Weight-Loss Pill Matches Injections, but Experts Skeptical

GLP-1 receptor agonists are now well established as weight-loss treatments, but until recently, they have been available exclusively as injections. 

Lilly, headquartered in Indianapolis, announced that the oral GLP-1 receptor agonist orforglipron reduced the average body weight by 12.4% in a phase 3 trial.

The effect was comparable to that seen with injectable semaglutide, and German experts remain cautious about the findings.

“The results show that the oral GLP-1 receptor agonist orforglipron leads to a more than 10% reduction in body weight compared to placebo. This reduction is only slightly lower than that achieved with semaglutide, which must be injected weekly. There are also no significant differences in side effects,” said Stephan Martin, MD, chief physician for diabetology and director of the West German Diabetes and Health Center, Düsseldorf, Germany, in a statement to the Science Media Center, Germany.

Trial Design

The ATTAIN-1 trial enrolled 3127 adults with obesity (BMI ≥ 30) or overweight (BMI ≥ 27) with at least one weight-related comorbidity. 

Participants were randomly assigned to receive orforglipron at doses of 6 mg, 12 mg, or 36 mg, or to a placebo. All groups received counselling on healthy eating and regular physical activity.

Weight Reduction

At 72 weeks, patients receiving 36 mg of orforglipron lost an average of 12.4% of body weight (-12.4 kg) compared with 0.9% (-1 kg) with placebo. In the highest-dose group, 59.6% lost at least 10%, and 39.6% lost at least 15%.

Cardiovascular risk markers also improved, including non-high-density lipoprotein cholesterol, triglycerides, and systolic blood pressure, and the inflammatory marker high-sensitivity C-reactive protein level decreased by 47.7%. 

These results were slightly lower than those of Novo Nordisk’s OASIS 1 phase 3 trial of oral semaglutide 50 mg, which showed a 15.1% reduction in body weight. The inflammatory marker high-sensitivity C-reactive protein level decreased by 47.7%.

Adverse Effects

The safety profile of orforglipron was consistent with that of other GLP-1 receptor agonists. Gastrointestinal events, including nausea, vomiting, diarrhea, and constipation, were the most frequent adverse effects. The discontinuation rates were dose-dependent, reaching 24.4% in the 36 mg group. The dropout rate in the placebo group was also relatively high at 29.9%.

Expert Views

Stefan Kabisch, MD, clinical investigator at the Department of Endocrinology and Metabolism Medicine, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, and German Center for Diabetes Research, Berlin, Germany, described the findings as noteworthy but not transformative.

“The preliminary results are similar to those described in studies with the latest GLP-1-based injection therapies: significant average weight loss, large proportions of the cohort with clinically significant weight reduction of more than 10% or more than 15% of baseline weight, and additional accompanying improvements in obesity-related risk factors such as blood pressure, blood lipids, and inflammation levels. What is new is that the active ingredient can be designed to also function as a tablet,” he said.

He criticized the exclusive comparison with placebo, noting that the effect might appear greater than it would in a head-to-head trial against injectable GLP-1 receptor agonists or intensive nutritional therapy. Under strictly controlled conditions, such as those in the phase 3 study, these interventions could also achieve similarly strong results.

“The fundamental problems of GLP-1-based weight loss will not change with oral administration. We know from semaglutide that discontinuation leads to a yo-yo effect and that muscle mass decreases alongside fat mass. This means that those unwilling to undergo lifelong therapy with it will only gain fat after discontinuation; in other words, they will replace muscle with fat.” Martin warned.

Oral Risks

Kabisch noted that regular injections represent a psychological barrier for many patients that a tablet would eliminate. While this could make therapy more pleasant, it also carries risks: “People with a slightly elevated BMI who do not require treatment (especially older people) could be enticed to lose weight without any benefit in terms of metabolism or longevity.”

Kabisch noted the risk of a shift in treatment priorities: “Nutritional therapies causally effective rather than symptom-oriented could continue to lose importance in the perception of patients and therapists,” said Kabisch.

Whether the weight loss pill surpasses the established injection therapy will likely depend primarily on its price and effectiveness.

“The price of orforglipron will certainly determine how widespread its use will be,” said Martin.

Kabisch added that logistical challenges also need funding: “After its approval, it will likely only be prescribed in this combination, just like its predecessor injectable drugs. Sufficient counseling staff would then have to be available for nutritional and exercise therapy.” 

Eli Lilly plans to submit orforglipron to regulators worldwide by the end of the year. Detailed findings will be presented in September at the annual meeting of the European Association for the Study of Diabetes.

This story was translated from Medscape’s German edition.