Orforglipron, the oral alternative to Ozempic that could usher in a new era in obesity treatment.

GLP-1 receptor agonists like the famous Ozempic, originally developed to combat type 2 diabetes, have revolutionized the approach to another disease: obesity . Thousands of people in countries like Spain are already using them in the form of prefilled pens with injectable solution.

Now, a new drug developed by the pharmaceutical company Lilly could take this line of medications a step further by allowing patients to administer this class of therapies orally. This means patients could have the option of taking the drug as a pill, rather than through injections. Results from its latest Phase 3 clinical trial for orforglipron, as the compound is called, show that it is equally effective as its injectable counterparts; however, it's important to note some key differences.

What are GLP-1 agonists and what do they do in the body?

Orforglipron, along with other active ingredients such as semaglutide (Ozempic) or liraglutide (Saxenda), belongs to a family of drugs known as GLP-1 (glucagon-like peptide-1) agonists . They all work in a similar way: according to specialist M. Regina Castro in an article published by the prestigious Mayo Clinic (United States), they mimic the function of this hormone and stimulate the body to produce more insulin when blood glucose levels begin to rise after a meal.

On an immediate level, it's easy to understand why this is very useful for type 2 diabetes, a condition in which the body doesn't produce enough insulin to properly regulate blood glucose levels. However, it was later discovered that its benefits are not limited to this condition.

Although we don't know exactly why, GLP-1 agonists also help control appetite, which is why they are increasingly used in the treatment of metabolic disorders such as obesity or overweight. It is thought that this could be because these drugs slow the movement of food from the stomach to the intestines, increasing the feeling of satiety.

Currently, in many countries around the world (including Spain), this use is contemplated by regulatory authorities, although it is specified that it should always be accompanied by changes in diet and lifestyle .

On the other hand, we have evidence that treatments with this class of drugs can reduce the risk of certain major cardiovascular pathologies , such as heart failure, stroke, and even some kidney diseases. All of these conditions are significantly associated with diabetes and obesity, so improvements in this regard are likely a consequence of successful therapy.

A new step in weight loss drugs

Specifically, and as reported by the medical news site Medscape , Stephan Martin, head of diabetology and director of the West German Center for Diabetes and Health, told the Scientific Media Center that "the oral GLP-1 receptor agonist orforglipron leads to a weight loss of more than 10% compared to placebo. This reduction is only slightly lower than that achieved by semaglutide, which must be injected weekly. Furthermore, there are no significant differences in side effects."

This is evident from the results of the ATTAIN-1 trial, published in The New England Journal of Medicine, which included 3,127 adults with obesity (diagnosed based on a body mass index or BMI greater than or equal to 30) and overweight (BMI greater than or equal to 27) who had at least one associated comorbidity.

These individuals were randomly assigned to receive treatment with orforglipron at doses of 6, 12, or 36 mg or placebo. They also received advice on healthy nutrition and regular exercise.

Results comparable to injections

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

Cardiovascular risk markers also improved, including non-high-density lipoprotein cholesterol, or non-HDL cholesterol (the presence of all types of cholesterol in the blood except the so-called "good cholesterol," HDL cholesterol); triglycerides; and systolic blood pressure; finally, the inflammatory marker C-reactive protein was reduced by up to 47.7%.

These results are only slightly lower than those of the Phase 3 OASIS 1 trial conducted by Novo Nordisk testing oral semaglutide 50 mg, which showed a 15.1% reduction in body weight.

It should be noted that the safety profile of orforglipron was consistent with that of other GLP-1 receptor agonists. Gastrointestinal side effects , including diarrhea, vomiting, and constipation, were the most common. Withdrawal rates were dose-dependent (up to 24.4% in the highest dose group) but were lower than in the placebo group (29.9%).

Reasons for caution

Without losing sight of all the above, experts agree that there are reasons for caution . For example, Dr. Stefan Kabisch, a researcher at the Department of Endocrinology and Metabolic Medicine at the Benjamin Franklin Campus of Charité-Universitätsmedizin Berlin and the German Diabetes Research Center, said these are notable findings, but not transformative.

"The preliminary results," he told Medscape , "are similar to those described in recent studies with GLP-1 drug injections: significant mean weight loss, large proportions of the cohort with clinically important weight reductions of more than 10% to 15% of baseline weight , and additional improvements in obesity risk factors such as blood pressure, blood lipids, or inflammation levels. What's new is that the active ingredient can work in a pill."

On the other hand, he criticized the fact that the comparison was made exclusively with a placebo, and emphasized that the effect may appear greater than it would in a trial against injectable GLP-1 agonists or intensive nutritional therapy. Under strictly controlled conditions, such as those required by a Phase 3 trial like this one, these interventions could also achieve similarly potent results.

"The fundamental problems with weight loss based on GLP-1 drugs don't change with oral administration," adds Stephan Martin. "We know that discontinuing semaglutide (Ozempic) leads to a yo-yo effect , with muscle mass decreasing along with fat mass. This means that those unwilling to undergo lifelong therapy will gain weight after discontinuing the drug; in other words, they will replace muscle with fat."

Potential risks of oral therapies

Kabisch noted that routine injections represent a psychological barrier for many patients that oral therapy could eliminate. While this might make treatment more enjoyable , it also poses risks: "People with a slightly elevated body mass index who don't require treatment (especially older adults) might be forced to lose weight without any metabolic or longevity benefits."

More specifically, he warns of a possible shift in treatment priorities: "Nutritional therapies achieve causal effectiveness , rather than symptomatic improvement," he argues. "And they could continue to lose importance in the perception of patients and therapists."

It also suggests that the price of orforglipron will determine how common its use becomes. Lilly has already announced that it intends to submit orforglipron documentation to regulatory agencies worldwide by the end of this year .

References

M. Regina Castro. GLP-1 Agonists: Diabetes Drugs and Weight Loss - Are there drugs for type 2 diabetes that can help people lose weight and lower their blood sugar? Are there side effects? Mayo Clinic. Accessed online at https://www.mayoclinic.org/diseases-conditions/type-2-diabetes/expert-answers/byetta/faq-20057955 on September 18, 2025.

Nadine Eckert. Weight-Loss Pill Matches Injections, but Experts Skeptical. Medscape (2025). Viewed online at https://www.medscape.com/viewarticle/weight-loss-pill-matches-injections-experts-skeptical-2025a1000mba on September 18, 2025.

Sean Wharton, Louis J. Aronne, Adam Stefanski, Nasreen F. Alfaris, Andrea Ciudin, Koutaro Yokote, Bruno Halpern. Orforglipron, an Oral Small-Molecule GLP-1 Receptor Agonist for Obesity Treatment. The New England Journal of Medicine (2025). DOI: 10.1056/NEJMoa2511774

Scientific Media Center Germany (2025). Diet pill instead of injection: Eli Lilly publishes first clinical data. Accessed online at https://www.sciencemediacenter.de/angebote/abnehmpille-statt--spritze-eli-lilly-veroeffentlicht-erste-klinische-daten-25139 on September 18, 2025.

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