Orforglipron, an oral non-peptide GLP-1 receptor agonist, reduced hemoglobin A1C (HbA1C) levels and body weight significantly more than dapagliflozin in adults with type 2 diabetes inadequately controlled on metformin, according to results presented at the American Diabetes Association’s 86th Scientific Sessions and simultaneously published in The Lancet.
According to the authors, the 40-week, phase 3 ACHIEVE-2 trial (NCT06192108) is the first randomized head-to-head comparison of a non-peptide oral GLP-1 receptor agonist against an SGLT2 inhibitor, two drug classes used for treatment intensification after metformin within a patient-centered, comorbidity-driven approach to type 2 diabetes management.
Study Design and Patients
The study enrolled 962 adults with type 2 diabetes who were above glycemic goal (HbA1c 7.0%–10.5%) despite treatment with metformin at 1,500 mg/day or more. Eligible participants had a BMI of 23 kg/m2 or higher, an eGFR of 45 mL/min/1.73 m2 or higher, and no history of pancreatitis or gastric emptying abnormalities. Mean HbA1c at baseline was 8.1%, BMI was 32.6 kg/m2 and age was 56 years.
Participants were randomized 1:1:1:1 to once-daily orforglipron (3 mg, 12 mg or 36 mg) or dapagliflozin (10 mg). Orforglipron was started at 1 mg and escalated every 4 weeks, whereas dapagliflozin began at full dose from day one. Participants who could not tolerate their assigned orforglipron dose had to discontinue, as dose de-escalation was not permitted.
Glycemic Outcomes
All three orforglipron doses were superior to dapagliflozin in HbA1c reduction at week 40. For the treatment-regimen estimand, mean HbA1c changes from baseline at week 40 were –1.23%, –1.50%, and –1.56% with orforglipron 3 mg, 12 mg, and 36 mg, respectively, versus –0.81% with dapagliflozin.
Every orforglipron arm brought mean HbA1c below 7% by week 40. A higher proportion of participants in the orforglipron arms reached an HbA1c below 7.0% (59%–70%) than those in the dapagliflozin arm (37%). Up to 58% of participants in the higher-dose groups reached an HbA1c of 6.5% or below, compared with 20% on dapagliflozin.
Weight and Cardiometabolic Effects
For the treatment-regimen estimand, mean percent bodyweight changes at week 40 were –5.7% (–5.2 kg) and –6.8% (–6.3 kg) with orforglipron 12 mg and 36 mg, respectively, versus –2.4% (–2.2 kg) with dapagliflozin; both orforglipron doses were superior to dapagliflozin. At 36 mg, 59% of participants lost at least 5% of their body weight, and 28% lost at least 10%, compared with 26% and 5%, respectively, on dapagliflozin.
Orforglipron at the 36 mg also produced significantly greater reductions in triglycerides (−14.1% vs. −2.4%; p=0.0005), non-HDL cholesterol (−5.2% vs. −0.1%; p=0.031), and systolic blood pressure (−5.4 vs. −3.0 mm Hg; p=0.011).
Safety
According to the authors, orforglipron demonstrated a safety profile consistent with the GLP-1 RA class. Gastrointestinal events were the most common adverse events associated with orforglipron but were generally mild to moderate and most commonly occurred during dose escalation. Nausea, diarrhea, vomiting, and constipation were all more common in the orforglipron arms than in the dapagliflozin arm.
Treatment discontinuation due to adverse events was higher with orforglipron (9%–12%) than with dapagliflozin (1%). No severe hypoglycemia was reported in any group, and serious adverse events were low and comparable across arms (3%–6% with orforglipron versus 5% with dapagliflozin). There were no cases of thyroid malignancy or findings meeting Hy's law criteria for drug-induced liver injury.
Orforglipron is currently FDA-approved in combination 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 adults with overweight in the presence of at least one weight-related comorbid condition (see prescribing information), and remains under investigation for type 2 diabetes.
Collage by Diana Connolly
