GLP-1 Clinical Practice Updates: September 2025 Key Developments
September 2025 brought several notable developments in the GLP-1 and weight management space, including new clinical trial data, regulatory guidance changes, and policy updates from the WHO. This monthly update summarizes what clinicians need to know.
In this GLP-1 round up:
- Oral GLP-1 delivers up to 12.4% weight loss in Phase III trial, offering injection-free alternative
- High-dose semaglutide achieves 25%+ weight loss in one-third of patients without added safety concerns
- FDA provides regulatory clarity for muscle-preserving drugs to break through the weight loss plateau
- WHO issues first recommendation for GLP-1s in obesity, framing it as chronic disease requiring long-term treatment
Table of Contents
New Drug Formulations and Clinical Trial Data
Orforglipron: Phase III Data for Oral GLP-1
Eli Lilly’s orforglipron, an oral GLP-1 receptor agonist, reported Phase III results from the ATTAIN-1 trial in the New England Journal of Medicine. The 72-week study enrolled 3,127 non-diabetic patients with obesity or overweight with complications.
- Results
- 6 mg daily: 7.8% weight loss
- 12 mg daily: 9.3% weight loss
- 36 mg daily: 12.4% weight loss
- Placebo: 2.1% weight loss
The study also showed improvements in waist circumference, blood pressure, non-HDL cholesterol, triglycerides, and glycated hemoglobin. Side effects were consistent with other GLP-1s—primarily mild to moderate gastrointestinal symptoms.
Clinical implications: While weight loss was somewhat less than injectable GLP-1s, the oral formulation may appeal to patients who prefer not to use injections. The drug doesn’t require refrigeration, which simplifies distribution and storage.
High-Dose Semaglutide: STEP UP Trial Results
The STEP UP trials, published in The Lancet Diabetes & Endocrinology, evaluated a 7.2 mg dose of semaglutide compared to the standard 2.4 mg dose.
- STEP UP Diabetes (patients with obesity and T2D):
- 7.2 mg: 13.2% average weight loss
- 2.4 mg: 10.4% average weight loss
- Placebo: 3.9% average weight loss
- STEP UP Obesity (patients without diabetes):
- Nearly one-third of patients on 7.2 mg lost 25% or more of starting weight
- 15% on 2.4 mg achieved this level of weight loss
- No patients on placebo reached 25% weight loss
The higher dose did not increase serious side effects. Gastrointestinal symptoms occurred in approximately 50% of patients on either dose (versus 25% on placebo) and typically improved after dose escalation.
Clinical implications: The higher dose may be appropriate for patients who need greater weight loss or who plateau on the standard dose. The safety profile appears similar to the 2.4 mg dose.
High-Dose Semaglutide: STEP UP Trial Results
Metsera reported Phase 2b results for MET-097i, an ultra-long-acting GLP-1 receptor agonist being developed for monthly dosing. The VESPER-1 trial enrolled 239 participants with overweight or obesity without type 2 diabetes.
- Results at 28 weeks:
- Placebo-subtracted weight loss: up to 14.1% (1.2 mg dose)
- Individual responses: as high as 26.5%
- Discontinuation rate: 2.9% total, with only 2 of 239 participants stopping due to adverse events
The drug showed favorable tolerability compared to current GLP-1s, with lower rates of nausea and vomiting. At 36 weeks, patients continued to lose weight without reaching a plateau.
Clinical implications: If approved, monthly dosing could improve adherence for some patients. The company plans to initiate Phase 3 trials in late 2025.
Muscle Preservation: An Emerging Focus
The Weight Loss Plateau Issue
Enobosarm: FDA Provides Regulatory Clarity
Veru Inc. announced results from an FDA meeting regarding enobosarm, a selective androgen receptor modulator (SARM) being studied for muscle preservation during GLP-1 therapy.
- Key FDA guidance:
- Incremental weight loss (enobosarm + GLP-1 versus GLP-1 alone) is an acceptable primary endpoint for approval
- The 3 mg dose is appropriate for continued development
- FDA encouraged including younger patients, not just older populations
- Phase 2 QUALITY study data:
- 16 weeks of enobosarm in older patients taking semaglutide
- Preserved lean mass and burned additional fat mass
- Improved physical function
- During the maintenance period (12 weeks after semaglutide discontinuation), enobosarm prevented weight regain by 46% compared to placebo
Next steps: Veru plans to initiate the Phase 2b PLATEAU trial in Q1 2026, enrolling approximately 180 patients (both older and younger) with obesity taking tirzepatide. The 72-week study will assess whether enobosarm can increase total weight loss beyond GLP-1 therapy alone.
Clinical implications: The FDA’s acceptance of incremental weight loss as a primary endpoint provides a clearer regulatory pathway for this class of drugs. If successful, muscle-preserving agents could address the plateau issue and improve long-term outcomes.
Bimagrumab Development Continues
Eli Lilly discontinued one Phase IIb trial of bimagrumab (an activin receptor type-2B inhibitor) combined with tirzepatide in patients with obesity and type 2 diabetes, citing “strategic business reasons.” However, a parallel study in patients with obesity alone continues, with results expected in 2026.
Earlier data from Versanis Bio’s BELIEVE study showed that bimagrumab combined with semaglutide improved fat loss and muscle retention compared to either treatment alone.
Clinical implications: Multiple companies are developing muscle-preserving therapies, suggesting this will be an active area of development. TD Cowen analysts estimate the market potential at over $30 billion by 2035.
WHO Recommends GLP-1s for Obesity Treatment
The World Health Organization released draft guidance in September 2025 recommending GLP-1 drugs for long-term obesity treatment in adults with a BMI of 30 or above. This is the first time WHO has recommended GLP-1s specifically for obesity.
- Key points from the guidance:
- GLP-1 drugs should be part of long-term obesity treatment
- Obesity is characterized as a “chronic, progressive and relapsing disease”
- The guidance emphasizes moving away from viewing obesity as primarily a lifestyle issue
The draft guidance was open for consultation through September 27, 2025. Separate guidelines for children and adolescents are in development.
Context: Earlier in September, WHO stopped short of adding GLP-1s to its essential medicines list for obesity treatment, citing high prices that limit access in low- and middle-income countries. The drugs were added to the list only for patients with type 2 diabetes combined with another health condition.
Clinical implications: The WHO guidance may influence how governments and health systems approach obesity treatment globally. It reinforces the position that obesity requires ongoing medical management rather than episodic intervention.
Expanding Indications: Stroke Prevention
The American Heart Association published a case report in Stroke journal in September 2025 illustrating the use of GLP-1 receptor agonists for primary stroke prevention, consistent with the 2024 AHA/ASA guidelines for stroke prevention.
Clinical implications: GLP-1s are increasingly recognized for cardiovascular and cerebrovascular benefits beyond weight loss and glycemic control. These include improvements in blood pressure, inflammation, and lipid profiles.
Technology and AI in Obesity Care
Vanderbilt AI Project
Vanderbilt University Medical Center launched a two-year project (funded by a $1 million grant from Eli Lilly) to use AI to improve obesity care continuity. The project will analyze electronic health records to identify why patients discontinue treatment and develop a patient-facing mobile app to enhance engagement.
Clinical implications: Poor care continuity is a significant challenge in obesity management. AI-based tools may help identify at-risk patients and improve long-term outcomes.
DECODE GenAI Model
Analysis Group developed DECODE (Dynamic Evaluation of Cardiometabolic Obesity Disease), a generative AI model trained on US electronic health records and claims data. The model simulates the long-term progression of obesity and related conditions. An initial application found that 10% weight loss over 10 years was associated with a 26% lower risk of heart failure and a 12% lower risk of bariatric surgery.
Clinical implications: These models may help clinicians and patients understand the long-term benefits of sustained weight loss across multiple comorbidities.
Key Takeaways for Providers
- Immediate Opportunities (Next 30 Days)
- Review patients for higher-dose semaglutide candidates
- Assess plateau patients for muscle-preserving therapies
- Update patient education about oral
- GLP-1 options Begin body composition monitoring
- Strategic Planning (Next 90 Days)
- Prepare workflows for oral GLP-1 management
- Develop cardiovascular risk reduction protocols
- Consider integrating technology/AI tools
- Stay informed on ultra-long-acting formulation results
Conclusion
September’s developments reflect the continued maturation of GLP-1 therapy in 2025. The publication of oral GLP-1 data and ultra-long-acting formulations addresses patient preference and adherence challenges, while higher-dose semaglutide results demonstrate that greater efficacy is achievable without compromising safety.
The convergence of muscle preservation strategies, WHO’s global policy shift recognizing obesity as a chronic disease, and expanding indications beyond weight loss positions GLP-1 therapy as a comprehensive cardiometabolic intervention. For providers, these developments require both immediate clinical adjustments—such as body composition monitoring and patient education updates—and longer-term strategic planning for oral formulations and combination therapies.
As the field continues to evolve monthly, staying current with clinical trial results, regulatory guidance, and emerging treatment options remains essential for delivering evidence-based, patient-centered obesity care.
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