Recommendations for Titration and Administration of Oral Semaglutide for the Treatment of Type 2 Diabetes during Ramadan

There is an increasing availability of effective glucose-lowering medications, yet a high proportion of patients with type 2 diabetes mellitus (T2DM) experience delayed treatment intensification despite suboptimal glycaemic control, commonly referred to as clinical inertia [1]. There is a need for glucose-lowering therapies that are easy to use and effectively control blood glucose levels to decrease the risk of microvascular and macrovascular complications [2].

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are established treatments for T2DM. They effectively reduce hyperglycaemia by stimulating insulin and suppressing glucagon secretion and also promote weight loss by delaying gastric emptying and reducing appetite [3]. These beneficial effects may contribute to additional benefits, as GLP-1RA treatment results in a significant reduction in the incidence of cardiovascular and kidney events [4, 5]. Several GLP-1RAs are currently recommended by the American Diabetes Association and the European Association for the Study of Diabetes as second-line therapy after metformin for the treatment of T2DM, and more recently, as part of a more patient-centric and individualized treatment approach, GLP-1RAs have been recommended earlier depending on comorbidities (e.g., cardiovascular disease or chronic kidney disease) or individual factors [6‒8].

Semaglutide is a GLP-1RA, available as a once-weekly subcutaneous (at doses 0.25 mg, 0.5 mg, and 1.0 mg) and once-daily oral formulation. Both semaglutide formulations have comparable effects on hyperglycaemia and body weight [9]. As the first available oral GLP-1RA, oral semaglutide may provide additional treatment options for patients and facilitate adoption of earlier GLP-1RA treatment by offering glucose-lowering and weight loss-promoting benefits of a GLP-1RA as a tablet. Treatment with oral semaglutide is initiated with a 4-week dose-escalation regimen, starting with the lowest dose of 3 mg, followed by 7 and 14 mg maintenance doses.

The efficacy of oral semaglutide has been demonstrated in the phase 3 PIONEER (Peptide InnOvatioN for Early diabEtes tReatment) clinical programme, involving patients with T2DM treated with oral semaglutide monotherapy through insulin add-on for up to 78 weeks in global populations and two trials on Japanese populations only [10]. Oral semaglutide was more efficacious with a greater reduction in HbA_1c and greater or similar weight reductions compared with a dipeptidyl peptidase-4 inhibitor (sitagliptin), a sodium-glucose cotransporter-2 inhibitor (empagliflozin), or placebo, and in a Japanese study compared with the once-weekly subcutaneous GLP-1RA dulaglutide [11‒17]. The efficacy of oral semaglutide is non-inferior to the injectable GLP-1RA liraglutide [12, 16].

In order to increase the absorption of semaglutide taken orally, the peptide is co-formulated with an absorption enhancer, sodium N-(8-[2-hydroxybenzoyl]amino) caprylate, and it is accompanied with specific dosing considerations for optimal absorption in the stomach [18]. It should be taken daily on an empty stomach at least 30 min before the first meal of the day with up to half (approximately 120 mL/4 oz) a glass of water [19].

During the month of Ramadan, there is no intake of food, water, or fluids during the day, which increases the risk of hyperglycaemia and hypoglycaemia, results in larger fluctuations in blood glucose, and increases the risk of dehydration [20, 21]. Randomized clinical trials assessing the impact of injectable GLP-1RAs added to metformin in patients with T2DM during Ramadan have reported a reduced incidence of symptomatic hypoglycaemia, improved glycaemic control, and weight loss compared with sulphonylureas [22‒25]. Recent guidelines have accordingly incorporated the use of GLP-1RAs as an option during Ramadan into their treatment algorithms for patients with T2DM, considering them a well-tolerated therapy for lowering HbA_1c levels, without the need for dose modifications [21, 26].

During Ramadan, persistent deviations in oral semaglutide dosing, such as prior food intake before dosing or an increased water volume (more than 120 mL/4 oz) with tablet intake, or a decrease in post-dosing fasting time (less than 30 min) may result in decreased absorption and consequently lower semaglutide plasma exposure, which may impact treatment efficacy [18, 27, 28]. However, there are currently no published data on the effect of oral semaglutide during Ramadan. A panel of experts from India, Malaysia, Qatar, Saudi Arabia, Singapore, and the United Arab Emirates were convened by Novo Nordisk to consider the dosing and potential impact on the efficacy and safety of oral semaglutide to inform healthcare professionals and provide practical recommendations for patients with T2DM intending to fast during Ramadan.

On January 13, 2022, 13 experts (the authors of this paper), including endocrinologists and general practitioners with considerable experience in treatment with GLP-1RAs and the development of practical management guidelines for diabetes during Ramadan, attended a virtual meeting and discussed recommendations for oral semaglutide administration during the Ramadan fast [21, 26]. Based on current dosing instructions of oral semaglutide and taking into account drug pharmacokinetics after gastric absorption, advisory board members formulated a practical consensus for the titration and administration of oral semaglutide during Ramadan (Table 1; Fig. 1).

Regarding co-administration of oral semaglutide with other therapies, the same dosing recommendations apply as when using oral semaglutide outside of the Ramadan fast. It should be noted that semaglutide delays gastric emptying which may influence the absorption of other oral medicinal products [29]. After administering semaglutide, the patients should wait 30 min before taking other oral medicinal products, such as levothyroxine, according to the oral semaglutide dosing schedule to avoid that the absorption of semaglutide is influenced by the presence of multiple tablets in the stomach [19]. According to guidelines, levothyroxine should be administered, preferably on an empty stomach 30 min to 1 h before breakfast and at least 4 h before or after drugs known to interfere with levothyroxine absorption [30]. Alternatively, levothyroxine can also be administered at bedtime at least 3 h after the evening meal, which results in similar exposure rates [31, 32]. In a clinical pharmacology trial, it was shown that after administration of a single supratherapeutic dose of levothyroxine co-administered with oral semaglutide, the total exposure of thyroxine increased by 33%, with the maximum exposure remaining unchanged [33]. An option to consider is to follow the dosing schedule for oral semaglutide when co-administered with levothyroxine and follow bedtime dosing schedules for levothyroxine in combination with increased monitoring of thyroid parameters [31‒33]. Clinical assessments demonstrated that oral semaglutide had no significant effect on several other co-administered drugs [34].

High inter-individual variability in gastrointestinal degradation of peptides, such as GLP-1RAs, might result in varying absorption rates of oral semaglutide if deviating from the optimized dosing schedule [27]. The potential impact of deviations from the oral semaglutide dosing schedule is outlined in Table 2.

Any reduction in semaglutide absorption could potentially result in a reduced treatment efficacy. Multiple deviations may reduce the absorption of oral semaglutide.

The efficacy of oral semaglutide may be affected in patients with T2DM who fast during Ramadan due to altered absorption based on the timing of tablet intake in relation to fasting, water, and food intake [18, 27, 28]. Until robust, real-world evidence of people with T2DM who fast during Ramadan while taking oral semaglutide is available, the recommendations proposed may help in the initiation, titration, and administration of oral semaglutide to patients with T2DM during Ramadan.

The authors thank Novo Nordisk A/S for the organization of the virtual meeting to discuss the current recommendations for oral semaglutide administration during the Ramadan fast. The authors also thank Petra Őrsy (Novo Nordisk) for reviewing and inputting to the manuscript, and Leni Vandekerckhove, PhD, (AXON Communications) for medical writing and editorial assistance. All contributors received funding from Novo Nordisk.

Mohamed Hassanein received honoraria and/or support for attending meetings from Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck, MSD, Novo Nordisk, Sanofi, and Servier and served as a consultant in advisory boards for Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Lifescan, Merck, MSD, Novo Nordisk, Sanofi, and Servier. Fatheya F. Alawadi received honoraria from AstraZeneca, Eli Lilly, Merck, Novo Nordisk, and Sev Pharmaceuticals; served as a consultant for data safety monitoring or advisory boards for Merck and Novo Nordisk; and is an unpaid member of the EMA & EDES & ICE committees. Hussein Elbadawi received honoraria from AstraZeneca, Boehringer Ingelheim, MSD, Novo Nordisk, and Sanofi. Rakesh Kumar Sahay received grants/contracts from ICMR and Telangana State Council of Science & Technology; received honoraria from Eris Life Sciences, India Pvt Ltd, Novo Nordisk, and USV India Ltd; participated on a Data Safety Monitoring Board or Advisory Board for Torrent Pharma India Ltd; and is the President of the Endocrine Society of India and Vice-President of the South Asian Federation of Endocrine Societies. Rayaz Malik received honoraria for lectures with Eli Lilly, Novo Nordisk, Proctor & Gamble, and Sanofi and was part of the writing advisory board for MEA-PACT epidemiological study on CV complications and management in MENA region with Novo Nordisk. Rohana Abdul Ghani received research grants for Industry-driven clinical trials, including the SOUL, COMBINE 3, and ZEUS study; received honoraria for lectures as speaker and participation in expert panels; and is an advisory board member for semaglutide. Sueziani Binte Zainudin received honoraria for participation in the Ramadan Virtual Advisory Board from Novo Nordisk. Yousef AL Saleh received consulting fees and/or honoraria from Aventis, Eli Lilly, Novo Nordisk, and Servier; received support for attending meetings from Eli Lily and Novo Nordisk; participated as a member of data safety monitoring or advisory boards for Boehringer Ingelheim, Eli Lily, and Servier; and is a member of the Gulf Association of Endocrinology and Diabetes. Abdulqawi Almansari, Ebtesam Ba-Essa, Salah Abusnana, Shehla Shaikh, and Tarik Elhadd have no conflicts of interest to declare.

The virtual meeting and writing of the manuscript were funded by Novo Nordisk A/S.

Mohamed Hassanein, Abdulqawi Almansari, Ebtesam Ba-Essa, Fatheya F. Alawadi, Hussein ElBadawi, Rakesh Kumar Sahay, Rayaz Malik, Rohana Abdul Ghani, Salah Abusnana, Shehla Shaikh, Sueziani Binte Zainudin, Tarik Elhadd, and Yousef AL Saleh discussed the current recommendations for oral semaglutide administration during the Ramadan fast during a virtual meeting, inputted on the development of the manuscript, and carefully reviewed and approved the final manuscript.