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Next-Generation GLP-1 Drugs: What's Coming After

**Table of Contents**

Semaglutide and tirzepatide changed obesity treatment. But they are first-generation tools. The next wave of drugs is designed to produce more weight loss, preserve muscle, come in a pill, require fewer injections, and treat liver disease alongside obesity. Here is what the pipeline actually contains — the mechanisms, the data, and the timelines.

Table of Contents

Why "Next Generation" Matters

Current GLP-1 drugs work. Semaglutide produces roughly 15-17% weight loss. Tirzepatide pushes that to 20-22.5%. But they also come with real limitations:

  • Gastrointestinal side effects (nausea, vomiting, diarrhea) cause 5-15% of trial participants to discontinue
  • Lean muscle loss accounts for 25-40% of total weight lost, which is a particular concern in older adults
  • Injectable administration creates barriers to initiation and adherence
  • Weight regain of roughly two-thirds of lost weight occurs within a year of stopping treatment
  • Supply constraints have limited access since these drugs launched

The obesity drug pipeline now contains over 157 clinical-stage assets spanning more than 60 mechanisms of action. The drugs described below are the ones closest to market or most likely to change clinical practice.

Triple Agonists: Adding Glucagon to the Mix

The Logic

Tirzepatide proved that hitting two receptors (GLP-1 and GIP) works better than one. Triple agonists take this further by adding glucagon receptor activation. The rationale: GLP-1 and GIP suppress appetite and improve insulin signaling, while glucagon increases energy expenditure and drives fat oxidation in the liver.

The risk: glucagon raises blood glucose. Getting the balance right — enough glucagon activity for metabolic benefit without destabilizing blood sugar — is the central challenge.

Retatrutide (Eli Lilly)

Retatrutide is the most advanced triple agonist. It is a single molecule that activates GLP-1, GIP, and glucagon receptors in one weekly injection.

The data: In the Phase 3 TRIUMPH-4 trial, retatrutide produced average weight loss of up to 28.7% (71.2 pounds) over 68 weeks. That is the highest weight loss ever reported for a pharmacological agent, exceeding tirzepatide's SURMOUNT results by roughly 6 percentage points. The drug also reduced non-HDL cholesterol, triglycerides, hsCRP, and systolic blood pressure (14.0 mmHg reduction at the highest dose).

Seven additional Phase 3 readouts are expected in 2026, covering obesity without diabetes, obesity with type 2 diabetes, cardiovascular disease, obstructive sleep apnea, and metabolic liver disease.

Timeline: GlobalData predicts a 2027 approval, with projected sales of $15.6 billion by 2031. Clarivate named retatrutide one of the two "defining GLP-1 drugs of the next decade."

Other Triple Agonists

Novo Nordisk is developing NN1706, its own GLP-1/GIP/glucagon triple agonist. Preclinical data showed body weight reduction in rodents, monkeys, and humans. Several academic groups and smaller biotechs are also exploring the mechanism, though none are close to Phase 3.

Oral GLP-1 Formulations: The End of the Needle

Why Oral Matters

The shift from injection to pill changes everything about patient access. Many people who resist starting an injectable will try a pill. Primary care physicians prescribe oral medications more comfortably than injectables. Manufacturing costs are lower. Cold-chain logistics disappear. Oral GLP-1 options are expected to capture about 20% of the $80 billion obesity GLP-1 market by the end of the decade.

Oral Wegovy (Novo Nordisk) — Already Approved

The FDA approved oral semaglutide 25 mg for obesity in December 2025. It hit 50,000 weekly prescriptions in under three weeks after launch. The starting dose costs $149 per month.

The catch: oral semaglutide requires a 30-minute fasting window (no food or drink besides a small sip of water). The drug is a peptide delivered with an absorption enhancer (SNAC) that protects it from stomach acid and facilitates uptake through the gastric lining.

Clinical data: oral semaglutide 25 mg achieved 16.6% mean weight loss at 64 weeks in the OASIS 4 trial.

Orforglipron (Eli Lilly) — Under FDA Review

Orforglipron is fundamentally different from oral semaglutide. It is not a peptide reformulated as a pill — it is a small molecule that happens to activate the GLP-1 receptor. This means it can be taken at any time of day, with food, with water, with coffee. No fasting window required.

Phase 3 data:

  • ATTAIN-1: Significant weight loss in obesity (full results in NEJM, September 2025)
  • ATTAIN-2: 10.5% weight loss at the 36 mg dose in type 2 diabetes
  • ATTAIN-MAINTAIN: Patients on injectable Wegovy or Zepbound maintained their weight loss after switching to orforglipron over 52 weeks

Lilly submitted a new drug application and received an FDA Commissioner's National Priority Voucher, which could compress the review to weeks instead of the standard 6-10 months. Pricing through LillyDirect: $149-$399 depending on dose. Clarivate projects $16 billion in sales by 2031.

The Next Wave of Oral Candidates

Viking Therapeutics VK2735: In Phase 2, the highest dose produced 10.9% placebo-adjusted weight loss in just 13 weeks — a remarkable rate. Viking is advancing toward Phase 3.

Structure Therapeutics Aleniglipron: Planning Phase 3 trials starting mid-2026 after an end-of-Phase 2 FDA meeting.

Novo Nordisk Amycretin (oral formulation): Novo plans to move both subcutaneous and oral formulations of amycretin — a novel single-molecule GLP-1 and amylin receptor agonist — into Phase 3 in Q1 2026. The company says amycretin could offer a "best-in-class" profile.

Amylin Analogs: The Third Appetite Hormone

Why Amylin?

Amylin is a peptide hormone co-secreted with insulin from pancreatic beta cells. It slows gastric emptying, suppresses glucagon secretion, and promotes satiety through direct action on brain appetite centers. GLP-1 and amylin suppress appetite through overlapping but partially distinct pathways, so combining them produces additive effects.

There is another potential advantage: some early evidence suggests amylin analogs may lead to a lower loss of lean muscle mass relative to fat mass — addressing one of the biggest drawbacks of current GLP-1 monotherapy.

CagriSema (Novo Nordisk)

CagriSema combines semaglutide with cagrilintide, a long-acting amylin analog, in a single weekly injection.

Phase 3 results: In REDEFINE 1, CagriSema achieved 20.4% average weight loss at 68 weeks in adults with obesity (23% among on-treatment completers). In REDEFINE 2, it produced 13.7% weight loss in patients with type 2 diabetes while 73.5% achieved HbA1c below 6.5%.

CagriSema is Novo Nordisk's answer to tirzepatide. An active head-to-head trial versus Zepbound is expected to report by end of March 2026. Evaluate's 2026 preview report placed CagriSema at the top of its list for the biggest potential drug launch of the year. Novo filed for FDA approval in December 2025.

Eloralintide (Eli Lilly)

Lilly's early-stage amylin analog produced 9.5-20.1% weight loss in early trials versus 0.4% for placebo. The wide range across dose groups suggests the optimal dose is still being determined. Some studies suggest the drug may preserve lean mass better than GLP-1 monotherapy — a claim that Phase 3 data will need to confirm.

Petrelintide (Zealand Pharma/Roche)

Petrelintide (ZP8396) has shown promising early-phase data with a clean safety profile and potential for combination with GLP-1 agonists. Zealand Pharma partnered with Roche to advance the program.

Amycretin (Novo Nordisk)

Amycretin is unique: a single molecule that activates both GLP-1 and amylin receptors. If the dual mechanism can be captured in one compound (rather than requiring two drugs combined, as with CagriSema), manufacturing and dosing become simpler. Novo is planning Phase 3 in early 2026 for both injectable and oral formulations.

Combination Therapies: Pairing Mechanisms

The Strategic Shift

Rather than designing single molecules that hit multiple receptors, some developers are combining separate drugs. The logic: each mechanism is optimized independently, and doses can be adjusted separately.

Survodutide (Boehringer Ingelheim)

Survodutide is a GLP-1/glucagon dual agonist with particularly strong liver data. Phase 2 showed 18.7% weight loss and 47-62% MASH resolution (versus 14% placebo). It received FDA Breakthrough Therapy designation for MASH.

Phase 3 SYNCHRONIZE trials (obesity with and without diabetes) are expected to complete in H1 2026. If the liver data translates to Phase 3, survodutide becomes the leading dual-agonist therapy for simultaneous treatment of obesity and fatty liver disease.

Pemvidutide (Altimmune)

Pemvidutide is another GLP-1/glucagon dual agonist, but with balanced 1:1 receptor activity. Its Phase 2b IMPACT trial showed MASH resolution without worsening fibrosis at 24 weeks, with 7.5% weight loss at 48 weeks and no plateau. The drug earned FDA Breakthrough Therapy designation in January 2026. Phase 3 is being designed for 2026 initiation.

Roche CT-388

Roche's dual GLP-1/GIP agonist produced 22.5% placebo-adjusted weight loss at 48 weeks in Phase 2 — with no signs of plateau. The company is fast-tracking Phase 3 in Q1 2026. This is a compound to watch because the weight loss trajectory was still declining at the end of the study.

Muscle-Sparing Approaches: Solving the Lean Mass Problem

The Problem

When patients lose 20-25% of their body weight on current GLP-1 drugs, 25-40% of that weight comes from lean tissue — primarily muscle. For younger, otherwise healthy adults, this is generally manageable. For older adults, where sarcopenia is already a concern, losing significant muscle mass accelerates functional decline and increases fall risk.

Bimagrumab

Bimagrumab is a monoclonal antibody that blocks activin type II receptors, inhibiting myostatin and related ligands that drive muscle breakdown. In Phase 2 trials in adults with obesity and type 2 diabetes, bimagrumab achieved a 20.5% reduction in body fat alongside a 3.6% increase in lean mass — meaning almost all weight lost was fat.

The Phase 2b BELIEVE study is currently evaluating bimagrumab both alone and in combination with semaglutide. If the combination works as hypothesized — GLP-1 driving weight loss, bimagrumab preserving muscle — it would be the first therapy to directly address the body composition problem.

Myostatin-Activin Pathway Inhibitors (MAPi)

Beyond bimagrumab, the broader category of myostatin and activin pathway inhibitors is attracting interest. These agents could be paired with any GLP-1 drug to shift the ratio of fat loss versus muscle loss. The evidence base is still early, but the unmet need is clear.

Selective Androgen Receptor Modulators (SARMs)

SARMs are being explored for their ability to preserve muscle during caloric restriction. Evidence is sparse and regulatory pathways are uncertain, but the mechanism is scientifically plausible — androgens are well-established drivers of muscle protein synthesis.

Built-In Preservation?

Some researchers believe that triple agonists (with glucagon activity) and amylin analogs may inherently preserve lean mass better than GLP-1 monotherapy. The body composition substudies within the Phase 3 programs for retatrutide and survodutide will be watched closely for evidence supporting this hypothesis.

Unconventional Mechanisms: GIP Antagonism and Beyond

MariTide (Amgen)

MariTide (maridebart cafraglutide) takes an approach that contradicts tirzepatide's mechanism. While tirzepatide agonizes both GLP-1 and GIP receptors, MariTide is a GLP-1 agonist combined with a GIP antagonist. It is an antibody-peptide conjugate — a large molecule that could potentially be dosed monthly or even less frequently.

Phase 2 data: Up to 20% weight loss in obesity without diabetes and 17% with type 2 diabetes over 52 weeks, with no weight loss plateau observed. HbA1c dropped up to 1.6 percentage points in the diabetes population.

Amgen's Phase 3 MARITIME program is enrolling patients across multiple indications: obesity, type 2 diabetes, cardiovascular disease, heart failure, kidney disease, and obstructive sleep apnea. The company is targeting a regulatory application in late 2026 to early 2027.

The less-frequent dosing is MariTide's differentiator. If a monthly injection can produce 20% weight loss with acceptable tolerability, it offers a genuine convenience advantage over weekly injections.

What Else Is in the Pipeline

The global obesity drug pipeline extends well beyond the programs described above:

Pfizer's danuglipron: Pfizer's oral GLP-1 candidate has had a troubled development — the twice-daily formulation was discontinued due to high discontinuation rates from side effects. A once-daily formulation is still in development, but Pfizer is significantly behind Lilly and Novo Nordisk in the oral race.

Altimmune's pemvidutide: A GLP-1/glucagon dual agonist with balanced 1:1 receptor activity, primarily targeting MASH (fatty liver disease). Pemvidutide received FDA Breakthrough Therapy designation in January 2026 after its IMPACT Phase 2b trial demonstrated MASH resolution and 7.5% weight loss at 48 weeks. Phase 3 is being designed for 2026.

Gene therapy and long-acting approaches: Several academic groups and early-stage companies are exploring gene therapy approaches that would produce sustained GLP-1 or related peptide expression from a single treatment — potentially eliminating the need for ongoing injections or pills. These remain preclinical but represent the ultimate long-term ambition in the field.

The global obesity drug market is projected to reach $150 billion by 2035, and the diversity of mechanisms being pursued ensures that even if several individual programs fail, the overall trajectory of treatment improvement will continue.

What Matters Most: The Patient Perspective

The clinical data and corporate pipelines are interesting, but the practical implications for patients are what matter. The next-generation drugs address five specific limitations that patients currently face:

  1. Weight regain after stopping: Current GLP-1 drugs produce significant weight regain when discontinued. Longer-acting formulations (MariTide's monthly dosing) and oral options (orforglipron's convenience) may improve long-term adherence and reduce the cycle of starting and stopping.

  2. Side effect burden: Nausea, vomiting, and diarrhea cause 5-15% of patients to quit current drugs. Several next-gen candidates (pemvidutide showed 0-1.2% discontinuation; MariTide's GI effects were mild and transient) suggest the tolerability bar can be raised.

  3. Muscle loss: The body composition problem is real. Losing 25-40% of weight as lean tissue is a clinical concern, especially for older adults. Bimagrumab and the potential muscle-sparing effects of amylin and glucagon receptor activation could address this directly.

  4. Access and affordability: Oral drugs are cheaper to manufacture than injectable biologics. Small-molecule GLP-1s (orforglipron) do not require cold-chain storage or injection training. The TrumpRx pricing deal has already dropped prices, and competition from next-gen drugs will push them lower.

  5. Personalization: Not every patient responds optimally to GLP-1 receptor agonism alone. Having amylin, glucagon, GIP antagonism, and muscle-sparing agents available gives physicians multiple pathways to match treatment to individual biology.

The Competitive Landscape

DrugDeveloperMechanismDosingWeight LossStatus
RetatrutideEli LillyTriple (GLP-1/GIP/GCG)Weekly injection28.7%Phase 3 (7 trials in 2026)
CagriSemaNovo NordiskGLP-1 + AmylinWeekly injection20.4%Filed with FDA (Dec 2025)
OrforglipronEli LillyOral GLP-1 (small molecule)Daily pill10.5%Under FDA review
Oral WegovyNovo NordiskOral GLP-1 (peptide)Daily pill16.6%Approved (Dec 2025)
SurvodutideBoehringer IngelheimGLP-1/Glucagon dualWeekly injection18.7% (Ph2)Phase 3
MariTideAmgenGLP-1 agonist / GIP antagonistMonthly injection20% (Ph2)Phase 3
AmycretinNovo NordiskGLP-1/Amylin single moleculeInjection + oralTBDEntering Phase 3
VK2735Viking TherapeuticsGLP-1/GIP dualOral10.9% (13 wk, Ph2)Advancing to Phase 3
CT-388RocheGLP-1/GIP dualWeekly injection22.5% (Ph2)Entering Phase 3
BimagrumabVariousMyostatin/activin inhibitorIV infusionFat loss + muscle gainPhase 2b

FAQ

Which next-generation drug will produce the most weight loss?

Based on available data, retatrutide leads at 28.7% in Phase 3. But head-to-head comparisons between these agents have not been conducted (except the pending CagriSema vs. Zepbound trial). Trial populations and designs differ, making cross-trial comparisons imprecise.

When will an oral GLP-1 pill be as effective as an injection?

Oral Wegovy (16.6% weight loss) already approaches injectable Wegovy's efficacy (~15-17%). Orforglipron at 10.5% is lower, but it offers no-fasting convenience. Viking's VK2735 showed a rapid trajectory (10.9% at 13 weeks) that could potentially reach 20%+ at full treatment duration. Oral formulations are closing the gap faster than many predicted.

Will these drugs preserve muscle mass?

This is an open question. Bimagrumab is the only drug specifically designed to preserve lean mass, and it is still in Phase 2. Some researchers hypothesize that triple agonists (retatrutide) and amylin analogs (CagriSema, eloralintide) may inherently spare muscle better than GLP-1 monotherapy, but the Phase 3 body composition data has not yet been released.

How do next-gen drugs compare on side effects?

Gastrointestinal side effects (nausea, vomiting, diarrhea) remain the primary concern across the class. MariTide's data suggested nausea and vomiting were mostly mild, transient, and concentrated at the first dose. Pemvidutide showed a remarkably low discontinuation rate (0-1.2%). In general, newer drugs are being developed with dose-escalation protocols designed to minimize GI side effects.

When will these drugs be available?

Orforglipron could be approved within weeks to months (FDA priority review). CagriSema could be approved late 2026. Retatrutide and survodutide are targeting 2027 approvals. MariTide is targeting late 2026 to early 2027 for a regulatory filing. Most other candidates are 2-4 years from market.

The Bottom Line

The GLP-1 market is about to fragment in the best possible way. Instead of one mechanism and two drugs, patients and physicians will soon choose from triple agonists that maximize weight loss, oral pills that remove injection barriers, amylin combinations that attack appetite from multiple angles, muscle-sparing agents that address body composition, and monthly dosing options that reduce treatment burden.

Not every pipeline candidate will survive Phase 3 — the history of drug development guarantees some failures. But the sheer diversity of approaches means the next few years will produce meaningful advances regardless. For patients, the practical question is shifting from "can I get a GLP-1?" to "which approach is right for my body?"

That is a fundamentally better question.

References

  1. Eli Lilly. "Lilly's triple agonist, retatrutide, delivered weight loss of up to 71.2 lbs." Press Release, December 2025.
  2. Eli Lilly. "Lilly's oral GLP-1, orforglipron, demonstrated statistically significant efficacy results." Press Release.
  3. Novo Nordisk. "FDA approves Novo Nordisk's Wegovy pill, the first and only oral GLP-1 for weight loss in adults." Press Release, December 2025.
  4. Novo Nordisk. "Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity." NEJM, 2025. DOI.
  5. Amgen. "Amgen Announces Robust Weight Loss with MariTide at 52 Weeks in Phase 2." Press Release, November 2024.
  6. Amgen. "Inside Amgen's Phase 3 MARITIME Program." June 2025.
  7. Boehringer Ingelheim. "Survodutide US FDA Breakthrough Therapy phase 3 trials." Company Page.
  8. Altimmune. "Pemvidutide Achieved Key Measures of Success at 48 Weeks in IMPACT Phase 2b MASH Trial." December 2025.
  9. Nature Biotechnology. "Can amylin-based drugs upstage GLP-1 agonists?" 2025.
  10. PMC. "Triple Agonism Based Therapies for Obesity." PMC12304053.
  11. Springer Nature. "New drugs for the treatment of obesity: do we need approaches to preserve muscle mass?" Reviews in Endocrine and Metabolic Disorders, 2025. Link.
  12. GoodRx. "5 Projected GLP-1 Trends in 2026." 2026.
  13. PharmExec. "Lilly's Orforglipron, Retatrutide Named as Defining GLP-1 Drugs of the Next Decade." 2025.