Orforglipron benefits extend to people with type 2 diabetes and overweight or obesity

medwireNews: The oral, small-molecule glucagon-like peptide (GLP)-1 receptor agonist orforglipron induces statistically significant and clinically meaningful bodyweight reductions in people with type 2 diabetes and overweight or obesity, show data from the phase 3 ATTAIN-2 trial.

In addition, the treatment, which was given as an adjunct to lifestyle modification, significantly improves glycemic control and cardiometabolic risk factors versus placebo, report Deborah Horn (University of Texas Center for Obesity Medicine and Metabolic Performance, Houston, USA) and co-authors in The Lancet.

They say that the results “exceed what is typically seen in this population with currently available oral medications for obesity management,” and were “consistent with previous orforglipron trials in people with obesity without diabetes (ATTAIN-1) and in people with early type 2 diabetes with a BMI of 23 kg/m² or higher (ACHIEVE-1).”

ATTAIN-2 included 1613 participants (mean age 57 years, 53% men) with a BMI of at least 27 kg/m² (mean 35.6 kg/m²) and glycated hemoglobin (HbA1c) of 7.0–10.0% (53–86 mmol/mol) from 136 sites in 10 countries.

At baseline, mean bodyweight among the participants was 101.4 kg. Horn and team report that the 329 individuals randomly assigned to receive once daily oral orforglipron 6 mg had a mean bodyweight reduction of 5.1%, or 5.3 kg, after 72 weeks of treatment. The mean reduction was 7.0% (7.2 kg) in the 332 people given orforglipron 12 mg and 9.6% (9.6 kg) in the 322 participants given orforglipron 36 mg.

By comparison, the mean bodyweight reduction among the 630 participants randomly assigned to receive placebo was 2.5% (2.7 kg), which was significantly lower than that observed with all three orforglipron doses.

Among participants given orforglipron 36 mg, 67.2%, 45.6%, 26.0%, and 10.8% reached bodyweight reductions of at least 5.0%, 10.0%, 15.0%, and 20.0% respectively, but the researchers note that treatment responses varied across all doses, “showing that even at the 6 mg dose of orforglipron, some patients lose 15–20% of their bodyweight or more.”

Mean baseline HbA1c was 8.05% (64.4 mmol/mol). By week 72, it had fallen by 1.22%, 1.50%, and 1.66% in the 6 mg, 12 mg, and 36 mg groups, respectively, and by a significantly lower 0.47% in the placebo group.

Furthermore, the proportion of participants reaching HbA1c concentrations of less than 7.0% at week 72 was significantly higher at all orforglipron doses verus placebo. For example, 75.5% of participants given orforglipron 36 mg had an HbA1c below 7.0% at the end of the study compared with 30.5% of those given placebo. For HbA1c concentrations of 6.5% (48 mmol/mol) or lower, the corresponding proportions were 66.6% and 15.4%.

Horn and team also found that people given orforglipron had significantly greater reductions in waist circumference, systolic blood pressure, non-high-density lipoprotein cholesterol, and triglycerides than those given placebo, suggesting that “orforglipron could offer broad cardiometabolic benefits, which is particularly important given the elevated cardiovascular risk in this population,” they write.

The adverse event (AE) rates were similar among the orforglipron and placebo groups overall but, consistent with other GLP-1 receptor agonists, people given orforglipron experienced more mild-to-moderate gastrointestinal AEs. These led to higher rates of treatment discontinuation for orforglipron versus placebo (6.1–9.9 vs 4.1%).

Horn et al say that their results “highlight the dual benefit of orforglipron for both weight reduction and glycaemic improvement, addressing the challenge of managing both obesity and diabetes simultaneously.”

They conclude: “Overall, the findings indicate that orforglipron could address the unmet need for oral therapy by achieving outcomes similar to those of injectable GLP-1 receptor agonists, potentially shifting treatment paradigms.”

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Lancet 2025; doi:10.1016/S0140-6736(25)02165-8