Lilly's oral GLP-1, orforglipron, delivered superior blood sugar control and weight loss compared to oral semaglutide in head-to-head type 2 diabetes trial published in The Lancet

Rhea-AI Summary

Eli Lilly (NYSE: LLY) reported 52-week ACHIEVE-3 results showing oral orforglipron outperformed oral semaglutide on A1C and weight. At 36 mg, orforglipron reduced A1C by 2.2% vs 1.4% and produced 9.2% weight loss (19.7 lbs) vs 5.3% (11.0 lbs).

Orforglipron improved multiple cardiovascular risk factors, had higher treatment discontinuation rates, and has regulatory submissions in >40 countries with potential U.S. obesity action in Q2 2026.

Positive

• A1C reduction of 2.2% with orforglipron 36 mg
• Weight loss of 9.2% (19.7 lbs) with orforglipron 36 mg
• 85.4% achieved A1C target with orforglipron 36 mg
• Regulatory submissions in over 40 countries; U.S. obesity action Q2 2026

Negative

• Higher treatment discontinuation: 9.7% (orforglipron 36 mg) vs 4.9% (oral semaglutide 14 mg)
• Common GI adverse events reported (nausea, diarrhea, vomiting, dyspepsia, decreased appetite)

Key Figures

A1C reduction (36 mg): 2.2% decrease A1C reduction (14 mg): 1.4% decrease Weight loss (36 mg): 19.7 lbs (9.2%) +5 more

8 metrics

A1C reduction (36 mg) 2.2% decrease Orforglipron 36 mg vs baseline 8.3% at week 52, efficacy estimand

A1C reduction (14 mg) 1.4% decrease Oral semaglutide 14 mg vs baseline 8.3% at week 52, efficacy estimand

Weight loss (36 mg) 19.7 lbs (9.2%) Orforglipron 36 mg at week 52, efficacy estimand

Weight loss (14 mg) 11.0 lbs (5.3%) Oral semaglutide 14 mg at week 52, efficacy estimand

Trial enrollment 1,698 participants ACHIEVE-3 Phase 3 type 2 diabetes trial, four treatment arms

A1C ≤6.5% (36 mg) 76.8% Participants achieving A1C ≤6.5% at week 52, efficacy estimand

Discontinuation (36 mg) 9.7% Orforglipron 36 mg discontinuation due to adverse events

Countries submitted Over 40 countries Orforglipron regulatory submissions worldwide

Market Reality Check

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Peers on Argus

LLY is down 1.28% while peers are mixed: ABBV -1.25%, AZN -0.29%, NVS -0.20%, JN...

LLY is down 1.28% while peers are mixed: ABBV -1.25%, AZN -0.29%, NVS -0.20%, JNJ +0.13%, NVO +1.21%, pointing to a stock-specific move.

Historical Context

5 past events · Latest: Feb 23 (Positive)

Pattern 5 events

Date	Event	Sentiment	Move	Catalyst
Feb 23	Product update	Positive	+4.9%	Zepbound KwikPen FDA approval and strong prior weight-loss data highlighted.
Feb 19	Clinical data	Positive	+0.3%	Omvoh long-term Crohn’s remission and reduced hospitalizations versus placebo.
Feb 18	Clinical data	Positive	-1.5%	TOGETHER-PsO Phase 3b trial met primary and key secondary endpoints.
Feb 17	Partnership milestone	Positive	-0.4%	Scribe CRISPR collaboration hit second success milestone and validates platform.
Feb 16	Conference participation	Neutral	-0.4%	Announcement of TD Cowen conference fireside chat and webcast details.

Pattern Detected

Recent fundamentally positive news has often seen modestly positive or mixed next-day reactions, with no consistent pattern of strong follow-through.

Recent Company History

Over the past weeks, Lilly has released a series of positive updates, including Zepbound KwikPen FDA approval with pricing from $299/month and notable weight-loss data, long-term Omvoh remission durability with up to 92.4% clinical remission at Week 152, and strong TOGETHER-PsO Phase 3b results combining Taltz and Zepbound. Collaboration progress with Scribe and upcoming conference participation were also highlighted. Today’s orforglipron head-to-head Phase 3 results extend this pattern of cardiometabolic strength.

Market Pulse Summary

This announcement details ACHIEVE-3 Phase 3 results, where orforglipron 36 mg achieved larger A1C re...

Analysis

This announcement details ACHIEVE-3 Phase 3 results, where orforglipron 36 mg achieved larger A1C reductions and 19.7 lbs mean weight loss versus oral semaglutide, with high proportions reaching A1C ≤6.5%. Lilly has submitted the drug in over 40 countries, with a planned U.S. type 2 diabetes submission. Investors may focus on efficacy versus existing GLP-1 options, discontinuation rates around 9–10%, cardiovascular risk-factor improvements, and upcoming regulatory decision timelines.

Key Terms

glp-1, a1c, phase 3, estimand, +4 more

8 terms

glp-1 medical

"orforglipron, a small molecule oral GLP-1 without food or water restrictions"

GLP-1 (glucagon-like peptide-1) is a natural hormone in the body that helps regulate blood sugar levels and appetite. Its significance to investors lies in its role as the basis for a class of medications that address conditions like type 2 diabetes and obesity, which are large and growing markets. Advances or investments in GLP-1-based treatments can signal opportunities in healthcare innovation and potentially impact pharmaceutical companies’ growth.

a1c medical

"orforglipron 36 mg lowered A1C by 2.2% vs. 1.4% with oral semaglutide"

A1C is a blood test that reports average blood sugar over about three months by measuring how much glucose sticks to hemoglobin, a protein in red blood cells. For investors, A1C acts like a long-term scorecard for diabetes treatments, devices and diagnostics: meaningful changes in A1C in clinical studies can affect regulatory approval, insurance coverage and commercial prospects, and thus influence a company's market value.

phase 3 medical

"the first head-to-head Phase 3 trial evaluating the safety and efficacy of orforglipron"

Phase 3 is the late-stage clinical testing step for a new drug or medical treatment, where the product is given to large groups of patients to confirm effectiveness, monitor side effects, and compare it to standard care. Successful Phase 3 results are often the final scientific hurdle before regulators decide on approval and market launch—like passing a final exam before graduation—and can sharply change a company's valuation and future revenue prospects.

estimand technical

"Change in A1C from baseline ... at week 52 | Efficacy estimand"

An estimand is the specific question a clinical study is designed to answer about a treatment’s effect — essentially the exact outcome the researchers will measure after deciding how to handle things that happen during the study, such as patients leaving, starting other treatments, or changing doses. For investors, the estimand matters because it determines how trial results should be interpreted and compared, like knowing whether a scoreboard counts only players who stayed the whole game or everyone who started it, which affects risk and valuation judgments.

non-hdl cholesterol medical

"improvements from baseline across key cardiovascular risk factors, including non-HDL cholesterol"

Non-HDL cholesterol is the total amount of blood cholesterol carried by all particles that can clog arteries, calculated by subtracting 'good' HDL cholesterol from total cholesterol; think of it as counting all the cars that can cause traffic jams rather than just one type. It matters to investors because higher non-HDL levels predict greater risk of heart disease across populations, which can influence healthcare costs, workforce productivity, insurance liabilities, and demand for drugs or medical services.

vldl cholesterol medical

"key cardiovascular risk factors, including non-HDL cholesterol, HDL cholesterol, VLDL cholesterol"

Very low-density lipoprotein (VLDL) cholesterol is a blood carrier that transports fats from the liver to other tissues; think of it like delivery trucks moving fat through the bloodstream. High VLDL levels are associated with buildup in arteries and greater risk of heart disease, so they matter to investors because population health trends, treatment demand, insurance and employer healthcare costs, and regulatory attention can all affect companies and markets.

triglycerides medical

"key cardiovascular risk factors, including ... systolic blood pressure and triglycerides"

Triglycerides are the main form of fat carried in the bloodstream, made from excess calories and used by the body for energy or stored in fat tissue; think of them as the oil reserves that fuel the body. They matter to investors because high or low levels influence demand for drugs, diagnostics, and healthcare services, affect regulatory reviews and insurance costs, and signal population health trends that can change market size and company risk.

type 2 diabetes medical

"adults with type 2 diabetes inadequately controlled with metformin"

Type 2 diabetes is a chronic condition where the body struggles to control blood sugar levels because it becomes less responsive to insulin, a hormone that helps regulate sugar in the blood. It matters to investors because it can lead to increased healthcare costs, affect workforce productivity, and influence the performance of companies in the healthcare and pharmaceutical sectors. Managing or preventing the condition has significant implications for public health and economic stability.

AI-generated analysis. Not financial advice.

For the primary endpoint, orforglipron 36 mg lowered A1C by 2.2% vs. 1.4% with oral semaglutide 14 mg in ACHIEVE-3

In a key secondary endpoint, participants on orforglipron 36 mg lost 19.7 lbs (9.2%) compared to 11.0 lbs (5.3%) with oral semaglutide 14 mg, representing a 73.6% greater relative weight loss

Lilly has submitted orforglipron to regulators in over 40 countries, with potential U.S. action for obesity in Q2 2026

INDIANAPOLIS, Feb. 26, 2026 /PRNewswire/ -- Eli Lilly and Company (NYSE: LLY) today announced detailed results from ACHIEVE-3, the first head-to-head Phase 3 trial evaluating the safety and efficacy of orforglipron, a small molecule oral GLP-1 without food or water restrictions, compared with oral semaglutide in adults with type 2 diabetes inadequately controlled with metformin. The 52-week trial enrolled 1,698 participants across four treatment arms: orforglipron 12 mg and 36 mg, and oral semaglutide 7 mg and 14 mg. In ACHIEVE-3, orforglipron outperformed oral semaglutide across the primary and all key secondary endpoints, delivering significantly greater improvements in A1C and weight.^1,2 The results were published today in The Lancet.

"ACHIEVE-3 gives us the first head-to-head comparison between two oral GLP-1 receptor agonist therapies in adults with type 2 diabetes, and the differences were clinically meaningful," said Dr. Julio Rosenstock, clinical professor of medicine at the University of Texas Southwestern Medical Center and lead investigator. "Orforglipron 12 mg and 36 mg doses outperformed oral semaglutide 7 mg and 14 mg diabetes-related doses on every key endpoint we measured, including A1C and weight loss, with improvements appearing as early as four weeks and sustained throughout the study."

ACHIEVE-3 Full Results
		Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Orforglipron 12 mg	Orforglipron 36 mg
Primary Endpoint
Change in A1C from baseline of 8.3% at week 52	Efficacy estimand2	-1.1 %	-1.4 %	-1.9%i,ii	-2.2%i,ii
	Treatment‑ regimen estimand3	-1.2 %	-1.5 %	-1.7%i,iii	-1.9%i,ii
Secondary Endpoints
Change in weight from baseline of 97.0 kg (213.9 lbs) at week 52iv	Efficacy estimand	-3.7%   (-3.6 kg; -7.9 lbs)	-5.3%   (-5.0 kg; -11.0 lbs)	-6.7%i,iii   (-6.6 kg; -14.6 lbs)	-9.2%i,ii   (-8.9 kg; -19.7 lbs)
	Treatment‑ regimen estimand	-3.9%   (-3.8 kg; -8.4 lbs)	-5.3%   (-5.2 kg; -11.5 lbs)	-6.1%i   (-6.2 kg; -13.7 lbs)	-8.2%i,ii   (-8.1 kg; -17.8 lbs)
Percentage of participants achieving A1C <7% at week 52	Efficacy estimand	54.6 %	66.1 %	80.0% i,ii	85.4% i,ii
	Treatment‑ regimen estimand	53.9 %	63.8 %	72.2% i,iii	75.8% i,ii
Percentage of participants achieving A1C ≤6.5% at week 52	Efficacy estimand	40.9 %	50.9 %	71.8%i,ii	76.8%i,ii
	Treatment‑ regimen estimand	38.4 %	48.3 %	62.7%i,ii	67.7%i,ii
Percentage of participants achieving A1C <5.7% at week 52iv	Efficacy estimand	7.8 %	12.5 %	25.4%i,ii	37.1%i,ii
	Treatment- regimen estimand	7.4 %	11.7 %	21.4%i,ii	31.4%i,ii

ip<0.001 vs. oral semaglutide 7 mg

iip<0.001 vs. oral semaglutide 14 mg

iiip<0.01 vs. oral semaglutide 14 mg

ivBody weight for orforglipron 12 mg vs. oral semaglutide 14 mg and percentage of participants achieving A1C <5.7% were not controlled for family-wise type 1 error.1

 

Orforglipron also showed clinically meaningful improvements from baseline across key cardiovascular risk factors, including non-HDL cholesterol, HDL cholesterol, VLDL cholesterol, total cholesterol, systolic blood pressure and triglycerides.⁴

"The results of ACHIEVE-3 highlight the potential advantages of orforglipron over oral semaglutide for type 2 diabetes: greater A1C reduction, more weight loss, and the ability to take it without food or water timing restrictions — that's a combination that could matter significantly to people managing their disease day in and day out," said Kenneth Custer, Ph.D., executive vice president and president of Lilly Cardiometabolic Health. "With global submissions underway and FDA action on obesity expected next quarter, we're focused on making this option available as quickly as possible."

The overall safety and tolerability profile of orforglipron in ACHIEVE-3 was consistent with previous trials. For orforglipron and oral semaglutide, the most common adverse events were nausea, diarrhea, vomiting, dyspepsia and decreased appetite. Treatment discontinuation rates due to adverse events were 8.7% (12 mg) and 9.7% (36 mg) for orforglipron vs. 4.5% (7 mg) and 4.9% (14 mg) for oral semaglutide.

Lilly has submitted orforglipron to regulators in over 40 countries, with submission for type 2 diabetes in the U.S. planned later this year.

About orforglipron
Orforglipron (or-for-GLIP-ron) is an investigational, once-daily small molecule (non-peptide) oral glucagon-like peptide-1 receptor agonist that can be taken any time of the day without restrictions on food and water intake.⁵ Orforglipron was discovered by Chugai Pharmaceutical Co., Ltd. and licensed by Lilly in 2018. Chugai and Lilly published the preclinical pharmacology data of this molecule together.⁶ Lilly is running Phase 3 studies on orforglipron for the treatment of type 2 diabetes and for weight management in adults with obesity or overweight with at least one weight-related medical problem. It is also being studied as a potential treatment for obstructive sleep apnea (OSA) and hypertension in adults with obesity.

About ACHIEVE-3 and ACHIEVE clinical trial program
ACHIEVE-3 (NCT06045221) is a Phase 3, 52-week, randomized, open-label trial evaluating the efficacy and safety of orforglipron compared with oral semaglutide in adults with type 2 diabetes inadequately controlled with metformin. The trial randomized 1,698 participants across the U.S., Argentina, China, Japan, Mexico and Puerto Rico to receive either 12 mg or 36 mg orforglipron or 7 mg or 14 mg oral semaglutide in a 1:1:1:1 ratio. The primary objective of the study was to demonstrate that orforglipron is non-inferior in A1C reduction from baseline after 52 weeks compared with oral semaglutide when comparing the lower and higher doses. All participants in the orforglipron treatment arms started the study at a dose of orforglipron 1 mg once-daily and then increased the dose in a step-wise approach at four-week intervals until reaching their randomized maintenance dose of 12 mg (via steps at 1 mg, 3 mg and 6 mg) or 36 mg (via steps at 1 mg, 3 mg, 6 mg, 12 mg and 24 mg). All participants in the oral semaglutide treatment arms started the study at a dose of oral semaglutide 3 mg once-daily and then increased the dose in a step-wise approach at four-week intervals until reaching their final randomized maintenance dose of 7 mg (via a step at 3 mg) or 14 mg (via steps at 3 mg and 7 mg). If participants were unable to tolerate a dose of orforglipron or oral semaglutide, they were allowed, once during the study, to reduce to the previous dose, with a minimum dose of orforglipron 3 mg or oral semaglutide 7 mg.

The ACHIEVE Phase 3 global clinical development program for orforglipron has enrolled more than 6,000 people with type 2 diabetes across five global registration trials. The program began in 2023 with detailed results from the three remaining registrational trials anticipated later this year.

Endnotes and References

1. All measures except for body weight for orforglipron 12 mg vs. oral semaglutide 14 mg and percentage of participants achieving A1C <5.7% were controlled for family-wise type 1 error using the efficacy estimand and treatment-regimen estimand. Body weight for orforglipron 12 mg vs. oral semaglutide 14 mg and percentage of participants achieving A1C <5.7% were prespecified secondary endpoints and showed nominal statistical significance using the efficacy estimand.
2. The efficacy estimand represents efficacy had all randomized participants remained on study intervention (with possible dose interruptions and/or dose modifications) for 52 weeks without initiating additional antihyperglycemic medications (>14 days of use).
3. The treatment-regimen estimand represents the estimated average treatment effect regardless of adherence to study intervention or initiation of additional antihyperglycemic medications.
4. Not controlled for family-wise type 1 error.
5. Ma X, Liu R, Pratt EJ, Benson CT, Bhattachar SN, Sloop KW. Effect of Food Consumption on the Pharmacokinetics, Safety, and Tolerability of Once-Daily Orally Administered Orforglipron (LY3502970), a Non-peptide GLP-1 Receptor Agonist. Diabetes Ther. 2024 Apr;15(4):819-832. https://doi.org/10.1007/s13300-024-01554-1. Epub 2024 Feb 24. PMID: 38402332; PMCID: PMC10951152.
6. Kawai T, Sun B, Yoshino H, Feng D, Suzuki Y, Fukazawa M, Nagao S, Wainscott DB, Showalter AD, Droz BA, Kobilka TS, Coghlan MP, Willard FS, Kawabe Y, Kobilka BK, & Sloop KW, Structural basis for GLP-1 receptor activation by LY3502970, an orally active nonpeptide agonist, Proc. Natl. Acad. Sci. U.S.A. 117 (47) 29959-29967, https://doi.org/10.1073/pnas.2014879117 (2020).

About Lilly
Lilly is a medicine company turning science into healing to make life better for people around the world. We've been pioneering life-changing discoveries for nearly 150 years, and today our medicines help tens of millions of people across the globe. Harnessing the power of biotechnology, chemistry and genetic medicine, our scientists are urgently advancing new discoveries to solve some of the world's most significant health challenges: redefining diabetes care; treating obesity and curtailing its most devastating long-term effects; advancing the fight against Alzheimer's disease; providing solutions to some of the most debilitating immune system disorders; and transforming the most difficult-to-treat cancers into manageable diseases. With each step toward a healthier world, we're motivated by one thing: making life better for millions more people. That includes delivering innovative clinical trials that reflect the diversity of our world and working to ensure our medicines are accessible and affordable. To learn more, visit Lilly.com and Lilly.com/news, or follow us on Facebook, Instagram and LinkedIn. P-LLY

Cautionary Statement Regarding Forward-Looking Statements
This press release contains forward-looking statements (as that term is defined in the Private Securities Litigation Reform Act of 1995) about orforglipron as a potential treatment for adults with type 2 diabetes, and the timeline for regulatory submissions and actions, future readouts, presentations, and other milestones relating to orforglipron and its clinical trials and reflects Lilly's current beliefs and expectations. However, as with any pharmaceutical product, there are substantial risks and uncertainties in the process of drug research, development, and commercialization. Among other things, there is no guarantee that planned or ongoing studies will be completed as planned, that future study results will be consistent with study results to date, that orforglipron will prove to be a safe and effective treatment for type 2 diabetes, that orforglipron will receive regulatory approval, or that Lilly will execute its strategy as expected. For further discussion of these and other risks and uncertainties that could cause actual results to differ from Lilly's expectations, see Lilly's Form 10-K and Form 10-Q filings with the United States Securities and Exchange Commission. Except as required by law, Lilly undertakes no duty to update forward-looking statements to reflect events after the date of this release.

Trademarks and Trade Names
All trademarks or trade names referred to in this press release are the property of the company, or, to the extent trademarks or trade names belonging to other companies are references in this press release, the property of their respective owners. Solely for convenience, the trademarks and trade names in this press release are referred to without the ® and ™ symbols, but such references should not be construed as any indicator that the company or, to the extent applicable, their respective owners will not assert, to the fullest extent under applicable law, the company's or their rights thereto. We do not intend the use or display of other companies' trademarks and trade names to imply a relationship with, or endorsement or sponsorship of us by, any other companies.

Refer to:	Niki Biro; niki_biro@lilly.com; 317-358-9074 (Media)
	Michael Czapar; czapar_michael_c@lilly.com; 317-617-0983 (Investors)

 

 

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SOURCE Eli Lilly and Company

FAQ

What did Eli Lilly (LLY) announce on Feb 26, 2026 about orforglipron?

They announced ACHIEVE-3 showed orforglipron outperformed oral semaglutide on A1C and weight. According to the company, orforglipron 36 mg reduced A1C by 2.2% and produced 9.2% weight loss at 52 weeks.

How much more did orforglipron (LLY) lower A1C versus oral semaglutide in ACHIEVE-3?

Orforglipron 36 mg lowered A1C by 2.2% versus 1.4% for oral semaglutide 14 mg. According to the company, that difference was statistically significant and sustained through 52 weeks.

How much weight loss did orforglipron (LLY) produce compared to oral semaglutide in ACHIEVE-3?

Orforglipron 36 mg produced 19.7 lbs (9.2%) weight loss vs 11.0 lbs (5.3%) with oral semaglutide 14 mg. According to the company, this is a 73.6% greater relative weight loss.

What safety or tolerability differences did ACHIEVE-3 report for orforglipron (LLY)?

Orforglipron had higher discontinuations: 9.7% (36 mg) versus 4.9% for oral semaglutide 14 mg. According to the company, common adverse events included nausea, diarrhea and vomiting.

What regulatory milestones did Eli Lilly (LLY) disclose for orforglipron on Feb 26, 2026?

Lilly said it has submitted orforglipron to regulators in over 40 countries and expects potential U.S. action on obesity in Q2 2026. According to the company, a U.S. diabetes submission is planned later in 2026.