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Research · Medication

Orforglipron

In ATTAIN-1, daily orforglipron cut body weight 11.2% at the highest dose over 72 weeks, against 2.1% on placebo. In early type 2 diabetes it lowered HbA1c 1.07 points more than placebo. Gastrointestinal effects were common, and a network meta-analysis placed its discontinuation for adverse events among the highest of obesity drugs.

Add to Bio HackChecked 2026-11-09
Status
Prescription drug in the US. FDA-approved in April 2026 as Foundayo, a once-daily tablet, used with a reduced-calorie diet and increased physical activity to reduce excess body weight and maintain weight reduction long term in adults with obesity, or with overweight and at least one weight-related condition. Its current label does not include type 2 diabetes as an indication. Orforglipron is a non-peptide, small-molecule GLP-1 receptor agonist taken by mouth, not a peptide.
Also called
Foundayo, oral GLP-1, GLP-1 pill, oral GLP-1 receptor agonist, non-peptide GLP-1, orforglipron calcium
Taken for
weight loss, blood sugar, type 2 diabetes, HbA1c, keeping weight off, appetite, switching from injectable GLP-1s

Strong several reviews agree · Moderate one review or consistent trials · Limited one or a few small studies · Untested no study in people, listed with what it rests on

Shown to help3

Reported risks6

What people take it for, and what was found

Shown to help3

StrongVery common

Weight loss

Shown to cut weight about 11% on the top dose against 2% on placebo over 72 weeks in adults with obesity, alongside lifestyle intervention.

The numbers and sources
How common
Very common: more than 1 in 10 people.
Effect
In ATTAIN-1, body weight changed by -7.5% on 6 mg, -8.4% on 12 mg and -11.2% (95% CI -12.0 to -10.4) on 36 mg, against -2.1% on placebo, at 72 weeks. On 36 mg, 54.6% lost 10% or more and 18.4% lost 20% or more, against 12.9% and 2.8% on placebo [1]. In adults with type 2 diabetes (ATTAIN-2), weight changed by -9.6% on 36 mg against -2.5% on placebo, a difference of -7.1 points (95% CI -8.2 to -6.1) [2]. A network meta-analysis of obesity drugs estimated -9.9% (95% CI -12.4 to -7.5) for orforglipron against lifestyle change alone at one year, with moderate to high certainty [3]. A second meta-analysis found dose-related weight loss, larger in people without diabetes [4]. A third found a pooled difference of -5.25 kg (95% CI -6.72 to -3.77) against placebo, with high heterogeneity [5].
Population
3,127 adults with obesity without diabetes [1]; 1,613 adults with a BMI of 27 or more and type 2 diabetes, 46.9% women, mean weight 101.4 kg [2]; 262 trials with 99,791 participants across 19 drugs [3]; 5 trials with 6,140 participants [4]; 5 trials with 2,672 participants [5].
Sources
[1], [2], [3], [4], [5]
Caveats
The meta-analyses draw on the same small set of trials, so they are not independent confirmations. Both phase 3 trials added lifestyle intervention and were funded by Eli Lilly, the maker [1][2]. The trial doses of 6, 12 and 36 mg correspond to label doses of 5.5, 9 and 17.2 mg [6].
Strong

Blood sugar in type 2 diabetes

Shown to lower HbA1c about 1.2 to 1.9 points in adults with type 2 diabetes, more than placebo, oral semaglutide or dapagliflozin. Not US approved for diabetes.

The numbers and sources
Effect
In early type 2 diabetes treated with diet and exercise, HbA1c fell 1.24 to 1.48 points across doses from a baseline of 8.0% at 40 weeks, against 0.41 on placebo, a difference of -1.07 points on 36 mg (95% CI -1.33 to -0.81) [7]. In people taking metformin, HbA1c fell 1.91 points on orforglipron 36 mg and 1.47 on oral semaglutide 14 mg at 52 weeks, a difference of -0.44 (95% CI -0.62 to -0.26) [8]. Against dapagliflozin it fell 1.56 points on 36 mg and 0.81 points, a difference of -0.75 (95% CI -0.96 to -0.55) [9]. Added to insulin glargine, it fell 1.82 points on 36 mg and 0.79 on placebo, a difference of -1.03 (95% CI -1.28 to -0.77) [10]. Meta-analyses reported pooled HbA1c reductions of 1.07 points [5] and 1.29 points [4].
Population
559 adults with early type 2 diabetes [7]; 1,698 adults on metformin [8]; 962 adults on metformin [9]; 546 adults on insulin glargine [10].
Sources
[7], [8], [9], [10], [4], [5]
Caveats
Type 2 diabetes is not an approved use in the US. The label covers weight management only [6]. The comparisons with oral semaglutide and dapagliflozin were open-label [8][9]. ACHIEVE-1, ACHIEVE-2 and ACHIEVE-3 were funded by Eli Lilly [7][8][9]. HbA1c is a blood marker, not a measure of diabetes complications.
Limited

Keeping weight off after switching from injectable drugs

One trial found people switched from tirzepatide or semaglutide kept about 75 to 79% of their weight loss at a year, against 38 to 49% on placebo.

The numbers and sources
Effect
People who had lost weight on tirzepatide or semaglutide and were switched to orforglipron kept a model-based estimate of 74.7% (after tirzepatide) and 79.3% (after semaglutide) of their weight reduction at week 52, against 49.2% and 37.6% on placebo. The differences were 25.5 points (95% CI 14.5 to 36.5) and 41.7 points (95% CI 24.4 to 59.0) [11].
Population
376 adults previously treated in SURMOUNT-5, 205 after tirzepatide and 171 after semaglutide [11].
Sources
[11]
Caveats
One trial, one year long, with no arm that stayed on the injectable drug, so it does not compare switching with continuing [11].

Doses studied

ATTAIN-1 and ATTAIN-2 used 6, 12 or 36 mg by mouth once daily, reached by dose escalation, for 72 weeks [1][2]. ACHIEVE-1, ACHIEVE-2 and ACHIEVE-5 used 3, 12 or 36 mg once daily for 40 weeks [7][9][10], and ACHIEVE-3 used 12 or 36 mg for 52 weeks [8]. These trials used an investigational formulation. The label presents the 6, 12 and 36 mg trial doses as the equivalent tablet doses of 5.5, 9 and 17.2 mg, with 17.2 mg once daily as the maximum [6], and the cardiovascular safety trial describes its 36 mg capsule as equivalent to the 17.2 mg tablet [12].

Risks

Reported risks6

ModerateVery common

Gastrointestinal effects and stopping treatment

Shown to raise gut side effects to about 60 to 69% against 37% on placebo, with 8% stopping for side effects against 3%.

The numbers and sources
How common
Very common: more than 1 in 10 people.
Effect
In the label's pool of the two weight trials, gastrointestinal adverse reactions occurred in 60% on 5.5 mg, 68% on 9 mg and 69% on 17.2 mg, against 37% on placebo. Nausea occurred in 26 to 35% against 10%, and vomiting in 13 to 24% against 4%. Adverse reactions led to permanent discontinuation in 8% against 3% [6]. In ATTAIN-1, adverse events led to discontinuation in 5.3 to 10.3% against 2.7% on placebo [1]. Against oral semaglutide, gastrointestinal events occurred in 58 to 59% against 37 to 45%, and discontinuation for adverse events in 9 to 10% against 4 to 5% [8]. A network meta-analysis placed orforglipron among the six obesity drugs with the most discontinuation for adverse events, with moderate to high certainty (risk ratios 1.9 to 4.2 for that group), and among the four with the largest rise in gastrointestinal events (risk ratios 3.1 to 4.2) [3].
Population
3,155 adults on orforglipron and 1,576 on placebo in the label pool [6]; 3,127 adults [1]; 1,698 adults [8]; 262 trials [3].
Sources
[6], [1], [8], [3]
Caveats
Most events were mild to moderate and occurred mainly during dose escalation [1][6].
ModerateCommon

Fatigue

Shown to raise fatigue, 6 to 9% against 4% on placebo.

The numbers and sources
How common
Common: between 1 in 100 and 1 in 10 people.
Effect
A network meta-analysis found fatigue risk raised with orforglipron (risk ratio 3.4), about 100 more cases per 1,000 people over one year [3]. In the label pool, fatigue occurred in 6 to 9% on orforglipron and 4% on placebo [6].
Population
262 trials [3]; label pool as above [6].
Sources
[3], [6]
Caveats
The meta-analysis estimate for orforglipron rests on a small number of trials.
ModerateCommon

Faster heart rate

Shown to raise heart rate about 4 to 5 beats per minute against 0.5 on placebo, with fast heart rate reported in 3% against 0.9%.

The numbers and sources
How common
Common: between 1 in 100 and 1 in 10 people.
Effect
Heart rate rose a mean 4 to 5 beats per minute on orforglipron against 0.5 on placebo, and tachycardia was reported in 3% against 0.9% [6]. A meta-analysis found a pooled rise of 6.38 beats per minute (95% CI 2.99 to 9.77), with high heterogeneity [5]. Against oral semaglutide, pulse rose 3.7 to 4.7 beats per minute against 1.0 to 1.5 [8].
Population
Label pool [6]; 5 trials with 2,672 participants [5]; 1,698 adults with type 2 diabetes [8].
Sources
[6], [5], [8]
Caveats
These trials did not test whether the rise affects heart outcomes.
ModerateCommon

Low blood sugar with other diabetes drugs

Low blood sugar was about as common as on placebo overall, but rose to 7% in people with type 2 diabetes also taking a sulfonylurea.

The numbers and sources
How common
Common: between 1 in 100 and 1 in 10 people.
Effect
In the weight trial in type 2 diabetes, glucose below 54 mg/dL was reported in 2% on orforglipron and 0.2% on placebo, and in 7% of those also taking a sulfonylurea against 0.5% of those not taking one [6]. Added to insulin glargine, orforglipron did not increase clinically significant hypoglycemia against placebo [10]. A meta-analysis found no difference in hypoglycemia against placebo (RR 1.05, 95% CI 0.23 to 4.86) [5].
Population
1,613 adults with type 2 diabetes [6]; 546 adults on insulin glargine [10]; 5 trials [5].
Sources
[6], [10], [5]
Caveats
The label warns that use with insulin or an insulin secretagogue may increase the risk of hypoglycemia, including severe hypoglycemia [6].
LimitedHow often is not known

Label warnings: thyroid tumors, pancreatitis and gallbladder

The label warns of thyroid C-cell tumors seen with related drugs in rodents, with human relevance not determined. Pancreatitis and gallstones were slightly more common.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
The label carries a boxed warning about thyroid C-cell tumors. Such tumors occurred in rodents with GLP-1 drugs that are active in rats and mice, while orforglipron is not active in rats or mice and did not produce tumors in them. The label states that the human relevance has not been determined, and the drug is contraindicated with a personal or family history of medullary thyroid carcinoma or MEN 2. In the weight trials, acute pancreatitis was confirmed in 6 people on orforglipron (0.14 per 100 years of exposure) against 1 on placebo (0.04), gallstones in 1% against 0.7%, acute kidney injury in 0.2% against 0.05%, low blood pressure in 2% against 0.5%, and hair loss in 4 to 5% against 2% [6].
Population
Label pool of the two weight trials and nonclinical studies [6].
Sources
[6]
Caveats
The thyroid warning rests on animal findings for the drug class. Pancreatitis events were few.
LimitedHow often is not known

Drug interactions

The label caps the dose at 9 mg with strong CYP3A4 inhibitors, says to avoid some others, and notes it may affect absorption of other oral medicines.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
The label states that strong CYP3A4 inhibitors raise orforglipron exposure and sets a maximum of 9 mg once daily with them. It states that strong CYP3A4 inhibitors that also inhibit OATP1B, such as ritonavir, and strong CYP3A4 inducers are to be avoided, and that simvastatin is not to exceed 20 mg a day. Orforglipron delays gastric emptying and may affect the absorption of other oral medicines [6].
Population
Label [6].
Sources
[6]
Caveats
Label guidance drawn from pharmacology studies, not outcome trials.

Checked, no increase found2

Limited

Heart attack, stroke and cardiovascular death

One open-label trial found major cardiovascular events about as common as on insulin glargine, 4.2% against 5.0%, in adults with type 2 diabetes at high risk.

The numbers and sources
How common
Common: between 1 in 100 and 1 in 10 people.
Effect
Against insulin glargine, a four-part major cardiovascular event outcome occurred in 4.2% on orforglipron and 5.0% on insulin glargine (HR 0.84, 95% CI 0.59 to 1.20), meeting the trial's non-inferiority margin. Deaths were 1.4% and 3.2%. Gastrointestinal events occurred in 62.1% and 14.2%, and clinically significant or severe hypoglycemia in 6.8% and 19.2% [12].
Population
2,749 adults with type 2 diabetes at increased cardiovascular risk, all with established cardiovascular or chronic kidney disease, mean age 63.1, median follow-up 2 years [12].
Sources
[12]
Caveats
One open-label trial, designed to rule out excess cardiovascular risk against insulin glargine rather than to show a benefit. Funded by Eli Lilly [12].
Why limited
This rests on one trial, of 2,749 people. Strength counts independent studies that agree, so one trial is limited at any size.
Moderate

Liver tests

Raised liver tests were about as common on orforglipron as on comparators across phase 3 trials, and other causes accounted for every serious case.

The numbers and sources
How common
Uncommon: between 1 in 1,000 and 1 in 100 people.
Effect
Across seven phase 3 trials, mean ALT and AST fell on orforglipron, and raised levels occurred at similar rates on orforglipron and comparators. Six people (0.1%) in each group had ALT or AST at 3 or more times the upper limit with bilirubin at 2 or more times, and other causes accounted for every orforglipron case [13].
Population
11,220 participants, 6,920 on orforglipron, for up to 104 weeks [13].
Sources
[13]
Caveats
A pooled analysis by the manufacturer's investigators. The trials excluded people with markedly raised liver enzymes at screening [13].

Sources

  1. Wharton S, Aronne LJ, Stefanski A, et al. Orforglipron, an Oral Small-Molecule GLP-1 Receptor Agonist for Obesity Treatment. New England Journal of Medicine. 2025. https://doi.org/10.1056/NEJMoa2511774
  2. Horn DB, Ryan DH, Kis SG, et al. Orforglipron, an oral small-molecule GLP-1 receptor agonist, for the treatment of obesity in people with type 2 diabetes (ATTAIN-2): a phase 3, double-blind, randomised, multicentre, placebo-controlled trial. The Lancet. 2025. https://doi.org/10.1016/S0140-6736(25)02165-8
  3. Nong K, Shi Q, Xie X, et al. Comparative effects of drugs for adults with overweight or obesity: systematic review and network meta-analysis. BMJ. 2026. https://doi.org/10.1136/bmj-2026-372161
  4. Hammad N, Ramadan AM, Nazmy A, et al. Efficacy and Safety of Oral GLP-1 RA Orforglipron on Weight and Glycemic Control According to Diabetes Status: A Systematic Review and Meta-Analysis. Diabetes Technology & Therapeutics. 2026. https://doi.org/10.1177/15209156261420404
  5. Jamal A, Khan S, Qadri M, et al. Efficacy and safety of orforglipron in type 2 diabetes mellitus and obesity: a GRADE-assessed meta-analysis and trial sequential analysis with subgroup evaluations by diabetic status, obesity status, and dose regimens. Acta Diabetologica. 2026. https://doi.org/10.1007/s00592-025-02635-8
  6. U.S. Food and Drug Administration. FOUNDAYO (orforglipron) tablets, prescribing information. 2026. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8ac446c5-feba-474f-a103-23facb9b5c62
  7. Rosenstock J, Hsia S, Nevarez Ruiz L, et al. Orforglipron, an Oral Small-Molecule GLP-1 Receptor Agonist, in Early Type 2 Diabetes. New England Journal of Medicine. 2025. https://doi.org/10.1056/NEJMoa2505669
  8. Rosenstock J, Yabe D, Cox D, et al. Efficacy and safety of once-daily oral orforglipron compared with oral semaglutide in adults with type 2 diabetes (ACHIEVE-3): a multinational, multicentre, non-inferiority, open-label, randomised, phase 3 trial. The Lancet. 2026. https://doi.org/10.1016/S0140-6736(26)00202-3
  9. Welch M, Forst T, Jia W, et al. Orforglipron compared with dapagliflozin in adults with type 2 diabetes and inadequate glycaemic control with metformin (ACHIEVE-2): a multicentre, randomised, non-inferiority, open-label, phase 3 trial. The Lancet. 2026. https://doi.org/10.1016/S0140-6736(26)00800-7
  10. Giorgino F, D'Souza S, Ludwig L, et al. Orforglipron Added to Titrated Insulin Glargine in Type 2 Diabetes: The ACHIEVE-5 Randomized Clinical Trial. JAMA. 2026. https://doi.org/10.1001/jama.2026.9512
  11. Aronne LJ, Horn DB, le Roux CW, et al. Orforglipron for maintenance of body weight reduction: the double-blind, randomized phase 3b ATTAIN-MAINTAIN trial. Nature Medicine. 2026. https://doi.org/10.1038/s41591-026-04386-7
  12. Klein KR, Wysham C, Tuttle KR, et al. Cardiovascular safety of orforglipron versus insulin glargine in adults with type 2 diabetes at increased cardiovascular risk (ACHIEVE-4): a phase 3, event-driven, randomised, open-label, non-inferiority, active comparator trial. The Lancet. 2026. https://doi.org/10.1016/S0140-6736(26)01865-9
  13. Wharton S, Stefanski A, Chen J, et al. Hepatic Safety of Orforglipron in Adults With Obesity or Overweight and/or Type 2 Diabetes: A Pooled Analysis of the Orforglipron Phase 3 Clinical Trials. Diabetes, Obesity and Metabolism. 2026. https://doi.org/10.1111/dom.71032

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