The next wave of obesity treatment includes triple agonists (retatrutide), amylin combinations (CagriSema), GLP-1/glucagon drugs (survodutide), muscle-preserving agents and precision-medicine approaches. Most remain investigational, but two oral GLP-1s are now approved: oral semaglutide 25 mg (December 2025) and orforglipron / Foundayo (April 2026), the first small-molecule oral GLP-1.
Why a "next generation" exists
Semaglutide and tirzepatide turned obesity from a condition with weak drug options into one with effective ones. Even so, average loss with the strongest approved drug is roughly 20% of body weight (tirzepatide, SURMOUNT-1, treatment-policy), short of what bariatric surgery achieves for many. Gastrointestinal effects and injection burden cause many people to stop; rapid loss reduces fat-free mass; stopping the drug generally returns the weight; and response to a given drug cannot be reliably predicted. The pipeline is aimed at those gaps. → Tirzepatide · GLP-1 & Muscle Loss · Weight Regain & Maintenance
What EASD 2026 changed. The efficacy ceiling moved up: the best triple-agonist data now put mean weight loss near 30%, approaching bariatric surgery. The standard of care did not change. The drugs that matter in practice remain the ones people tolerate and keep taking, and the quieter advances there are tolerability, dosing burden and persistence.
Triple agonists — retatrutide 🟡 Promising (phase 3 data)
Retatrutide activates three receptors at once — GLP-1, GIP and glucagon — the glucagon component thought to raise energy expenditure on top of the appetite effects of the other two.
The pivotal phase 3 TRIUMPH-1 trial reported a mean total weight loss of ~28.3% at 80 weeks on the 12 mg dose (-25.9% at 9 mg, -19.0% at 4 mg) in adults with obesity and without diabetes, the largest mean reduction from any completed phase 3 obesity programme to date; an earlier higher-BMI extension reached ~30.3% at 104 weeks. Tolerability is the trade-off: at 12 mg, nausea ran ~42%, vomiting ~25%, diarrhea ~32% and constipation ~26%, and discontinuation for side effects rose from ~7% at 9 mg to ~11% at 12 mg, close to a doubling of dropout for roughly one extra point of weight loss.
Current development phase. 🟡 Promising — phase 3 complete, not yet FDA-approved. Glucagon agonism can raise glucose and heart rate and affect the liver, and long-term outcomes, durability and muscle effects remain unknown. If approved, it would suit people needing loss beyond what dual agonists deliver.
GLP-1 / glucagon dual agonists — survodutide 🟠 Limited
Survodutide is a GLP-1/glucagon dual agonist whose glucagon component is of interest for the liver, where it may reduce hepatic fat and inflammation. Phase 3 data in 2026 reported ~13.1% mean weight loss at 76 weeks in people with obesity and type 2 diabetes, alongside meaningful reductions in liver fat and visceral fat. A related GLP-1/glucagon agent, mazdutide, is now approved in China.
Current development phase. 🟠 Limited / investigational — not yet approved for obesity or MASH. Glucagon cautions about glucose and heart rate apply, and comparative efficacy against approved drugs is unproven. The plausible role is where MASH and obesity occur together. → MASH Medications · GLP-1 & Fatty Liver
GLP-1 / amylin combinations — CagriSema 🟠 Limited
CagriSema combines cagrilintide, a long-acting amylin analogue, with semaglutide. Amylin is a second satiety hormone acting partly through different brain pathways than GLP-1, so the two signals may be complementary, and it is the most advanced non-incretin mechanism in late-stage obesity development.
In REDEFINE 1, CagriSema produced ~22.7% mean total weight loss. In REDEFINE 4 it produced ~23% but missed non-inferiority versus tirzepatide in the head-to-head comparison: adding amylin did not clearly beat the best approved dual agonist. Novo Nordisk filed CagriSema with the FDA in December 2025, with a decision expected in 2026, and next-generation amylin combinations (amycretin, eloralintide) are moving into phase 3.
Current development phase. 🟠 Limited / investigational — not FDA-approved. Whether amylin has a favourable body-composition profile is an open question, and the missed non-inferiority tempers the assumption that more mechanisms produce more loss. → Emerging-Therapy Database
Oral GLP-1 medicines
Oral semaglutide 25 mg 🟢 Established (approved Dec 2025)
A high-dose oral formulation of semaglutide for chronic weight management. In December 2025 it became the first oral GLP-1 approved for obesity, a milestone in delivery rather than mechanism, with EU approval following in July 2026. Efficacy, cautions and the medullary-thyroid and pregnancy warnings match the semaglutide class. → Semaglutide (/treat/glp1/semaglutide)
Orforglipron (Foundayo) 🟢 Established (FDA-approved Apr 2026)
A non-peptide, small-molecule oral GLP-1 agonist. Unlike oral semaglutide, a peptide with strict food and water dosing rules, a small molecule may be simpler to take and to manufacture at scale. It was FDA-approved in April 2026 under the brand name Foundayo for chronic weight management, with no food or water timing restrictions. In ATTAIN-1 it produced roughly ~12% mean weight loss, below the injectables; it is also approved in the UK (Aug 2026), with EU review ongoing. Its clearest use is where the needle, rather than the efficacy ceiling, is the barrier.
Monthly dosing — MariTide 🟠 Limited (phase 3)
MariTide is an antibody-peptide conjugate pairing a GLP-1 agonist with a GIP antagonist, the opposite GIP direction from tirzepatide, engineered for monthly dosing, which would reduce treatment burden relative to weekly drugs. 🟠 Limited / investigational — in phase 3 (MARITIME programme); not approved.
Also presented at EASD 2026 — early signals 🔴 Experimental
Several agents are worth knowing without being practice-changing: olatorepatide (~19.3% at 48 weeks), VK2735 (oral and injectable programmes advancing), ecnoglutide (approved in China, Mar 2026), KAI-4729 (~16% weight loss and ~67% liver-fat reduction, but only about 10 patients), ABBV-295 (up to ~9.8%), and Novo's OCTANE switch-to-oral maintenance data (~4.1% added).
Combination pharmacotherapy 🟡 Promising (as a strategy)
Stacking mechanisms follows the layered logic of hypertension and diabetes care. The strategy is 🟡 promising and increasingly validated (CagriSema reached ~22.7% in REDEFINE 1), but each combination has to be proven individually, and REDEFINE 4's missed non-inferiority shows that combining does not guarantee superiority.
Added mechanism is not free. At EASD 2026, adding eloralintide to tirzepatide raised mean weight loss from ~14.8% to ~23.3%, while nausea climbed from ~26% to ~49% and discontinuation for side effects jumped from ~3% to ~27%. Additive side effects, cost and adherence are the limits here.
Muscle-preserving treatment — bimagrumab and activin-pathway agents 🔴 Experimental
These agents target the activin/myostatin pathway to preserve muscle while fat is lost. Bimagrumab is the most-studied example, given alone or alongside a GLP-1. A newer anti-myostatin agent, trevogrumab, was reported at EASD 2026 to preserve roughly 69-72% of thigh muscle on MRI when added to semaglutide versus semaglutide alone. This is not an approved use. 🔴 Experimental.
MC4R-pathway therapies — setmelanotide 🟢 Established (rare genetic obesity only)
The melanocortin-4 receptor (MC4R) pathway is a core hunger-regulating circuit in the brain. Setmelanotide is an MC4R agonist already approved for rare monogenic obesity syndromes: POMC and LEPR (leptin-receptor) deficiency, and Bardet-Biedl syndrome. It is the clearest existing example of precision obesity medicine, targeting the broken pathway in a defined genetic group. 🟢 Established for its approved rare indications — and not a treatment for common polygenic obesity. Class effects include skin-pigmentation changes. → Genetics of Obesity
Precision obesity & pharmacogenomics 🔴 Experimental
Matching the drug to the person, using genetics, hormones, eating behaviour or metabolic subtype, would reduce wasted time, cost and side-effect burden. Heritability of body weight is high (~40–70%), and monogenic forms (MC4R most common; leptin/LEPR, POMC) already guide treatment for a small minority. For common polygenic obesity, drug response cannot yet be reliably predicted from a genetic test. 🔴 Experimental for routine care, with setmelanotide-style monogenic targeting the only precision approach currently clinical.
Questions patients ask
Is retatrutide available yet?
No. Retatrutide is in phase 3 (TRIUMPH-1) with ~28.3% mean weight loss at 80 weeks reported, but it is not FDA-approved and cannot be prescribed for obesity. Grade 🟠 Limited / investigational
Did CagriSema beat tirzepatide?
No — in REDEFINE 4 it reached about 23% but missed non-inferiority versus tirzepatide. Grade 🟠 Limited
Will these drugs cure obesity so I can stop taking them?
Nothing in the pipeline changes the core biology permanently, and weight generally returns when treatment stops. Grade A 🟢 → Weight Regain
Which approved treatment fits a particular person is decided on the individual metabolic picture at the practice.
Written by Darius A. Schneider, MD, PhD · Board-Certified Endocrinologist (ECNU) · Last updated: 2026-10-03 · References: TRIUMPH program (retatrutide); REDEFINE 1 and 4 (CagriSema); FDA approval of oral semaglutide 25 mg (Dec 2025); setmelanotide labeling; survodutide, orforglipron, bimagrumab and amylin-analogue development programs. Pipeline and regulatory status re-verified on update — see the "how to read this page" note. Educational only; not individualized advice, and pipeline agents are not available treatments.
