Orforglipron Shows Superior Glycemic Control Over Oral Semaglutide in Type 2 Diabetes
Orforglipron, an oral GLP-1 receptor agonist, demonstrated greater reductions in HbA1c and body weight compared to oral semaglutide in adults with type 2 diabetes, with more patients achieving strict glycemic targets at one year.
Once-daily orforglipron induced greater reductions in HbA1c and body weight than once-daily oral semaglutide for adults with type 2 diabetes, according to data from the ACHIEVE-3 trial published in The Lancet. The randomized, phase 3, open-label trial compared two oral GLP-1 receptor agonists in 1,698 adults with type 2 diabetes.
According to the treatment-regimen estimand, adults receiving orforglipron 12 mg had a 1.71 percentage point decline in HbA1c, and those receiving orforglipron 36 mg had a 1.91 percentage point drop in HbA1c at 1 year compared with a 1.23 percentage point reduction with semaglutide 7 mg and a 1.47 percentage point decrease with semaglutide 14 mg. Both orforglipron groups had greater HbA1c reductions than both oral semaglutide groups.
At 1 year, 72% of the orforglipron 12 mg group and 76% of those receiving orforglipron 36 mg reached an HbA1c of less than 7% vs. 54% of adults receiving semaglutide 7 mg and 64% of those receiving semaglutide 14 mg. An HbA1c of less than 6.5% was reached by 63% of adults receiving orforglipron 12 mg and 68% receiving orforglipron 36 mg compared with 38% of adults receiving semaglutide 7 mg and 48% receiving semaglutide 14 mg. The proportion of adults who had an HbA1c of less than 5.7% at 1 year was 21% with orforglipron 12 mg and 31% with orforglipron 36 mg compared with 7% with semaglutide 7 mg and 12% with semaglutide 14 mg.
Adults receiving orforglipron 12 mg had a 6.1% decline in body weight and those receiving orforglipron 36 mg had a body weight decrease of 8.2% from baseline to 1 year compared with a 3.9% weight loss with semaglutide 7 mg and a 5.3% reduction in weight with semaglutide 14 mg, according to the treatment-regimen estimand. The orforglipron 36 mg group had a greater decrease in body weight than both oral semaglutide groups, while weight loss with orforglipron 12 mg was greater than that observed with semaglutide 7 mg. The percentage of adults who lost at least 5% of their body weight was 59% with orforglipron 12 mg and 69% with orforglipron 36 mg vs. 37% with oral semaglutide 7 mg and 49% with semaglutide 14 mg.
The trial enrolled adults with type 2 diabetes who were unable to maintain glycemic control with metformin, had an HbA1c of 7% to 10%, BMI of 25 kg/m2 or higher, and less than 5% change in body weight in the 3 months before screening. The mean age was 53.9 years, 48.6% were women, mean HbA1c was 8.3%, and mean BMI was 35.1 kg/m2. Participants were randomly assigned to orforglipron 12 mg, orforglipron 36 mg, oral semaglutide 7 mg or oral semaglutide 14 mg for 1 year.
According to the efficacy estimand, decreases in non-HDL cholesterol, triglycerides, LDL cholesterol and total cholesterol were observed with most groups at 1 year, though the semaglutide 14 mg group had a 0.2% increase in total cholesterol and a 2% rise in LDL cholesterol from baseline to 1 year.
A meta-analysis of placebo-controlled phase 2 and phase 3 trials found that orforglipron produced dose-dependent improvements in major modifiable cardiovascular risk factors compared with placebo: body weight −6.08% (up to −9.31% at higher doses), HbA1c −0.85% (up to −1.36%), systolic blood pressure −4.32 mmHg (up to −5.78 mmHg at 45 mg), LDL-cholesterol −4.14%, triglycerides −10.90%, VLDL-cholesterol −10.81%, and HDL-cholesterol +3.31%. Heterogeneity was very low to absent for systolic blood pressure and all lipid outcomes.
Gastrointestinal adverse events were more common with orforglipron than semaglutide. Gastrointestinal side effects were common but typical of the GLP-1 class, with nausea risk ratio 5.22, vomiting risk ratio 3.24, and eructation risk ratio 6.80 compared to placebo.
Orforglipron is a novel once-daily oral non-peptide GLP-1 receptor agonist designed to provide comprehensive cardiometabolic risk reduction. Orforglipron represents a potential new therapeutic option for individuals with type 2 diabetes considering initiation of GLP-1 receptor agonist therapy who might prefer an alternative to the subcutaneous route of administration.