In Italy, the use of innovative drugs for diabetes management has been steadily increasing, with a significant proportion of patients intensifying treatment regimen by adding oral medications more often than injectable ones. However, despite the advances in therapeutic options, a considerable number of patients continue to fail to reach their therapeutic goals. This paradox suggests that although there are an ever-widening range of innovative medicines, addressing the multifaceted nature of diabetes remains a complex challenge. The unhalted occurrence of complications highlights the need for continued exploration and improvement of diabetes management. This includes strategies that reinforce the importance of tailoring treatment plans to individual patient needs, exploring novel therapeutic approaches, and enhancing patient education and engagement.

Among the latest innovative oral therapeutic option, results from clinical trials indicate that oral semaglutide is the most effective second-line oral therapy [1, 2].

Oral semaglutide is the first innovative orally delivered glucagon-like peptide 1 receptor agonist (GLP-1 RA) developed for oral administration for the treatment of type 2 diabetes (T2D) [3]. Co-formulation of semaglutide with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl]amino)caprylate (SNAC) increases its bioavailability, promoting absorption across the gastric epithelium. SNAC works by increasing the local pH in the stomach and thereby protecting the drug from proteolytic degradation by enzymes and stomach acid and facilitating its absorption in the intestinal tract via the transcellular route [4]. Thanks to its mechanism of action, by removing the injectable barrier, this formulation represents the first oral peptidic hormone-based therapy for the management of T2D. Trials and real-world data have established oral semaglutide as an extremely effective option for glycated hemoglobin (HbA1c) reduction across various durations of disease, backgrounds of therapy, and comorbidities [5, 6].

Semaglutide aids the management of hyperglycemia by stimulating insulin secretion in beta cells while diminishing glucagon secretion from alpha cells. Moreover, the medication slows the emptying of the stomach, fostering a feeling of fullness and aiding in weight loss [7, 8]. Semaglutide diminishes both body weight and fat mass by decreasing overall energy intake, with a general reduction in appetite. Moreover, it influences dietary choices by decreasing the inclination towards high-fat foods. Furthermore, semaglutide exhibits positive effects on lipid levels, contributes to lower systolic blood pressure, and mitigates diabetes-associated chronic inflammation [5, 9].

The current recommendations advise using oral semaglutide to treat people with T2D with inadequate metabolic control, along with diet and exercise. It can be used as an add-on therapy to other glucose-lowering agents or as monotherapy if metformin is not tolerated or contraindicated [10, 11].

In this manuscript, we describe the perspective of an Italian expert panel that addressed the potential challenges arising during the use of oral semaglutide in the free-living conditions of routine clinical care. We briefly review the available data on efficacy and effectiveness of oral semaglutide from randomized controlled trials (RCTs) and real-world studies, along with factors that determine tolerability and persistence on treatment. We critically address the debate over a fixed versus a flexible dosing schedule, providing anecdotical clues from a small case series and a real-world database. Case reports were shared by some of the authors and discussed during the expert panel and reported in Supplementary Material. We finally provide a set of recommendations for clinicians to consider when prescribing oral semaglutide and during the process of patient monitoring.

Ethical review by an ethics committee was not applicable as this article is based on previously conducted studies and direct observations from real-world clinical practice. Case reports derive from authors’ daily practice on clinical use of oral semaglutide. Written informed consent was obtained from each patient for the publication of the data reported in the case reports.

Overview of Evidence from Clinical Trials on Efficacy of Oral Semaglutide

The efficacy of oral semaglutide was widely assessed in the PIONEER (Peptide InnOvatioN for Early diabEtes tReatment) program of 10 RCTs, which included more than 9500 patients and examined the use of oral semaglutide in different phases of T2D, on various background therapies. Oral semaglutide showed significant improvements in glycemic control and weight reduction versus various comparators.

As for the comparison of oral semaglutide with other oral agents, in the PIONEER 2 open-label trial, oral semaglutide (14 mg once daily) was evaluated against the sodium-glucose co-transporter 2 inhibitor (SGLT2i) empagliflozin (25 mg once daily) for 52 weeks in 822 patients with T2D uncontrolled on metformin with a mean HbA1c level of 8.1%. Semaglutide was superior to empagliflozin in reducing HbA1c (− 1.3% vs. − 0.8%; p < 0.001) and body weight (− 4.7 kg vs. − 3.8 kg; p = 0.01) after 52 weeks of treatment. Moreover, a higher number of patients reached the composite endpoint (HbA1c < 7% without severe or symptomatic hypoglycemia and no weight gain) with oral semaglutide compared to empagliflozin. The likelihood of achieving this endpoint was significantly greater with oral semaglutide (OR 2.03, 95% CI 1.50–2.74) [12].

PIONEER 3 was a randomized double-blind trial that compared the efficacy of oral semaglutide vs. sitagliptin in patients with T2D not controlled on metformin with or without sulfonylurea. Among 1864 randomized patients, over 26 weeks, mean HbA1c changes from baseline were estimated as − 0.6%, − 1.0%, and − 1.3% for semaglutide at doses of 3, 7, and 14 mg/day, respectively, and − 0.8% for sitagliptin. Both 7 and 14 mg/day doses achieved statistically significant greater reduction in HbA1c when compared to sitagliptin (− 0.3% [95% CI − 0.4% to − 0.1%] and − 0.5% [95% CI − 0.6% to − 0.4%], respectively). Also, mean body weight changes from baseline were estimated as − 1.2, − 2.2, and − 3.1 kg for semaglutide 3, 7, and 14 mg/day, respectively, and − 0.6 kg for sitagliptin. A statistically significant greater reduction in body weight compared to sitagliptin was obtained (− 1.6 kg [95% CI − 2.0 to − 1.1 kg] and − 2.5 kg [95% CI − 3.0 to − 2.0 kg], for semaglutide 7 and 14 mg/day respectively). Furthermore, in both the 7 mg/day and 14 mg/day semaglutide groups, a significantly higher percentage of patients attained the composite outcome of achieving HbA1c levels below 7.0%, without experiencing hypoglycemia or weight gain, compared to the sitagliptin group (estimated treatment difference [ETD] 14%, 95% CI 8–14 for semaglutide 7 mg/day; ETD 26%, 95% CI 20–32 for semaglutide 14 mg/day) [13].

In the PIONEER 7 study, a 52-week, open-label, randomized trial, 504 patients with T2D uncontrolled with one or two oral glucose-lowering drugs were allocated to receive either oral semaglutide with flexible dose adjustments (3, 7, or 14 mg once daily) or sitagliptin 100 mg once daily. Oral semaglutide with flexible dose adjustment provided superior glycemic control and weight loss compared with sitagliptin 100 mg. Overall, 58% of patients treated with semaglutide reached the HbA1c target of < 7% vs. 25% of participants with sitagliptin. The odds of achieving HbA1c < 7% were higher with oral semaglutide than with sitagliptin (OR 4.40, 95% CI 2.89–6.70) [14]. The efficacy in HbA1c and weight reduction persisted over time as demonstrated in the extension phase of the PIONEER 7, representing the longest treatment period with oral semaglutide to date, spanning 2 years. A continuous treatment with oral semaglutide with flexible dose adjustments allowed a sustained improvement in glycemic control (− 1.5% at week 52 and − 1.3% at week 104) and resulted in further weight loss (− 2.8 kg at week 52 and − 3.7 kg at week 104). The switch from sitagliptin to oral semaglutide yielded HbA1c reductions with no need to add other glucose-lowering agents. This switch improved the likelihood of achieving an HbA1c target of < 7.0% (52.6% vs. 28.6% in the semaglutide and sitagliptin group, respectively; p = 0.0011) and may provide additional benefits on body weight. Finally, the “satisfaction with treatment” item of the DTSQ (Diabetes Treatment Satisfaction Questionnaire) was significantly improved with oral semaglutide versus sitagliptin (ETD 0.34, 95% CI 0.02–0.65) [15].

More than two-thirds of treated patients in the PIONEER program achieved the glycemic target of HbA1c < 7% [1, 5, 12,13,14, 16,17,18]. Subgroup analyses of PIONEER trials also highlighted that patients with higher baseline HbA1c achieved greater HbA1c reductions, irrespective of baseline body mass index (BMI) or background medication [19, 20].

Since the prevention of atherosclerotic cardiovascular disease (ASCVD) requires addressing its risk factors, early and effective intervention on modifiable risk factors can prevent or slow the progression of ASCVD. Oral semaglutide has demonstrated capacity to tackle cardiovascular risk biomarkers, encompassing improvements in blood pressure, lipid profiles, abdominal adiposity, ectopic fat deposition, and inflammation [12, 21].

The results of the PIONEER trial program have shown that oral semaglutide is the most effective medication for lowering blood glucose levels and body weight among the currently available oral agents for T2D [2].

These characteristics position oral semaglutide as an excellent option for initiating treatment in individuals with T2D after the failure of metformin or, as a monotherapy, when metformin cannot be used because of contraindications or intolerance. This underscores its potential for early intervention in such cases.

Standard Recommended Dosing Schedule

Prescribing information instructs taking oral semaglutide in the fasting state, followed by a post-dose fasting period of at least 30 min. This standardized recommendation is based on the pharmacokinetic properties of the drug and is designed to optimize its absorption through the gastric mucosa. Pre-dose fasting is required to protect the drugs from enzymatic degradation, while waiting less than 30 min to eat or drink after semaglutide dosing may decrease absorption due to dilution. Taking other oral medications within 30 min after semaglutide dosing may affect exposure to both semaglutide and the concomitantly administered medication. This may be particularly relevant for levothyroxine, which needs to be taken 30 min before breakfast itself. On the other side, the semaglutide exposure is not expected to be significantly modified by the pre-existence of upper gastrointestinal (GI) tract disease or symptoms [22]. Though GI side effects may be more common among patients with as compared to those without pre-existing upper GI tract disease, concomitant treatment with oral semaglutide and proton pump inhibitor (omeprazole) does not significantly modify semaglutide exposure [23].

A pharmacokinetic study performed among healthy subjects explored various dosing schedules [24] and found that the duration of pre-dose fasting is more important than the duration of post-dose fasting to ensure appropriate semaglutide exposure. Despite these data support dosing of oral semaglutide in accordance with prescribing information in the fasting state, it remains unclear to what extent these data obtained in healthy individuals translate into clinical benefits for people with T2D.

Real-World Evidence on Use of Oral Semaglutide in Patients with T2D

Data on the use of oral semaglutide in real-world settings are limited and new evidence is emerging.

One of the most important pieces of evidence came from the IGNITE study. This was a retrospective, observational cohort study based on electronic health records. It included 782 patients prescribed oral semaglutide, with a mean age of 57.8 years and a mean HbA1c baseline level of 8.4%; 54.5% of patients were woman and 66.0% received their prescription from a primary care practitioner. The population in which semaglutide was initiated was predominantly overweight (mean BMI 36.2 ± 7.6 kg/m2), affected by other comorbidities, and treated with different treatment backgrounds. Results indicated that oral semaglutide is effective in improving glycemic; in particular, a mean reduction of 0.9% in HbA1c was observed in 6 months. However, a significant proportion of patients (37%) were administered only the 3-mg starting dose, underlining a therapeutic inertia and a large room for improvement when using therapeutic dosages [25].

In a single-center retrospective observational study conducted in 88 Japanese patients with T2D treated with oral semaglutide, the use of this agent was effective in reducing HbA1c regardless of age, sex, BMI, renal function, or diabetes duration. Individuals receiving oral semaglutide experienced a reduction in HbA1c by 1.2% and a weight loss of 1.4 kg, typically with an average dose slightly above 7 mg. The proportion of patients reaching HbA1c < 7% underwent a significant increase, rising from 14% at baseline to 48%. Other cardiometabolic parameters were also reduced, such as alanine aminotransferase (from 24 IU/L to 23 IU/L; p = 0.008), total cholesterol (from 177 mg/dl to 172 mg/dl; p = 0.009), triglycerides (from 146 mg/dl to 144 mg/dl; p = 0.028), and non-high-density lipoprotein (HDL) cholesterol (from 120 mg/dl to 115 mg/dl; p = 0.002) [26].

In a real-world Italian retrospective study, the effectiveness and tolerability of oral semaglutide were assessed in 129 patients with T2D in add-on to background agents (ADD-ON group) or after switching from other glucose-lowering agents (SWITCH group), demonstrating both to be effective and safe. Patients were on average 72 years old and had baseline HbA1c levels of 7.2%. Oral semaglutide led to a significant reduction in both HbA1c levels and body weight among patients with T2D, reaching the target HbA1c recommended level of < 7%. Overall, despite the high mean age and the low baseline HbA1c levels in the ADD-ON and in the SWITCH groups, oral semaglutide resulted in a median decrease in HbA1c levels of − 0.4% and − 0.3%, respectively. When looking in specific subgroups in the SWITCH group, according to the glucose-lowering agent used before oral semaglutide, there was a significant HbA1c reduction in subgroups switching from dipeptidyl peptidase 4 (DPP4) inhibitors (p < 0.001) or SGLT2i (p = 0.01). As for BMI, there was a significantly greater reduction observed in the ADD-ON group (− 1.2 kg/m2) compared to the SWITCH group (− 0.7 kg/m2) [27].

The effectiveness of oral semaglutide was also observed in another retrospective study, using claims data. A total of 744 adult patients with at least one pharmacy claim for oral semaglutide and with a diagnosis code for T2D were selected. The study demonstrated an average HbA1c reduction of 0.8%; furthermore, patients with a higher starting HbA1c levels (HbA1c ≥ 9%) experienced greater HbA1c reductions than those with HbA1c < 9% (− 2.0% vs. − 0.4%; p < 0.001) within 6 months following initiation with oral semaglutide. Furthermore, patients that were persistent users of oral semaglutide (> 90 days) reached lower HbA1c levels. In this study, however, one-third of the involved population remained with the starting dose of 3 mg despite the recommendation reported in the summary of product characteristics and only 16% reached the maintenance dose of 14 mg [28].

Additionally, improvements in cardiovascular risk factors were observed. In particular, a noteworthy reduction of 6.2 mmHg in systolic blood pressure was observed after a 6-month period. There was also a significant decrease in low-density lipoprotein (LDL)-cholesterol levels after 6 months, and non-HDL-cholesterol levels showed a tendency to decrease over the same period. Furthermore, the urinary albumin to creatinine ratio (UACR) demonstrated a tendency to decrease after both 3 and 6 months. The decline in cardiovascular biomarkers plays a role in mitigating cardiovascular and renal events [29].

In a recent cross-sectional survey conducted among Italian endocrinologists and diabetologists, known as the PIONEERING EXPERIENCE study, there was strong support for the early implementation of oral semaglutide as a therapeutic approach to overcome therapeutic inertia and improve management patients with T2D. Patients identified as candidates for initiating therapy with oral semaglutide were aged 56–71 years, had a relatively short disease duration (42% of patients had < 5 years of diabetes duration) despite a high-to-very high cardiovascular risk (61% high cardiovascular [CV] risk; 34% very high risk), and had HbA1c levels ranging from 7.2% to 8.4%. When physicians were requested to indicate the reason behind initiating oral semaglutide for each patient, the most prevalent reasons were enhancing metabolic control (80.3%), reducing cardiovascular risk (82.9%), weight management (63.9%), lowering microvascular risk (29.3%), and mitigating the risk of hypoglycemia (14.5%). The adoption of oral semaglutide resulted in a significant reduction in the use of sulfonylureas, pioglitazone, DPP4 inhibitors, and insulin, with no substantial change in the utilization of SGLT2 inhibitors. In addition, assessment of the projected glycemic effectiveness associated with oral semaglutide based on trial data indicated that 62% of patients would achieve an HbA1c level below 7%, and 43% would achieve their optimal individualized HbA1c target. The achievement of HbA1c < 7% is much more often achieved with oral semaglutide (67%) than with empagliflozin (25%) or sitagliptin (31%) [30].

Recently, the GLIMPLES Italian multicenter retrospective study investigated the effectiveness on HbA1c levels and body weight of oral semaglutide in 166 patients with T2D who initiated the medication and were followed for 18 months. This study represents the longest real-world investigation of oral semaglutide to date. Over the observation period, a reduction of − 0.9% in HbA1c was observed, and 42.1% of patients with a baseline HbA1c above 7.0% achieved a value below 7.0%. Additionally, there was a significant decrease in body weight, with an estimated change of − 3.4 kg. At 6 months post-treatment initiation, systolic blood pressure decreased significantly by 6.2 mmHg (95% CI − 10.7 to − 1.8 mmHg) and total cholesterol significantly decreased by 14.4 mg/dl (95% CI − 21.0 to − 7.7 mg/dl) [6]. New data from matched cohorts of the GLIMPLES study illustrate that, in the specific population of early individuals with T2D who initiated oral semaglutide, the use or both formulations of semaglutide (injectable or oral) can exert similar effects on the improvement in HbA1c and body weight, despite greater persistence on injectable than on oral semaglutide [31].

Finally, results of the PIONEER REAL studies are becoming available for several countries [32,33,34]. This was a series of prospective observational studies of 34–44 weeks duration, performed with the aim of understanding clinical outcomes with oral semaglutide in adults with T2D. In the various studies, HbA1c declined by 0.9–1.2% and body weight declined by 4–6 kg, and around half of participants achieved an HbA1c levels < 7.0%.

Safety Profile of Oral Semaglutide

As a result of the stimulation of GLP-1 receptors in the GI tract, semaglutide may directly influence GI motility, secretion, and sensitivity, contributing to GI symptoms such as nausea, vomiting, diarrhea or constipation, and abdominal discomfort. It also affects delaying gastric emptying, slowing the absorption of nutrients, but also causing feelings of fullness, bloating, and nausea [35, 36].

GI side effects typically range from mild to moderate in severity, often occur temporarily, commonly beginning during the period of initiation and dose escalation and typically resolving after reaching the maintenance dose. The safety profile of oral semaglutide across the PIONEER clinical trials was consistent with the known profile of the GLP-1 RA class. Interruption of therapy as a result of GI tolerability issues was reported in 2–12% of patients in oral semaglutide groups [1, 9, 12,13,14, 16,17,18].

The most frequently reported adverse events are GI manifestations such as nausea (15%), diarrhea (10%), and vomiting (7%) [2, 12,13,14]. Data on side effects from observational studies are more heterogeneous. The diverse nature of real-world settings, patient populations, and treatment protocols in this type of study can contribute to a more varied and less standardized collection of side effect data. This variability may stem from differences in patient demographics, comorbidities, treatment adherence, and other factors, making the findings less uniform or consistent compared to the more controlled conditions of clinical trials.

In the Italian study by Candido et al. GI adverse events, nausea, and diarrhea were reported by 6.2% of patients, while hypoglycemic episodes occurred in 3% of patients. Discontinuation of oral semaglutide occurred in 10% of patients over 6 months; among these patients, almost 80% were due to an adverse event [27].

Persistence and Adherence to Therapy as Barriers to Optimal Care

The occurrence of GI side effects poses a potential challenge in garnering widespread patient acceptance of the medication and consequently it may result in suboptimal therapeutic adherence. This issue can limit the effectiveness of prescribed treatments, resulting in unmet treatment goals. In individuals with T2D, poor adherence and persistence represent barriers to achieving optimal care [37]. Furthermore, the onset of GI complications could limit or interfere with the recommended dose escalation up to 14 mg, which represents the dosage for which the maximum effectiveness of the product is appreciated.

In the diabetes pharmacotherapy area, a systematic review assessed that only 56.2% of patients with T2D continued their treatments at 1 year post-initiation [38]. Among the primary reasons reported for low adherence and persistence, the severity of adverse events was most common [37].

Overcoming these barriers becomes mandatory for diabetologists and healthcare providers. Efforts to address and manage GI side effects in the use of oral semaglutide, whether through patient education, proactive symptom management, or considering alternative strategies, are essential in promoting better patient tolerance and adherence to the prescribed medication regimen. By actively addressing and mitigating these challenges, healthcare professionals involved in diabetes care play a crucial role in ensuring that patients receive the full therapeutic benefits of the prescribed medication, contributing to more effective diabetes management and improved overall patient outcomes.

Need for Comprehensive Practical Guidance and Expert Insights

From clinical trials and observational data, oral semaglutide has proven to be an effective therapeutic approach to the management of patients with T2D. However, physicians face various practical questions that cannot be answered by guidelines or recently published clinical trials or observational studies results.

This article aims to provide practical guidance on the use of oral semaglutide to optimize therapeutic effects, while minimizing possible GI effects. A group of experts discuss and generate insights into these topics to try to fill the gaps that have been found in the use of the agent in conditions of normal clinical practice. It is a commentary based on the expert opinion and clinical experience of the authors. It does not involve new studies with human participants performed by any of the authors.

Topics included the effectiveness of oral semaglutide in clinical practice, the positioning of oral semaglutide to optimize the treatment benefits, critical issues encountered, the role of patient communication and information in the importance of dose escalation and management of adverse events.