ATLANTA -- A once-daily oral nonpeptide GLP-1 conferred significant improvements in body weight, HbA1c and other cardiometabolic parameters for adults with obesity and type 2 diabetes, according to findings from the ATTAIN-2 trial.
As Healio previously reported, data from the ATTAIN-1 trial presented at the European Association for the Study of Diabetes meeting and published in The New England Journal of Medicine showed orforglipron (Eli Lilly) conferred weight loss of up to 12.4% at 72 weeks for adults with obesity but no diabetes. In new data from the ATTAIN-2 trial presented at ObesityWeek, researchers revealed the oral GLP-1 also induced similar benefits for adults with overweight or obesity and type 2 diabetes.
"All doses of orforglipron in the ATTAIN-2 trial demonstrated a dose-dependent reduction in body weight and HbA1c at 72 weeks," Nasreen Alfaris, MD, MPH, consultant at the Obesity, Endocrine and Metabolism Center at King Fahad Medical City in Riyadh, Saudi Arabia, said during a presentation. "It also demonstrated improvements in all prespecified cardiometabolic parameters. Orforglipron had a similar safety profile as other GLP-1 receptor agonists."
For ATTAIN-2, researchers enrolled 1,613 adults aged 18 years and older with obesity or overweight plus one weight-related comorbidity, and with type 2 diabetes with an HbA1c between 7% and 10% at baseline (mean age, 56.8 years; 46.9% women). All participants were required to be on stable treatment at baseline with three or fewer oral antihyperglycemic medications or on diet and exercise intervention alone. Adults were randomly assigned, 1:1:1:2, to once-daily 6 mg orforglipron, 12 mg orforglipron, 36 mg orforglipron or placebo for 72 weeks. Mean change in body weight was the trial's primary endpoint.
In the efficacy estimand, weight loss at 72 weeks was 10.5% with 36 mg orforglipron, 7.8% with the 12 mg dose, and 5.5% with 6 mg orforglipron compared with a 2.2% weight reduction for the placebo group (P < .001 for all). In the treatment-regimen estimand, weight loss at 72 weeks was 9.6% for the 36 mg orforglipron group, 7% for the 12 mg group, 5.1% with 6 mg orforglipron and 2.5% with placebo (P < .001 for all).
Deborah B. Horn, DO, MPH, DABOM, MFOMA, medical director at the University of Texas Center for Obesity Medicine and Metabolic Performance and clinical assistant professor in the department of surgery at University of Texas McGovern Medical School in Houston, said the weight loss observed in ATTAIN-2 was lower than what was observed in ATTAIN-1, but added that adults with type 2 diabetes usually lose less weight with obesity pharmacotherapy than the nondiabetes population.
"What gets me really excited is it's another option in our toolbox that lands us in double-digit weight loss for individuals struggling with obesity and diabetes," Horn said during a presentation.
A larger percentage of adults receiving orforglipron achieved weight loss of at least 5%, 10%, 15% and 20% vs. placebo. Among adults receiving 36 mg orforglipron, 50.1% lost at least 10% of their body weight at 72 weeks.
At 72 weeks, the mean reduction in HbA1c was 1.29 percentage points with 6 mg orforglipron, 1.6 percentage points with the 12 mg dose and 1.78 percentage points with 36 mg orforglipron vs. 0.14 percentage points with placebo, according to the efficacy estimand (P < .001 for all). More than half of all adults receiving orforglipron, regardless of dose, achieved an HbA1c of 6.5% or less, and 28.1% of those in the 36 mg orforglipron group achieved an HbA1c of less than 5.7%.
All three orforglipron groups had significantly greater improvements in multiple cardiometabolic risk factors than placebo, including waist circumference, fasting serum glucose, systolic blood pressure, lipids and high-sensitivity C-reactive protein.
Horn said the wide range of cardiometabolic improvements observed in the trial was exciting.
"Not only am I changing the weight of the patient sitting in front of me, but more importantly, I'm changing their overall health," Horn said.
At least one treatment-emergent adverse event occurred in 86.4% of all participants, with a similar proportion of orforglipron participants experiencing an adverse event as placebo. At least one serious adverse event occurred among 10.9% of the 36 mg orforglipron group, 10.3% of the 12 mg orforglipron group, 7.3% of those receiving 6 mg orforglipron and 8.8% of the placebo group.
The most common adverse events with orforglipron were gastrointestinal in nature and included nausea, diarrhea, constipation, vomiting and dyspepsia. Alfaris said gastrointestinal adverse events were more common with orforglipron than placebo and were consistent with those seen in other incretin-based drugs. She added that most cases of nausea, vomiting and diarrhea occurred during dose escalation in the first 24 weeks of the study.
Clinically significant hypoglycemia occurred in 20 adults receiving orforglipron, and severe hypoglycemia occurred in one participant. Persistent hyperglycemia requiring rescue therapy was more common among placebo participants than those receiving orforglipron.
Incidence of diabetic retinopathy did not differ between the orforglipron and placebo groups, and no hepatic safety signals were observed in the trial. Alfaris said the lack of hepatic safety signals was important for orforglipron, as research into earlier generations of small molecules was halted due to hepatic safety concerns.
"We looked at [alanine transaminase] and [aspartate aminotransferase] levels throughout the study, and similar to other GLP-1 receptor agonists, the levels were reduced throughout the study and stayed that way for 72 weeks," Alfaris said.
During a commentary, Donna H. Ryan, MD, professor emerita at Pennington Biomedical Research Center, discussed some of the advantages orforglipron has over other incretin-based drugs. She said orforglipron does not need to be refrigerated, has no food and water restriction and has a manageable adverse event profile. Ryan added that the medication's ability to be mass manufactured at a lower cost could allow it to be accessed by more patients.
"It's the first nonpeptide small molecule GLP-1 receptor agonist with some very appealing characteristics for patients and prescribers," Ryan said during a presentation. "It's a valuable asset."
Orforglipron is currently under FDA review and has not yet been approved by the agency. If it is approved, Ryan said it will be important to monitor the drug for safety in the real-world population during the postmarketing surveillance period, as real-world populations differ from people enrolled in a clinical trial.
"We'll be watching for liver effects very carefully," Ryan said. "We've done the very best job we can in our clinical trial population in ensuring safety, and we've looked at every outlier in terms of liver enzyme elevations. We see no signals. But we're still going to watch this drug in postmarketing."