After Semaglutide: The Next Generation of GLP-1 and Multi-Agonist Molecules (2026-2027)

Abstract illustration of a molecule pipeline progressing upward, clean laboratory style, navy, cyan and green tones

The Essentials in Three Minutes

The generation succeeding semaglutide is advancing along three axes. First, the oral route, embodied by Lilly's orforglipron, the first non-peptide GLP-1 agonist in tablet form, approved by the FDA on April 1, 2026 for obesity after the ATTAIN phase 3 program (12.4% mean weight loss at 72 weeks at the highest dose). Second, GLP-1/glucagon dual agonists, with Boehringer Ingelheim's survodutide (16.6% weight loss in phase 3, MASH program under way) and Innovent/Lilly's mazdutide, already approved in China.

Third, amylin combinations. Novo Nordisk's CagriSema (cagrilintide + semaglutide) reached 22.7% weight loss in REDEFINE 1 and is now under FDA review, while amycretin, a single molecule targeting both amylin and GLP-1 receptors, is entering phase 3 in injectable and oral forms. In the background, candidates such as ecnoglutide and preclinical concepts such as the GLP-1/GIP/PPAR pentagonist published in Nature in April 2026 sketch out what comes next. This article reports trials and company announcements strictly factually, with no medical purpose whatsoever.

Why a New Generation?

First-generation GLP-1 agonists validated the concept, but their limitations are well documented in the literature. The first is an efficacy plateau: semaglutide 2.4 mg levels off around 15% mean weight loss at 68 weeks, and a fraction of trial participants respond weakly. The second is gastrointestinal tolerability: nausea, vomiting and constipation affect a substantial share of participants, especially during dose escalation, and drive part of treatment discontinuations.

Two structural constraints add to this. Weekly injections limit acceptability and complicate the worldwide manufacturing logistics of peptides and injection pens. Finally, the composition of the weight lost raises questions: depending on the study, 25 to 40% of weight lost on a GLP-1 agonist corresponds to lean mass, including skeletal muscle. The new generation therefore simultaneously pursues greater efficacy, better tolerability, oral formulations and a qualitatively different weight loss, notably through the glucagon receptor or amylin.

Orforglipron: Lilly's Oral Non-Peptide GLP-1

Orforglipron is a small non-peptide molecule, a biased partial agonist of the GLP-1 receptor, taken as one daily tablet with no food or water restrictions. In ATTAIN-1 (3,127 participants with obesity, 72 weeks), mean weight loss reached 7.8%, 9.3% and 12.4% at the 6, 12 and 36 mg doses versus 0.9% on placebo, with nausea in 33.7% of participants at the top dose and 10.3% discontinuations for adverse events. In ATTAIN-2 (obesity plus type 2 diabetes), weight loss was 10.5% with a 1.8-point HbA1c reduction; the ACHIEVE program in type 2 diabetes had previously shown HbA1c reductions comparable to injectable GLP-1s.

The FDA approved orforglipron on April 1, 2026 under the brand name Foundayo for weight management, making it the first unrestricted oral GLP-1 agonist. A maintenance trial also showed that switching from an injectable incretin to orforglipron preserved the weight lost. The type 2 diabetes filing is progressing through 2026. For research, the interest is twofold: a purely chemical synthesis, free from peptide manufacturing constraints, and small-molecule pharmacology at a receptor so far dominated by peptides.

Survodutide: The GLP-1/Glucagon Dual Agonist Targeting Obesity and MASH

Survodutide (Boehringer Ingelheim / Zealand Pharma) couples GLP-1 agonism with activation of the glucagon receptor, which raises energy expenditure and acts directly on hepatic metabolism. In the SYNCHRONIZE-1 phase 3 trial, announced on April 30, 2026, mean weight loss reached 16.6% at 76 weeks versus 3.2% on placebo, with 85.1% of participants losing at least 5% of their body weight. A pre-specified analysis presented in June 2026 reported a targeted 34% reduction in visceral fat and 63% in liver fat, with a limited contribution of lean mass to total loss.

The other side of the program is metabolic dysfunction-associated steatohepatitis (MASH): in phase 2, published in the New England Journal of Medicine, up to 62% of treated participants showed histological improvement of MASH without worsening of fibrosis, versus 14% on placebo. The LIVERAGE and LIVERAGE-Cirrhosis phase 3 trials are ongoing, and further phase 3 obesity readouts are expected by the end of 2026. Survodutide could thus become the first glucagon/GLP-1 dual agonist positioned in both obesity and MASH.

Mazdutide: The Chinese GLORY Data and a First Approval

Mazdutide, a GLP-1/glucagon dual agonist originating from Lilly research and developed in China by Innovent, was the first of its class to reach the market: China's NMPA approved it in mid-2025 for weight management, based on the GLORY-1 trial (around 14% weight loss at 48 weeks at the 6 mg dose, published in the New England Journal of Medicine).

The GLORY-2 study, announced in November 2025, tested a higher 9 mg dose in 462 Chinese adults with moderate to severe obesity: mean weight loss of 18.6% at 60 weeks (20.1% in participants without diabetes) versus 3.0% on placebo, with 44% of participants losing at least 20% of their body weight. In participants with a baseline liver fat fraction of at least 10%, the mean liver fat reduction reached 71.9%. A supplementary application for the 9 mg dose has been filed with the NMPA, and the program is expanding into type 2 diabetes and sleep apnea. Mazdutide illustrates the growing weight of Chinese clinical data in the metabolic field.

CagriSema: Novo Nordisk's Cagrilintide + Semaglutide Combination

CagriSema combines semaglutide 2.4 mg and cagrilintide 2.4 mg, a long-acting amylin analogue, in one weekly injection. Amylin, co-secreted with insulin, acts on satiety through pathways distinct from GLP-1, hence the rationale for the combination. In REDEFINE 1 (3,417 adults, 68 weeks, published in the New England Journal of Medicine in June 2025), mean weight loss reached 22.7% versus 2.3% on placebo; 40.4% of adherent participants lost at least 25% of their body weight. In REDEFINE 2, conducted in people with type 2 diabetes, weight loss was around 15.7%.

The picture became more nuanced in early 2026: in the head-to-head REDEFINE 4 trial (84 weeks), CagriSema produced about 23% weight loss but failed to demonstrate non-inferiority to tirzepatide 15 mg, a result widely described as a relative disappointment. Novo Nordisk filed for FDA approval for chronic weight management at the end of 2025; a decision is expected between late 2026 and 2027. Data from the REIMAGINE program in type 2 diabetes, presented at ADA 2026, complete the file with HbA1c reductions of up to 1.91 points.

Amycretin: Amylin and GLP-1 in a Single Molecule, Oral and Injectable

Where CagriSema combines two separate peptides, Novo Nordisk's amycretin is a single molecule activating both amylin and GLP-1 receptors. The early-phase data published in The Lancet in June 2025 made a mark on the field: up to 24.3% mean weight loss at 36 weeks for the weekly subcutaneous form (phase 1b/2a), and 13.1% in just 12 weeks for the oral form (phase 1), among the fastest weight-loss kinetics reported at this stage of development.

In November 2025, a phase 2 trial in type 2 diabetes reported up to 14.5% weight loss and a 1.8-point HbA1c reduction for the injectable form, and 10.1% and 1.5 points for the oral form. Novo Nordisk started phase 3 development in obesity in early 2026 for both formulations, with phase 3 trials in type 2 diabetes also planned. Amycretin is thus the first unimolecular amylin/GLP-1 co-agonist to reach this stage, with the particularity of existing as an oral peptide.

Ecnoglutide, Pentagonist and Beyond: A Widening Pipeline

Other candidates round out the landscape. Ecnoglutide (Sciwind Biosciences) is a GLP-1 analogue biased toward cAMP signalling, designed to maximize the metabolic effect relative to pathways associated with tolerability issues. In the SLIMMER phase 3 trial (664 participants, published in The Lancet Diabetes & Endocrinology), weight loss at 40 weeks reached 9.1%, 10.9% and 13.2% at weekly doses of 1.2, 1.8 and 2.4 mg, versus stable weight on placebo; a phase 3 trial in type 2 diabetes was published in Nature Communications.

Further upstream, a paper published in Nature on April 30, 2026 describes a pentagonist: a peptide-drug conjugate linking a GLP-1/GIP co-agonist to lanifibranor, a pan-PPAR agonist, thereby activating five targets (GLP-1 and GIP receptors, plus PPAR alpha, gamma and delta). In obese, diabetic mice, placebo-corrected weight loss was markedly greater than with incretin comparators, with pronounced effects on fat mass and glycemia. The concept remains strictly preclinical, but it illustrates the targeted-polypharmacology logic that now dominates the design of these molecules, alongside retatrutide (a GLP-1/GIP/glucagon triple agonist) awaiting its phase 3 readouts.

What This Changes for Metabolic Research

For laboratories, this second generation reshapes the research questions. Comparing signalling profiles (the biased agonism of orforglipron and ecnoglutide, glucagon or amylin co-agonism) offers a far richer field for studying energy-balance mechanisms than the GLP-1 axis alone. Survodutide's body-composition data and the liver results from mazdutide and the MASH programs strengthen the case for preclinical models combining visceral adiposity, muscle and liver, rather than total body weight alone.

This work also feeds fundamental receptor research: the structure of receptor-ligand complexes, desensitization, amylin-calcitonin receptor interactions, and the role of glucagon in energy expenditure. An important reminder: the molecules discussed here are experimental drugs, or drugs approved in certain countries, evaluated in regulated clinical trials. Research peptides sold by RUO (Research Use Only) suppliers are intended exclusively for in vitro research and must never be used in humans or animals. This article is neither medical advice nor an encouragement to use these substances.

Molecule-by-Molecule Recap

Orforglipron (Lilly) — oral non-peptide GLP-1 agonist, one tablet daily. Phase 3 ATTAIN-1: -12.4% body weight at 72 weeks. FDA-approved April 1, 2026 (obesity); type 2 diabetes filing in progress. Survodutide (Boehringer/Zealand) — weekly injectable GLP-1/glucagon dual agonist. SYNCHRONIZE-1: -16.6% at 76 weeks; phase 3 MASH program (LIVERAGE) ongoing; regulatory filings expected after the 2026 readouts. Mazdutide (Innovent/Lilly) — GLP-1/glucagon dual agonist. Approved in China (2025); GLORY-2: -18.6% at 60 weeks at 9 mg; higher-dose application under review.

CagriSema (Novo Nordisk) — semaglutide + cagrilintide (amylin analogue), weekly. REDEFINE 1: -22.7% at 68 weeks; non-inferiority versus tirzepatide not demonstrated (REDEFINE 4); FDA application filed, decision expected 2026-2027. Amycretin (Novo Nordisk) — unimolecular amylin/GLP-1 co-agonist, injectable and oral. Up to -24.3% at 36 weeks in early-phase trials; obesity phase 3 started in 2026. Ecnoglutide (Sciwind) — cAMP-biased GLP-1 analogue; phase 3 SLIMMER: -13.2% at 40 weeks; development led in China. GLP-1/GIP/PPAR pentagonist (Nature, April 2026) — five-target peptide-drug conjugate, preclinical stage (mice).

Sources

Keep reading

EncyclopediaTirzepatide