Oral GLP-1s are HERE

What the data shows

Author

Hunter Williams
August 25, 2025

Happy Monday!

I hope that after reading today’s email, you are as excited as I am about the future of metabolic medicine.

For years, people have been chasing the “holy grail” of weight loss and glucose control without injections.

We’ve witnessed the meteoric rise of semaglutide, tirzepatide, and retatrutide.

But behind the scenes, researchers have been working on a small-molecule pill that acts like a GLP-1 receptor agonist.

That drug is orforglipron, and it represents a completely new era.

Unlike peptide-based GLP-1s that require refrigeration and injections, orforglipron is a stable, easy-to-produce pill that is highly bioavailable.

Chugai Pharmaceutical originally discovered it, and Eli Lilly quickly licensed it in 2018.

Since then, it’s moved through Phase 1, Phase 2, and now Phase 3 trials with remarkable results.

For clinicians and researchers like us, this is one of the most exciting metabolic drugs we’ve seen in decades.

How Orforglipron Works

Mechanistically, orforglipron is fascinating.

It’s a partial agonist of the GLP-1 receptor, but it’s Gs-biased, meaning it drives the cAMP pathway (insulin release, glucagon suppression, appetite regulation) while barely engaging β-arrestin.

In plain English, why does that matter?

Lower β-arrestin activity could mean less receptor desensitization over time.

In other words, orforglipron might hold its effect longer without the rapid desensitization some patients see on peptide GLP-1s.

It binds with high affinity (Ki ~1 nM), and in preclinical models, even low receptor occupancy was enough to mimic the full GLP-1 effect.

This resulted in stronger insulin release when glucose is high, slower gastric emptying, reduced hunger signals, and decreased food intake.

In short, it activates the same pathways that have made semaglutide and tirzepatide world-famous.

But this comes in a pill form, with a slightly different signaling profile that could offer unique advantages.

What the Studies Show (Part 1 – Obesity)

In the NEJM Phase 2 obesity trial (Wharton et al., 2023), adults with obesity or overweight were randomized to placebo or daily orforglipron (12–45 mg). The results after 36 weeks were jaw-dropping.

  • Placebo: –2.3% weight loss

  • Orforglipron 12 mg: –9.4%

  • Orforglipron 24 mg: ~–12%

  • Orforglipron 45 mg: –14.7%

Even more impressive, 46–75% of participants hit ≥10% total body weight reduction, depending on dose.

And every prespecified cardiometabolic risk factor (blood pressure, waist circumference, lipid markers) improved significantly compared to placebo.

These numbers put orforglipron in the same league as semaglutide 2.4 mg weekly.

And remember, this was achieved with a daily pill, no injections, no storage headaches, and no reconstitution needed.

What the Studies Show (Part 2 – Diabetes)

In the Lancet Phase 2 T2DM trial (Frias et al., 2023), 383 patients with type 2 diabetes (mean baseline HbA1c ~8.1%) received orforglipron (3–45 mg), dulaglutide 1.5 mg weekly, or placebo.

By 26 weeks:

  • Placebo: –0.43% HbA1c, –2.2 kg weight loss

  • Dulaglutide: –1.10% HbA1c, –3.9 kg weight loss

  • Orforglipron (high dose): –2.10% HbA1c, –10.1 kg weight loss

As you can see, it resulted in nearly double the glucose reduction and weight loss of dulaglutide, a standard injectable GLP-1. Over 80% of patients on orforglipron achieved HbA1c <7%.

And in Phase 3 ACHIEVE-1 (2025):

  • HbA1c dropped –1.3% to –1.6% at 40 weeks.

  • Body weight decreased by 4.7% to –7.9%.

  • No hepatic safety signal.

What Benefits Can You Expect?

The benefits of orforglipron fall into three main categories:

  1. Appetite suppression and weight loss – Clinical data shows ~10–15% body weight reduction in under a year. Unlike injectables that can cause nausea, many patients report a cleaner “I’m just not hungry” feeling.

  2. Improved glycemic control – HbA1c reductions of up to –2% rival the most powerful GLP-1s. It improves fasting glucose, post-prandial spikes, and overall insulin sensitivity.

  3. Cardiometabolic improvements – Lower blood pressure, improved lipid profiles, reduced waist circumference

When combined with resistance training, protein-sufficient nutrition, and hormone optimization, the body recomposition potential is enormous.

Less fat, more muscle preserved, improved labs, and better overall metabolic resilience.

Dosing & Titration

Orforglipron is long-acting, with a 29–49 hour half-life. That means one capsule a day provides steady coverage.

In trials, patients started as low as 1–3 mg daily and titrated up over weeks. Doses of 12–36 mg daily are the sweet spot for weight and glucose efficacy, with 45 mg being the highest tested.

For research purposes, our BioZapetite capsules at BioLongevity Labs will deliver 6 mg per cap. Here’s what I would recommend based on my personal experience so far:

  • Start at 6 mg daily (1 cap).

  • After 1–2 weeks, increase to 12 mg (2 caps).

  • Continue titrating upward every 2–3 weeks as needed, depending on tolerance and research objectives.

The key is the slow buildup.

GI events (nausea, diarrhea, dyspepsia) are most common early on. Careful titration smooths the ride.

My Personal Experience

In our livestream last night, I shared my first days on BioZapetite.

Day 1, I took 12 mg in the morning.

Nothing dramatic at first. But by mid-afternoon, I felt a wave of satiety that shut off food noise.

Dinner rolled around and I wasn’t forcing myself to resist food.

I just wasn’t interested.

Unlike semaglutide or tirzepatide, the appetite suppression didn’t cause nausea.

There also was no stomach pain.

It was clean, mental appetite suppression.

Over the next days, that feeling stabilized.

By Day 3 or 4, it hit earlier in the day, and I noticed a tighter control on caloric intake without feeling deprived.

For someone who’s experimented with every GLP-1 in the book, this felt as good if not better than tirzepatide.

Why This Matters

Obesity and diabetes are epidemics of untold proportions.

Billions of people worldwide are at risk, and while injectables have been a revolution, they aren’t accessible to everyone.

Orforglipron represents a democratization of GLP-1 therapy.

As a pill, scalable to produce, stable without refrigeration, and affordable, it could reach far more people than injectables ever will.

But beyond accessibility, it also comes down to quality of life.

No needles. No storage hassles. Just a pill you can take once a day and move on with your life.

For biohackers, clinicians, and researchers at the tip of the spear, this is a molecule worth paying attention to.

Coming Soon to BioLongevity Labs

At BioLongevity Labs, our mission has always been to put the most advanced molecules into the hands of researchers.

Orforglipron (branded as BioZapetite) is next.

We’ll soon be offering 6 mg capsules for research use only.

It’s the perfect entry point for titration, allowing flexibility to scale from 6 mg up to 12, 18, 24 mg and beyond as needed.

So stay tuned. BioZapetite is coming very soon to BioLongevity Labs.

And when it does, it’s going to change the landscape for researchers worldwide.

You can go here to get notified as soon as it’s ready to purchase: https://biolongevitylabs.com/product/biozapetite/

Also, stay tuned as we have some epic sales coming later this week!

Best,

Hunter Williams

Further Reading