Optimizing Therapeutic Outcomes With Oral Semaglutide: A Patient-Centered Approach

GLP-1 receptor agonists address multiple pathways involved in the pathophysiology of type 2 diabetes. These agents promote insulin secretion and suppress the release of glucagon in a glucose-dependent manner, ultimately helping to normalize blood glucose levels (1,12). GLP-1 receptor agonists also have beneficial effects on body weight, which are mediated, in part, by increased satiety and slower gastric emptying (12,14–16). As a result of their glucose-dependent mechanism of action, GLP-1 receptor agonists convey a very low risk of hypoglycemia (2,17). In addition, some GLP-1 receptor agonists (dulaglutide, liraglutide, and subcutaneous semaglutide) have demonstrated superior CV outcomes compared with placebo in patients with a high CV risk or history of cardiovascular disease (CVD) (18–20). As a result, these agents have an FDA indication for reducing the risk of major adverse cardiovascular events (MACE) in adults with type 2 diabetes and established CVD (21–23); dulaglutide is also indicated in patients with type 2 diabetes who have multiple CV risk factors (22). To date, the only other class of type 2 diabetes therapy with an indication for reducing CV risk is the sodium–glucose cotransporter 2 (SGLT2) inhibitor class (8,24,25).

GLP-1 receptor agonists or SGLT2 inhibitors demonstrating CV benefit are recommended by the ADA as the preferred second choice after metformin for patients in whom atherosclerotic cardiovascular disease (ASCVD) predominates, independent of baseline A1C levels or individualized A1C targets (8). Among patients with chronic kidney disease (CKD) or those with or at high risk of heart failure (HF), GLP-1 receptor agonists with proven CVD benefits are recommended if SGLT2 inhibitors are contraindicated or not tolerated (8). In addition, in patients without established ASCVD, CKD, or HF, GLP-1 receptor agonists are currently one of the preferred second-line therapy options after metformin when there is a compelling need to minimize hypoglycemia or manage body weight (8). Furthermore, AACE/ACE guidelines recommend the use of GLP-1 receptor agonists as second-line therapy after metformin regardless of CV risk, with GLP-1 receptor agonists or SGLT2 inhibitors also indicated as preferred treatment options in patients with established or high risk for ASCVD or CKD, independent of glycemic control (9).

Seven GLP-1 receptor agonists are currently available in the United States for the treatment of adults with type 2 diabetes (13,21–23,26–28) (Table 1). Despite sharing an underlying mechanism of action, these agents differ in a number of ways, including duration of action, dosing conditions, injection device, and effects on glycemic control (12,29,30). A key practical difference among the agents is the route and frequency of administration: injectable GLP-1 receptor agonists are administered subcutaneously either twice daily, once daily, or once weekly, whereas oral semaglutide is administered in tablet form once daily (13,21–23,26–28).

Despite their proven efficacy for glycemic control and weight loss, GLP-1 receptor agonists are underutilized, which could be attributable to gastrointestinal (GI) side effects, their relatively high cost, and the requirement for injections (8,31–33). In addition, suboptimal adherence and persistence to antihyperglycemic medications, including GLP-1 receptor agonists, is a relatively common issue associated with clear medical and economic consequences (34–40).

Although significant advancements have been made to reduce dosing frequency and pain associated with injectable GLP-1 receptor agonists, barriers to the initiation of and adherence to GLP-1 receptor agonists still exist from the perspectives of both patients and the health care providers (HCPs). From patients’ perspective, there may be reluctance to administer injectable therapies, perhaps owing to concerns relating to self-administration of an injectable medication, pain, timing of dosage, convenience, and social acceptance (41–44). These concerns have been associated with delayed treatment initiation and/or low adherence (typically defined as taking <80% of doses) (36,41–45). In addition, a review evaluating important attributes driving patient preferences found that patients with type 2 diabetes generally prefer medications that are dosed less frequently, require minimal injection preparation, and are associated with improved glycemic control and fewer adverse events (46). HCPs’ reluctance to prescribe injectable therapies may result from various factors, including a belief that patients prefer oral therapy or will not adhere to injectable therapy, challenges in becoming familiar with the variety of dosing schedules and administration devices, and/or lack of time and resources to educate patients on how to administer and titrate these therapies (33,47–52). By helping to address some of these barriers, once-daily oral semaglutide may facilitate initiation of and adherence to treatment with a GLP-1 receptor agonist (53–55).

Oral semaglutide is a coformulation of semaglutide and an absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC), administered in tablet form (56,57). In general, peptide-based drugs such as GLP-1 receptor agonists have very low bioavailability when administered orally because of their extensive degradation in the stomach by proteolytic enzymes and poor absorption across the GI mucosa (57,58). The mode of action of SNAC involves a buffering effect that increases local pH, protecting semaglutide from proteolytic degradation and facilitating transcellular absorption of semaglutide across the gastric mucosa (56).

The efficacy and safety of oral semaglutide were evaluated in an extensive global phase 3a clinical trial program (Peptide InnOvatioN for Early diabEtes tReatment [PIONEER]) against several comparators across the continuum of type 2 diabetes care and different background treatments (59–64) and in patients with moderate renal impairment (65) (Table 2). A global CV outcomes trial was also performed in patients with high CV risk (66), and two additional studies that are not discussed further here investigated the efficacy and safety of oral semaglutide in people from Japan with type 2 diabetes (67,68).

A key component of DSMES is counseling people with type 2 diabetes as they initiate treatment with a new medication by informing them about their treatment options, how the medication works, administration instructions, and what to expect with regard to efficacy and potential side effects (6). An overview of key communication points for patients initiating treatment with oral semaglutide is shown in Figure 1.

Newly diagnosed patients or those no longer meeting individualized glycemic targets should be made aware of their treatment options so they can be involved in making informed decisions about how they could meet their treatment goals (6). From the outset, it is important to communicate to people with type 2 diabetes that, because of the progressive nature of the disease, treatment will change over time, and changes in therapy do not mean that the patient has failed (6). As the treatment landscape for type 2 diabetes has evolved substantially over recent years, HCPs and people with type 2 diabetes now have a large selection of second-line pharmacological therapies from which to choose for additional glycemic management after metformin; as a consequence, management plans can now be tailored to individual patients (8,31).

During discussions about treatment options, considerations such as lifestyle, medical history, comorbidities (e.g., renal impairment and high CV risk), cost/insurance coverage, drug interactions, and patient preferences should be taken into account alongside efficacy and safety (8). In particular, discussions about economic factors should be included and are important in determining the best medication for people with type 2 diabetes (5). As part of the shared decision-making process, it is necessary to discuss insurance coverage and out-of-pocket costs, especially in fixed-income situations or for people subject to the Medicare Part D “donut hole” coverage gap. Any patient assistance and pharmacy discount programs available also need to be included in this discussion (69).

When discussing the benefits of a medication, potential barriers to its proper use should also be taken into consideration (51,69). For example, people with type 2 diabetes who do not follow a consistent daily routine, perhaps because they have variable working hours, may find it more difficult to take a daily medication compared with a once-weekly injection, whereas others may find that a daily medication fits more conveniently into their routine. Either way, consistency in the use of medications is key for achieving optimal treatment outcomes (36,70).

Oral semaglutide should be administered with a sip of plain water (up to ∼4 fl oz/120 mL) in a fasted state upon waking, at least 30 minutes before the first food, beverage, or other oral medications of the day (Figure 1) (13). Taking oral semaglutide with food or other medications will decrease absorption of the drug and lessen its effectiveness; thus, it is important to closely adhere to these administration instructions (13).

Because many people with type 2 diabetes take several different medications for comorbidities, it is important to consider how administration of oral semaglutide might influence the exposure and efficacy of these other drugs. Indeed, oral semaglutide causes a delay in gastric emptying and has the potential to affect the absorption of other oral medications (13). Figure 2 lists common concomitant medications that may require special considerations for their use alongside oral semaglutide. Drug-drug interaction studies for oral semaglutide did not show any clinically relevant changes in exposure of other oral medications commonly used in people with type 2 diabetes, including omeprazole (71); lisinopril, warfarin, digoxin, and metformin (72); furosemide and rosuvastatin (73); and ethinylestradiol and levonorgestrel (74). Dose adjustments of these drugs are not recommended (13), and patients on any of these oral medications should be encouraged to closely follow the administration instructions for oral semaglutide. In addition, increased monitoring may be necessary in the case of concomitant medications that have a narrow window of effect (e.g., levothyroxine or warfarin) or that require clinical monitoring (13).

Any missed dose of oral semaglutide should be skipped for that day and the next dose taken on the following day in accordance with the above instructions (13). The long half-life of oral semaglutide (∼1 week) results in an overlap in exposure from consecutive doses when the drug is taken on a daily basis; as a consequence, the impact of a missed or incorrectly taken single dose on the effectiveness of oral semaglutide is minimal (75).

Although the administration instructions for oral semaglutide may appear to be more complex than for other oral antihyperglycemic medications, patients in the PIONEER 7 trial reported similar perceptions of convenience for oral semaglutide and the dipeptidyl peptidase-4 inhibitor sitagliptin, which has fewer dosing restrictions (60,76). Moreover, patients may be reassured to know that the administration instructions for oral semaglutide are not as stringent as those of oral bisphosphonates, which require patients to take the medication upon waking for the day with a full glass of water (6–8 fl oz) and to refrain from eating, drinking, taking other medications, or lying down for either 30 (alendronate and risedronate) or 60 (ibandronate) minutes thereafter (77–79).

To encourage adherence when initiating treatment with any new medication, it is important that patients are informed about what they can realistically expect from the treatment, particularly with regard to efficacy, possible side effects, and additional beneficial outcomes such as weight loss and reduced risk of complications associated with type 2 diabetes. Results from the PIONEER clinical trial program can be used to support discussions about the efficacy of oral semaglutide (Figure 1). Across the global PIONEER trials, after 26 weeks of treatment, patients treated with oral semaglutide achieved statistically significant improvements in glycemic control versus placebo (oral semaglutide 3, 7, and 14 mg) (59,61,64), empagliflozin 25 mg (oral semaglutide 14 mg) (62), and sitagliptin 100 mg (oral semaglutide 7 and 14 mg) (63), while being noninferior versus liraglutide 1.8 mg (oral semaglutide 14 mg) (61) (Table 2). Improvements in glycemic control were statistically significant at the end of the treatment period versus all comparators, including liraglutide 1.8 mg (60–64). Moreover, oral semaglutide 14 mg was shown to reduce A1C by ∼1–1.4 percentage points after 26 weeks of treatment in patients from across the spectrum of type 2 diabetes, ranging from those with early disease managed with diet and exercise, to those with more advanced disease requiring insulin therapy (59,61–65). Although further investigation is required, subgroup analyses of the PIONEER trial data demonstrate that there are similar reductions in A1C regardless of type 2 diabetes duration (80), and A1C reductions are greater with higher baseline A1C (81). It should be explained to patients that, because the effects of oral semaglutide are reported as averages, the clinical outcome could vary for individual patients depending on their unique factors.

Body weight reductions were significantly greater with oral semaglutide versus placebo (oral semaglutide 3, 7, and 14 mg) (59,61,64), sitagliptin 100 mg (oral semaglutide 3, 7, and 14 mg at 26 weeks in PIONEER 3; flexible dose adjustment of oral semaglutide in PIONEER 7) (60,63), and liraglutide 1.8 mg (oral semaglutide 14 mg) (61) (Table 2). Because reductions of 3.1–4.4 kg were reported after 26 weeks for patients treated with oral semaglutide 14 mg (59,61–65), patients should be made aware that this may be another positive outcome of treatment with this medication.

In the PIONEER program, patients treated with oral semaglutide generally perceived improvements in their health-related quality of life and had higher treatment satisfaction scores compared with placebo (64). In active-comparator trials, there were notable improvements in food craving control, social functioning, and general health with oral semaglutide compared with empagliflozin (62). Patient-reported outcomes were generally comparable between oral semaglutide and sitagliptin, although significant improvements in physical, psychosocial, and physical functioning scores were reported with oral semaglutide in PIONEER 3 (63), and reduced feelings of unacceptably high blood glucose levels were reported with a flexible dosing regimen of oral semaglutide in PIONEER 7 (60).

In the PIONEER program, oral semaglutide demonstrated a safety profile in line with that of subcutaneous semaglutide and other GLP-1 receptor agonists currently available (Table 2) (10,17,29,61). Patients initiating treatment with oral semaglutide should be informed about potential side effects that may occur, and, importantly, they should be provided with guidance on how to mitigate these side effects to encourage treatment adherence.

A population pharmacokinetic model has demonstrated consistent GI safety profiles for oral and subcutaneous semaglutide (82); therefore, the anticipated side effects, timeframe for resolution of these effects, and approach taken to mitigate them are similar for both formulations. The most common side effects of oral semaglutide are GI side effects such as nausea, diarrhea, vomiting, abdominal pain, reduced appetite, and constipation (13). In the PIONEER trials investigating the efficacy and safety of oral semaglutide in patients without renal impairment or high CV risk (PIONEER 1–4 and 8), 15.1–23.2% of patients experienced nausea, 5.1–15.1% experienced diarrhea, and 6.9–9.9% experienced vomiting when treated with oral semaglutide 14 mg. The majority of reports of nausea, vomiting, and/or diarrhea occurred during the dose escalation period, but <11% of patients prematurely discontinued oral semaglutide because of GI adverse events in any of these trials (13,59,61–64). Therefore, patients initiating treatment with oral semaglutide should be informed that these side effects are most common when they first start taking the medication (13) and that data from the PIONEER trials have shown them to be mild to moderate in severity and transient in nature (59–66).

To mitigate GI side effects, it is recommended to adopt a dose-titration strategy (83,84), starting treatment with 3 mg oral semaglutide (13). It is important that patients understand that this dose is intended for treatment initiation and is not effective for glycemic control; thus, they should not expect to see immediate benefits after initiating treatment (13). After 30 days, the dose of oral semaglutide should be increased to 7 mg once daily, and if additional glycemic control is needed after at least 30 days on the 7-mg dose, the dose can be increased to 14 mg (13). Other strategies for relieving GI side effects are suggested in Figure 1.

In the PIONEER program, there was generally a low rate of severe or blood glucose–confirmed symptomatic hypoglycemic events (<3.1 mmol/L [56 mg/dL]) in patients receiving oral semaglutide (59,61,62,65), as anticipated owing to its mechanism of action. More of these episodes occurred in patients receiving concomitant insulin or sulfonylureas, in whom the rate would be expected to be higher (60,63–65). Depending on patients’ current level of glycemic control and risk of hypoglycemia, the dosage and/or frequency of administration of these concomitant medications may need to be reduced (13,84).

Because many patients treated with oral semaglutide will be receiving these and other antihyperglycemic medications that carry a risk of hypoglycemia, they should be encouraged to regularly check their glucose levels and be provided with guidance on doing so. Patients and their families should also be educated on preventing, recognizing, and managing episodes of hypoglycemia (85). Symptoms of hypoglycemia may include, but are not limited to, dizziness, sweating, and confusion (86). If patients suspect that they may be experiencing hypoglycemia, they should be advised to consume glucose- or carbohydrate-containing foods, take glucose tablets, or drink fruit juice to raise their blood glucose levels (86).

Because type 2 diabetes is commonly associated with renal impairment, the efficacy and safety of oral semaglutide was evaluated in 324 patients with moderate renal impairment (defined as an estimated glomerular filtration rate of 30–59 mL/min/1.73 m²) in PIONEER 5 (65). No safety concerns were identified; therefore, oral semaglutide may be a useful option for patients with type 2 diabetes and moderate renal impairment for whom current treatment options are limited (65).

The CV outcomes trial PIONEER 6 evaluated CV safety of oral semaglutide in 3,183 patients at high CV risk (aged ≥50 years with established CVD or CKD, or aged ≥60 years with CV risk factors only) (66). The trial met its primary objective of ruling out an 80% excess CV risk with oral semaglutide, with MACE occurring in 3.8 and 4.8% of patients receiving oral semaglutide and placebo, respectively. This result confirmed its noninferiority to placebo for the primary outcome of time from randomization to the first MACE occurrence (hazard ratio 0.79, 95% CI 0.57–1.11) (66). It is important to note that PIONEER 6 had a relatively short trial duration (median time in trial, including follow-up, of 15.9 months) to allow for the determination of CV safety of oral semaglutide early in the clinical development program (87). However, long-term CV outcomes of treatment with oral semaglutide are currently being evaluated in the ongoing SOUL trial (NCT03914326).

Patients treated with once-weekly subcutaneous semaglutide 0.5 mg can be transitioned to oral semaglutide 7 or 14 mg and can start taking the oral formulation up to 7 days after their last subcutaneous dose (13). Similarly, patients treated with daily oral semaglutide 14 mg can be transitioned to subcutaneous semaglutide 0.5 mg once weekly by starting subcutaneous semaglutide the day after their last oral dose (13). There are currently no data available on switching from other injectable GLP-1 receptor agonists to oral semaglutide; therefore, HCPs are advised to use their judgment and knowledge of the pharmacology and half-life of the injectable GLP-1 receptor agonist being discontinued.

It is important to note that the prescribing information for oral semaglutide includes a boxed warning to advise HCPs and people with type 2 diabetes about the potential increased risk of thyroid C-cell tumors (13). In rodents, semaglutide has been shown to cause dose-dependent and treatment duration–dependent thyroid C-cell tumors to develop at clinically relevant exposures; however, the human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined (13). Oral semaglutide is therefore contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with multiple endocrine neoplasia syndrome type 2 (13).

It may be reassuring for patients to understand that this boxed warning is not exclusive to oral semaglutide; the prescribing information for exenatide extended release, dulaglutide, liraglutide, and subcutaneous semaglutide contain similar warnings about thyroid tumors (21–23,27). Moreover, across the global PIONEER program, malignant tumors, including malignant thyroid tumors, were rare (three thyroid tumors were reported in 8,842 patients treated with oral semaglutide), and there was no clear indication of clustering of events in any particular system organ class (59–66).

Patients initiating treatment with oral semaglutide should be counseled on the potential risk for MTC and the symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, and persistent hoarseness) but should be reassured that MTC is one of the rarest forms of thyroid cancer (88–91). There is no contraindication to oral semaglutide use in relation to the more common papillary thyroid cancer, nor in the case of hypo- or hyperthyroidism (13).

People with type 2 diabetes have an increased risk for developing pancreatitis (92,93). A recent meta-analysis demonstrated that there is no substantial or significant change in the risk of pancreatitis with GLP-1 receptor agonists (94); however, a small number of cases of acute pancreatitis were reported in the PIONEER trials, with similar rates between oral semaglutide and comparators (59–66). Importantly, patients should be advised to stop using oral semaglutide and call their HCP immediately if they experience severe abdominal pain, with or without vomiting, which could be a sign of pancreatitis (13).

In some patients, a transient worsening of diabetic retinopathy has been observed after initiation of intensive antihyperglycemic treatment (95). In the global PIONEER trials, the incidence of diabetic retinopathy complications in patients treated with oral semaglutide was comparable to that seen with placebo and active comparators, and most cases did not require active treatment (59–66); however, any changes in vision during treatment with oral semaglutide should be reported to the HCP (13).

Despite proven efficacy and safety for treating people with type 2 diabetes, GLP-1 receptor agonists as a class are underutilized, possibly because of the need for subcutaneous administration. The approval by the FDA of oral semaglutide gives people with type 2 diabetes in the United States access to the significant benefits offered by this efficacious class of drugs, namely improved glycemic control and weight reductions, with the added advantage of a convenient route of administration that may appeal to many patients and HCPs. It is possible that the convenience granted by oral semaglutide may pave the way for greater adherence to treatment and consequently for improved therapeutic outcomes versus subcutaneous GLP-1 receptor agonists (55,96). To ensure optimal therapeutic outcomes with oral semaglutide, it is important that diabetes care and education specialists effectively counsel patients on initiating treatment with oral semaglutide and provide them with the support needed to continue treatment, particularly regarding correct administration and mitigation of GI side effects.

The authors thank Nicola Beadle, PhD, of Axis, a division of Spirit Medical Communications Group Ltd., for assistance with medical writing and editorial support.

This article was supported by Novo Nordisk, which was provided with the opportunity to perform a medical accuracy review. Writing/editorial support for this article was also funded by Novo Nordisk.

D.M.I. has attended an advisory board for Novo Nordisk and served on speakers’ bureaus for Abbott, Dexcom, LifeScan, and Xeris. D.F.K. has attended advisory boards for Abbott, Boehringer Ingelheim, Dexcom, Eli Lilly, Janssen Pharmaceuticals, Novo Nordisk, and Sanofi-Aventis; has served on speakers’ bureaus for Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Janssen Pharmaceuticals, Novo Nordisk, and Valeritas; and has received research support from Abbott, Bristol-Myers Squibb, Calibra/Johnson & Johnson, Dexcom, Eli Lilly, the Helmsley Charitable Trust, IDC, Lexicon, the National Institutes of Health, Novo Nordisk, and Teva. G.R.S. has served as an advisory board member for and received honoraria for speaking engagements from Eli Lilly and Sanofi and has been a consultant to AstraZeneca and Eli Lilly. No other potential conflicts of interest relevant to this article were reported.

All authors critically reviewed all manuscript drafts and provided comments. All authors gave their approval for the final version to be published. D.M.I. is the guarantor of this work and, as such, takes full responsibility for the integrity of the data and the accuracy of the data analysis.