The Lancet June 08, 2026

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

Welch M, Forst T, Jia W, et al.

Bottom Line

In adults with type 2 diabetes inadequately controlled on metformin, the novel oral non-peptide GLP-1 receptor agonist orforglipron demonstrated superior glycemic control and greater weight loss compared to the SGLT2 inhibitor dapagliflozin, though with higher rates of gastrointestinal side effects.

Key Findings

1. At 40 weeks, mean HbA1c reductions from baseline were -1.23% for 3 mg, -1.50% for 12 mg, and -1.56% for 36 mg of orforglipron, compared to -0.81% for dapagliflozin 10 mg.

2. All tested doses of orforglipron met prespecified criteria for both non-inferiority (0.3% margin) and superiority against dapagliflozin for the primary endpoint of HbA1c reduction.

3. A significantly greater proportion of participants taking orforglipron achieved an HbA1c target of <7.0% (up to 69%).

4. Higher doses of orforglipron (12 mg and 36 mg) yielded superior body weight reduction compared to dapagliflozin.

5. Gastrointestinal adverse events were the most frequent side effects, typically mild-to-moderate and occurring during dose escalation, which led to higher study drug discontinuation rates with orforglipron compared to dapagliflozin.

Study Design

Design

RCT

Open-Label

Sample

962

Patients

Duration

40 wk

Median

Setting

6 countries

Population Adults with type 2 diabetes (HbA1c 7.0 to 10.5%) and BMI >=23.0 kg/m2 inadequately controlled on metformin (>=1500 mg/day)

Intervention Once-daily oral orforglipron (3 mg, 12 mg, or 36 mg)

Comparator Once-daily oral dapagliflozin 10 mg

Outcome Change in HbA1c from baseline at week 40

Study Limitations

• The open-label design for the comparator arm may introduce reporting bias for subjective adverse events, although orforglipron dosing remained blinded.

• The 40-week follow-up period is insufficient to assess long-term durability of glycemic control and definitive cardiovascular or microvascular outcomes.

• Higher discontinuation rates in the orforglipron arms due to gastrointestinal intolerability could limit real-world effectiveness and adherence compared to well-tolerated SGLT2 inhibitors.

Clinical Significance

Orforglipron provides highly efficacious oral glycemic and weight management that outperforms a standard-of-care SGLT2 inhibitor (dapagliflozin) as a second-line therapy. As a small-molecule, non-peptide GLP-1 receptor agonist, it avoids the strict fasting and water-intake requirements of oral semaglutide as well as the adherence barriers of injectable therapies, representing a major practical advancement in T2D care.

Historical Context

While injectable GLP-1 receptor agonists have revolutionized T2D management, many patients hesitate to initiate injectable therapies. The first oral GLP-1, semaglutide, was a breakthrough but requires a strict fasting regimen due to its peptide nature and low bioavailability. Orforglipron is a pioneering small-molecule non-peptide GLP-1 receptor agonist designed for straightforward oral administration. The ACHIEVE-2 trial establishes its robust efficacy over dapagliflozin, a leading SGLT2 inhibitor, solidifying its potential as a highly potent, convenient option early in the treatment algorithm.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How does the structure of orforglipron differ from oral semaglutide, and why is this molecular difference clinically relevant for patient administration?

Key Response

Oral semaglutide is a peptide that requires co-formulation with the absorption enhancer SNAC and strict fasting conditions to avoid degradation by gastric enzymes. In contrast, orforglipron is a small-molecule, non-peptide GLP-1 receptor agonist. This structure prevents degradation in the GI tract, meaning it can be taken without regard to food or water restrictions, significantly simplifying the daily routine and potentially improving patient adherence.

Resident

In a patient with type 2 diabetes inadequately controlled on metformin who needs a second agent, how do the results of the ACHIEVE-2 trial help you navigate the choice between orforglipron and dapagliflozin?

Key Response

ACHIEVE-2 demonstrates that orforglipron provides superior HbA1c reduction and weight loss compared to dapagliflozin. However, this must be weighed against a higher rate of gastrointestinal adverse effects. The choice should be individualized: prioritize orforglipron for patients where marked weight loss and aggressive glycemic efficacy are the primary goals, but favor dapagliflozin if the patient has clinical heart failure, chronic kidney disease, or is particularly sensitive to GI side effects.

Fellow

Given that orforglipron showed superior weight loss and glycemic control compared to an SGLT2 inhibitor in ACHIEVE-2, what critical data is still required before it can be considered a full equivalent to injectable GLP-1 RAs for high-risk patients?

Key Response

While the glycemic and weight benefits of orforglipron are clearly established, we currently lack dedicated cardiovascular outcome trial (CVOT) data for this agent. Many injectable GLP-1 RAs (like liraglutide, semaglutide, and dulaglutide) have proven Major Adverse Cardiovascular Event (MACE) reduction benefits. Until a CVOT for orforglipron is completed, subspecialists must recognize that superior HbA1c reduction does not automatically guarantee equivalent cardiovascular protection.

Attending

How might the introduction of a highly effective, non-fasting oral GLP-1 RA like orforglipron shift our real-world practice management paradigm for primary care patients who are reluctant to start injectable therapies?

Key Response

A major barrier to GLP-1 RA initiation is needle phobia, and the strict fasting rules of oral semaglutide limit its uptake. Orforglipron removes both of these barriers. This is likely to shift potent GLP-1 RAs earlier in the treatment algorithm in real-world practice, improving the early, aggressive management of 'diabesity.' However, attendings must proactively manage the expected initial GI side effects through careful titration and extensive patient education to prevent early discontinuation.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The ACHIEVE-2 trial utilized an open-label, non-inferiority design that transitioned to superiority testing. How does the open-label nature complicate the interpretation of efficacy drop-outs, and what statistical estimand is most appropriate to mitigate this bias?

Key Response

Open-label designs can introduce expectation bias, particularly for subjective adverse events like nausea, potentially leading to differential dropout rates between treatment arms. A treatment-policy estimand utilizing mixed models for repeated measures (MMRM) or multiple imputation is crucial here. It handles data from patients who discontinue the study drug due to GI effects, ensuring the intention-to-treat analysis remains robust against informative censoring and overestimation of the drug's effectiveness.

Journal Editor

As a peer reviewer, what are the primary threats to validity regarding safety and tolerability endpoints in the ACHIEVE-2 trial given its open-label design comparing drugs with vastly different adverse event profiles?

Key Response

The open-label design is a significant threat to the validity of safety reporting. Patients aware they are receiving a potent, novel weight-loss drug (orforglipron) might tolerate higher levels of nausea, or conversely, over-report expected GI symptoms compared to the relatively silent early side-effect profile of dapagliflozin. A double-dummy design would have been methodologically superior to blind the side-effect profiles and prevent differential ascertainment bias for subjective endpoints.

Guideline Committee

Current ADA/EASD guidelines recommend GLP-1 RAs or SGLT2is as preferred second-line agents after metformin based on comorbidities. How should the ACHIEVE-2 data influence the future guideline positioning of oral GLP-1 RAs versus SGLT2is in patients without established cardiovascular or renal disease?

Key Response

For patients without established ASCVD, HF, or CKD, where weight management and glycemic efficacy are the primary goals, ACHIEVE-2 provides strong evidence that orforglipron is superior to dapagliflozin. Guidelines may need to explicitly stratify non-peptide oral GLP-1 RAs as preferred step-2 agents for the 'weight-centric' or 'glycemic-centric' pathways due to their ease of use and efficacy, while maintaining SGLT2is as the priority for the cardio-renal pathway.

Clinical Landscape

Noteworthy Related Trials

2019

PIONEER 2 Trial

n = 822 · Diabetes Care

Tested

Oral semaglutide 14 mg daily

Population

Adults with T2DM uncontrolled on metformin

Comparator

Empagliflozin 25 mg daily

Endpoint

Change in HbA1c at 26 weeks

Key result: Oral semaglutide provided superior reduction in HbA1c compared to empagliflozin at 26 weeks.

2019

DECLARE-TIMI 58 Trial

n = 17,160 · NEJM

Tested

Dapagliflozin 10 mg daily

Population

Adults with T2DM and high CV risk

Comparator

Placebo

Endpoint

3-point MACE and CV death or HHF

Key result: Dapagliflozin was non-inferior for MACE and significantly reduced cardiovascular death or hospitalization for heart failure compared to placebo.

2019

SUSTAIN 8 Trial

n = 788 · Lancet

Tested

Subcutaneous semaglutide 1.0 mg weekly

Population

Adults with T2DM uncontrolled on metformin

Comparator

Canagliflozin 300 mg daily

Endpoint

Change in HbA1c at 52 weeks

Key result: Semaglutide was superior to canagliflozin in reducing both HbA1c and bodyweight over 52 weeks.

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