Subject: Orforglipron: Does It Work? Yes. Is It Better Than Subq? Not Even Close.
From: Derek from Research Radar <[email-masked]>
To: [email-masked]
Date: Thu, 23 Apr 2026 18:51:24 +0000
List-Id: <derekpruski.substack.com>

View this post on the web at https://derekpruski.substack.com/p/orforglipron-does-it-work-yes-is

An honest look at the first oral GLP-1 that actually works — and where it actually fits in a field dominated by injectables
Let’s have an honest conversation about orforglipron.
It’s the headline GLP-1 story of the last eighteen months. The first oral small-molecule GLP-1 agonist to successfully complete Phase 3. Eli Lilly has already submitted it to the FDA for both obesity and type 2 diabetes. Likely trade name: Foundayo. The marketing engine is about to go into overdrive.
Here’s the honest take before we dive in. It works. The data is real. The Phase 3 program is rigorous. But subcutaneous administration is always going to hit harder — and that’s not a limitation of orforglipron specifically, it’s physics. Bypassing the digestive tract means better bioavailability, more predictable pharmacokinetics, and stronger downstream effects. Always.
Orforglipron doesn’t break that rule. It just offers a real option for people who were never going to consider subq in the first place.
This post is going to walk through the data, compare it to the rest of the field, and land on the honest answer about where orforglipron actually fits. Which is a narrower space than the coverage suggests.
As always, this is research and educational content. Not medical advice.
The Framing Most Headlines Miss
Before we get into the numbers, it’s worth being clear about what orforglipron is and isn’t.
It is:
A legitimate GLP-1 receptor agonist with real Phase 3 efficacy
The first oral GLP-1 without the empty-stomach ritual that handicaps oral semaglutide
A breakthrough in delivery chemistry — taking something that should be destroyed by digestion and getting it absorbed orally is genuinely hard
A real option for the population that was never going to use injectables
It is not:
A competitor to tirzepatide, retatrutide, or cagrisema on efficacy
Going to replace subq GLP-1s for people seeking maximum weight loss
A gimmick — the science is solid
The “future of GLP-1s” the way some headlines are framing it
Here’s the frame I’d encourage you to hold throughout this piece. Subq GLP-1s will always outperform oral GLP-1s for the same fundamental reasons real food beats supplements. The gut is a hostile environment for drug delivery. Every oral molecule fights absorption, degradation, and first-pass metabolism before it reaches circulation. Subcutaneous administration skips all of that.
What orforglipron solves is not an efficacy problem. It’s an access and acceptance problem. That distinction matters.
What Orforglipron Actually Is
Orforglipron is a once-daily oral GLP-1 receptor agonist. The key distinction — the one that makes this whole story possible — is that it’s a small molecule, not a peptide.
Why that matters:
Semaglutide, tirzepatide, and every other mainstream GLP-1 is a peptide. Peptides are chains of amino acids. Amino acid chains get obliterated by stomach acid and digestive enzymes. That’s why most GLP-1s have to be administered subcutaneously — put them in your stomach and they’re just expensive protein.
Oral semaglutide exists as a workaround, using a penetration enhancer called SNAC to sneak semaglutide across the gastric lining. But it requires empty-stomach dosing, a precise amount of water, and a 30-minute wait before food or other medications. The inconvenience is significant, and the absorbed dose is tiny compared to subq.
Orforglipron is a completely different chemical species. It’s a non-peptide small molecule — more like a conventional pharmaceutical drug than a biologic — that binds the GLP-1 receptor and triggers the same signaling. Because it’s not made of amino acids, it survives digestion. Take it any time of day, with or without food. No water restrictions, no waiting period.
It was discovered by Chugai Pharmaceutical in Japan and licensed by Lilly in 2018. The Phase 3 program is massive — the ACHIEVE trials for type 2 diabetes enrolled over 6,000 participants across five studies, and the ATTAIN program for obesity enrolled over 4,500 more.
That’s a significant commitment of capital, and it signals that Lilly believes this molecule has real commercial legs.
The Mechanism: Nothing New, Different Delivery
Orforglipron binds the exact same GLP-1 receptor that semaglutide does. Same signaling. Same downstream effects. The novelty is entirely in the chemistry of how it gets to that receptor, not in what it does once it arrives.
GLP-1 signaling accomplishes four things that matter for obesity and diabetes:
It slows gastric emptying. Food stays in your stomach longer, which means you feel full sooner and stay full longer. This is a significant contributor to reduced caloric intake.
It stimulates glucose-dependent insulin release. When blood sugar is elevated, GLP-1 tells the pancreas to release insulin. The “glucose-dependent” qualifier is important — GLP-1 only triggers insulin release when it’s actually needed, which is why GLP-1 agonists rarely cause hypoglycemia on their own.
It suppresses glucagon. Glucagon is the hormone that tells the liver to produce glucose. Dialing that signal down reduces hepatic glucose output and helps glycemic control.
It acts directly on the brain. This is the big one. GLP-1 receptors are expressed throughout appetite-regulating regions of the central nervous system. Activating them reduces hunger, decreases cravings, and changes the reward valence of food. This is where most of the weight loss actually comes from.
Orforglipron triggers all of this. It’s the same pharmacology as every other GLP-1 agonist. The engineering achievement is getting that pharmacology delivered orally at therapeutic levels.
The Phase 3 Data
Four trials matter most. Let’s walk through them.
ATTAIN-1 — The Obesity Headliner
Published in the New England Journal of Medicine in September 2025.
The design was straightforward. 3,127 adults with obesity but no diabetes, randomized to 6 mg, 12 mg, or 36 mg daily orforglipron or placebo. All doses titrated up gradually from 1 mg. Duration: 72 weeks, which is the standard for modern obesity trials.
Results at the highest dose:
Average weight loss: 12.4% (27.3 lbs)
Placebo: 0.9% (2.2 lbs)
59.6% of participants lost at least 10% of body weight
39.6% lost at least 15%
18.4% lost at least 20%
Meaningful improvements in waist circumference, systolic blood pressure, triglycerides, non-HDL cholesterol, and hsCRP (an inflammation marker)
Reference: PMID 40960239
ATTAIN-2 — Obesity Plus Diabetes
Same design, different population — adults with both obesity and type 2 diabetes.
Results at 36 mg:
Weight loss: 10.5% (22.9 lbs)
A1C reduction: 1.3% to 1.8% across doses
75% of participants on the highest dose achieved A1C ≤6.5%, which is at or below the diabetes diagnostic threshold
hsCRP reduced by 50.6% at the highest dose
Note that weight loss is consistently lower in diabetic populations across all GLP-1 trials — this isn’t specific to orforglipron. It’s a phenomenon you see with semaglutide, tirzepatide, and every other agent in the class.
ACHIEVE-3 — The One Head-to-Head That Exists
This is the most important trial for context, because it’s the only direct comparison between orforglipron and the existing oral GLP-1 option.
1,698 adults with type 2 diabetes on metformin were randomized to orforglipron (12 mg or 36 mg) or oral semaglutide (7 mg or 14 mg) for 52 weeks.
At the highest doses — orforglipron 36 mg versus oral semaglutide 14 mg:
Weight loss: 9.2% vs 5.3%
Nearly three times as many participants reached near-normal blood sugar on orforglipron
Orforglipron delivered 73.6% greater relative weight loss
Orforglipron beat oral semaglutide decisively on both endpoints. If oral GLP-1 is the category you’re evaluating, orforglipron is the clear winner within that category.
ATTAIN-MAINTAIN — The Step-Down Study
Released December 2025. This one answers a real-world question: can orforglipron maintain weight loss after somebody tapers off a subq GLP-1?
Participants from the earlier SURMOUNT-5 study who had been on maximum tolerated Wegovy or Zepbound for 72 weeks were re-randomized to orforglipron or placebo for an additional 52 weeks.
Results:
Orforglipron met the primary and all key secondary endpoints
Superior weight maintenance compared to placebo
Suggests orforglipron can function as a step-down or maintenance option after injectable therapy
This is a legitimately useful indication. The transition off subq GLP-1s has been a practical problem for patients and clinicians alike — weight regain is common. Having a lower-intensity oral option to hold the losses is genuinely valuable.
Side Effects: Same Class, Same Profile
The adverse event profile is consistent with every other GLP-1 — GI-dominant, mostly mild to moderate, worst during dose titration.
From ATTAIN-1 at the 36 mg dose:
Nausea: 33.7% (vs 10.4% placebo)
Constipation: 25.4% (vs 9.3%)
Diarrhea: 23.1% (vs 9.6%)
Vomiting: 24.0% (vs 3.5%)
Dyspepsia: 14.1% (vs 5.0%)
Discontinuation specifically due to adverse events scaled with dose: 5.1% at 6 mg, 7.7% at 12 mg, 10.3% at 36 mg, versus 2.6% on placebo.
Interesting footnote — total study dropout was actually higher on placebo than on any active dose. Nearly 30% of placebo participants left the study versus 22-24% on orforglipron. The most likely explanation: people on placebo weren’t seeing results and lost motivation to continue.
The Honest Comparison: Why Subq Wins
This is the section the marketing narrative doesn’t want you to think about.
Here’s the approximate peak-dose weight loss across the modern GLP-1 field:
Retatrutide 12 mg (subq, weekly): ~28.7%
Cagrisema (subq, weekly): ~22.7%
Tirzepatide 15 mg (subq, weekly): ~20.9%
Semaglutide 2.4 mg (subq, weekly): ~14.9%
Orforglipron 36 mg (oral, daily): ~12.4%
Oral semaglutide 14 mg: ~5.3%
Orforglipron sits at the bottom of the new-generation efficacy ladder. Not by a little. By a lot. Let’s walk through each comparison honestly.
Versus Subq Semaglutide (Wegovy/Ozempic)
Subq semaglutide delivers roughly 14.9% weight loss in non-diabetic obesity. Orforglipron delivers 12.4%. That’s a 2.5 percentage point gap in favor of subq.
Orforglipron holds up reasonably well here. This is the closest comparison in the entire field. But it still loses to the oldest subq GLP-1 in the modern class — and that’s with orforglipron at its highest tested dose against semaglutide at its standard dose.
One caveat worth noting: a recent indirect comparison (the ORION analysis) using OASIS-4 data suggested that oral semaglutide at the newer 25 mg dose may actually outperform orforglipron in non-diabetic populations. Indirect comparison, not head-to-head, so take it with appropriate skepticism. But it’s worth watching.
Versus Tirzepatide (Mounjaro/Zepbound)
Subq tirzepatide at 15 mg delivers roughly 20.9% weight loss. Orforglipron 36 mg delivers 12.4%. That’s an eight percentage point gap.
Eight percentage points is enormous. On a 250-pound baseline, that’s the difference between losing 31 pounds and losing 52 pounds. Tirzepatide is the current efficacy leader among FDA-approved options, and if someone can tolerate subq administration and is seeking maximum results, there is no serious comparison to be made with orforglipron.
Versus Retatrutide (Triple Agonist)
This is where the gap becomes absurd. Subq retatrutide at 12 mg delivered 28.7% weight loss at 68 weeks in TRIUMPH-4. Break that down further:
58.6% of participants on 12 mg achieved at least 25% weight loss
39.4% achieved at least 30%
23.7% achieved at least 35%
Orforglipron 36 mg: 12.4%.
Retatrutide is in a different universe — roughly 2.3x the efficacy at the same time horizon. It’s still investigational and won’t hit the market until 2026 or 2027, but when it does, it’s going to reset expectations for what GLP-class therapy can achieve.
One thing worth flagging on the retatrutide side: a new dysesthesia signal emerged in TRIUMPH-4 (abnormal skin sensations like tingling) that wasn’t seen in the Phase 2 data. Discontinuation at 12 mg hit 18.2%, notably higher than with orforglipron or tirzepatide. Part of this was attributed to “perceived excessive weight loss” in lower-BMI participants, which is its own interesting signal. Worth watching as more Phase 3 data reads out through 2026.
Versus Cagrisema (Cagrilintide + Semaglutide)
Novo Nordisk’s entry in the dual-agonist space combines a GLP-1 (semaglutide) with an amylin analog (cagrilintide). Subq, once-weekly.
Cagrisema delivered 22.7% weight loss in REDEFINE 1 under the full-adherence estimand. That roughly doubles orforglipron’s efficacy.
Worth noting: REDEFINE 4, the head-to-head against tirzepatide, failed to show noninferiority. So cagrisema doesn’t displace tirz at the top of the efficacy hierarchy. But it absolutely demolishes orforglipron.
So Who Is Orforglipron Actually For
This is the real question, and the honest answer is narrower than the marketing will suggest.
It’s a legitimate option for:
The single largest population is people who won’t use subq, period. Needle aversion is real and prevalent. A significant portion of patients who would otherwise benefit from GLP-1 therapy refuse it outright because of the self-administration requirement. For that population, getting 12% weight loss through a pill is infinitely better than getting 0% because they won’t inject. This is not a small group.
Beyond that, orforglipron is reasonable for:
Early intervention or less extreme cases where 12-13% weight loss is clinically sufficient
Step-down maintenance after subq therapy — the ATTAIN-MAINTAIN data supports this specifically
Global access populations, particularly in regions where cold-chain storage and injectable distribution are infrastructure problems. Small-molecule oral drugs are dramatically easier to distribute than peptide injectables
Type 2 diabetes management when oral dosing is strongly preferred — the ACHIEVE data is solid on glycemic control
It is not the right choice for:
Anyone who can tolerate subq administration and is seeking maximum weight loss
Patients with severe obesity who genuinely need 20%+ reduction to reach clinical targets
Anyone choosing between orforglipron and tirzepatide, retatrutide, or cagrisema purely on efficacy
What We Still Don’t Know
The Phase 3 package is robust, but there are genuine unknowns:
Long-term cardiovascular outcomes data is still pending (the trial is ongoing)
Real-world adherence outside controlled trial settings
Head-to-head data versus tirzepatide (doesn’t exist and likely never will)
Head-to-head versus subq semaglutide for obesity specifically (doesn’t exist)
How efficacy holds past 72 weeks — the known treatment horizon
The Bottom Line
Orforglipron is not a gimmick. The science is legitimate. The Phase 3 data is rigorous. It’s going to help a real population that would never otherwise benefit from GLP-1 therapy. That is genuinely valuable, and I don’t want any of the honest framing above to obscure that point.
But let’s call it what it is. Orforglipron is the entry-level modern GLP-1. It trades efficacy for oral convenience. For people averse to subcutaneous administration, that tradeoff makes sense and the oral option is better than nothing. For everyone else, subq is going to outperform it — often by enormous margins.
The marketing is going to frame this as “GLP-1s for everyone.” The reality is it’s a real option for a specific slice of the population. That slice is meaningful. It’s just not the whole market.
If you’re comfortable with subq administration and seeking maximum results, the tirzepatide, retatrutide, and cagrisema tier is where the action is. If oral is the only pathway you’ll accept, orforglipron is a genuine option — and a meaningfully better one than any oral GLP-1 that came before it.
Just don’t confuse what it is with what it isn’t.
Key References
Wharton S, et al. Orforglipron for Obesity (ATTAIN-1). N Engl J Med. 2025;393(18). PMID 40960239
Rosenstock J, et al. Orforglipron in early type 2 diabetes (ACHIEVE-1). N Engl J Med. 2025;393:1065-1076
Horn DB, et al. Orforglipron in T2D with obesity (ATTAIN-2). Lancet. 2025
Novo Nordisk. REDEFINE 1 — Cagrilintide plus Semaglutide (CagriSema). N Engl J Med. 2025
Jastreboff AM, et al. Tirzepatide Once Weekly for the Treatment of Obesity (SURMOUNT-1). N Engl J Med. 2022
Wilding JPH, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity (STEP 1). N Engl J Med. 2021
Jastreboff AM, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. N Engl J Med. 2023
Eli Lilly press releases: TRIUMPH-4 (Dec 2025), ATTAIN-MAINTAIN (Dec 2025), ATTAIN-2 (Aug 2025), ACHIEVE-3 (Sept 2025)
This post is for research and educational purposes only. Orforglipron is not currently FDA approved. Any decisions about GLP-1 therapy should involve qualified medical professionals.

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