Orforglipron Demonstrates Superior Glycaemic Control Over Dapagliflozin in Type 2 DiabetesNew oral medication shows better blood sugar control for diabetes

Lancet (London, England) Published July 12, 2026 Study authors: Welch Michelle, Forst Thomas, Jia Weiping, Del Pino Pedro Orozco, Denning Max, Wu Wen-Shuo, Li Jiang… PubMed ↗ NCT06192108 ↗ DOI ↗ Editorial oversight: Dr. Amelia Tan, PhD · Internal Medicine & Chronic Disease

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Key Takeaway

Orforglipron showed statistically significant superiority over dapagliflozin in reducing HbA1c levels at 40 weeks.

This Phase 3 multicentre randomized controlled trial evaluated the efficacy and safety of orforglipron, a non-peptide oral GLP-1 receptor agonist, against dapagliflozin in patients with type 2 diabetes. The study enrolled 962 adults who demonstrated inadequate glycaemic control despite metformin therapy. Patients were randomized to receive one of three doses of orforglipron (3 mg, 12 mg, or 36 mg) or a standard dose of dapagliflozin (10 mg) over a 40-week period across 73 sites in six countries.

The primary endpoint was the change from baseline in HbA1c at week 40. Results indicated that all three doses of orforglipron achieved statistically significant superiority over dapagliflozin. Specifically, the 3 mg dose reduced HbA1c by 1.23% compared to 0.81% for dapagliflozin (p<0.0001). The 12 mg and 36 mg doses showed even greater efficacy, with reductions of 1.50% and 1.56% respectively, compared to the 0.81% reduction observed in the dapagliflozin cohort.

From a clinical perspective, the dose-dependent response of orforglipron suggests a robust pharmacological profile for glucose management. The absolute differences in HbA1c reduction between orforglipron and dapagliflozin were statistically significant across all tested doses (p<0.0001). This highlights the potential of oral GLP-1 receptor agonists to provide potent glycaemic control comparable to, or exceeding, established SGLT2 inhibitors in certain clinical contexts.

Safety profiles were consistent with the expected characteristics of the GLP-1 receptor agonist class. While orforglipron was associated with higher rates of mild-to-moderate gastrointestinal events compared to dapagliflozin (ranging from 46% to 54% for orforglipron versus 12% for dapagliflozin), these were generally manageable. However, the study noted higher discontinuation rates for orforglipron due to adverse events—15% at 3 mg, 18% at 12 mg, and 20% at 36 mg—compared to only 6% in the dapagliflozin group.

Notably, no severe episodes of hypoglycaemia were reported in any treatment arm. The trial provides high-certainty evidence that orforglipron is a potent option for patients requiring additional glucose-lowering therapy beyond metformin. While gastrointestinal side effects are more prevalent with orforglipron than with SGLT2 inhibitors, the superior HbA1c reduction may offer significant clinical benefits for patients prioritizing intensive glycaemic control.

In conclusion, orforglipron demonstrates a favorable efficacy profile in this Phase 3 trial. It provides a potent oral alternative for managing type 2 diabetes. Clinicians can consider it a viable option when superior HbA1c reduction is the primary goal, while counseling patients on potential gastrointestinal side effects common to the GLP-1 class.

How this fits prior evidence

How this fits prior evidence This finding extends the evidence for oral small-molecule GLP-1RAs, which were previously shown to reduce HbA1c by 0.94 but also increase gastrointestinal adverse events. While orforglipron showed superior HbA1c reduction compared to dapagliflozin (up to -1.56% vs -0.81%), it maintained the expected tolerability profile for its class, including higher rates of gastrointestinal issues compared to SGLT2 inhibitors.

Managing type 2 diabetes is a daily challenge for millions of people. For those whose blood sugar remains high even while taking metformin, finding an effective oral medication that works well can make a significant difference in their long-term health and quality of life.

A large clinical trial involving 962 adults with type 2 diabetes was conducted to compare the effectiveness of a new drug called orforglipron against an existing treatment, dapagliflozin. The study took place across 73 sites in six different countries over a period of 40 weeks. Participants were given different doses of orforglipron (3 mg, 12 mg, or 36 mg) to see how they performed against the standard dose of dapagliflozin.

The results showed that all three doses of orforglipron were more effective at lowering HbA1c levels than dapagliflozin. HbA1c is a common test used by doctors to measure average blood sugar levels over several months. For example, the 3 mg dose reduced HbA1c by 1.23% compared to 0.81% for dapagliflozin. The higher doses of orforglipron (12 mg and 36 mg) showed even greater reductions, reaching approximately 1.50% and 1.56% respectively. These results were statistically significant, meaning the difference was clear enough to be attributed to the medication rather than chance.

In terms of safety, the study noted that orforglipron caused more gastrointestinal issues, such as upset stomach or nausea, compared to dapagliflozin. About 46% to 54% of patients taking orforglipron reported these issues, while only about 12% of those on dapagliflozin did. Additionally, more people stopped taking orforglipron during the study due to these side effects compared to those on the other medication. However, no serious episodes of low blood sugar (hypoglycemia) were reported for anyone taking orforglipron.

It is important to remember that while these results are promising, this is one specific study comparing two different types of medications. Because people react differently to drugs based on their unique health profiles, these results may not be identical for everyone. Patients should not switch medications based on this report alone.

For patients today, this means there is a new oral option that shows strong potential for better blood sugar control. If you are struggling to manage your levels with current treatments, talk to your doctor about whether orforglipron might be a suitable next step for your specific health needs.

What this means for you:

Orforglipron showed stronger blood sugar reduction than dapagliflozin but had more common stomach-related side effects.

Study Details

Study typeRct

Sample sizen = 240

EvidenceLevel 2

Follow-up9.2 mo

PublishedJul 2026

PMID42259339

TrialNCT06192108

View Original Abstract ↓

BACKGROUND: Type 2 diabetes is a complex metabolic disorder often requiring combination therapy for optimal glycaemic control. This study assessed the efficacy and safety of orforglipron, an oral, non-peptide GLP-1 receptor agonist, versus dapagliflozin, an oral SGLT2 inhibitor, in participants with type 2 diabetes and inadequate glycaemic control with metformin. METHODS: This 40-week, phase 3, multicentre, open-label (orforglipron dose-blinded), randomised study was conducted in 73 sites across six countries. The study included adults with type 2 diabetes using metformin (≥1500 mg/day) with glycated haemoglobin (HbA) concentrations between 7·0% and 10·5% (53-91 mmol/mol), stable bodyweight (±5%), and a BMI of 23·0 kg/m or more. Participants were randomly assigned in a 1:1:1:1 ratio to receive once-daily oral orforglipron (3 mg, 12 mg, or 36 mg) or dapagliflozin 10 mg. The primary endpoint was change from baseline in HbA at week 40, using a non-inferiority margin of 0·3% for orforglipron versus dapagliflozin; analysis was based on the treatment-regimen estimand (data obtained regardless of study intervention discontinuation or initiation of additional glucose-lowering agents). The treatment regimen estimand was the primary estimand, with the efficacy estimand considered supportive. Safety was assessed in all randomised participants who received at least one dose of study drug. This trial is registered at ClinicalTrials.gov (NCT06192108, completed). FINDINGS: From Jan 10, 2024, to Sept 26, 2025, 1404 adults were assessed and 962 participants were randomly assigned to orforglipron 3 mg (n=240), 12 mg (n=241), or 36 mg (n=241), or dapagliflozin 10 mg (n=240). The baseline population included 474 (49%) females and had a mean age of 56·1 years (SD 11·5), HbA of 8·14% (1·04), type 2 diabetes duration of 8·0 years (6·7), and BMI of 32·6 kg/m (6·6). At week 40, for the treatment regimen estimand, all orforglipron doses were non-inferior to dapagliflozin in reducing HbA. Change from baseline in mean HbA was -1·23% (SE 0·08), -1·50% (0·08), and -1·56% (0·09) with orforglipron 3 mg, 12 mg, and 36 mg, respectively, versus -0·81% (0·07) with dapagliflozin 10 mg; estimated treatment difference versus dapagliflozin was -0·42% (95% CI -0·62 to -0·23), -0·70% (-0·90 to -0·49), and -0·75% (-0·96 to -0·55) with orforglipron 3 mg, 12 mg, and 36 mg, respectively (all p<0·0001). The most frequent adverse events associated with orforglipron were mild-to-moderate gastrointestinal events, observed in 112 (47%) of 240 participants receiving orforglipron 3 mg, 112 (46%) of 241 receiving 12 mg, and 130 (54%) of 241 receiving 36 mg, versus 29 (12%) of 240 receiving dapagliflozin. More study intervention discontinuations were observed with orforglipron 3 mg (35 [15%] of 240), 12 mg (44 [18%] of 241), and 36 mg (47 [20%] of 241) than with dapagliflozin (14 [6%] of 240). No severe episode of hypoglycaemia was reported. INTERPRETATION: Orforglipron demonstrated superior glycaemic control compared with dapagliflozin, with a tolerability profile consistent with the GLP-1 receptor agonist class, including increased rates of discontinuation due to adverse events, positioning it as a potential effective oral treatment option for type 2 diabetes. FUNDING: Eli Lilly and Company.

Orforglipron Demonstrates Superior Glycaemic Control Over Dapagliflozin in Type 2 DiabetesNew oral medication shows better blood sugar control for diabetes

How this fits prior evidence

Study Details

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Orforglipron Demonstrates Superior Glycaemic Control Over Dapagliflozin in Type 2 DiabetesNew oral medication shows better blood sugar control for diabetes

How this fits prior evidence

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