EASD 2025 Orforglipron offers meaningful improvements in bodyweight, glycemic control

medwireNews: Orforglipron significantly reduces bodyweight in people with obesity and significantly lowers glycated hemoglobin (HbA1c) levels in those with type 2 diabetes, show data from two phase 3 studies presented at the 61st EASD Annual Meeting 2025 in Vienna, Austria.

ATTAIN-1: Orforglipron for obesity treatment

In ATTAIN-1, 3127 people (mean age 45 years, 64% women) with a BMI of at least 30 kg/m² or a BMI of 27–30 kg/m² and at least one obesity-related complication but no diabetes, were randomly assigned to receive the oral nonpeptide glucagon-like peptide (GLP)-1 receptor agonist at once-daily doses of 6 mg (n=723), 12 mg (n=725), or 36 mg (n=730), or placebo (n=949) for 72 weeks.

All participants also received individualized lifestyle counseling focused on adhering to a healthy, balanced diet combined with physical activity throughout the trial. At baseline, their mean bodyweight was 103 kg, mean BMI was 37 kg/m², and 36% had prediabetes.

The study, by Sean Wharton (Wharton Weight Management Clinic, Burlington, Ontario, Canada) and colleagues, showed that, at week 72, the mean bodyweight reduction was significantly greater with orforglipron 6 mg, 12 mg, or 36 mg than with placebo, at a respective 7.5%, 8.4%, and 11.2% versus 2.1%.

In line with this, significantly more patients across the orforglipron groups met weight-reduction thresholds of at least 5%, 10%, 15%, and 20% at week 72 than did those in the placebo group.

For example, 71.8% of patients given orforglipron 36 mg had a bodyweight reduction of at least 5%, while 54.6%, 36.0%, and 18.4% had bodyweight reductions of at least 10%, 15%, and 20%, respectively. By comparison, the respective proportions of patients meeting the same weight loss targets in the placebo group were 26.8%, 12.9%, 5.9%, and 2.8%.

The researchers also found that waist circumference and blood pressure, as well as triglyceride, non-high-density lipoprotein cholesterol, high-sensitivity C-reactive protein, HbA1c, fasting glucose, and fasting insulin levels all showed significantly greater improvements during treatment with orforglipron relative to placebo.

ACHIEVE-1: Orforglipron in early type 2 diabetes

In ACHIEVE-1, Julio Rosenstock (Velocity Clinical Research Center at Medical City Dallas, Texas, USA) and colleagues randomly assigned 559 people (mean age 53 years, 48% women) with type 2 diabetes that was inadequately controlled by diet and exercise alone to receive oral orforglipron 3 mg (n=143), 12 mg (n=137), 36 mg (n=141), or placebo (n=138) once daily for 40 weeks.

At baseline, participants had a mean diabetes duration of 4.4 years, a mean HbA1c of 8.0% (64 mmol/mol), mean bodyweight of 90.2 kg, and a mean BMI of 33.0 kg/m². Just over one-third (38.3%) had previously received a glucose-lowering agent, most commonly metformin.

The primary outcome in ACHIEVE-1 was the change in HbA1c from baseline to week 40, and the researchers found that this was significantly greater with all three doses of orforglipron relative to placebo.

Specifically, at week 40, patients given orforglipron 3 mg had an estimated mean HbA1c reduction from baseline of 1.24 percentage points, with reductions of 1.47 and 1.48 percentage points among those given orforglipron 12 mg and 36 mg, respectively. By comparison, the mean HbA1c reduction in the placebo group was 0.41 percentage points.

This meant that the mean HbA1c level at week 40 was 6.5–6.7% (48–50 mmol/mol) among the patients given any dose of orforglipron compared with 7.8% (62 mmol/mol) among those given placebo.

Furthermore, significantly more participants given orforglipron achieved the HbA1c target of below 7.0% (53 mmol/mol) than did those given placebo, at rates of 68%, 73%, 73%, and 33% in the orforglipron 3 mg, 12 mg, 36 mg, and placebo groups, respectively. The corresponding proportions achieving an HbA1c of 6.5% (48 mmol/mol) or lower were 57%, 58%, 62%, and 15%.

Rosenstock and colleagues also found that patients given orforglipron 12 mg or 36 mg had significantly greater reductions in bodyweight than those given placebo, at 5.8% and 7.6% versus 1.7%, as well as significantly greater reductions in fasting serum glucose (37 and 35 vs 11 mg/dL) and triglyceride levels (14.9 and 14.0 vs 4.2 mg/dL).

Adverse events

The most common adverse events (AEs) in both studies were mild-to-moderate gastrointestinal events. Of note, in ACHIEVE-1 there were no cases of severe hypoglycemia, an AE of special interest for the participants with diabetes.

The rates of discontinuation due to AEs were similar in both studies, ranging from 5.1–10.3% of orforglipron-treated patients in ATTAIN-1 and from 4.4–7.8% in ACHIEVE-1. The corresponding rates among placebo-treated patients were 2.6% and 1.4%.

Clinically meaningful conclusions

The ATTAIN-1 trial investigators conclude that orforglipron treatment leads to “significant and clinically meaningful dose-dependent reduction in body weight” in people with obesity.

This conclusion is echoed by the ACHIEVE-1 trial investigators who say: “In participants with early type 2 diabetes treated with diet and exercise, the new small-molecule, nonpeptide oral GLP-1 receptor agonist orforglipron led to significant and clinically meaningful improvements in glycemic control.”

The results of both trials are also published in The New England Journal of Medicine.

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New Engl J Med 2025; doi:10.1056/NEJMoa2511774
New Engl J Med 2025; 393: 1065–1076
EASD Annual Meeting 2025; Vienna, Austria: 15–19 September