GLP-1 RAs (glucagon-like peptide 1 receptor agonists) are a preferred class of glucose-lowering drug. |
Subcutaneous treatment with GLP-1 RAs is limited by their injectable mode of administration. |
Orally administered semaglutide, a recently developed GLP-1 RA formulation, offers good glucose control in a safe and well-tolerated manner. |
This review describes the basic and clinical pharmacology of orally administered semaglutide. |
Introduction
Classification of GLP-1 RA
Parameter | Classification | Compound |
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Classification based on duration of action | Short acting (half-life < 12 h) | Exenatide Lixisenatide |
Intermediate acting (half-life 12–24 h) | Liraglutide | |
Long acting (half-life 24 h to 1 month) | Exenatide LAR Albiglutide Semaglutide Orally administered semaglutide | |
Continuous acting (half-life > 1 month) | ITCA 650 | |
Based on structure | Exendin-based therapy | Exenatide Exenatide LAR Lixisenatide |
Human GLP-1-based therapy | Liraglutide Dulaglutide Semaglutide Orally administered semaglutide | |
Based on mode of delivery | Subcutaneous injection | Exenatide Exenatide LAR Albiglutide Lixisenatide Liraglutide Semaglutide |
Subcutaneous implant | ITCA 650 | |
Oral ingestion | Orally administered semaglutide |
Semaglutide
Barriers to Injectable GLP-1 RA Therapy
Orally Administered Semaglutide
Clinical Pharmacology
Role of SNAC in Absorption of Orally Administered Semaglutide
Orally Administered Semaglutide Clinical Data: Summary of PIONEER Trials
Trial | Comparator | Design | Number of patients | Treatment arm | Key results | Specific comments |
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PIONEER 1 [35] | 26-week, phase 3a, randomised, double-blind, placebo-controlled, parallel-group trial | 703 | Randomised (1:1:1:1) to once-daily orally administered semaglutide 3 mg, 7 mg, 14 mg or placebo | Significant HbA1c reduction for all doses between 0.6% and 1.1% Significant weight reduction with 14 mg dose (3.4 kg vs 1.8 kg) | Orally administered semaglutide monotherapy demonstrated superior and clinically relevant improvements in HbA1c (all doses) and body weight loss (14 mg dose) versus placebo | |
PIONEER 2 [36] | Empagliflozin 25 mg | 52-week, randomised, open-labelled, active comparator, parallel-group trial | 821 | Randomised (1:1) orally administered semaglutide 14 mg or empagliflozin 25 mg | Significantly better HbA1c reduction at week 26 (1.9% vs 0.9%) and week 52 (1.3% vs 0.8%). Significant better weight reduction at week 52 (1.3 kg vs 0.9 kg) | Gastrointestinal adverse events were more common with orally administered semaglutide Weight reduction not significant at week 26 |
PIONEER 3 [37] | Sitagliptin 100 mg | 26-week, randomised, double-blind, double-dummy, parallel-group, phase 3a trial | 1864 | Randomised (1:1:1:1) orally administered semaglutide, 3 mg, 7 mg or 14 mg or sitagliptin, 100 mg | Significantly better reduction in HbA1c and body weight with 7 mg (0.2% HbA1c and − 1.6 kg weight) and 14 mg (0.5% HbA1c and − 2.5 kg weight) semaglutide | Non-inferiority of semaglutide, 3 mg/d, with respect to HbA1c was not demonstrated |
PIONEER 4 [38] | Liraglutide 1.8 mg | 52-week, randomised, double-blind, double-dummy, phase 3a trial | 711 | Randomly assigned (2:2:1) to once-daily orally administered semaglutide (dose escalated to 14 mg), once-daily subcutaneously administered liraglutide (dose escalated to 1.8 mg), or placebo | Semaglutide and liraglutide produced average HbA1c reductions that were similar to each other and significantly better than that of placebo, at 1.2% and 1.1% Semaglutide produced significantly greater weight loss than liraglutide, at an average of 4.4 versus 3.1 kg | Orally administered semaglutide was non-inferior to subcutaneously administered liraglutide and superior to placebo in decreasing HbA1c, and superior in decreasing body weight compared with both liraglutide and placebo |
PIONEER 5 [39] | 26-week, randomised, double-blind, phase 3a trial aiming to investigate the efficacy and safety of orally administered semaglutide in patients with type 2 diabetes and moderate renal impairment | 324, with moderately impaired renal function, estimated glomerular filtration rate of 30–59 mL/min per 1.73 m2 | 1:1 randomised to receive orally administered semaglutide (dose escalated to 14 mg once daily) or matching placebo | Orally administered semaglutide (dose escalated to 14 mg/day) was associated with an average 1.0% reduction in HbA1c, versus a 0.2% reduction with placebo Weight reduction of 3.4 kg vs 0.9 kg | Renal function remained unchanged in both groups during the 26 weeks of treatment | |
PIONEER 6 [40] | CVOT, event-driven, randomised, double-blind, placebo-controlled trial involving patients at high cardiovascular risk, median time in the trial was 15.9 months | 3183 | 1:1 randomised to once-daily orally administered semaglutide (target dose, 14 mg) or placebo | From baseline to end of study, orally administered semaglutide was associated with a reduction compared with placebo in both HbA1c (− 1.0% versus − 0.3%, respectively) and body weight (− 4.2 kg versus − 0.8 kg, respectively) | Patients with type 2 diabetes and high cardiovascular risk (85% with established disease) | |
PIONEER 7 [41] | Sitagliptin 100 mg | 52-week, multicentre, randomised, open-label, phase 3a trial | 504 | 1:1 randomised orally administered semaglutide with flexible dose adjustments to 3, 7 or 14 mg once daily or sitagliptin 100 mg once daily | Orally administered semaglutide group experienced a statistically significant reduction in HbA1c of 1.3% compared to 0.8% with sitagliptin Significant weight reduction of 2.6 kg vs 0.7 kg with sitagliptin | Compared the flexible dose adjustment of orally administered semaglutide with sitagliptin |
PIONEER 8 [42] | 52-week, multicentre, randomised, double-blind, placebo-controlled, parallel-group trial | 731 | Patients with T2DM on a stable regimen of basal, basal-bolus (in any combination) or premixed insulin (including combinations of soluble insulin) randomised 1:1:1:1 to either orally administered semaglutide 3 mg, 7 mg, 14 mg or placebo | 3, 7 and 14 mg/day doses of orally administered semaglutide achieved average HbA1c reductions of 0.6%, 0.9% and 1.3%, respectively, versus 0.1% for those taking placebo. The corresponding average body weight reductions were 1.4, 2.4 and 3.7 kg versus 0.4 kg | Patients with type 2 diabetes uncontrolled on insulin with or without metformin | |
PIONEER 9 [43] | Liraglutide 0.9 mg | 52-week, phase 2/3a, randomised, controlled trial | 243 | Randomly assigned 1:1:1:1:1 to receive double-blind, once-daily treatment with 3 mg, 7 mg or 14 mg orally administered semaglutide or placebo, or open-label treatment with liraglutide 0.9 mg | HbA1c reductions at week 26 (the primary endpoint) ranged from 1.1% to 1.7% (all significant) with 3, 7 and 14 mg/day orally administered semaglutide versus placebo. At the highest dose there was also a significant reduction of 0.3% versus liraglutide 0.9 mg, although this was not sustained at week 52. Weight reduction was − 2.6 kg with orally administered semaglutide 14 mg vs 0.4 kg with 0.9 mg of liraglutide | Trial population: Japanese people with type 2 diabetes taking one antidiabetes medication or treated with diet/exercise only |
PIONEER 10 [44] | Dulaglutide 0.75 mg | 52-week, open-label, randomised, active-controlled, phase 3a trial | 458 | Patients aged 20 years and older with uncontrolled type 2 diabetes were randomly assigned (2:2:2:1) to receive once-daily orally administered semaglutide 3 mg, 7 mg or 14 mg, or once-weekly subcutaneously administered dulaglutide 0.75 mg | The 14 mg dose of semaglutide produced a significant 0.3% HbA1c reduction versus dulaglutide at a dose of 0.75 mg and with estimated treatment difference of − 2.6 kg for orally administered semaglutide 14 mg vs dulaglutide 0.75 mg | Orally administered semaglutide was well tolerated in Japanese patients with type 2 diabetes. Once-daily orally administered semaglutide significantly reduced HbA1c (14 mg dose) and body weight (7 mg and 14 mg doses) versus weekly subcutaneously administered dulaglutide 0.75 mg by week 52 |
Cardiovascular Outcomes with Orally Administered Semaglutide
Safety of Orally Administered Semaglutide
Cost of Oral vs Injectable and Other Therapies
Dosing and Administration
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Orally administered semaglutide should be taken on an empty stomach.
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Orally administered semaglutide should be swallowed whole with up to half a glass of water equivalent to 120 mL.
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Do not split, crush or chew the tablet.
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Wait at least 30 min before the first meal or drink of the day or taking other oral medicinal products. Waiting less than 30 min may decrease the absorption of semaglutide.