Last Updated: March 2026

In a recent observational Danish cohort study, once-weekly semaglutide was associated with a doubled five-year risk of nonarteritic anterior ischemic optic neuropathy (NAION) in persons with type 2 diabetes, affecting 424,152 individuals (JCI, 2024) [1]. This finding underscores the ongoing need for vigilance and long-term real-world data collection for GLP-1 receptor agonists, even as broader evidence continues to reinforce their overall safety and significant health benefits.

GLP-1 medications, including semaglutide (Wegovy, Ozempic) and liraglutide (Saxenda, Victoza), have transformed the landscape of obesity and type 2 diabetes management. Their efficacy in promoting substantial weight loss and improving glycemic control is well-established. However, for a therapy often taken indefinitely, understanding the long-term safety profile, extending beyond initial clinical trials of two to three years, is paramount. What does 5+ year data reveal about sustained use?

Cardiovascular Benefits: A Consistent Long-Term Signal

Perhaps the most compelling long-term safety data for GLP-1s comes from their impact on cardiovascular outcomes. The SELECT trial, a five-year study involving 17,604 participants with overweight or obesity and established cardiovascular disease but without diabetes, demonstrated that once-weekly semaglutide 2.4 mg significantly reduced the risk of major adverse cardiovascular events (MACE). Over a median follow-up of 39.8 months, semaglutide reduced the composite endpoint of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke by 20% compared to placebo (HR 0.80; 95% CI, 0.72 to 0.90; P<0.001) [2]. This sustained cardiovascular benefit over several years represents a critical aspect of their long-term safety and value proposition.

Similar cardiovascular protective effects have been observed in trials like LEADER (liraglutide) and SUSTAIN-6 (semaglutide in type 2 diabetes), further solidifying this benefit across the GLP-1 class when used long-term in at-risk populations.

Understanding Rare but Serious Long-Term Risks

While the overall safety profile of GLP-1s remains favorable, extended use has allowed for the identification and closer examination of rare, potentially serious adverse events.

Pancreatitis and Gallbladder Disease

Acute pancreatitis and gallbladder-related events (cholelithiasis and cholecystitis) have been identified as potential risks with GLP-1 agonists. While these events are rare, their incidence has been observed to be slightly higher in GLP-1 users compared to placebo in some long-term studies. For example, in the SELECT trial, the incidence of gallstones was 2.8% in the semaglutide group versus 2.3% in the placebo group [2]. These events typically occur within the first few years of treatment, but the risk persists with sustained use. Patients experiencing severe abdominal pain should seek immediate medical attention.

Thyroid C-Cell Tumors (Medullary Thyroid Carcinoma)

A persistent concern, initially identified in rodent studies, has been the potential for GLP-1s to cause thyroid C-cell tumors. However, human data from more than 15 years, including large-scale observational databases and ongoing registries, have consistently shown no clear signal for increased thyroid cancer risk above background rates in treated populations (Healthoper, 2025) [3]. This long-term human evidence significantly mitigates the concern raised by the preclinical animal models. The FDA, in its reviews, has noted this discrepancy, maintaining that the risk to humans is uncertain but not clearly demonstrated.

Retinopathy and Ocular Events

The recent finding regarding NAION from the Danish cohort study (JCI, 2024) warrants attention [1]. NAION is a condition that causes sudden, painless vision loss due to insufficient blood supply to the optic nerve. The observed doubling of risk with once-weekly semaglutide in this large, real-world population of type 2 diabetes patients, while statistically significant, means the absolute increase in risk remains low due to the rarity of the condition. For example, if the baseline five-year risk is 0.1%, doubling it means it rises to 0.2%. This specific finding highlights the importance of continuous post-market surveillance and real-world data analysis, especially for medications used by millions globally.

Suicidal Ideation and Behavior

Early reports and post-marketing surveillance prompted a review of potential links between GLP-1 medications and suicidal thoughts or actions. In January 2024, after reviewing reports, the U.S. Food and Drug Administration (FDA) concluded that “no causal relationship has been established” between GLP-1 receptor agonists and suicidal thoughts or actions [4]. This determination, based on extensive analysis, provides significant reassurance regarding this specific, serious concern for long-term users.

Common Adverse Events: Persistence and Management

While most common side effects of GLP-1s are gastrointestinal (nausea, vomiting, diarrhea, constipation) and tend to be transient, often improving over the first few weeks or months of treatment, some individuals may experience persistent symptoms with long-term use. These are typically managed through dose titration, dietary adjustments, and supportive care. Unlike rare serious events, these common side effects are well-documented in studies extending several years, such as the STEP trials, and are generally not considered to pose a significant long-term health risk, though they can impact quality of life if unmanaged.

The Rise of Oral GLP-1s: Long-Term Safety in a New Formulation

The landscape of GLP-1 therapy is evolving with the introduction of oral formulations. The FDA approved oral semaglutide (Rybelsus) for type 2 diabetes in 2019, and in late 2025, approved oral semaglutide (Wegovy) 25 mg as the first GLP-1 pill specifically for chronic weight management, with a planned launch in early January 2026 [5]. This approval was supported by Phase III OASIS 4 data, which demonstrated substantial weight loss and “favorable safety,” as highlighted in the approval summaries.

“The FDA approval of oral semaglutide marks the first GLP-1 pill for chronic weight management, supported by Phase III OASIS 4 data demonstrating substantial weight loss, favorable safety, and improvements in cardiometabolic risk factors,” noted one publication summarizing the approval [5].

While the pharmacokinetic profile differs, the active ingredient, semaglutide, is the same as in injectable forms. Long-term safety data for oral semaglutide for weight loss will continue to accrue post-launch, but current understanding suggests a safety profile largely consistent with its injectable counterpart, with gastrointestinal side effects remaining prominent.

Long-Term Safety Profile Overview

To summarize the key long-term safety considerations for GLP-1 medications, the following table provides a snapshot of current evidence:

Adverse Event Category	Long-Term Data (5+ Years) Status	Key Findings & Evidence
Cardiovascular Events	Significantly Improved	Sustained 20% reduction in MACE (cardiovascular death, MI, stroke) vs. placebo (SELECT trial) [2].
Acute Pancreatitis	Small Increased Risk	Rare, but consistently observed slightly higher rates than placebo in long-term trials.
Gallbladder Disease	Small Increased Risk	Higher incidence of gallstones/cholecystitis (e.g., 2.8% vs. 2.3% in SELECT trial) [2].
Thyroid C-Cell Tumors	No Causal Link in Humans	No clear signal for increased risk above background rates in 15+ years of human data [3].
Nonarteritic Anterior Ischemic Optic Neuropathy (NAION)	Observed Increased Risk (Semaglutide)	Doubled five-year risk observed in large Danish cohort of T2D patients (JCI, 2024) [1]. Absolute risk remains low.
Suicidal Ideation/Behavior	No Causal Link Established	FDA review concluded no causal relationship after extensive analysis (Jan 2024) [4].
Gastrointestinal Issues	Common, Often Transient	Nausea, vomiting, diarrhea, constipation common, often improve over time, but can persist in some individuals. Generally manageable.

Conclusion: Weighing Benefits Against Risks

The extensive and growing body of evidence, including data spanning five years or more, largely supports a favorable long-term safety profile for GLP-1 medications. The sustained cardiovascular benefits, in particular, mark a significant advantage for millions at risk. While common gastrointestinal side effects are a reality, they are generally manageable. The ongoing surveillance of rare events, such as the observed increased risk of NAION, underscores the necessity of continuous post-market research and real-world data analysis to refine our understanding of these powerful therapies. For most patients, the substantial benefits in weight management, glycemic control, and cardiovascular protection continue to outweigh the identified long-term risks.

Sources

Fung, K. W., et al. (2024). The science of safety: adverse effects of GLP-1 receptor agonists as glucose-lowering and obesity medications. Journal of Clinical Investigation. 2024;10(1):97. https://www.jci.org/articles/view/194740
Lincoff, A. M., et al. (2023). Semaglutide and Cardiovascular Outcomes in Patients with Overweight or Obesity. New England Journal of Medicine, 389(24), 2221-2232. https://www.nejm.org/doi/full/10.1056/NEJMoa2307527
Healthoper Editorial Team. (2025). Long Term Side Effects of GLP-1 | What the Latest Evidence Shows in 2025. Healthoper. https://healthoper.com/long-term-side-effects-of-glp-1/
Reuters. (2024, January 24). US FDA review finds no causal link between GLP-1 drugs, suicidal thoughts. Reuters. https://www.reuters.com/business/healthcare-pharmaceuticals/us-fda-review-finds-no-causal-link-between-glp-1-drugs-suicidal-thoughts-2024-01-24/
AJMC. (2025, December 10). FDA Approves Oral Semaglutide as First GLP-1 Pill for Weight Loss. AJMC. [https://www.ajmc.com/view/fda-approves-oral-semaglutide-as-first-glp-1-pill-for-weight-loss](https://www.ajmc

GLP-1s: What 5+ Year Safety Data Reveals About Sustained Use