PeptideJournal
Research11 min read

Orforglipron Oral GLP-1 Phase 3 Updates

For years, the GLP-1 receptor agonist story was defined by needles. Semaglutide, tirzepatide, liraglutide — all delivered by subcutaneous injection.

For years, the GLP-1 receptor agonist story was defined by needles. Semaglutide, tirzepatide, liraglutide — all delivered by subcutaneous injection. Oral semaglutide (Rybelsus) broke that pattern in 2019, but it came with baggage: take it on an empty stomach, limit water to four ounces, wait 30 minutes before eating. Not exactly seamless.

Eli Lilly's orforglipron is built differently. It is a small-molecule, non-peptide GLP-1 receptor agonist — meaning it survives stomach acid without the fasting rituals that peptide-based oral drugs require. You take it once a day, any time, with or without food.

Between 2023 and early 2026, Lilly ran orforglipron through a massive Phase 3 program spanning more than 10,000 participants across two parallel trial series: ATTAIN (obesity) and ACHIEVE (type 2 diabetes). The results are now largely public, and the FDA has the drug under priority review with a target decision date of April 10, 2026.

Here is everything we know.

Table of Contents

  1. What Makes Orforglipron Different
  2. Phase 2 Groundwork (2023)
  3. ATTAIN-1: Obesity Without Diabetes
  4. ATTAIN-2: Obesity With Type 2 Diabetes
  5. ATTAIN-MAINTAIN: Switching From Injectables
  6. ACHIEVE Trials: Type 2 Diabetes Program
  7. ACHIEVE-3: Head-to-Head vs. Oral Semaglutide
  8. Safety Across All Trials
  9. How Orforglipron Stacks Up
  10. Regulatory Timeline and What Comes Next
  11. The Bottom Line
  12. References

What Makes Orforglipron Different

Most GLP-1 receptor agonists are peptides — short chains of amino acids that mimic the natural hormone GLP-1. Peptides break down in the gut, which is why semaglutide and tirzepatide are given by injection. Oral semaglutide gets around this with a permeation enhancer called SNAC, but the process is fragile. Food, water volume, and timing all interfere with absorption.

Orforglipron sidesteps all of that. Discovered by Chugai Pharmaceutical and licensed by Lilly in 2018, it is a small molecule — not a peptide. It activates the same GLP-1 receptor but resists enzymatic breakdown in the stomach without needing special formulation tricks.

The practical result: no fasting, no water restrictions, no waiting. Patients can take it with breakfast, at lunch, or before bed. That flexibility matters. Adherence to oral medications drops when dosing instructions are complicated, and oral semaglutide's fasting requirement has long been a barrier for real-world compliance.

Phase 2 Groundwork (2023)

Before launching the Phase 3 program, Lilly published Phase 2 data in the New England Journal of Medicine (June 2023). The trial randomized 272 adults with obesity or overweight (without diabetes) to one of four orforglipron doses (12 mg, 24 mg, 36 mg, or 45 mg) or placebo for 36 weeks.

The headline: up to 14.7% mean weight reduction at 36 weeks — and the weight-loss curves were still trending downward when the trial ended. The GI side effects tracked with the known GLP-1 class profile: nausea, vomiting, diarrhea.

These results were strong enough to justify two separate Phase 3 development programs: ATTAIN for obesity and ACHIEVE for type 2 diabetes. Together, these programs enrolled over 10,000 participants at hundreds of sites across more than a dozen countries.

ATTAIN-1: Obesity Without Diabetes

Published: New England Journal of Medicine, September 2025 (DOI: 10.1056/NEJMoa2511774) ClinicalTrials.gov: NCT05869903

ATTAIN-1 is the flagship obesity trial. Researchers randomized 3,127 adults with obesity (BMI ≥30, or ≥27 with a weight-related condition) and without diabetes across nine countries. Participants received orforglipron at 6 mg, 12 mg, or 36 mg — or placebo — daily for 72 weeks alongside diet and exercise counseling.

Weight Loss Results

DoseMean Weight Loss (%)Mean Weight Loss (lbs)≥10% Loss≥15% Loss≥20% Loss
6 mg−7.5%————
12 mg−8.4%————
36 mg−11.2%−27.3 lbs54.6%36.0%18.4%
Placebo−2.1%—12.9%5.9%2.8%

All orforglipron doses hit the primary endpoint of superior weight loss versus placebo (P<0.001 for all comparisons).

Beyond the Scale

The metabolic ripple effects were significant. Across doses, orforglipron improved waist circumference, systolic blood pressure, triglycerides, and non-HDL cholesterol. The 36 mg dose cut high-sensitivity C-reactive protein (hsCRP), a marker of systemic inflammation, by 47.7%.

Among the 1,127 participants with prediabetes at baseline, up to 91% of those on orforglipron reached near-normal blood sugar levels, compared with 42% on placebo. For a drug primarily studied for weight management, that is a striking glycemic finding.

ATTAIN-2: Obesity With Type 2 Diabetes

Published: The Lancet, November 2025 (DOI: 10.1016/S0140-6736(25)02165-8)

Weight loss is harder when type 2 diabetes is in the picture — insulin resistance, diabetes medications that promote weight gain, and altered metabolism all conspire against it. ATTAIN-2 tested orforglipron in this tougher population.

The trial enrolled more than 1,600 participants with a BMI ≥27 and HbA1c between 7% and 10% across 136 sites in ten countries. Treatment lasted 72 weeks.

Key Results

OutcomeOrforglipron 36 mgPlacebo
Mean weight loss−10.5% (−22.9 lbs)−2.2% (−5.1 lbs)
A1C reduction (from 8.1% baseline)−1.8%—
Achieved A1C ≤6.5%75%—
hsCRP reduction−50.6%—

All three doses (6 mg, 12 mg, 36 mg) met primary and key secondary endpoints. The A1C reductions — ranging from 1.3% to 1.8% across doses — are in the same ballpark as what injectable GLP-1s typically deliver. At the highest dose, three out of four participants reached an A1C of 6.5% or below, which is at or under the American Diabetes Association's diagnostic threshold for diabetes.

Orforglipron also moved the needle on non-HDL cholesterol, systolic blood pressure, and triglycerides — cardiovascular risk factors that matter independently of weight.

ATTAIN-MAINTAIN: Switching From Injectables

Announced: December 18, 2025

This trial asked a question no one had answered before: can patients who have lost weight on injectable GLP-1s switch to an oral drug and keep the weight off?

ATTAIN-MAINTAIN enrolled 376 participants who had completed the SURMOUNT-5 trial (which compared tirzepatide to semaglutide). These patients had achieved weight plateaus after 72 weeks on the highest tolerated doses of either Wegovy (semaglutide 2.4 mg) or Zepbound (tirzepatide). They were then randomized 3:2 to oral orforglipron (up to 36 mg) or placebo for 52 weeks.

Maintenance Results (24-Week Analysis)

Switch FromOrforglipron Weight ChangePlacebo Weight Change
Wegovy (semaglutide)−0.1 kg+9.4 kg
Zepbound (tirzepatide)+2.6 kg+9.1 kg

The 24-week data point is cleaner because placebo patients were eligible for rescue therapy after that mark. The message is clear: patients switching to orforglipron from Wegovy held virtually all their weight loss (less than 1 kg difference on average). Those switching from Zepbound — which produces larger total weight loss — saw a modest 5 kg regain over 52 weeks, but still far less than the 9+ kg regain seen with placebo.

For the millions of patients on injectable GLP-1s who would prefer a pill, these are the first data showing a viable off-ramp from injections that does not mean giving back most of your progress.

ACHIEVE Trials: Type 2 Diabetes Program

The ACHIEVE program is Lilly's registration trial series for orforglipron in type 2 diabetes. It enrolled over 6,000 participants across five trials. Here is what has been reported so far.

ACHIEVE-1: Orforglipron vs. Placebo

A 40-week trial comparing orforglipron (3 mg, 12 mg, 36 mg) to placebo in adults with inadequately controlled type 2 diabetes. The highest dose lowered A1C by 1.6% and reduced body weight by 7.9% (about 16 lbs). All doses met primary and key secondary endpoints.

ACHIEVE-2: Orforglipron vs. Dapagliflozin

This 40-week open-label study pitted orforglipron against dapagliflozin (Farxiga), an SGLT-2 inhibitor, in 962 adults with type 2 diabetes on background metformin. Orforglipron delivered A1C reductions of up to 1.7%, compared with 0.8% for dapagliflozin — more than double. It met non-inferiority and superiority endpoints.

ACHIEVE-5: Orforglipron Added to Insulin

ACHIEVE-5 tested orforglipron as an add-on to insulin glargine (with or without metformin and/or SGLT-2 inhibitors) in 546 participants over 40 weeks. Adding orforglipron on top of insulin cut A1C by an additional 2.1%, versus 0.8% with placebo. This is a meaningful finding for patients whose diabetes is not adequately controlled on insulin alone.

ACHIEVE-4: Pending

ACHIEVE-4 (NCT05803421), the final registration trial in the ACHIEVE program, has results expected in the first quarter of 2026. The full ACHIEVE dataset will form the basis of Lilly's FDA submission for the type 2 diabetes indication.

ACHIEVE-3: Head-to-Head vs. Oral Semaglutide

Announced: September 17, 2025

ACHIEVE-3 is the trial everyone in the GLP-1 space was watching. It ran head-to-head against oral semaglutide (Rybelsus) in 1,698 adults with type 2 diabetes inadequately controlled on metformin. The study was open-label, 52 weeks long, and compared two doses of each drug.

Head-to-Head Comparison

OutcomeOrforglipron 12 mgOrforglipron 36 mgOral Semaglutide 7 mgOral Semaglutide 14 mg
A1C reduction−1.9%−2.2%−1.1%−1.4%
Achieved A1C <5.7%21.4%37.1%7.4%12.5%
Weight loss (%)−6.7%−9.2%−3.7%−5.3%

At the highest dose comparison, orforglipron drove nearly three times as many patients to an A1C below 5.7% (37.1% vs. 12.5%) and produced 73.6% greater relative weight loss. Orforglipron also showed improvements in non-HDL cholesterol, systolic blood pressure, and triglycerides.

The Caveat Worth Noting

ACHIEVE-3 compared orforglipron against oral semaglutide at 7 mg and 14 mg — the doses available at the time as Rybelsus. But in December 2025, the FDA approved oral Wegovy (semaglutide 25 mg) for weight management, and the OASIS 4 trial showed that dose producing 16.6% weight loss at 64 weeks with full adherence.

No head-to-head data exist between orforglipron 36 mg and oral semaglutide 25 mg. That comparison would be far more informative, and researchers have flagged this gap. The ACHIEVE-3 results are real, but they compare orforglipron against what may no longer be the best version of its competitor.

The trial was also open-label (not blinded), partly because Rybelsus's fasting protocol made a double-blind design impractical.

Safety Across All Trials

The safety profile across ATTAIN and ACHIEVE trials is consistent and tracks closely with other GLP-1 receptor agonists. There are no major surprises, but the numbers deserve careful examination.

Most Common Adverse Events (ATTAIN-1, 36 mg Dose)

Adverse EventOrforglipron 36 mgPlacebo
Nausea33.7%10.4%
Constipation25.4%9.3%
Vomiting24.0%—
Diarrhea23.1%9.6%

GI side effects were most common during dose escalation and generally improved over time. Most were classified as mild to moderate.

Discontinuation Rates

Treatment discontinuation due to adverse events ranged from 5% to 11% across trials at the highest dose. In ATTAIN-2, the numbers were 6.1% (6 mg), 10.6% (12 mg), and 10.6% (36 mg) versus 4.6% for placebo.

In the ACHIEVE-3 head-to-head, discontinuation rates were notably higher for orforglipron (8.7% at 12 mg, 9.7% at 36 mg) than for oral semaglutide (4.5% at 7 mg, 4.9% at 14 mg). That is a meaningful difference, and it is fair to say orforglipron's GI burden, while manageable, is on the heavier end of the GLP-1 spectrum.

Serious Events

Serious adverse events occurred in 3.8% to 5.5% of orforglipron patients versus 4.9% in placebo groups. Five cases of confirmed mild pancreatitis occurred in the ATTAIN-1 trial (all in orforglipron groups), with no complications. No hepatic safety signal was observed across any trial. A 2026 meta-analysis of five orforglipron RCTs (6,140 total participants) found no significant difference in acute pancreatitis rates versus placebo.

How Orforglipron Stacks Up

With multiple oral and injectable GLP-1 options now on the market or in late development, here is how orforglipron fits into the broader picture. For a full comparison, see the branded GLP-1 drugs comparison.

Orforglipron vs. Oral Semaglutide (Rybelsus 14 mg)

Orforglipron outperformed oral semaglutide at currently available doses in head-to-head trials for both A1C reduction and weight loss. And it does not require fasting. But with the 25 mg oral Wegovy formulation now approved, the comparison is less straightforward. No direct data yet.

Orforglipron vs. Injectable Semaglutide (Wegovy 2.4 mg)

Injectable semaglutide 2.4 mg has shown approximately 14.9% weight loss in the STEP trials. Orforglipron's 11.2% at 36 mg falls short of that number. The trade-off is obvious: less weight loss, but no injection. For many patients, that trade will be worth it.

Orforglipron vs. Tirzepatide (Zepbound)

Tirzepatide, a dual GIP/GLP-1 agonist, has produced weight loss of 20% or more in trials. Orforglipron is not in the same weight-loss tier. But the ATTAIN-MAINTAIN trial showed orforglipron can serve as a maintenance therapy after tirzepatide — a potentially important role as clinicians figure out long-term treatment strategies for obesity management.

Regulatory Timeline and What Comes Next

Lilly submitted a New Drug Application for orforglipron in obesity in late 2025. The FDA granted it a Commissioner's National Priority Voucher — a new expedited pathway that compresses the standard 10–12 month review to roughly 1–2 months.

The current FDA target action date is April 10, 2026, pushed back slightly from an initial estimate of March 28. If approved, Lilly has indicated self-pay pricing starting at $149 per month for the lowest dose and up to $399 for the highest dose, available through LillyDirect.

The type 2 diabetes submission is expected separately in 2026, pending ACHIEVE-4 results.

Beyond weight management and diabetes, Lilly is also studying orforglipron for obstructive sleep apnea, hypertension, knee osteoarthritis in adults with obesity, stress urinary incontinence, and cardiovascular and renal outcomes. The same broadening of indications that happened with semaglutide and tirzepatide appears to be underway.

The Bottom Line

Orforglipron is not the most powerful GLP-1 receptor agonist in clinical development. Injectable tirzepatide and semaglutide both produce more weight loss. But power is not the only variable that matters.

What orforglipron offers is a genuine oral GLP-1 that works without the fasting constraints of oral semaglutide and without needles. In Phase 3 trials, it produced 11.2% weight loss in adults with obesity, up to 2.2% A1C reduction in type 2 diabetes, and — in a first-of-its-kind study — allowed patients to maintain their weight loss after switching from injectable therapy.

The GI side effects are real. Roughly one in ten patients at the highest dose discontinued treatment because of them, and the discontinuation rates ran higher than those seen with oral semaglutide in head-to-head trials. That is worth an honest conversation between patients and their physicians.

The comparison with oral semaglutide 25 mg — now FDA-approved for weight loss — remains the critical missing piece of evidence. Until that head-to-head study happens, the relative positioning of these two oral options will involve some educated guessing.

If the FDA approves orforglipron by its April 2026 target date, it will enter a market where the demand for effective, convenient GLP-1 therapies far outstrips supply. Whether it becomes a first-line treatment, an alternative for patients who cannot tolerate injections, or a maintenance option after injectable weight loss, orforglipron adds a tool that the field has been waiting for — an oral GLP-1 that works on your schedule, not the other way around.

References

  1. Wharton S, Aronne LJ, Stefanski A, et al. Orforglipron, an oral small-molecule GLP-1 receptor agonist for obesity treatment. N Engl J Med. 2025;393(18):1796-1806. doi:10.1056/NEJMoa2511774

  2. Horn DB, Ryan DH, Giljanovic Kis S, et al. Orforglipron for the treatment of obesity in people with type 2 diabetes (ATTAIN-2). The Lancet. November 2025. doi:10.1016/S0140-6736(25)02165-8

  3. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Daily oral GLP-1 receptor agonist orforglipron for adults with obesity. N Engl J Med. 2023;389:877-888. PubMed: 37351564

  4. Eli Lilly and Company. Lilly's oral GLP-1, orforglipron, superior to oral semaglutide in head-to-head trial (ACHIEVE-3). September 2025. Press Release

  5. Eli Lilly and Company. Orforglipron demonstrated superior glycemic control in ACHIEVE-2 and ACHIEVE-5 Phase 3 trials. 2025. Press Release

  6. Eli Lilly and Company. Orforglipron helped people maintain weight loss after switching from injectable incretins (ATTAIN-MAINTAIN). December 2025. Press Release

  7. Hammad N, Ramadan AM, Nazmy A, et al. Efficacy and safety of oral GLP-1 RA orforglipron: a systematic review and meta-analysis. SAGE Journals. 2026. doi:10.1177/15209156261420404

  8. ClinicalTrials.gov. A study of orforglipron in adult participants with obesity (ATTAIN-1). NCT05869903

  9. ClinicalTrials.gov. Orforglipron vs. oral semaglutide in type 2 diabetes (ACHIEVE-3). NCT06045221

  10. Novo Nordisk. FDA approves oral Wegovy for weight management. December 2025. AJMC Coverage