In December of 2017, the U.S. Food and Drug Administration (FDA) approved semaglutide injection to be marketed for glycemic control in adult patients with type 2 diabetes. In September of 2019, the more convenient oral semaglutide was approved for marketing to combine diet and exercise to improve glycemic control in patients with type 2 diabetes. Because of its excellent curative effect, it is recommended by many diabetes prevention and treatment guidelines [13,14,15]. Semaglutide is an oral glucagon-like peptide (GLP-1) receptor protein therapeutic drug [16]. Based on PIONEER 1–10 global clinical trials [17,18,19,20], it has been confirmed that it can significantly improve blood glucose control and weight loss in patients with type 2 diabetes, and can also improve cardiovascular outcomes, which has attracted much attention at present.

How can oral preparations based on tablets achieve the same efficiency and specificity as therapeutic peptides for injection? Studies have found that the absorption of oral semaglutide, a glucagon-like peptide-1 analog, is co formulated in tablets with the absorption enhancer n-[8-(2-hydroxybenzoyl) sodium aminooctanoate] (SNAC) [21]. Therefore, although oral semaglutide has different absorption characteristics, once the drug is absorbed, the pharmacokinetic properties and effects of semaglutide are similar regardless of the route of administration. Pharmacokinetic analysis showed that due to the long half-life of oral semaglutide, once-daily administration can achieve a stable steady-state concentration [22]. Upper gastrointestinal disease and kidney and liver damage did not affect the pharmacokinetic profile.

By conducting a meticulous examination of the FAERS database spanning from Q3 2019 to Q3 2023, this inquiry has methodically appraised the adverse reactions associated with oral semaglutide. In the course of this analysis, the research not only corroborated extant safety data but also unearthed novel potential hazards. Such revelations furnish a more expansive and precise data foundation for clinical application and the formulation of public health policies. An elaborate discourse on the findings of this research ensues below.

Our analysis discerned a year-on-year escalation in the frequency of adverse event reports for oral semaglutide, a trend that appears to be in lockstep with the uptick in the drug’s cumulative user base. Notably, a substantial fraction of the collected data is devoid of precise age-specific details, thereby impeding a thorough understanding of the prevalence of adverse events across various age segments. Future research endeavors should aim to harness accurate age-related data to thoroughly investigate the differential responses to the drug among distinct age groups. It is also significant to highlight that a majority of the adverse reaction reports, accounting for 41.12%, were furnished by consumers rather than medical professionals, which may have implications for the data’s reliability and scope.

This may indicate that patients are more inclined to report adverse reactions directly after the use of oral semaglutide or reflect deficiencies reported by medical professionals. Since most of the reports came from the United States (84.45%), this can also reflect the reporting trends of specific regions or cultures. This requires further investigation to confirm potential regional or cultural biases. Most reports do not provide the occurrence time of adverse events after medication. Due to the indications approved by FDA, oral semaglutide is mainly used for type 2 diabetes (27.63%), and a few are used for weight control and weight decreased (both less than 1%).

GLP-1RAs drugs can delay gastric emptying and inhibit appetite, so the most common adverse events are gastrointestinal adverse events [23], including nausea, vomiting diarrhea and constipation. Studies have shown that the severity of such adverse events of oral semaglutide is mostly mild to moderate [24, 25], which also reflects the consistency in our study.

Although the clinical trial clearly reported that semaglutide tablets have the risk of acute pancreatitis and pancreatic cancer [24, 26], another study [27] did not observe clear evidence of pancreatitis risk. A systematic review also showed that semaglutide tablets do not increase the risk of pancreatitis [28, 29]. The bias in these conclusions may be due to the limited sample size and the lack of updated real-world evidence. However, our post-marketing pharmacovigilance analysis based on big data showed that there was a strong correlation between semaglutide exposure and the occurrence of pancreatitis and pancreatic cancer. Pancreatitis (n = 117, ROR 23.12, PRR 22.64, IC 4.49, EBGM 22.49) had high frequency and signal intensity; pancreatic cancer (n = 3, ROR 34.16, PRR 34.14, IC 5.08, EBGM 33.80) had high signal intensity, although the frequency of adverse reactions was not high. This also further confirms the results of clinical trials. Moreover, in hepatobiliary disorders, we observe that acute cholecystitis (n = 18, ROR 50.41, PRR 50.24, IC 5.63, EBGM 49.69) and bile duct stones (gallstones) (n = 6, ROR 25.33, PRR 25.31, IC 4.65, EBGM 25.12) also present strong signals that warrant our vigilance in routine clinical practice. In conclusion, as more reports are submitted, the safety signal spectrum of semaglutide tablets may change over time.

The study showed that the total number of hypoglycemic episodes of oral semaglutide, subcutaneous semaglutide, and placebo was low and similar [16]. A systematic review and meta-analysis of randomized trials also suggested that there was a risk of key safety outcomes (severe hypoglycemia, retinopathy, or pancreatic adverse reactions) with GLP-1RAs, but there was no increase [30]. At the PT level, our study also found that the pancreatitis, diabetic retinopathy, and blood glucose decrease mentioned in the manual all showed strong signals. This may lead to retinopathy progression on the basis of baseline retinopathy status. Particularly in metabolism and nutrition disorders, both ketosis (ROR 46.87, PRR 46.84, IC 5.53, EBGM 46.18) and hyperglycemic hyperosmolar nonketotic syndrome (ROR 22.43, PRR 22.42, IC 4.48, EBGM 22.27) show strong signals, indicating a high potential risk of diabetic ketoacidosis. Due to the risks of these adverse reactions, close monitoring is required during administration.

The manual warns that the personal or family history of patients with medullary thyroid cancer is prohibited. Our study suggests that semaglutide tablets do affect the thyroid system, such as the strongest signal of adverse reactions of thyroid cysts (ROR 70.04, PRR 70.00, IC 6.1, EBGM 68.55). In addition, although ketosis and adenocarcinoma pancreas are rare, they have strong signal intensity and deserve special attention.

Patients with type 2 diabetes mellitus are prone to developing complications involving impaired renal function. Renal dysfunction complicates medication management in these patients. Patients with T2DM with CKD are affected by renal function status, and there are certain limitations in drug selection, which increases the difficulty of treatment in clinical practice. Semaglutide tablets are the first oral GLP-1RAs to fully confirm its efficacy and safety in clinical studies. Studies have shown that different degrees of impaired renal function have no significant impact on its pharmacokinetic characteristics, and there is no need to adjust the dose for patients with T2DM with mild, moderate, and severe renal dysfunction [31]. Another study showed that GLP-1RAs reduced the composite renal outcome (including the occurrence of macroalbuminuria, doubling of serum creatinine, and deterioration of renal function based on EGFR changes) by 21% (HR 0.79 [95% CI 0.73–0.87]; p < 0.0001) [30]. In this study, there was only renal pain on the PT level, indicating that the renal safety risk of oral semaglutide was not high, but there might be renal benefit.

Oral semaglutide has been confirmed to have a clear cardiovascular benefit [32]. Our study has not seen reports of major adverse cardiovascular events (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). Furthermore, according to the SOC report on cardiac disorders, n = 80, ROR 0.71 (0.57, 0.88), PRR 0.71 (0.57, 0.88), IC – 0.49 ( – 0.8), EBGM 0.71 (0.59), all four algorithms indicate a low signal for adverse reactions, confirming its cardiovascular safety and effectiveness.

At the same time, the related adverse reactions and allergic reactions caused by subcutaneous injection have not been reported in this study, which is also the advantage of the oral dosage form.

This study also found adverse events that were not mentioned in the drug instructions, such as acute cholecystitis, nerve palsy, vertigo location, etc. This indicates the value of quantitative signal detection technology in the monitoring of adverse drug events, which can provide potential risk information, and is worthy of further attention and investigation.

In conclusion, oral semaglutide does have multi-system adverse reactions with varying severity. These adverse reactions should be monitored when using oral semaglutide, and medical professionals should be immediately consulted if there are any symptoms.

Although the study in question has provided reliable empirical evidence for the safety assessment of oral semaglutide from several perspectives, it is not without certain limitations. Firstly, the main limitation is the reporting of adverse events, which often relies on consumer reporting and may therefore compromise objectivity. Secondly, there are limited data available to adjust for factors such as age, BMI, HbA1c, and comorbidities, or to provide clinical context for the findings. This also limits the ability to understand the exact adverse event observed. Furthermore, the paucity of information accessible via adverse event reporting systems is insufficient to tackle pivotal clinical inquiries but serves merely as a directional tool for specialized clinical research endeavors. To cultivate an encompassing and precise comprehension, forthcoming studies are advised to integrate stringent prospective methodologies amalgamated with clinical experiments and epidemiological scrutiny to enhance the precision in evaluating safety hazards linked with oral semaglutide consumption.