As GLP-1 Use Expands, Long-Term Safety Questions Remain Under Watch

The growing use of glucagon-like peptide-1 (GLP-1) receptor agonists in obesity and cardiometabolic care is prompting renewed attention regarding long-term safety, particularly as newer oral agents enter the market. A recent report of liver failure in a patient taking orforglipron (Foundayo; Eli Lilly and Company), approved by the FDA on April 1, 2026, has drawn scrutiny, though experts emphasize that isolated adverse event (AE) reports should be interpreted cautiously.^1,2

The case, which was captured in the FDA Adverse Event Reporting System (FAERS), “raised concerns about the drug’s overall safety profile,” but both analysts and the manufacturer have urged restraint in drawing conclusions.¹

Interpreting Early Safety Signals in Real-World Use

FAERS serves as a broad pharmacovigilance database that collects reports from clinicians, manufacturers, and patients, but the FDA cautions that “there is no certainty that the reported event…was due to [orforglipron].”¹

Eli Lilly stated that its internal safety review did not support a causal relationship. “In line with our standard procedures, Lilly Global Patient Safety thoroughly assessed the individual report, which was submitted within days of commercial availability, and determined it was not reasonably related to Foundayo,” a company spokesperson said.¹

Market analysts echoed this perspective. RBC Capital Markets described the subsequent decline in Lilly’s stock as an “overreaction,” noting that the overall safety profile remains favorable and emphasizing that “one liver case does not make a signal.”¹

Similarly, Evercore ISI analysts cautioned against overinterpretation, writing that “we cannot look at this single liver case in a silo,” particularly given that hepatic events have been reported across the GLP-1 class and may reflect confounding factors.¹

These perspectives highlight a key challenge in postmarketing surveillance: distinguishing meaningful safety signals from background incidence and reporting variability.

Established and Emerging Safety Considerations

Although GLP-1 receptor agonists are widely regarded as effective and generally well tolerated, their safety profile extends beyond commonly reported gastrointestinal AEs such as nausea, vomiting, and diarrhea.³

Labeling for orforglipron and related agents includes warnings for acute pancreatitis, gallbladder disease, acute kidney injury (often secondary to dehydration), hypersensitivity reactions, and diabetic retinopathy complications.³ These risks may be particularly relevant in patients with complex comorbidities or rapid metabolic changes.

Importantly, liver-related concerns have historically not been a dominant safety signal for GLP-1 therapies. In clinical development, Lilly reported that orforglipron was evaluated in approximately 11,000 patients for up to 2 years, with a hepatic safety profile comparable to placebo and other treatments.¹ According to the company, “no cases of drug-induced liver injury (Hy’s Law) were observed, and there was no hepatic safety signal.”¹

However, rare AEs may only become apparent with broader real-world use, reinforcing the need for ongoing monitoring.

Psychiatric Safety

Another area of ongoing evaluation has been psychiatric safety. The FDA recently reported that its review of clinical trial and real-world data did not demonstrate an increased risk of suicidal ideation or behavior associated with GLP-1 receptor agonists.⁴

Following this review, the agency requested removal of the suicidal ideation warning from certain GLP-1 product labels, but surveillance efforts are ongoing as use expands.⁴

Expanding Access, Introducing Tradeoffs

The approval of orforglipron represents a notable evolution in GLP-1 therapy as a nonpeptide oral agent that does not require fasting or specific administration conditions. In an interview with Pharmacy Times, Richard Frank, MD, explained that this innovation may improve patient access and adherence, particularly among individuals who are unwilling or unable to use injectable therapies.⁵

However, increased convenience may come with tradeoffs. Frank noted that oral GLP-1 agents may be associated with a higher incidence of gastrointestinal AEs, which could affect tolerability in some patients.⁵ As these therapies are incorporated into clinical practice, clinicians may increasingly use oral agents as entry points or maintenance options while balancing efficacy, tolerability, and patient preference.

The Pharmacist’s Role in Long-Term Risk Management

As GLP-1 therapies are used earlier and more broadly, pharmacists are playing an increasingly important role in optimizing treatment outcomes. This includes counseling patients on expected AEs, identifying warning signs of serious complications, and supporting appropriate dose titration.

Frank emphasized that pharmacists could help patients navigate therapy and integrate pharmacologic treatment with lifestyle interventions, which remain essential for sustained weight management and cardiometabolic risk reduction.⁵

The expanding GLP-1 landscape reflects both therapeutic progress and the need for continued vigilance. Although current evidence supports a favorable benefit-risk profile, interpreting emerging safety signals will be critical as real-world data further define long-term risks.

REFERENCES

1. Manalac T. Foundayo’s liver failure blip weighs down Lilly shares but analysts unconcerned. BioSpace. May 5, 2026. Accessed May 8, 2026. https://www.biospace.com/drug-development/foundayos-liver-failure-blip-weighs-down-lilly-shares-but-analysts-unconcerned

2. McGovern G. FDA approves Orforglipron, First GLP-1 Pill without time, food, or water restrictions. Pharmacy Times. April 1, 2026. Accessed May 8, 2026. https://www.pharmacytimes.com/view/fda-approves-orforglipron-first-glp-1-pill-without-time-food-or-water-restrictions

3. FDA approves first new molecular entity under national voucher program. News release. FDA. April 1, 2026. Accessed May 8, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-first-new-molecular-entity-under-national-priority-voucher-program

4. Update on FDA’s ongoing evaluation of reports of suicidal thoughts or actions in patients taking a certain type of medicines approved for type 2 diabetes and obesity. FDA. January 13, 2026. Accessed May 8, 2026. https://www.fda.gov/drugs/drug-safety-communications/update-fdas-ongoing-evaluation-reports-suicidal-thoughts-or-actions-patients-taking-certain-type

5. Frank R. Valletti D. Could orforglipron change obesity treatment forever? Pharmacy Times. May 5, 2026. Accessed May 8, 2026. https://www.pharmacytimes.com/view/could-orforglipron-change-obesity-treatment-forever-