Oral Semaglutide

Today, we’re diving into an exciting development in obesity treatment—oral semaglutide. 

Last week, the FDA approved Novo Nordisk’s Wegovy pill as the first and only oral GLP-1 for weight loss in adults. This approval is based on results from the OASIS-4 phase 3 clinical trial showing that a once-daily oral version of semaglutide can deliver nearly the same weight loss results as the injectable form. 

So, what does that really mean for patients and treatment options? Let’s break it down.

What the OASIS-4 Trial Found

In the OASIS-4 trial, adults with obesity took 25 mg of oral semaglutide once daily, alongside lifestyle counseling that included nutrition guidance and physical activity support, for a total of 64 weeks. On average, participants lost about 13.7% of their body weight over that period.

Comparing Oral vs. Injectable Semaglutide for Weight Loss

So how does this compare to injectable semaglutide (Wegovy) for weight loss? 

Clinical trials of injectable semaglutide have shown weight loss in the range of about 14 to 17% over similar periods, and the injections are given once weekly. Some studies with higher doses of the injectable have even shown weight loss exceeding 17%

That means the oral version’s average weight loss of 13.7% over 64 weeks is remarkably close to the injectable, especially when you consider the differences in dosing schedule and how the drug is delivered. 

With injectable semaglutide, many of the cardiovascular and metabolic benefits—like improvements in blood pressure, cholesterol, glucose, and inflammation — have been confirmed in dedicated outcomes trials or as predefined secondary endpoints in the STEP trials. This means the data were specifically collected and analyzed to show that these benefits are statistically robust and clinically meaningful.

For oral semaglutide, the improvements in blood pressure, blood sugar, lipids, and inflammation seen in OASIS‑4 come from post hoc or secondary analyses, not as primary trial endpoints. 

But what does this mean? 

When we say a finding comes from a post hoc or secondary analysis, it means the result wasn’t the main goal of the study. In a clinical trial, researchers define primary endpoints—the main outcomes they want to measure, like weight loss in the OASIS‑4 trial. Secondary endpoints are additional outcomes they plan to look at, such as changes in blood pressure or cholesterol.

A post hoc analysis goes a step further: it’s an analysis the researchers decide to do after the data are collected, often to explore trends or patterns they weren’t specifically testing for. These analyses can provide useful insights, but because they weren’t the trial’s original focus, the results are considered less definitive than primary endpoints.

So, when we see improvements in blood pressure or lipids with oral semaglutide, these findings are encouraging—but they’re based on secondary or post hoc analyses, not the trial’s main goal of measuring weight loss.

That means while the results are promising and suggest broader cardiometabolic benefits beyond weight loss, they are not yet as rigorously established as the cardiovascular outcomes demonstrated with the injectable version.

Oral vs Injectable Medications — What’s the Difference?

When it comes to medications, most people assume that pills are always easier than injections, and in many cases, that’s true. But there’s a lot happening behind the scenes that can affect how well a drug works.

Peptides are fragile and can be broken down in the digestive tract, and when a drug is swallowed, it normally passes through the liver before reaching the rest of the body—a process called first-pass metabolism, which can destroy much of the active medication. That’s why many drugs simply can’t be given orally.

Oral semaglutide overcomes this challenge with a special additive called SNAC, which protects the peptide from stomach acid and helps it be absorbed directly through the stomach lining. This allows some of the drug to enter the bloodstream straight from the stomach, partially bypassing first-pass metabolism. Because absorption is still limited, oral semaglutide requires higher daily doses than the injectable and must be taken on an empty stomach with a little water, waiting at least 30 minutes before eating or taking other medications.

Injectable semaglutide, on the other hand, goes straight into the bloodstream, bypassing the digestive tract and first-pass metabolism entirely. This makes injections more potent, predictable, and efficient, while the oral version relies on SNAC to survive digestion and reach effective levels in the blood.

Compliance & Convenience

Finally I would like to talk about compliance and convenience. When it comes to following a treatment plan and ease of use, both oral and injectable medications have their pros and cons. 

Oral medications obviously have the advantage of no needles, which is appealing to many people, especially those with needle anxiety, and they fit easily into a daily routine.

Injectables, on the other hand, are usually given once a week, which some people find more convenient than remembering a daily pill. They also bypass first-pass metabolism, which often means better bioavailability, and they can achieve higher effective drug levels in the body. Some people actually prefer injections because they have gastrointestinal sensitivity to oral medications, or simply because a weekly shot feels like “one less thing to think about” each day.

From a real-world perspective, compliance—whether someone takes their medication as prescribed—is just as important as how effective the drug is. Missing a daily pill can reduce its benefits, whereas a weekly injection is often easier to remember and maintain consistently.

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Until next time, be well, and have a happy, healthy week.