By Dr. Asnat Raziel, bariatric surgeon specializing in obesity treatment, metabolic health and healthy longevity; Director of the Multidisciplinary Center for Obesity Treatment, Assia Medical, Assuta Ramat HaChayal, Tel Aviv
Foundayo and liver safety: between great promise and caution
Foundayo and liver safety became a hot topic right after the pill was approved in the United States. Behind the brand name is orforglipron, a daily weight-loss pill made by Eli Lilly. The FDA, the U.S. Food and Drug Administration, approved it on April 1, 2026 for adults with obesity, or with overweight and related conditions. About two weeks later, it emerged that the approval included a requirement for more safety data, mainly about the liver.
It is important to say right away that this is not a halt and not an unusual warning. Rather, it is a request to complete data from studies that are already under way. Still, the request highlights a central challenge in modern medicine: how to balance rapid innovation with long-term safety.
What exactly did the FDA ask to examine?
According to the published approval documents, the FDA required Lilly to analyze the liver data from the ACHIEVE-4 trial. This is a large study in patients with type 2 diabetes and increased cardiovascular risk. The review focuses on three points. First, unexpected rises in liver enzymes, a sensitive marker of an unwanted reaction to a drug. Second, cases that meet the criteria of Hy’s Law, a combination of raised enzymes and raised bilirubin that suggests real liver injury. Finally, the share of patients who stopped treatment because of liver-related effects.
At the same time, the FDA asked for additional data on heart attacks, strokes and delayed stomach emptying. In addition, it required at least 15 years of follow-up on thyroid cancer risk. The list also includes a registry for children with obesity who receive weight-loss drugs and a pregnancy registry. Lilly described the requirements as routine and consistent with the FDA’s usual approach to new drugs.
Why the liver?
Foundayo belongs to a new generation of GLP-1 drugs. Unlike semaglutide, which is a small protein, orforglipron is a small molecule that is not a protein. That is why patients can swallow it as a pill, with no food or water restrictions. However, the liver breaks down small molecules, so regulators examine them closely.
There is also a historical background. In April 2025, Pfizer stopped developing the pill danuglipron. One participant developed possible drug-induced liver injury, which resolved after stopping the drug. This case reminded everyone that every new drug in this class must prove its liver safety on its own.
Foundayo and liver safety: what do the data show?
So far, the data are reassuring. According to the ATTAIN-1 safety analysis, eight participants had liver enzyme rises of 10 times the upper limit of normal or more. Seven of them received orforglipron and one received placebo. Even so, in all seven, the researchers identified another cause for the rise. Also, two participants who received the drug had a combined rise in bilirubin and enzymes. In their case, too, the researchers found another cause, and they did not attribute these cases to drug-induced liver injury.
Lilly reports that no worrying liver signal appeared across the entire phase 3 program. Likewise, there was no unusual rise in enzymes compared with semaglutide. But one important point needs to be understood. Even large, carefully run trials do not always detect rare side effects. Some appear only after millions of people have used a drug for years. Therefore, the FDA’s request does not contradict the data. Instead, it expands them.
ACHIEVE-4 results: the trial the FDA was waiting for
In September 2026, The Lancet published the full results of ACHIEVE-4. The trial included 2,749 adults with type 2 diabetes and increased cardiovascular risk. The researchers compared orforglipron with insulin glargine over a median of two years. Major cardiovascular events occurred in 4.2% of the orforglipron group, compared with 5.0% of the insulin group. In other words, the drug met its cardiovascular safety goal.
Moreover, according to the company’s announcement, an in-depth analysis of drug-induced liver injury did not raise a worrying signal. This is the most important answer so far on Foundayo and liver safety. On the other hand, digestive side effects were common: 62.1% in the orforglipron group, compared with 14.2% in the insulin group. I wrote more about the drug’s role in preventing heart disease and diabetes in my article on Foundayo, diabetes and heart disease.
Foundayo and liver safety: why now?
This is where the regulatory context comes in. Regulators first approved most GLP-1 drugs for diabetes. On that path, drugmakers must first run long trials that prove heart and liver safety, and only then comes approval for obesity. With Foundayo, the order flipped. The drug received approval for obesity first, so some of the long-term data were not yet in the FDA’s hands at the time of approval. In other words, the FDA asked to complete the puzzle. As a result, the question of Foundayo and liver safety came up at precisely this stage.
The pill wars: not only efficacy, but also trust
The request came in the middle of a race between Lilly and Novo Nordisk. In January 2026, Novo launched the Wegovy pill in the United States. A detailed comparison of the two pills appears in my article on the Wegovy pill vs. Foundayo. At this stage, the question is not only which one works better, but also which one will earn a reputation for safety over time. When millions of patients take these drugs for years, trust becomes the key currency.
What about Israel?
Since the FDA approval, the pill has become more widely available. The UK approved it in August 2026, and in October 2026, the scientific committee of the European Medicines Agency recommended its approval. In Israel, Foundayo has been available since September 15, 2026. A full guide to using it correctly is available in my article on treatment with the pill and follow-up.
Foundayo and liver safety: what it means for patients
The message is not dramatic, but it is precise. There is no evidence of an immediate or unusual liver risk. Nevertheless, follow-up matters. As with any advanced metabolic treatment, it is wise to have periodic blood tests, especially in the first few months. People with fatty liver or another liver disease should tell their doctor before starting treatment. You can find more on this in my guide to diagnosing and treating fatty liver.
The right approach is not fear, but awareness. We look for early signs, listen to the body and tailor treatment to each person. For example, unusual fatigue, yellowing of the eyes or dark urine call for a visit to the doctor.
Bottom line: not a warning sign, but a high standard
The FDA’s request does not point to a problem. Rather, it reflects a high bar. This is how new drugs become truly safe for wide use. The data gathered since then, including ACHIEVE-4, have not shown a worrying liver signal. Ultimately, the goal is not only weight loss, but whole-body health over time. So our role is to understand the data, support our patients and balance enthusiasm for what is new with clinical judgment.
The information in this article is general and does not replace personal medical advice.
References
FDA asks Lilly to evaluate obesity pill’s liver risk
Eli Lilly Releases Updated Safety Data for Foundayo Following FDA’s Request
Pfizer Discontinues Development of Oral GLP-1 Receptor Agonist Danuglipron
Eli Lilly, the drug’s manufacturer, funded the ATTAIN-1 and ACHIEVE-4 trials.
