An Oral Milestone for GLP-1
Week Of December 20 – December 26, 2025
Oral Wegovy became the first pill-form GLP-1 to receive FDA approval for weight management this week. It’s definitely a milestone, although the strict dosing requirements (empty stomach, limited water) may limit its appeal compared to injectables. For the Trial Spotlight, I chose Lilly’s gastric emptying study, which aims to give anesthesiologists evidence-based guidance on preoperative fasting for patients on these drugs. The Mechanism Explained section covers how Novo got a peptide into a pill using SNAC technology, and how this compares to the simpler approach of small molecules like orforglipron.
🔥 THIS WEEK’S KEY DEVELOPMENTS
FDA approves oral Wegovy for weight management.
Novo Nordisk announced that the US FDA has approved the Wegovy® pill (once-daily oral semaglutide 25 mg) to reduce excess body weight, maintain weight reduction, and reduce the risk of major adverse cardiovascular events. The approval, which marks the first oral GLP-1 therapy for weight management, was based on the OASIS trial program, where the OASIS 4 trial demonstrated a 16.6% mean weight loss. Novo Nordisk expects to launch the Wegovy® pill in the US in early January 2026.
Press | Trials: NCT05564117 | NCT03574597 | Mechanism: glucagon-like peptide-1 (GLP-1) receptor agonist
🆕 NEWLY REGISTERED TRIALS (5 in last week)
Metabolic correction with GLP-1 drugs to improve cardiovascular disease diagnosis and treatment in Kazakhstan (Nazarbayev University, n=120)
[New Indications]
Trials: NCT07303556 (ICDDTKZ26) | Mechanism: Dual GLP-1/GIP agonist
Liraglutide Phase 4 real-world study evaluating the drug alone and combined with Orlistat for weight loss in overweight/obese patients (The Fourth Affiliated Hospital of Zhejiang University School of Medicine, n=120)
[Weight Loss/Efficacy]
Trials: NCT07301437 | Mechanism: GLP-1 RA
Tirzepatide Phase 1 study to determine how fasting and withholding the drug affects stomach emptying in adults with T2D or obesity (Eli Lilly, n=40)
[Weight Loss/Efficacy]
Trials: NCT07299084 | Mechanism: Dual GLP-1/GIP agonist
EXER-MED Phase 3 comparing exercise versus tirzepatide on weight and health outcomes (University of Virginia, n=24)
[Weight Loss/Efficacy]
Trials: NCT07298915 (EXER-MED) | Mechanism: Dual GLP-1/GIP agonist
Exploratory trial investigating GLP-1’s effect on intestinal barrier function in patients with Short Bowel Syndrome with Intestinal Failure (SBS-IF) (Jinling Hospital, n=20)
[New Indications]
Trials: NCT07297238 | Mechanism: GLP-1 receptor agonist
💡 TRIAL SPOTLIGHT
Educational spotlight selected by editors
A Study to Evaluate the Effect of Fasting Duration and Tirzepatide Withholding on the Amount of Food and Fluid in the Stomach in Participants With Type 2 Diabetes Mellitus and Participants With Overweight or Obesity Without Type 2 Diabetes Mellitus
In response to growing concerns about perioperative safety, Eli Lilly has designed a crucial Phase 1 study (NCT07299084) to generate data on gastric emptying in patients taking tirzepatide. As a dual GLP-1/GIP agonist, tirzepatide’s mechanism inherently slows the passage of food from the stomach, which has led to debate among anesthesiologists about the risk of aspiration during procedures. This open-label trial will enroll 40 participants with type 2 diabetes or obesity to directly measure stomach contents after test meals, evaluating different fasting durations and withholding the drug. The study, set to begin recruiting in early 2026, is strategically significant as it aims to provide the first direct clinical evidence to inform and refine preoperative fasting guidelines for this major drug class, addressing a critical knowledge gap highlighted by medical societies.
🔬 MECHANISM EXPLAINED
Understanding the science behind the therapeutics
Oral Peptide Delivery & The “SNAC” Shield (Example: Oral Wegovy (semaglutide))
The FDA’s approval of oral Wegovy (semaglutide) relies on a clever formulation trick to bypass the stomach’s natural defenses, which typically destroy peptide drugs like GLP-1s. The pill co-formulates semaglutide with an absorption enhancer called SNAC (salcaprozate sodium), which acts as a local buffer to neutralize stomach acid immediately around the dissolving tablet. This creates a transient, pH-neutral “bubble” that protects the peptide from enzymatic breakdown and fluidizes the stomach lining, allowing the large molecule to slip into the bloodstream intact.
This delicate chemical choreography explains the strict dosing requirements: patients must take it on an empty stomach because food or excess water disrupts that protective pH bubble, destroying the drug before it absorbs. In contrast, emerging competitors like orforglipron are non-peptide “small molecules” chemically designed to survive digestion naturally, promising similar efficacy without the rigid fasting rules—positioning oral Wegovy as a bridge between today’s injectables and the next generation of more convenient oral therapies.
This newsletter compiles publicly available information from company press releases and ClinicalTrials.gov. Not investment advice.