GLP-1 Clinical Practice Updates: October 2025 Key Developments
In this GLP-1 round up:
- Why tirzepatide now outperforms semaglutide in both cardiovascular outcomes and tolerability.
- How new research on “non-responders” is shaping precision obesity medicine.
- The updated ACS position on integrating GLP-1 therapy with metabolic surgery.
- Why human-AI hybrid coaching drives better adherence than digital apps alone.
- What the SELECT trial revealed about heart protection independent of weight loss.
- How the upcoming oral GLP-1, orforglipron, could transform access and adherence.
Table of Contents
Tirzepatide Takes the Lead in Cardiovascular Protection
While our June 2025 update highlighted tirzepatide’s weight-loss superiority in the SURMOUNT-5 trial, October delivered the first direct evidence of its cardiovascular superiority in a high-risk population.
In a large comparative study of nearly 31,000 patients, Cleveland Clinic researchers found that tirzepatide was linked to significantly lower risks of major adverse cardiovascular events (MACE), all-cause mortality, and hospitalizations compared to semaglutide. Importantly, investigators also observed that tirzepatide had a more tolerable gastrointestinal side-effect profile, a key factor in long-term adherence to GLP-1 therapy.
- What This Means for Your Practice:
Understanding the “Non-Responder”: The Rise of Precision GLP-1 Medicine
Every clinician has seen it—the patient who follows the plan, tolerates the medication, but simply doesn’t lose weight on a GLP-1. Until now, that inconsistency has been difficult to explain. For the first time, an emerging clinical framework for “precision obesity medicine” is beginning to shed light on why this happens.
A new report in Scientific American synthesizes research on biological and genetic factors that may predict variability in response. The concept centers on distinct biological phenotypes—for example, the “hungry brain” versus the “hungry gut.”
Patients with a “hungry brain” phenotype (driven by central appetite dysregulation) may respond better to phentermine-topiramate, while those with a “hungry gut” phenotype (characterized by rapid gastric emptying or poor satiety signaling) may be ideal candidates for GLP-1 receptor agonists.
- What This Means for Your Practice:
This insight opens the door to more personalized, evidence-informed care.
Routine phenotyping isn’t standard yet, it offers a valuable new clinical lens when evaluating treatment response. Begin by asking targeted questions about eating patterns, such as:
- “Do you stop eating because you feel full, or because you think you should?”
- “Do you get hungry again quickly after meals?”
GLP-1s and Surgery: A New Multimodal Model of Care
In October, the American College of Surgeons (ACS) released a pivotal statement reframing obesity as a treatable medical condition—not a personal failure of willpower—and redefining how surgical and pharmacologic treatments work together in modern care.
The ACS called for a multimodal treatment continuum that includes GLP-1 receptor agonists alongside metabolic surgery, emphasizing that obesity is a chronic, complex disease requiring the full spectrum of evidence-based interventions.
While GLP-1s have proven transformative—achieving an average of ~15% total body-weight reduction—bariatric surgery remains the most effective tool for ~30% weight loss and the reversal of serious comorbidities. Importantly, the ACS also highlighted the synergistic potential of combining these approaches: using GLP-1s pre-operatively to improve surgical safety and post-operatively to help patients sustain weight loss over time.
- What This Means for Your Practice:
This evolving framework moves beyond “either/or” thinking. It supports initiating earlier, evidence-based discussions with appropriate patients about the full range of treatment options, including metabolic surgery when clinically justified.
Human + AI Coaching: Technology That Works With You
A new large-scale study from the University of Michigan provides the strongest evidence yet that human connection still matters most in digital health models. Analyzing data from approximately 65,000 users, researchers found that participants in a hybrid human–AI coaching program lost 74% more weight over three months than those relying on AI alone. The findings highlight how technology can enhance—but not replace—the empathy, accountability, and nuance that human providers bring to the table.
This builds on insights from our July 2025 update, which showed that digital tools improve GLP-1 adherence when integrated thoughtfully into patient care. Together, these findings underscore that the most effective and scalable models are human-led and technology-supported—not the other way around.
- What This Means for Your Practice:
Cardiovascular Protection Independent of Weight Loss
A landmark analysis from the SELECT trial has provided new insight into why GLP-1s are so cardioprotective—showing for the first time that their benefits extend well beyond weight loss itself.
Analyzing data from more than 17,000 patients, researchers found that the 20% reduction in major adverse cardiovascular events (MACE) was consistent across all weight categories—even among individuals who were only overweight (BMI ≥27). In other words, GLP-1s appear to function as true cardioprotective agents, likely through direct, pleiotropic effects on the cardiovascular system rather than through weight reduction alone.
These findings build on our August 2025 update, which detailed the expanding FDA indications for GLP-1s in metabolic conditions such as MASH, further reinforcing the shift toward viewing these medications as comprehensive metabolic therapies—not just weight loss drugs.
- What This Means for Your Practice:
The Race to Oral GLP-1s: Orforglipron Moves Forward
Following the encouraging Phase 3 results highlighted in our September 2025 update, Eli Lilly’s oral GLP-1, orforglipron, is now on a fast-track path to FDA approval. This once-daily, non-peptide formulation could dramatically expand access to GLP-1 therapy for patients who prefer to avoid injections.
New late-stage trial data released in October also showed that orforglipron achieved superior blood-sugar control compared to a leading SGLT2 inhibitor, underscoring its potential as a potent and convenient oral option for patients with type 2 diabetes.
- What This Means for Your Practice:
Key Takeaways for Providers
- Immediate Opportunities (Next 30 Days)
- Review current GLP-1 patients with cardiovascular risk factors who may benefit from transitioning to tirzepatide, based on new outcome data.
- Identify partial or non-responders and begin informal phenotyping conversations (e.g., “hungry brain” vs. “hungry gut”) to guide next-step decisions.
- Reinforce patient education around the broader health benefits of GLP-1 therapy—including cardiovascular protection—even before large weight changes occur.
- Evaluate digital tools or coaching programs to ensure patients have access to human-led support in addition to automated reminders or AI platforms.
- Start preparing educational materials introducing upcoming oral GLP-1 options like orforglipron for patients hesitant about injections.
- Strategic Planning (Next 90 Days)
- Design internal workflows for managing oral GLP-1 prescriptions, patient onboarding, and adherence tracking ahead of orforglipron’s anticipated approval.
- Update cardiovascular protocols to incorporate GLP-1 therapy as a cardiometabolic intervention, aligning with new SELECT trial data and outcome measures.
- Integrate multimodal care pathways—linking pharmacotherapy, nutritional counseling, and surgical referrals—based on the ACS guidance on comprehensive obesity treatment.
- Audit digital and AI-based patient-support tools to ensure they include human coaching components, leveraging new evidence for improved outcomes.
- Continue clinical education on upcoming dual-agonist and ultra-long-acting GLP-1 trials expected in early 2026 to stay current with evolving standards of care.
Conclusion
October 2025 delivered a clear message: GLP-1 therapy has evolved far beyond weight loss. From tirzepatide’s cardiovascular superiority and the rise of precision prescribing, to hybrid coaching models and the coming wave of oral agents, the field is moving toward personalized, multimodal, and accessible obesity care. For physicians and nurse practitioners, the opportunity lies in integration—combining pharmacologic therapy, metabolic surgery, lifestyle intervention, and technology to support lasting results. Staying informed isn’t just about clinical knowledge; it’s about positioning your practice to meet growing patient demand with evidence-based confidence. 💡 In short: the future of medical weight management is comprehensive, collaborative, and data-driven.
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