can help. In the world of beauty products, there's perhaps no category more saturated than the anti-aging market. What to Look for in an Anti-Aging Product a. Vitamin C An antioxidant powerhouse, vitamin C is directly involved with collagen production in the body. Vitamin C is beneficial in anti-aging products for several reasons: It protects skin from environmental stressors, promotes cell turnover, and can fade dark spots which contribute to the appearance of aging skin. Products containing vitamin C can irritate sensitive skin, so be sure to start out using a low concentration if your skin is reactive. b. Retinoids Retinoids are a category of ingredients, and retin...
Read more

Archive

Show more