Semaglutide tablet (Rybelsus), the first GLP-1RA developed for oral administration, heralds a milestone for diabetes management in the 15 years since the introduction of the first glucagon-like peptide-1 receptor agonist (GLP-1RA). Rybelsus and its parenteral counterpart, Semaglutide (Ozempic), are approved for use in the treatment of type 2 diabetes mellitus (T2DM) as:
- Mono-therapy in patients who are not candidates for metformin or;
- Adjunct to other glucose-lowering therapies in patients with inadequate glycemic control.
GLP-1RAs are peptide-based incretin mimetics that activate GLP-1 receptors in the pancreas, leading to enhanced insulin release and reduced glucagon secretion in a glucose-dependent manner, with a consequent low risk for hypoglycaemia. Mechanistically, GLP-1 receptor activation in the central nervous system (CNS) and gastrointestinal (GI) tract also curbs appetite and delays glucose absorption due to slower gastric emptying.
The approval of an oral GLP-1RA marks a breakthrough advancement in pharmaceutical formulation development. Obtaining sufficient systemic exposure of orally administered peptide-based drugs has been long plagued by difficulties arising from the acidic environment and presence of proteolytic enzymes in the stomach, as well as limited GI epithelium permeability. Oral semaglutide is formulated with an absorption enhancer, salcaprozate sodium (SNAC), to facilitate transport across the GI mucosa, aiming to provide the benefits of parenteral GLP-1RAs without the need for injections.
Drug Profile
Semaglutide (Rybelsus) is available in Singapore as 3mg, 7mg and 14mg tablets.
- Dosage: The drug is dosed at 3mg once daily for 30 days followed by a maintenance dose of 7mg once daily. The dose may be increased to 14mg once daily after 30 days as tolerated.
- Administration: Semaglutide has strict posology requirements. The tablet must be taken on an empty stomach and swallowed whole with a sip of water (equivalent to 120mL). Tablets should not be split, crushed or chewed as it is not known if absorption will be affected. Patients should wait at least 30 minutes before eating, drinking or taking any other oral medicinal products. Waiting less than 30 minutes decreases the absorption of semaglutide.
- Adverse Effects (AE): The most common AE reported in the PIONEER trials was GI-related, with nausea and diarrhoea the most common manifestations. These mostly occurred earlier in the study during dose initiation and escalation but led to 1.7-12% of premature treatment discontinuation across the oral semaglutide study groups.
- Cautions: Semaglutide should not be used in patients with type 1 diabetes mellitus (T1DM) or for the treatment of diabetic ketoacidosis. There is no therapeutic experience in patients with congestive heart failure NYHA class IV, pancreatitis, malignant neoplasms in the last 5 years, and proliferative retinopathy or maculopathy. Semaglutide is therefore not recommended in these patients. There is no therapeutic experience with semaglutide in patients with bariatric surgery. Semaglutide delays gastric emptying and has the potential to impact the rate of absorption of concomitantly administered oral medicinal products. It should be used with caution in patients receiving oral medicinal products that require rapid gastrointestinal absorption. Concomitant administration with levothyroxine has caused a rise the latter’s serum drug levels.
Place in Therapy
The principal goal of T2DM disease management is to stave off both microvascular and macro vascular complications through the good glycemic control and, where necessary, weight loss and cardiovascular (CV) risk management. The Singapore Burden of Diseases study conducted in 2017 found obesity to be the largest single contributor to the national disease burden of diabetes (73%). For patients without established atherosclerotic CV disease (ASCVD) or chronic kidney disease (CKD), and for whom there is a compelling need to minimise weight gain or promote weight loss, the AACE, ADA and EASD diabetes guidelines recommend the use of a GLP-1RA or sodium-glucose co-transporter-2 inhibitor (SGLT2i) as the preferred second-line treatment option for patients with inadequate glycemic control despite use of metformin. The guidelines also recommend either a SGLT2i or GLP-1RA with proven CVD benefit as the preferred treatment option for patients with T2DM and ASCVD or CKD.
The PIONEER Clinical Trial Program
The efficacy and safety of oral semaglutide was demonstrated in the Peptide InnOvatioN for Early diabetes tReatment (PIONEER) clinical trial program comprising 8 global and 2 Japan-specific Phase IIIa randomised controlled trials (RCTs) across a wide spectrum of the T2DM disease course and settings of renal impairment (PIONEER 5) and CVD (PIONEER 6). Common inclusion criteria for the PIONEER trials were adults aged at least 18 years old, a diagnosis of T2DM at least 90 days prior to screening and inadequate glycemic control.
In 9 trials (PIONEER 1 – 5 and PIONEER 7 – 10), the primary and secondary confirmatory endpoints were change from baseline HbA1c and body weight, respectively. In general, oral semaglutide demonstrated glycemic benefit over oral alternatives, empagliflozin and sitagliptin, with suggestion of dose-related superiority. Within-class comparisons evaluating HbA1c outcomes were less compelling as oral semaglutide found to be non-inferior to liraglutide (PIONEER 4 and PIONEER 9), less effective than its parenteral counterpart semaglutide (Ozempic) via a network meta-analysis by BB Hansen et al., and more effective than dulaglutide only at the maximum oral dose of 14mg once daily (PIONEER 10).
PIONEER 6, a 16-month event-driven CV outcomes trial (CVOT), demonstrated a 21% reduction in major cardiovascular events (MACE) compared to placebo in high risk patients. The data confirmed non-inferiority (p<0.001) but was not significant for superiority (p=0.17). With significant heterogeneity between GLP-1RA CVOTs limiting a class-effect extrapolation of CV benefit, we await results from SOUL, a second CVOT, to better understand the oral semaglutide’s CV risk reduction profile over a longer 5-year time course.
Evidence to Practice Considerations
The advent of oral semaglutide presents an exciting opportunity for clinicians to harness a useful drug-class where parenteral administration inconvenience may have previously limited treatment uptake or persistence. Prevailing evidence has also provided compelling argument for its relative superiority over alternative oral agents. However, utilisation may be potentially limited by the high cost of new technology and the finicky administration requirements that patients may struggle to comply to.
In the absence of local pharmacoeconomic data, a recent analysis by Guzauskas et al. provides a US-payer perspective on the cost-efficacy argument against oral semaglutide. The calculations were based on drug costs updated to May 2020 estimates and included a lifetime time horizon discount rate of 3% for costs and outcomes. The study concluded that oral semaglutide was cost prohibitive compared with empagliflozin based on an incremental cost effectiveness ratio (ICER) of $458,00 per quality adjusted life year (QALY). Encouragingly, oral semaglutide was estimated to be cost-effective compared with liraglutide and moderately cost-effective compared to sitagliptin.
Notwithstanding, these are early days and further insights into the real-world use of the novel agent are needed to better support its incorporation in routine clinical practice. Details of the PIONEER clinical trial program are summarised in the table below. The writer has also summarised considerations for the clinical application of trial data to better inform the clinician’s treatment strategy.
| Population
(Study Design and Baseline Characteristics) |
Intervention vs Comparator | Primary/ Secondary Outcomes
Treatment policy and results reported ETD: estimated treatment difference |
The long and short of it |
| PIONEER-1
N=703, 26-weeks double blinded Background therapy of diet and exercise Mean Age: 55y BMI: 31.8 HbA1c: 8.0% |
Oral semaglutide 3mg, 7mg, 14mg OD
vs Placebo |
Efficacy
Safety GI events were dose-related and the most common AE in the semaglutide arm (nausea 5.1-16% across groups). Treatment discontinuation occurred in 2.3-7.4% with oral semaglutide and 2.2% with placebo, with the predominant reason for discontinuation due to GI disturbance. |
All doses of oral semaglutide were superior to placebo in terms of glycemic and weight loss efficacy, dose related increase in BW reduction seen. |
| PIONEER-2
N=822, 52-weeks open-labelled Background therapy of metformin Mean Age: 57.5y Weight: 91.6lg HbA1c: 8.1% |
Semaglutide 14mg OD
vs Empagliflozin 25mg OD |
Efficacy
Safety GI events were more common with semaglutide |
More efficacious than empagliflozin in terms of HbA1c lowering but mixed results with BW reduction. |
| PIONEER-3
N=1,864, 72-weeks double-blinded, double-dummy Background therapy of metformin and/or sulfonylurea Mean Age: 58y BMI: 32.5 HbA1c: 8.3% |
Semaglutide 3mg, 7mg or 14mg OD
vs Sitagliptin 100mg OD |
Efficacy
Safety
|
Superior efficacy to sitagliptin with HbA1c lowering appears dose related – no comparative benefit seen with the 3mg semaglutide dose |
| PIONEER-4
N=711, 52-weeks, double-blinded, double-dummy Background therapy of metformin and/or SGLT2i Mean Age: 56y BMI: 33.0 HbA1c: 8.0% |
Semaglutide 14mg OD
vs SC liraglutide 1.8mg OD vs Placebo OD |
Efficacy
Safety
|
Non-inferior to liraglutide in glycemic control and associated with more frequent AEs. |
| PIONEER-5
N=324, 26-week double-blinded CKD Stage 3 patients (eGFR 30-59ml/min/1.73m2) with background therapy of pre-trial antidiabetic regimen which included metformin, sulfonylurea and/or basal insulin Mean Age: 70y BMI: 32.4 HbA1c: 8.0% |
Semaglutide 14mg OD
vs Placebo OD |
Efficacy
Safety
|
Demonstrated safety and efficacy in CKD Stage 3 patients.
Notably slightly lower ETD vs placebo in the CKD population via an indirect comparison to PIONEER-1. |
| PIONEER-6
N=3,183, 16-months double-blinded At baseline, patients were at high CV risk – 56.5% had established ASCVD without CKD, 11.1% had CKD only, 17.1% had both ASCVD + CKD; background standard of care DM treatment |
Semaglutide 14mg OD
vs Placebo OD |
Efficacy
Safety
|
No increase in CV events when compared to placebo.
Did not demonstrate CV benefit. However, authors have commented that the study was not sufficiently powered to demonstrate superiority. |
| PIONEER-7
N=504, 52-weeks, open-labelled Background therapy of 1-2 OHGAs i.e. metformin, SGLT2i, sulfonylurea or thiazolidinedione Mean Age: 57.4y BMI: 31.5 HbA1c: 8.3% |
Semaglutide 3mg, 7mg or 14mg (flexible dose adjustment every 8 weeks based on glycemic response and GI tolerability)
vs Sitagliptin 100mg OD (fixed) |
Efficacy
Safety
|
Dosing strategy in PIONEER 7 more closely replicates an individualised approach in clinical practice. |
| PIONEER-8
N=731, 52-weeks double-blinded Background therapy of insulin and/or metformin Mean Age: 61y Weight: 88.1kg HbA1c: 8.2% |
Semaglutide 3mg, 7mg or 14mg
vs Placebo OD |
Efficacy
Safety
|
Demonstrated safety and superior dose-dependent efficacy when added on to insulin.
Similar rates of hypoglycemia reported in both arms. |
| PIONEER-9
Japanese patients N=243, 52 weeks Background therapy of diet and exercise Mean Age: 59y Weight: 71.1kg HbA1c: 8.2% |
Semaglutide 3mg, 7mg or 14mg
vs SC liraglutide 0.9mg vs Placebo OD |
Efficacy
Safety
|
Results were replicated in the Japanese population with a similar efficacy and safety profile. |
| PIONEER-10
Japanese patients N=, 52 weeks Background therapy of 1 oral antidiabetic e.g. sulfonylurea, acarbose, SGLT2i etc. Mean Age: 58y Weight: 72.1kg HbA1c: 8.3% |
Semaglutide 3mg, 7mg or 14mg
vs SC dulaglutide 0.75mg |
Efficacy
Safety
|
Semaglutide 14mg alone provides superior HbA1c and bodyweight lowering over dulaglutide.
Lower doses did not show superiority. |
