New Metrics, New Molecules, and New Directions in Obesity Medicine

Ann Metz
14 hours ago
4 min read

Original posted at obesity.news/ on Dec , 2025

This week brought a series of significant developments across obesity medicine, metabolic therapeutics, and neurodegenerative research, each with implications for how clinicians and patients approach diagnosis, treatment, and long-term metabolic health. From new obesity classification models to advances in oral incretins and procedural therapies, the landscape continues to shift rapidly. Here is a comprehensive breakdown of the most consequential updates.

Rethinking Obesity: New Metrics Suggest Nearly 70% of Adults Qualify

Harvard and Mass General researchers released data proposing an updated clinical framework for defining obesity, one that supplements BMI with waist circumference, a more accurate marker of visceral adiposity and metabolic dysfunction.

Under this revised metric, the percentage of U.S. adults who meet criteria for obesity rises from 43% to nearly 69%.

This dramatic increase underscores what clinicians frequently observe: many individuals with “normal” BMIs still experience hyperphagia, excessive food noise, insulin resistance, and early metabolic dysregulation. For these patients, traditional BMI often fails to validate lived experience.

The updated model better aligns diagnosis with underlying biology — not appearance — and may facilitate earlier intervention, including pharmacotherapy when appropriate.

A Promising Oral Triple Agonist with Breakthrough Bioavailability

Early preclinical data from Ascletis introduced a potentially transformative oral triple agonist targeting GLP-1, GIP, and glucagon receptors, the same receptor triad modulated by retatrutide, one of the most potent injectable obesity drugs in development.

The pharmacokinetic profile reported by the company is striking:

9× higher oral bioavailability than tirzepatide
30× higher than oral semaglutide
6× higher than oral retatrutide
57× higher drug exposure
Approximate 56-hour half-life

While these findings are limited to primate studies, the implications are significant. Oral incretin therapies have historically been constrained by low bioavailability. If even part of this signal holds in human trials, it could mark a major advance in oral metabolic therapeutics, offering a viable alternative for patients who cannot or prefer not to use injectable incretins.

Revita Procedure Shows Weight Stabilization After GLP-1 Discontinuation

Another milestone this week came from Fractal Health’s Revita study, an endoscopic duodenal mucosal resurfacing procedure designed to restore metabolic signaling in the gut.

Participants in the Reveal-1 trial:

Achieved an average 24% weight loss on GLP-1 therapy
Stopped their GLP-1 medication entirely
Received one Revita procedure
Used no maintenance drugs

At the six-month mark, outcomes were compelling:

Average weight change: +1.5%
HbA1c remained stable
Safety profile remained strong

In standard GLP-1 discontinuation data, patients often regain ~10% of body weight within six months. Revita’s results suggest the possibility of durable metabolic resetting, a concept that challenges the assumption that obesity pharmacotherapy must be lifelong.

While longer-term data are needed, these findings represent one of the most promising pathways for patients seeking sustained outcomes without indefinite medication use.

Zepbound Cash-Pay Prices Decline

Eli Lilly reduced cash-pay pricing across its Zepbound vial formulations:

2.5 mg: $299
5 mg: $399
7.5–15 mg: $449

Although these reductions may not immediately shift patients away from compounded formulations, community polling suggests many would transition to branded medications at a price point of $200–$300.

Under the federal Most Favored Nations pricing agreement, GLP-1 costs are expected to decrease toward $250/month over the next two years. If implemented as planned, this change could significantly reshape access for millions of patients.

Clarifying the EVOKE Alzheimer’s Trial Results

Novo Nordisk released topline results for the EVOKE and EVOKE+ Alzheimer’s trials, which evaluated Rybelsus (14 mg oral semaglutide) in early Alzheimer’s disease.

Key outcomes included:

Improvement in some biomarkers
No slowing of clinical progression
No preservation of daily function
Failure to meet the primary endpoint

While disappointing, these results require nuanced interpretation:

Rybelsus is a low-potency oral formulation chosen intentionally to avoid excessive weight loss, a significant concern for elderly patients with Alzheimer’s disease.
This was a first-in-class, nearly $700 million exploratory trial.
Early biomarker changes indicate relevant mechanistic activity, even without clinical improvement.
Both Novo Nordisk and Eli Lilly are now developing incretin-based compounds that target neurological pathways while minimizing appetite suppression.

The EVOKE data represent an initial step, not a definitive verdict, on the role of incretins in neurodegenerative disease.

The Biology of Hunger: A Clinical Reality

A recurring theme in patient reports, including recent clinical experience shared within the On The Pen community, is the intensity of hunger returning after GLP-1 discontinuation. This is not psychological; it reflects reactivated metabolic, hormonal, and hypothalamic signaling.

The rapid resurgence of hunger underscores why GLP-1 therapies remain transformative: they modulate pathways deeply rooted in survival biology, not behavior. Understanding that distinction is central to destigmatizing both obesity and its treatment.

Looking Ahead

From new diagnostic criteria to advances in oral pharmacology, procedural innovation, and neurological research, this week illustrates just how dynamic obesity medicine has become. As access expands, particularly through anticipated pricing shifts and forthcoming Medicare updates, millions more patients will enter the conversation.

The goal now is to ensure they have accurate, unbiased, patient-centered information when they do.

At On The Pen, we remain committed to providing that clarity.

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