Andreas Andersen
Andreas Andersen
https://doi.org/10.1007/s40265-021-01499-w
REVIEW ARTICLE
Abstract
Oral semaglutide ( Rybelsus®) is a glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1RA) with 94% homology to human
GLP-1. It is the first GLP-1RA developed for oral administration, and it comprises a co-formulation of the peptide semaglutide
with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino) caprylate, which overcomes the challenges of peptide
absorption in the acidic conditions of the stomach. Oral semaglutide is indicated for use as an add-on combination therapy (with
other glucose-lowering agents, including insulin) or as a monotherapy (in patients who are intolerant to metformin) for type 2
diabetes when diet and exercise do not provide adequate glycemic control. In an extensive phase III clinical program including
patients from across the disease spectrum, treatment with oral semaglutide resulted in effective glycemic control, reductions in
body weight, and decreases in systolic blood pressure when used as monotherapy or in combination with other glucose-lowering
therapies. Studies showed that oral semaglutide was well tolerated, with a safety profile consistent with the GLP-1RA drug
class. The risk of hypoglycemia was low, and the most common adverse events were gastrointestinal, with nausea and diarrhea
generally being the most frequently reported manifestations. Cardiovascular (CV) safety was shown to be noninferior to placebo
and observations suggest that the CV profile of oral semaglutide is likely to be similar to that of subcutaneous semaglutide. The
evolution of the GLP-1RA class to include an oral agent could facilitate the use of these agents earlier in the diabetes treatment
cascade owing to wider acceptance from patients and healthcare professionals.
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1004 A. Andersen et al.
been published). This review includes 46 cited articles for 2.2 Absorption and Pharmacokinetics of Oral
studies or analyses investigating oral semaglutide in T2D, Semaglutide
of which 23 relate to its efficacy/tolerability. One publica-
tion was updated and a recent publication added during the Oral semaglutide is absorbed from the stomach, and this pro-
peer-review process. cess may be hindered by the presence of food. A food-effect
study carried out in healthy volunteers (N = 78) reported
that individuals receiving once-daily oral semaglutide in the
2 Pharmacological Properties fasting state (n = 26) had measurable exposure, whereas this
was not the case in the fed state where exposure was either
2.1 Pharmacology limited (11 of 25 individuals) or not observed (14 out of
25 individuals) [25, 28]. It is therefore recommended that
Semaglutide was first identified as part of a series administration of the oral formulation of semaglutide should
of studies that aimed to design a once-weekly s.c. be in the fasting state [27–29]. Studies have also evaluated
GLP-1 analog with increased albumin affinity and the effects of water volume (when swallowing the tablet) on
security against metabolic degradation [21]. Its effi- the pharmacokinetics of semaglutide. A study in 26 healthy
cacy was first described in a dose-response study in male individuals found that tablet erosion of oral semaglu-
db/db mice, which confirmed the potency and dura- tide was slower with 50 mL versus 240 mL of water [30].
tion of action, with an E D50 below 2 nmol/kg [21, 22]. This study also showed that delayed delivery of the drug to
Semaglutide has 94% homology to human GLP-1, with two the small intestine was associated with higher plasma expo-
amino acid substitutions (Aib8 and Arg34), and is derivatized sure [30]. Another study conducted in 158 healthy male vol-
at lysine 26 (Fig. 1a) [21–23]. It is fully metabolized in the unteers assessed the impact of different water volumes and
human body by the same processes as other peptides and post-dosing fasting periods on semaglutide exposure, and the
fatty acids [22, 24]. Unlike liraglutide, semaglutide contains authors concluded that administration of oral semaglutide in
an amino acid (α-aminoisobutyric acid) described in nature the fasting state with up to 120 mL of water and a post-dose
but not in humans, and it appears that more metabolites of fasting period of at least 30 min resulted in clinically rel-
semaglutide are excreted in the feces [22]. evant semaglutide exposure [31]. Finally, co-administration
For researchers developing oral formulations of of placebo tablets with oral semaglutide has been reported
GLP-1RAs, including oral semaglutide, the fact that to reduce semaglutide exposure by 34% in a two-part, open-
absorption takes place in the stomach presents a challenge. label, crossover trial in 45 healthy subjects [32]. Therefore,
Obtaining sufficient systemic exposure of peptide-based the dosing conditions used in the phase III clinical trial
drugs following oral administration is difficult owing to the program were for oral semaglutide to be administered once
acidic environment and presence of proteolytic enzymes in daily on waking, in a fasting state, with up to 120 mL of
the stomach, and the limited permeability of peptides and water, and then waiting for 30 min before consumption of
proteins through the gastrointestinal epithelium [20, 25]. any food, drink, or other oral medications.
An absorption enhancer may help mitigate these barriers Plasma exposure for oral semaglutide was shown to be
[25]. Consequently, the tablet formulation of semaglutide dose-dependent in a multiple-dose study (N = 84 healthy
has been developed with the peptide co-formulated with male individuals and 23 male individuals with T2D). Expo-
an absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] sure was approximately twofold higher with a 40 mg versus
amino) caprylate (SNAC) (Fig. 1a) [25, 26]. SNAC is a a 20 mg dose, and there was no difference in exposure for the
small fatty-acid derivative that has been shown to provide a 40 mg dose between healthy individuals and those with T2D.
local increase in pH, which helps protect semaglutide from The half-life (t½) of oral semaglutide was shown to be simi-
proteolytic degradation in the stomach, and to facilitate the lar to that of s.c. semaglutide, being approximately 1 week
absorption of semaglutide across the gastric epithelium in [26]. This long t½ of semaglutide may help mitigate any
a concentration-dependent manner, primarily through the day-to-day variability in exposure that may occur with oral
transcellular route [25] (Fig. 1b). Research has shown that administration. Indeed, a comparison of exposure–response
absorption of semaglutide in the stomach is confined to an relationships for oral and s.c. semaglutide from their respec-
area in close proximity to the tablet [27]. As part of the tive phase III clinical trial programs in T2D revealed that,
development process, it was important to determine the although there is a greater variability in semaglutide plasma
amount of SNAC needed for optimal semaglutide exposure. concentrations following daily oral administration, this does
A single-dose study in healthy males (n = 135) found that not impact efficacy response. Indeed, considerable overlap
oral semaglutide exposure levels were greatest with 300 mg was observed between the exposure-response seen with
SNAC, and thus this amount was selected for further clinical once-daily oral semaglutide (7 and 14 mg) and that seen
development [26]. with once-weekly s.c. semaglutide (0.5 and 1.0 mg) [33].
1006 A. Andersen et al.
Fig. 1 Structure of semaglutide and SNAC (a) and the mechanism of SNAC on semaglutide absorption (b). DPP-4 dipeptidyl peptidase-4,
GLP-1 glucagon-like peptide-1, GLP-1RA glucagon-like peptide-1 receptor agonist, SNAC sodium N-(8-[2-hydroxybenzoyl] amino) caprylate
A Pharmacological and Clinical Overview of Oral Semaglutide for the Treatment of Type 2 Diabetes 1007
As the enhanced absorption of oral semaglutide from the semaglutide significantly improved fasting and post-prandial
stomach is facilitated by SNAC in a pH-dependent man- glucose metabolism and lipid metabolism, and delayed gas-
ner, the impact of agents that influence gastric pH on the tric emptying during the first post-prandial hour, which is
pharmacokinetics of oral semaglutide required investigation. consistent with observations for s.c. semaglutide in subjects
In healthy volunteers (N = 54), administration of a proton with obesity [38, 39]. The effect of oral semaglutide treat-
pump inhibitor, omeprazole (40 mg once daily), resulted ment on appetite and energy intake was also assessed, and
in a slight non-statistically significant increase in exposure the study incorporated the Control of Eating Questionnaire
to semaglutide that was not considered to be clinically rel- (CoEQ). After 12 weeks of treatment with oral semaglutide,
evant and no dose adjustment is recommended with these energy intake was reduced, control of eating was improved,
agents [34]. Given the site of absorption of oral semaglutide, and patients experienced weight loss and fewer food crav-
the impact of upper gastrointestinal disease on the pharma- ings. There was no change in appetite in this study, a finding
cokinetics of oral semaglutide would also be of interest. In that is inconsistent with observations for the s.c. formulation
a study of individuals with (N = 36) or without (N = 19) [40, 41].
upper gastrointestinal disease (gastritis and/or gastroesopha-
geal reflux disease), no significant difference in exposure to 2.4 Drug–Drug Interactions
semaglutide was observed between individuals with or with-
out gastrointestinal disease and the agent was well tolerated The impact of concomitant administration of this new oral
in these patients [35]. formulation of semaglutide with other drug classes that
Many patients with T2D also have underlying comorbidi- are commonly administered in patients with T2D has also
ties that may affect the pharmacokinetic profile of treatment, been evaluated (Table 1). Two open-label, single-sequence,
and of particular importance is the impact of renal or hepatic crossover trials of healthy volunteers (trial 1: N = 52; trial 2:
impairment. The effect of renal impairment on exposure to N = 32) demonstrated that there were no clinically relevant
oral semaglutide was investigated in individuals (N = 71) effects of oral semaglutide (20 mg) on the plasma concentra-
with varying degrees of renal impairment [normal func- tion-time curve (AUC) and maximum plasma concentration
tion, mild, moderate, severe, and end-stage renal disease (Cmax) for the antihypertensive drug lisinopril (20 mg sin-
(ESRD)] [36]. After 10 consecutive days of once-daily oral gle dose [trial 1]), the anticoagulant agent warfarin (25 mg
administration, no consistent or clinically relevant pattern of single dose [trial 1]), or digoxin (500 μg [trial 2]) [42]. The
increase or decrease in semaglutide exposure was observed AUC of metformin (administered at 850 mg twice daily for
between individuals with varying degrees of renal function. 4 days [trial 2]) was increased by 32% [90% confidence
Hemodialysis did not appear to affect the pharmacokinetics interval (CI) 1.23−1.43] in individuals receiving oral sema-
of oral semaglutide or SNAC [36]. The pharmacokinetics, glutide and metformin versus those receiving metformin
safety, and tolerability of oral semaglutide were also studied alone. Given the broad therapeutic window for metformin,
in patients (N = 56) with varying degrees of hepatic impair- it was concluded that the increase in exposure was not clini-
ment (normal function, mild, moderate, and severe) over cally relevant, and is likely due to the known effect of GLP-
ten doses [37]. This study was important as there had been 1RAs for delaying gastric emptying. Administration of SNAC
no previous reported data on the possible effects of hepatic (300 mg) alone did not affect exposure/absorption of any of
impairment on the pharmacokinetics of SNAC, which is the agents [42].
metabolized via β-oxidation and glucuronidation and is Statins and diuretics may be used in patients with T2D
highly bound to albumin. Semaglutide exposure appeared for the management of dyslipidemia and hypertension,
to be similar across all four hepatic impairment groups, and respectively. A study of healthy volunteers (N = 41) investi-
no semaglutide was detected in any of the urine samples. gated whether oral semaglutide could potentially influence
SNAC exposure did increase with decreases in hepatic func- exposure to furosemide or rosuvastatin. Single doses of
tion, with the greatest increase seen in patients with severe furosemide (40 mg) and rosuvastatin (20 mg) alone were
hepatic impairment (3.64 times higher than patients with co-administered with SNAC (300 mg) or oral semaglutide
normal hepatic function). This increase in SNAC was not [43]. Co-administration of single-dose furosemide with
considered clinically relevant as it has no anticipated phar- steady-state oral semaglutide resulted in a 28% increase in
macodynamic effects [37]. total furosemide exposure (AUC0––∞) and a 34% decrease
in Cmax compared with patients not receiving oral semaglu-
2.3 Pharmacodynamics tide. When co-administered with SNAC alone, there was
no effect on the AUC0–∞ of single-dose furosemide, while
The effects of oral semaglutide on fasting and post-prandial Cmax decreased by 10%. Administration of single-dose
glucose and on lipid metabolism were investigated in a dou- rosuvastatin with oral semaglutide at steady state resulted
ble-blinded crossover trial of 15 individuals with T2D. Oral in a 41% increase in AUC0–∞ and a 10% increase in Cmax
1008 A. Andersen et al.
for rosuvastatin compared with patients not receiving oral no change in clinical practice is required as close monitoring
semaglutide. Pharmacokinetic parameters for rosuvasta- of thyroxine is already part of medical guidance [32].
tin were unchanged by co-administration of SNAC alone. Female patients with T2D may also take concomitant
Changes in exposure of furosemide and rosuvastatin when birth control medication and, therefore, an open-label study
co-administered with semaglutide may also be related to of healthy postmenopausal women (N = 25) was conducted
the known effect of GLP-1RAs for delaying gastric empty- to assess the effect of oral semaglutide on the pharmacoki-
ing. The authors concluded that the changes in exposure netics of the combined oral contraceptive ethinylestradiol
observed for furosemide and rosuvastatin are unlikely to be (0.03 mg)/levonorgestrel (0.15 mg). Exposure to ethinyle-
clinically relevant [43]. It has been suggested that a delay stradiol and levonorgestrel was similar when administered
in gastric emptying may also contribute to the changes in alone or with oral semaglutide, indicating that their bio-
pharmacokinetics (33% increase in AUC0–48 h) observed for availability is not affected by co-administration with oral
levothyroxine when coadministered with oral semaglutide in semaglutide [44].
a study of 45 healthy volunteers. Although the pharmacoki-
netics of levothyroxine were influenced by oral semaglutide,
A Pharmacological and Clinical Overview of Oral Semaglutide for the Treatment of Type 2 Diabetes 1009
3 Oral Semaglutide Clinical Trial Program premature trial product discontinuation) was the primary
estimand in all trials except PIONEER 9 [46–50, 52–55],
A phase II dose-finding study paved the way for the large and data for this estimand are reported in our review.
phase III clinical program for oral semaglutide [45]. This
dose-finding study included 632 patients with T2D (mean
diabetes duration 6.3 years and mean baseline H bA1c 7.9%) 4 Therapeutic Efficacy
and assessed the dose–response relationship on glycemic
control [mean change in hemoglobin A1c (HbA1c)] of once- 4.1 Glycemic Control
daily oral semaglutide (2.5, 5, 10, 20, and 40 mg dose esca-
lated over 4 weeks) versus placebo (double-blind) and s.c. The results for HbA1c changes from baseline in active-com-
semaglutide (open-label). Mean change in H bA1c from base- parator trials, placebo and active-comparator trials, and
line to week 26 was − 0.7 to − 1.9% with increasing doses of placebo-controlled trials are shown in Fig. 2.
oral semaglutide, − 1.9% with once-weekly s.c. semaglutide,
and − 0.3% with placebo. Reductions with oral semaglu- 4.1.1 Active‑Comparator Trials
tide were significant versus placebo [dose-dependent esti-
mated treatment difference (ETD) range for oral semaglutide The effects of oral semaglutide were investigated versus both
vs. placebo was − 0.4 to − 1.6% (p < 0.05 for 2.5 mg and oral and s.c. comparators. Oral semaglutide 14 mg was found
p < 0.001 for all other doses)]. Fewer adverse events (AEs) to be superior in reducing HbA1c versus empagliflozin (25
were reported when patients initiated oral semaglutide at a mg) (PIONEER 2) at 26 weeks (ETD − 0.4%; p < 0.001)
low (2.5 mg) versus a higher dose (5 mg) [45]. when used as second-line treatment in patients uncon-
Based on the findings of this phase II study, the efficacy trolled on metformin. The glucose-lowering effects were
and safety of three doses of oral semaglutide (3, 7, and sustained to week 52 [47]. Oral semaglutide (7 and 14 mg)
14 mg) were investigated in the Peptide InnOvatioN for also provided superior improvements in H bA1c versus sit-
Early diabEtes tReatment (PIONEER) phase III clinical agliptin (100 mg) at week 26 (ETD − 0.3% and − 0.5%,
trial program, which included eight multinational studies respectively; both p < 0.001) in patients with T2D uncon-
(PIONEER 1−8) [44–53] and two Japan-specific studies trolled on metformin with or without an SU (PIONEER 3)
(PIONEER 9 and 10) [54, 55]. Individuals recruited for [48]. The glycemic effects of oral semaglutide versus sitag-
this program were patients with T2D from across a broad liptin were maintained at both week 52 [ETD − 0.3 (7 mg)
range of disease durations and background therapies, and and − 0.5 (14 mg), respectively; p < 0.001] and week 78
representative of many patients typically encountered in [ETD − 0.4% (14 mg); p < 0.001] [48]. The observations
clinical practice (Table 2). The comparators in the PIO- from both studies indicate that oral semaglutide is an effec-
NEER program were placebo (PIONEER 1, 4, 5, 6, and tive strategy for intensification of glycemic therapy in
8), empagliflozin 25 mg (PIONEER 2), sitagliptin 100 patients with T2D uncontrolled on metformin in the context
mg (PIONEER 3 and 7), liraglutide 1.8 mg (PIONEER 4) of other oral glucose-lowering agents.
and 0.9 mg (PIONEER 9), and dulaglutide 0.75 mg (PIO- A study investigating a flexible dose-adjustment approach
NEER 10). It is important to note that the doses of lira- for oral semaglutide (increasing or decreasing dose depend-
glutide (0.9 mg) and dulaglutide (0.75 mg) used in the ing on efficacy and gastrointestinal tolerability) noted that
Japanese studies (PIONEER 9 and 10, respectively) were oral semaglutide was more effective than sitagliptin (100 mg)
selected as these were the approved maintenance doses of in reducing H bA1c at week 52 (ETD − 0.5%; p < 0.001)
these GLP-1RAs in Japan at the time of trial design, and [52]. This is of particular interest because a flexible dose-
they are not the maximum doses typically used in global adjustment approach perhaps more closely replicates the
populations. Common inclusion criteria for the trials were: individualized approach of adjusting treatment dose accord-
adults (typically aged ≥ 18 years, although slightly older age ing to efficacy and tolerability that could be implemented in
criteria were used in some countries), a diagnosis of T2D clinical practice [52].
at least 30−90 days prior to screening, and H bA1c within Oral semaglutide was compared with the s.c. GLP-1RA
a prespecified range [this range differed slightly between dulaglutide (0.75 mg) in Japanese patients (PIONEER 10)
trials (Table 2)] [46–50, 52–55]. The primary and con- [55]. Reductions in HbA1c with oral semaglutide 7 mg were
firmatory secondary endpoints in most of the trials were similar to those seen with s.c. dulaglutide at weeks 26 and
change from baseline in HbA1c and body weight, respec- 52; however, oral semaglutide (14 mg) reduced HbA1c sig-
tively, at week 26, with the exception of the PIONEER 6, nificantly more than dulaglutide at weeks 26 (ETD − 0.4;
7, and 10 trials (Table 2). The treatment policy estimand p < 0.001) and 52 (ETD − 0.3; p < 0.05).
(data assessed regardless of rescue medication use or
Table 2 Overview of the design and baseline patient characteristics from the PIONEER trial program
1010
Study duration 52 weeks 78 weeks 52 weeks 52 weeks 52 weeks 52 weeks 52 weeks 26 weeks 26 weeks Event-driven
Patient popula- Multinational; Multinational; Multinational; Japan; T2D Japan; T2D Multinational; Multinational; Multinational; Multinational; Multinational;
tion T2D T2D T2D T2D T2D T2D T2D and T2D and high
moderate CV risk
renal impair-
ment
Number of 822a 1,864 504 458 243 711 731 703 324 3,183
patients
Comparators Oral sema 14 mg Oral sema 3 mg Oral sema flex Oral sema 3 mg Oral sema 3 mg Oral sema 14 mg Oral sema 3 mg Oral sema 3 mg Oral sema 14 mg Oral sema 14 mg
Empa 25 mg Oral sema 7 mg Sita 100 mg Oral sema 7 mg Oral sema 7 mg Lira 1.8 mg Oral sema 7 mg Oral sema 7 mg Placebo Placebo
Oral sema 14 mg Oral sema 14 mg Oral sema 14 mg Placebo Oral sema 14 mg Oral sema 14 mg
Sita 100 mg Dula 0.75 mg Lira 0.9 mg Placebo Placebo
Placebo
Background Met Met ± SU 1–2 OADsb 1 OADc Diet and Met ± SGLT2i Ins ± met Diet and exer- Met ± SU, SU Standard of care
medication exercised cise alone, or ins
± met
HbA1c inclu- 7.0–10.5% 7.0–10.5% 7.5–9.5% 7.0–10.5% 6.5–9.5% 7.0–9.5% 7.0–9.5% 7.0–9.5% 7.0–9.5% –
sion criteria
Primary end- Change in Change in Achievement Number of Change in Change in Change in Change in Change in Time to first
point HbA1c from HbA1c from of HbA1c treatment- HbA1c from HbA1c from HbA1c from HbA1c from HbA1c from occurrence of
baseline to baseline to < 7.0% emergent baseline to baseline to baseline to baseline to baseline to MACEe
week 26 week 26 (53 mmol/ AEs at week 26 week 26 week 26 week 26 week 26
mol) at week week 57
52
Key secondary Change in body Change in body Change in body Change in Change in body Change in body Change in body Change in body Change in body Expanded
endpoint(s) weight from weight from weight from HbA1c and weight from weight from weight from weight from weight from composite
baseline to baseline to baseline to body weight baseline to baseline to baseline to baseline to baseline to outcomef
weeks 26 and weeks 26, 52, week 52 at weeks 26 weeks 26 and weeks 26 and weeks 26 and week 26 week 26
52 and 78 and 52 52 52 52
Baseline characteristics
Mean age, 58 58 57 58 59 56 61 55 70 66
years
Mean HbA1c, 8.1 (65) 8.3 (67) 8.3 (67) 8.3 (68) 8.2 (66) 8.0 (64) 8.2 (66) 8.0 (63) 8.0 (64) 8.2 (66)
% (mmol/
mol)g
A. Andersen et al.
Table 2 (continued)
Active-controlled trials Active- and placebo-controlled Placebo-controlled trials
trials
PIONEER 2 PIONEER 3 PIONEER 7 PIONEER 10 PIONEER 9 PIONEER 4 PIONEER 8 PIONEER 1 PIONEER 5 PIONEER 6
[47] [48] [52] [55] [54] [49] [53] [46] [50] [51, 64]
Mean duration 7.4 8.6 8.8 9.4 7.6 7.6 15.0 3.5 14.0 14.9
of diabetes,
years
Mean body 91.6 91.2 88.6 72.1 71.1 94.0 85.9 88.1 90.8 90.9
weight, kg
Study: PIONEER 2 PIONEER 3 PIONEER 7 PIONEER 10 PIONEER 9 PIONEER 4 PIONEER 8 PIONEER 1 PIONEER 5
Population: T2D T2D T2D Japanese T2D Japanese T2D T2D T2D T2D T2D + MRI
Study duration: 52 weeks 78 weeks 52 weeks 52 weeks 52 weeks 52 weeks 52 weeks 26 weeks 26 weeks
Background therapy: Met Met ± SU 1–2 OAD 1 OAD Diet/exercise Met ± SGLT2i Ins ± met Diet/exercise Met ± SU,
SU alone,
or ins ± met
BL HbA1c: 8.1 8.3 8.3 8.3 8.2 8.0 8.2 8.0 8.0
0.0
–0.1
–0.2 –0.2
Change from baseline
–0.3
–0.5 –0.4
in HbA1c (%)
–0.6 –0.6
Week 26
§§ ***
–0.8
–1.0 –0.9 –0.9 –0.9
–1.0 *** *** –1.0
††† –1.1 –1.1 –1.1 ***
§§ *** –1.2 –1.2
–1.3 –1.3 *** –1.3 *** –1.4
–1.5 ††† ††† –1.4 ***
–1.5 ***
–1.6
–1.7 *** –1.8
–2.0 ***
–2.0
††
†††
0.0
–0.1
–0.2 –0.2
Change from baseline
–0.5
in HbA1c (%)
–0.6 –0.6
Week 52
–2.0 †
0.0
Change from baseline
–0.5
in HbA1c (%)
–0.6
Week 78
–0.7
–0.8
–1.0
–1.1
†††
–1.5
–2.0
Oral semaglutide 3 mg Oral semaglutide 7 mg Oral semaglutide 14 mg Oral semaglutide flexible dose Placebo
Empagliflozin 25 mg Sitagliptin 100 mg Liraglutide 1.8 mg Liraglutide 0.9 mg Dulaglutide 0.75 mg
Fig. 2 Reductions in H
bA1c with oral semaglutide in the PIO- are for the treatment policy estimand (regardless of premature treat-
NEER program. *p < 0.05, **p < 0.01, ***p < 0.001 favoring oral ment discontinuation or rescue medication use). BL baseline, HbA1c
semaglutide vs. placebo. †p < 0.05, ††p < 0.01, †††p < 0.001 favor- glycated hemoglobin, ins insulin, met metformin, MRI moderate renal
ing oral semaglutide vs. active comparator. §p < 0.05, §§p < 0.01, impairment, OAD oral antidiabetes drug, SGLT2i sodium-glucose co-
§§§
p < 0.001 favoring active comparator vs. oral semaglutide. Data transporter-2 inhibitor, SU sulfonylurea, T2D type 2 diabetes
4.1.2 Active‑ and Placebo‑Controlled Trials In another study (PIONEER 4), oral semaglutide (14 mg)
was compared with both placebo and liraglutide (1.8 mg),
Oral semaglutide was compared with both placebo and liraglu- with liraglutide used at a dose more commonly used globally
tide (0.9 mg) in a Japanese patient population (PIONEER 9) in routine clinical practice [49]. Oral semaglutide was found
[54]. Oral semaglutide significantly reduced HbA1c ver- to be superior to placebo in reducing HbA1c at week 26
sus placebo at all doses (ETD − 0.8 to − 1.4%; p < 0.001) in patients with T2D uncontrolled on metformin with or
at weeks 26 and 52. The change in HbA1c at week 26 was without an SGLT2i (ETD − 1.1%; p < 0.001) [49]. HbA1c
similar for the 7 mg dose of oral semaglutide versus lira- reductions at week 26 were found to be similar with oral
glutide; however, a significantly greater reduction in H
bA1c semaglutide (14 mg) versus s.c. liraglutide (1.8 mg) at
was observed for the 14 mg dose (ETD − 0.4; p < 0.01). At 26 weeks (ETD − 0.1%; p = ns), but a significant improve-
week 52, the difference between oral semaglutide 14 mg and ment in HbA1c reduction was seen with oral semaglutide
liraglutide (ETD − 0.3) was no longer significant.
A Pharmacological and Clinical Overview of Oral Semaglutide for the Treatment of Type 2 Diabetes 1013
compared with liraglutide (ETD − 0.3; p < 0.001) and pla- reductions in body weight compared with sitagliptin (100 mg)
cebo (ETD − 1.0; p < 0.001) at week 52. [ETD − 0.6 kg (3 mg) to − 2.5 kg (14 mg); p < 0.05 for all
doses] at week 26, and these effects were sustained for the
4.1.3 Placebo‑Controlled Trials duration of the trial (PIONEER 3) [48]. When flexible dose-
adjustment of oral semaglutide was used, body weight was
In patients with T2D uncontrolled by diet and exercise (PIO- also reduced significantly compared with sitagliptin (100 mg)
NEER 1), once-daily oral semaglutide monotherapy (3, 7, (ETD − 1.9 kg at week 52; p < 0.001) [52]. Benefits on
and 14 mg) demonstrated superior improvements in H bA1c body weight were also observed in a Japanese patient popu-
versus placebo at week 26 [ETD − 0.6% (3 mg) to − 1.1% lation (PIONEER 10) in which treatment with oral sema-
(14 mg); p < 0.001 for all] [46]. glutide (7 and 14 mg) resulted in significantly reduced body
Benefits were also observed in patients with more weight compared with once-weekly dulaglutide at week 26
advanced T2D receiving background insulin (PIONEER 8). (ETD − 1.3 kg; p < 0.01 and − 2.5 kg; p < 0.001, respec-
Oral semaglutide reduced H bA1c significantly more than tively) and at week 52 (ETD − 1.9 kg; p < 0.001 and − 2.6;
placebo at week 26 [ETD − 0.5% (3 mg), − 0.9% (7 mg), p < 0.001) [55].
− 1.2% (14 mg); p < 0.001 for all] [53]. Significant reduc-
tions in H
bA1c for all doses were also observed at week 52. 4.2.2 Active‑ and Placebo‑Controlled Trials
These findings indicate that addition of oral semaglutide is
an effective treatment intensification strategy for patients Significant reductions in body weight were observed in Japa-
who are unable to reach, or maintain, HbA1c targets with nese patients treated with oral semaglutide (14 mg) com-
insulin alone. pared with both placebo (ETD − 1.2 kg; p < 0.01) and lira-
glutide (− 2.3 kg; p < 0.001) at week 26, and these benefits
4.1.4 Special Populations were maintained at week 52 (PIONEER 9) [54]. Oral sema-
glutide (14 mg) also provided a significantly greater body
As mentioned previously, many patients with T2D have weight reduction compared with placebo (ETD − 3.8 kg;
accompanying comorbidities, with CV and renal comor- p < 0.001) and liraglutide (1.8 mg) at week 26 in a global
bidities being the most common [56, 57]. Oral semaglutide population [ETD − 1.2 kg; p < 0.001 (PIONEER 4)], and
was therefore investigated in these patient populations. In again these effects were sustained at week 52 [49]. These
the PIONEER 5 trial, which enrolled patients with moder- observations suggest that oral semaglutide may provide
ate renal impairment (estimated glomerular filtration rate some weight management benefits versus other commonly
30–59 mL/min/1.73 m2), oral semaglutide 14 mg was found prescribed s.c. GLP-1RAs.
to be significantly more effective than placebo in reducing
HbA1c at week 26 (ETD − 0.8%; p < 0.001), highlighting 4.2.3 Placebo‑Controlled Trials
that oral semaglutide is a suitable option for achieving glyce-
mic control in this patient group [50]. In patients at high CV In patients with T2D uncontrolled on lifestyle modifications,
risk, HbA1c levels decreased by 1.0% with oral semaglutide oral semaglutide (14 mg) monotherapy significantly reduced
and by 0.3% with placebo at the end of the trial; however, body weight versus placebo (ETD − 2.3 kg at week 26;
no statistical comparison of the H bA1c reductions was per- p < 0.001). No significant changes versus placebo were
formed [51]. observed for the oral semaglutide 3 and 7 mg doses (PIO-
NEER 1) [46]. Weight management is particularly important
4.2 Body‑Weight Reduction for patients managed with insulin-based regimens, as insulin
treatment is commonly associated with weight gain [1]. Oral
In addition to the glycemic benefits described, oral semaglu- semaglutide was shown to be a suitable treatment option
tide has also been shown to be effective in reducing body in this patient population, with body weight being reduced
weight in patients with T2D on a variety of different back- versus placebo at week 26 [ETD − 0.9 kg (3 mg) to − 3.3 kg
ground glucose-lowering therapies (Fig. 3). (14 mg); p < 0.05 for all], and the effects being sustained to
week 52 (PIONEER 8) [53].
4.2.1 Active‑Comparator Trials
4.2.4 Special Populations
Body-weight reductions were found to be similar for oral
semaglutide compared with empagliflozin [ETD − 0.1 kg In patients with moderate renal impairment, body-weight
(p = 0.76) and − 0.2 kg (p = 0.62) at weeks 26 and 52, reductions were observed with oral semaglutide (14 mg)
respectively] (PIONEER 2; Fig. 3) [47]. All three doses of compared with placebo (ETD − 2.5 kg at 26 weeks;
oral semaglutide were associated with significantly greater p < 0.001) [50]. Although there was no statistical
1014 A. Andersen et al.
Study: PIONEER 2 PIONEER 3 PIONEER 7 PIONEER 10 PIONEER 9 PIONEER 4 PIONEER 8 PIONEER 1 PIONEER 5
Population: T2D T2D T2D Japanese T2D Japanese T2D T2D T2D T2D T2D + MRI
Study duration: 52 weeks 78 weeks 52 weeks 52 weeks 52 weeks 52 weeks 52 weeks 26 weeks 26 weeks
Background therapy: Met Met ± SU 1–2 OAD 1 OAD Diet/exercise Met ± SGLT2i Ins ± met Diet/exercise Met ± SU,
SU alone,
or ins ± met
BL body weight (kg): 91.6 91.2 88.6 72.1 71.1 94.0 85.9 88.1 90.8
1.0
0.3
0.0
Change from baseline
in body weight (kg)
–0.0
–0.2 –0.4
–0.6 –0.6 –0.5
–1.0 –0.9
–1.0
Week 26
0.0
–0.3
† –0.6
–1.0 –0.8 –0.7
–0.9 –0.8 –0.8
–1.0
Week 52
††† *
–2.0 –1.6 –1.6
†† ††† –2.0
–2.4 ***
–3.0 –2.6 –2.6
†††
††† *** –3.0
–3.4 †††
–4.0 –3.6 –3.7
–3.8 †††
***
–4.3
–5.0 ***
††
1.0
0.0
Change from baseline
in body weight (kg)
–1.0
–1.0
Week 78
–2.0
–1.8
†
–3.0 –2.7
††† –3.2
–4.0 †††
–5.0
Oral semaglutide 3 mg Oral semaglutide 7 mg Oral semaglutide 14 mg Oral semaglutide flexible dose Placebo
Empagliflozin 25 mg Sitagliptin 100 mg Liraglutide 1.8 mg Liraglutide 0.9 mg Dulaglutide 0.75 mg
Fig. 3 Reductions in body weight with oral semaglutide in the PIO- are for the treatment policy estimand (regardless of premature
NEER program. *p < 0.05, **p < 0.01, ***p < 0.001 favoring oral treatment discontinuation or rescue medication use). BL baseline,
semaglutide vs. placebo. †p < 0.05, ††p < 0.01, †††p < 0.001 favor- ins insulin, met metformin, MRI moderate renal impairment, OAD
ing oral semaglutide vs. active comparator. §p < 0.05, §§p < 0.01, oral antidiabetes drug, SGLT2i sodium-glucose co-transporter-2
§§§
p < 0.001 favoring active comparator vs. oral semaglutide. Data inhibitor, SU sulfonylurea, T2D type 2 diabetes
comparison of bodyweight changes with treatment in the the active comparators (except liraglutide in PIONEER 4) or
CV safety trial, by the end of that study in patients at high placebo in each study (Table 3) [46–50, 53–55]. The propor-
CV risk, body weight had decreased by 4.2 kg with oral tion of patients achieving H bA1c < 7% at later time points
semaglutide and by 0.8 kg with placebo [51]. (weeks 52 and 78) with oral semaglutide was maintained in
some studies, while in others a slight decrease in the propor-
4.3 Additional Secondary Endpoints of Interest tion of patients achieving this target was observed (Table 3)
[47–49, 53–55], which is perhaps not surprising given the
Achieving a target HbA1c of < 7.0% (53 mmol/mol) is progressive nature of T2D.
another established measure of glycemic control [58]. The The benefits of flexible dose-adjustment of oral semaglu-
proportion of patients achieving this target with oral sema- tide on glycemic control versus sitagliptin occurred despite
glutide (14 mg or flexibly dosed) at the time point for the greater use of rescue medication in patients receiving sitag-
primary endpoint [i.e., week 26 except for PIONEER 7 liptin [52]. In general, across the PIONEER clinical trials,
(week 52)] was consistently greater than that seen with all the use of rescue medication was low, occurring in less than
A Pharmacological and Clinical Overview of Oral Semaglutide for the Treatment of Type 2 Diabetes 1015
5% of patients who received oral semaglutide 7 or 14 mg important, oral semaglutide (14 mg) reduced SBP by
after 26 weeks of treatment, and this was typically less than 7 mmHg versus 0 mmHg with placebo (p < 0.001) [51].
the prevalence of rescue medication use seen with placebo
(5–15% at week 26) [46–50, 53–55]. 4.4 Patient‑Reported Outcomes
For patients with T2D receiving insulin therapy (PIO-
NEER 8), incorporation of oral semaglutide into the treat- While the effects of oral semaglutide on glycemic con-
ment regimen permitted reductions in insulin dosage for the trol and body weight are of prime importance, it is widely
majority of patients. Indeed, after 26 weeks on oral sema- accepted that there is a need for healthcare professionals
glutide 14 mg, patients were on average receiving 8 units/ to consider other factors when managing T2D [1]. These
day less insulin than patients on placebo (p < 0.001), and factors include patient-reported outcomes (PROs), which
by 52 weeks the disparity in insulin requirements was even can assess the impact of treatment on physical function and
greater (ETD –17 units/day; p < 0.001) [53]. psychological aspects, such as treatment satisfaction, patient
The effects of oral semaglutide on a composite endpoint wellbeing, and quality of life (QoL) [60]. In the PIONEER
of HbA1c < 7% (53 nmol/mol) without severe or blood glu- clinical program, five PRO tools were used to measure
cose-confirmed [<3.1 mmol/L (56 mg/dL)] hypoglycemia patient satisfaction about treatment with semaglutide versus
and with no weight gain were also examined. In general, comparators, and the impact of treatment with semaglutide
a greater proportion of patients achieved this endpoint at on wellbeing, QoL, physical functioning, and so forth.
week 26 when treated with the 7 and 14 mg doses versus oral Observations from the Diabetes Treatment Satisfaction
active comparators (empagliflozin and sitagliptin) (Table 3) Questionnaire revealed that satisfaction with treatment,
[47, 48]. In Japanese studies, a greater proportion of patients and convenience and flexibility of treatment were similar
achieved the composite endpoint of H bA1c < 7% (53 nmol/ between patients receiving flexibly dosed oral semaglutide
mol) without hypoglycemia and no weight gain with oral and a commonly used glucose-lowering agent, sitagliptin
semaglutide (14 mg) compared with the s.c. GLP-1RAs [52]. This may suggest that the dosing conditions of oral
liraglutide (0.9 mg) (week 26: 70% vs. 33%; p < 0.001 for semaglutide are not a major factor in treatment satisfac-
estimated odds ratio) and dulaglutide (0.75 mg) (week 26: tion relative to another oral glucose-lowering agent. Patient
66% vs. 39%; p < 0.001 for estimated odds ratio) [54, 55]. It perceptions about treatment and, more specifically, dosing
is, however, important to note that the GLP-1RA compara- conditions with oral semaglutide, were also investigated as
tors in both these Japanese studies were investigated at doses part of a survey of study staff (N = 1,140) from the PIO-
that are lower than used in many other countries. Indeed, NEER trials. Of the study staff responders (n = 544) the
the odds of achieving this composite endpoint were not oral semaglutide dosing conditions were perceived to be
significantly different with oral semaglutide 14 mg versus easy/very easy, neutral, or hard by 79.1%, 19.1%, and 1.8%,
liraglutide 1.8 mg [49], a dose more commonly used in rou- respectively [61].
tine clinical practice worldwide. As expected, more patients The CoEQ is a validated PRO tool designed to assess the
achieved the composite endpoint HbA1c < 7% (53 nmol/mol) intensity and type of food cravings in addition to subjective
without hypoglycemia and no weight gain for all investigated sensations of appetite and mood [62]. Improvements in favor
doses of oral semaglutide versus placebo, including in the of oral semaglutide versus empagliflozin were observed for
study of patients with moderate renal impairment [46, 49, the “craving control” and “craving for savory” domains in
50, 53, 54]. the PIONEER 2 study [47]. This is an interesting finding
A post hoc analysis of the PIONEER 1−5 and 8 trials given that body-weight changes reported in this study were
evaluated the response of any reduction in HbA1c (%) and/ similar for both treatments.
or body weight (%), and a clinically relevant composite end- The Impact of Weight on Quality of Life questionnaire
point of H
bA1c reduction ≥ 1% and body-weight loss ≥ 5%, Clinical Trial Version (IWQOL-Lite-CT) was used to assess
with oral semaglutide (14 mg) versus comparators at the end weight management in the PIONEER 3 and 8 studies. Rosen-
of treatment (26−78 weeks). Oral semaglutide was shown stock et al. reported that the ETDs significantly favored
to be more effective than comparators in providing both an oral semaglutide (7 and 14 mg) over sitagliptin (100 mg)
HbA1c reduction ≥ 1% and body-weight loss ≥ 5% [59]. at week 52 for physical function domains. Moreover, oral
Across most of the PIONEER studies, oral semaglu- semaglutide improved psychosocial (7 mg) and physical
tide reduced systolic blood pressure (SBP) by 1–6 mmHg, (14 mg) domains, and IWQOL-Lite-CT total scores (7 mg)
with many reductions achieving statistical significance for at week 52 compared with sitagliptin [48]. However, these
oral semaglutide (14 mg) versus placebo (Table 3) [46–49, effects were not apparent at earlier or later time points. For
52–55]. In patients with T2D and renal impairment, for patients receiving insulin in PIONEER 8, the ETD favored
whom effective blood pressure regulation is particularly oral semaglutide (14 mg) over placebo for the psychosocial
domain and for the IWQOL-Lite-CT total score at weeks 26
1016 A. Andersen et al.
Table 3 Efficacy of oral semaglutide in patients with T2D, summary of observations from key supportive secondary endpoints in the phase III
clinical trials
Trial Time Treatment (no. of patients) Endpoint
point
% achieving % achieving compos- Estimated
HbA1c < 7% (53 ite HbA1c < 7% (53 mean change
mmol/mol) mmol/mol) without from baseline
hypoglycemiaa and no SBP (mmHg)
weight gain (on-treatment
period)
Active-comparator trials
PIONEER 2 [47] Week 26 Oral semaglutide 14 mg (n = 411) 66.8††† 60.5††† −5
Population and back- Empagliflozin 25 mg (n = 410) 40.0 35.7 −5
ground therapy: patients
Week 52 Oral semaglutide 14 mg (n = 411) 66.1††† 55.7††† −5
with T2D on metformin
Empagliflozin 25 mg (n = 410) 43.2 39.0 −4
PIONEER 3 [48] Week 26 Oral semaglutide 3 mg (n = 466) 27 20 −1
Population and back- Oral semaglutide 7 mg (n = 465) 42††† 34††† −3
ground therapy: patients
Oral semaglutide 14 mg (n = 465) 55††† 46††† −3
with T2D on metformin
± SU Sitagliptin 100 mg (n = 467) 32 20 −2
Week 52 Oral semaglutide 3 mg (n = 466) 27 20 −2
Oral semaglutide 7 mg (n = 465) 38† 30††† − 4†††
Oral semaglutide 14 mg (n = 465) 53††† 43††† − 3††
Sitagliptin 100 mg (n = 467) 31 20 −1
Week 78 Oral semaglutide 3 mg (n = 466) 27 20 −2
Oral semaglutide 7 mg (n = 465) 37† 31††† − 3††
Oral semaglutide 14 mg (n = 465) 44††† 34††† − 3†
Sitagliptin 100 mg (n = 467) 29 19 0
PIONEER 7b [52] Week 52 Oral semaglutide flexible dose (n = 253) 58††† 45††† −4
Population and back- Sitagliptin 100 mg (n = 251) 25 15 −2
ground therapy: patients
with T2D on 1–2 oral
glucose-lowering drugsc
PIONEER 10 [55] Week 26 Oral semaglutide 3 mg (n = 131) 46§§§ 30 −3
Population and back- Oral semaglutide 7 mg (n = 132) 75 49 −5
ground therapy: Japa-
Oral semaglutide 14 mg (n = 130) 82† 66††† −6
nese patients with T2D
on one oral glucose- Dulaglutide 0.75 mg (n = 65) 70 39 −3
lowering drugd Week 52 Oral semaglutide 3 mg (n = 131) 34§§ 18 −2
Oral semaglutide 7 mg (n = 132) 60 41† −2
Oral semaglutide 14 mg (n = 130) 71†† 56††† −2
Dulaglutide 0.75 mg (n = 65) 51 25 −1
Active- and placebo-controlled trials
PIONEER 9 [54] Week 26 Oral semaglutide 3 mg (n = 49) 52*** 33** −3
Population and back- Oral semaglutide 7 mg (n = 49) 69*** 53*** −4
ground therapy: Japa-
Oral semaglutide 14 mg (n = 48) 81***† 70***†† −2
nese patients with T2D
on diet and exercise Liraglutide 0.9 mg (n = 48) 53 33 −1
Placebo (n = 49) 16 8 −4
Week 52 Oral semaglutide 3 mg (n = 49) 43** 28* −1
Oral semaglutide 7 mg (n = 49) 63*** 53***†† −1
Oral semaglutide 14 mg (n = 48) 72*** 62***†† −2
Liraglutide 0.9 mg (n = 48) 49 24 1
Placebo (n = 49) 14 8 −3
A Pharmacological and Clinical Overview of Oral Semaglutide for the Treatment of Type 2 Diabetes 1017
Table 3 (continued)
Trial Time Treatment (no. of patients) Endpoint
point
% achieving % achieving compos- Estimated
HbA1c < 7% (53 ite HbA1c < 7% (53 mean change
mmol/mol) mmol/mol) without from baseline
hypoglycemiaa and no SBP (mmHg)
weight gain (on-treatment
period)
All data presented are for the treatment policy estimand (regardless of treatment discontinuation or rescue medication use). Data have been
rounded to the nearest whole number. Systolic blood pressure data expressed are on-treatment
For patients achieving H
bA1c or composite targets, observed proportions are given except for PIONEER 3 (where estimated proportions were
reported) and p values are for the odds of achieving target
HbA1c glycated hemoglobin, SBP systolic blood pressure, SGLT2i sodium-glucose co-transporter-2 inhibitor, SU sulfonylurea, T2D type 2 diabe-
tes, TZD thiazolidinedione
*
p < 0.05, **p < 0.01, ***p < 0.001 favoring oral semaglutide vs. placebo
†
p < 0.05, ††p < 0.01, †††p < 0.001 favoring oral semaglutide vs. active comparator
§
p < 0.05, §§p < 0.01, §§§p < 0.001 favoring active comparator vs. oral semaglutide
a
Severe hypoglycemia (based on the American Diabetes Association classification) or confirmed hypoglycemia based on blood glucose <56 mg/
dL (< 3.1 mmol/L) with symptoms consistent with hypoglycemia
b
Oral semaglutide was initiated at 3 mg once daily; dose adjustment was performed every 8 weeks, with doses increased (to 7 mg and then
14 mg) if HbA1c was ≥ 7.0% (≥ 53 mmol/mol), maintained if HbA1c was < 7.0% (< 53 mmol/mol), and reduced (minimum dose of 3 mg) if
moderate-to-severe nausea or vomiting was reported in the 3 days within the week prior to the dose adjustment assessment (regardless of HbA1c
level). Achievement of H
bA1c < 7% (53 mmol/mol) was the primary endpoint in this study
c
Including metformin, SU, SGLT2i, or TZD
d
Including SU, glinide, TZD, alpha-glucosidase inhibitor, or SGLT2i
e
Estimated glomerular filtration rate 30–59 mL/min/1.73 m2
1018 A. Andersen et al.
and 52 [53]. For these patients, it may be that reductions in (Table 4). The peak occurrence of nausea was also reported
body weight are associated with improvements in patient to be earlier with liraglutide (approximately 2 weeks) com-
mood. Improvements were also observed in some health- pared with oral semaglutide (8 weeks) [49], potentially
related QoL domains and component summaries in patients reflecting the quicker dose escalation that occurs with lira-
with T2D and moderate renal impairment (PIONEER 5) and glutide. Constipation was also a common AE reported by
in those receiving insulin (PIONEER 8), as measured using patients in the Japan-specific PIONEER 9 and 10 trials,
the well-established Short Form (SF)-36v2™ questionnaire occurring in 9–15% of patients with oral semaglutide ver-
[50, 53]. sus 9% with dulaglutide (0.75 mg) and 19% with liraglutide
In the Japanese patient population, total scores for the (0.9 mg) [54, 55].
Diabetes Therapy-Related Quality of Life questionnaire Currently, the only clinical trial reporting an incidence
for oral semaglutide (7 and 14 mg) were similar to those of gastrointestinal AEs for both s.c. and oral formulations
observed with liraglutide and slightly better than those seen of semaglutide is the 26-week, phase II, dose-ranging study
with placebo (PIONEER 9), while improvements in Diabe- [45]. Gastrointestinal AEs were reported in similar propor-
tes Therapy-Related Quality of Life scores for anxiety and tions of patients in the s.c. semaglutide (1.0 mg) and oral
dissatisfaction with treatment, and total score, were observed semaglutide (10 and 20 mg) groups, which were the doses
with oral semaglutide (7 and 14 mg) compared with dulaglu- of oral semaglutide closest to the maximum approved oral
tide at week 52 in PIONEER 10 [54, 55]. These observations semaglutide dose (14 mg) in the study [45]. An exposure-
may reflect the oral versus s.c. delivery. response analysis of data from the SUSTAIN and PIONEER
programs for s.c. and oral semaglutide has demonstrated a
consistent relationship between greater exposure to semaglu-
5 Safety and Tolerability tide and increases in the incidence of gastrointestinal AEs
regardless of formulation [33], suggesting that exposure,
Safety and tolerability findings for oral semaglutide in rather than route of administration, is the determinant of
the PIONEER studies are summarized in Table 4, and are such events.
broadly consistent with the known safety and tolerability In the PIONEER 1−8 studies, discontinuation due to
profile of a GLP-1RA. Overall, the doses of oral semaglutide gastrointestinal AEs was the most common cause of prema-
investigated in the PIONEER trials were generally well tol- ture trial product discontinuations (Table 4), occurring in
erated, with AEs typically reported in similar proportions of 1.7–12% of patients across oral semaglutide study groups
patients in the oral semaglutide, placebo, and active-compar- [46–53].
ator groups across all of the studies [46–50, 52–55]. Serious
AEs (SAEs) were generally reported in similar proportions 5.1.2 Hypoglycemia
of patients in the oral semaglutide, placebo, and active-com-
parator groups across studies [46–50, 52–55]. GLP-1RAs are considered to have a low inherent risk of
hypoglycemia [3, 63], owing to their glucose-dependent
5.1 Adverse Events of Special Interest mechanism of action [63]. Consistent with observations
for the GLP-1RA class as a whole, severe hypoglycemic
5.1.1 Gastrointestinal Adverse Events episodes were found to be rare in all the PIONEER stud-
ies (Table 4). For most PIONEER trials the combined inci-
Consistent with what has been reported for other GLP-1RAs dence of severe or symptomatic blood glucose-confirmed
[63], the most common AEs encountered with oral sema- [< 56 mg/dL (< 3.1 mmol/L)] hypoglycemia with oral sema-
glutide in the PIONEER trials tended to be gastrointestinal, glutide was similar to that seen with active comparators (lira-
with nausea and diarrhea generally the most common mani- glutide, empagliflozin, and sitagliptin) and placebo [46–49,
festations (Table 4) [46–50, 52–55]. In general, gastroin- 52, 54]. The proportion of patients with severe or blood
testinal AEs such as nausea mostly occurred earlier in the glucose-confirmed symptomatic hypoglycemia appeared to
study during dose initiation and escalation (i.e., during the be greater in the PIONEER 3, 5, 7, and 8 trials [48, 50, 52,
first 8−16 weeks) [46–50, 53–55]. Cases of nausea were 53] relative to the other PIONEER trials (Table 4), but this
typically mild to moderate in intensity, and transient [46–50, may be attributed to the background therapies allowed in
52–55]. In PIONEER trials that studied oral semaglutide 3, those trials, namely SUs (PIONEER 3, 5, and 7) and insulin
7, and 14 mg, the proportion of patients with gastrointestinal (PIONEER 5 and 8). Nevertheless, in these studies, the rate
AEs and the proportion of patients who discontinued treat- of severe or blood glucose-confirmed symptomatic hypogly-
ment due to gastrointestinal AEs appeared to increase with cemia with oral semaglutide was found to be similar to that
dose [46, 48, 53–55] (Table 4). As expected, gastrointestinal of sitagliptin or placebo [48, 52, 53].
AEs also occurred on treatment with GLP-1RA comparators
Table 4 Incidence of select adverse events (on-treatment) of interest during treatment in phase III clinical trials
Overall AE incidence Incidence of select GI AEsa Premature trial product discon- Hypoglycemia
tinuation
Any AE Serious AEs Nausea Diarrhea Vomiting Due to any AE Due to GI AE Severeb or Severe episodeb
n (%) n (%) n (%) n (%) n (%) n (%) n (%) BG-confirmed n (%)
symptomatic
episodec
n (%)
Active-controlled trials
PIONEER 2 [47] Oral semaglutide 289 (70) 27 (7) 81 (20) 38 (9) 30 (7) 44 (11) 33 (8) 7 (2) 1 (0)
Patient population: T2D; 14 mg (n = 410)
background therapy: metformin; Empagliflozin 283 (69) 37 (9) 10 (2) 13 (3) 7 (2) 18 (4) 3 (1) 8 (2) 1 (0)
duration: 52 weeks 25 mg (n = 409)
PIONEER 3 [48] Oral semaglutide 370 (79) 64 (14) 34 (7) 45 (10) 13 (3) 26 (6) 11 (2) 23 (5) 0 (0)
Patient population: T2D; 3 mg (n = 466)
background therapy: metformin ± SU; Oral semaglutide 363 (78) 47 (10) 62 (13) 53 (11) 28 (6) 27 (6) 16 (3) 24 (5) 0 (0)
duration: 78 weeks 7 mg (n = 464)
Oral semaglutide 370 (80) 44 (9) 70 (15) 57 (12) 42 (9) 54 (12) 32 (7) 36 (8) 1 (0)
14 mg (n = 465)
Sitagliptin 100 mg 388 (83) 58 (12) 32 (7) 37 (8) 19 (4) 24 (5) 12 (3) 39 (8) 4 (1)
(n = 466)
PIONEER 7 [52] Oral semaglutide 197 (78) 24 (9) 53 (21) 22 (9) 14 (6) 22 (9) 14 (6) 14 (6) 0 (0)
Patient population: T2D; with flexible dose
background therapy: 1–2 oral glucose- adjustmente
lowering drugsd; duration: 52 weeks (n = 253)
Sitagliptin 100 mg 172 (69) 24 (10) 6 (2) 8 (3) 2 (1) 8 (3) 2 (1) 14 (6) 0 (0)
(n = 250)
PIONEER 10 [55] Oral semaglutide 101 (77) 9 (7) 7 (5) 2 (2) 3 (2) 4 (3) 2 (2) 3 (2) 0 (0)
Patient population: Japanese patients 3 mg (n = 131)
A Pharmacological and Clinical Overview of Oral Semaglutide for the Treatment of Type 2 Diabetes
with T2D; background therapy: one oral Oral semaglutide 106 (80) 4 (3) 11 (8) 2 (2) 1 (1) 8 (6) 4 (3) 3 (2) 0 (0)
glucose-lowering drugsf; duration: 7 mg (n = 132)
52 weeks
Oral semaglutide 111 (85) 7 (5) 12 (9) 10 (8) 9 (7) 8 (6) 5 (4) 4 (3) 0 (0)
14 mg (n = 130)
Dulaglutide 0.75 mg 53 (82) 1 (2) 6 (9) 4 (6) 1 (2) 2 (3) 1 (2) 0 (0) 0 (0)
(n = 65)
1019
Table 4 (continued)
1020
Overall AE incidence Incidence of select GI AEsa Premature trial product discon- Hypoglycemia
tinuation
Any AE Serious AEs Nausea Diarrhea Vomiting Due to any AE Due to GI AE Severeb or Severe episodeb
n (%) n (%) n (%) n (%) n (%) n (%) n (%) BG-confirmed n (%)
symptomatic
episodec
n (%)
Active- and placebo-controlled trials
PIONEER 9 [54] Oral semaglutide 37 (76) 2 (4) 2 (4) 4 (8) NR 1 (2) 1 (2) 0 (0) 0 (0)
Patient population: Japanese patients 3 mg (n = 49)
with T2D background therapy: diet and
exercise; duration: 52 weeks Oral semaglutide 37 (76) 3 (6) 5 (10) 1 (2) NR 1 (2) 1 (2) 0 (0) 0 (0)
7 mg (n = 49)
Oral semaglutide 34 (71) 0 (0) 4 (8) 3 (6) NR 2 (4) 1 (2) 0 (0) 0 (0)
14 mg (n = 48)
Liraglutide 0.9 mg 32 (67) 0 (0) 0 (0) 2 (4) NR 0 (0) 0 (0) 2 (4) 0 (0)
(n = 48)
Placebo (n = 49) 39 (80) 3 (6) 1 (2) 1 (2) NR 0 (0) 0 (0) 0 (0) 0 (0)
PIONEER 4 [49] Oral semaglutide 229 (80) 31 (11) 56 (20) 43 (15) 25 (9) 31 (11) 22 (8) 2 (1) NR
Patient population: T2D; background 14 mg (n = 285)
therapy: metformin ± SGLT2i; Liraglutide 1.8 mg 211 (74) 22 (8) 51 (18) 31 (11) 13 (5) 26 (9) 17 (6) 7 (2) NR
duration: 52 weeks (n = 284)
Placebo (n = 142) 95 (67) 15 (11) 5 (4) 11 (8) 3 (2) 5 (4) 3 (2) 3 (2) NR
Placebo-controlled trials
PIONEER 8 [53] Oral semaglutide 137 (74) 25 (14) 21 (11) 16 (9) 11 (6) 13 (7) 9 (5) 52 (28) 5 (3)
Patient population: T2D; background 3 mg (n = 184)
therapy: insulin ± metformin; duration: Oral semaglutide 142 (78) 19 (10) 30 (17) 22 (12) 14 (8) 16 (9) 12 (7) 47 (26) 1 (1)
52 weeks 7 mg (n = 181)
Oral semaglutide 151 (83) 12 (7) 42 (23) 27 (15) 18 (10) 24 (13) 19 (10) 48 (27) 2 (1)
14 mg (n = 181)
Placebo (n = 184) 139 (76) 17 (9) 13 (7) 11 (6) 7 (4) 5 (3) 1 (1) 54 (29) 1 (1)
PIONEER 1 [46] Oral semaglutide 101 (58) 5 (3) 14 (8) 15 (9) 5 (3) 4 (2) 3 (2) 5 (3) 0 (0)
Patient population: T2D; background 3 mg (n = 175)
therapy: diet and exercise alone;
duration: 52 weeks Oral semaglutide 93 (53) 3 (2) 9 (5) 9 (5) 8 (5) 7 (4) 4 (2) 2 (1) 1 (1)
7 mg (n = 175)
Oral semaglutide 99 (57) 2 (1) 28 (16) 9 (5) 12 (7) 13 (7) 9 (5) 1 (1) 0 (0)
14 mg (n = 175)
Placebo (n = 178) 99 (56) 8 (4) 10 (6) 4 (2) 4 (2) 4 (2) 1 (1) 1 (1) 0 (0)
A. Andersen et al.
Table 4 (continued)
Overall AE incidence Incidence of select GI AEsa Premature trial product discon- Hypoglycemia
tinuation
Any AE Serious AEs Nausea Diarrhea Vomiting Due to any AE Due to GI AE Severeb or Severe episodeb
n (%) n (%) n (%) n (%) n (%) n (%) n (%) BG-confirmed n (%)
symptomatic
episodec
n (%)
PIONEER 5 [50] Oral semaglutide 122 (75) 17 (10) 31 (19) 17 (10) 19 (12) 24 (15) 19 (12) 9 (6) 0 (0)
Patient population: T2D with moderate renal 14 mg (n = 163)
impairmentg; background therapy: met- Placebo (n = 161) 109 (68) 17 (11) 12 (7) 6 (4) 2 (1) 8 (5) 3 (2) 3 (2) 0 (0)
formin, SU or metformin + SU, or basal
insulin ± metformin; duration: 26 weeks
PIONEER 6 [51] Oral semaglutide NR 301 (19) NR NR NR 184 (12) 108 (7) NR 23 (1)
Patient population: T2D at high CV riskh; 14 mg (n = 1591)
background therapy: standard of care; Placebo (n = 1592) NR 358 (22) NR NR NR 104 (7) 26 (2) NR 13 (1)
duration: Event driven. Median follow-up
of 16 months
All data are number of patients (% of patients); percentages have been rounded to the nearest whole number
All study drugs were given once daily
AE adverse event, BG blood glucose, CV cardiovascular, GI gastrointestinal, HbA1c glycated hemoglobin, NR not reported, SGLT2i sodium-glucose co-transporter-2 inhibitor, SU sulfonylurea,
T2D type 2 diabetes, TZD thiazolidinedione
a
GI events were only reported if occurring in > 5% of patients in any group
b
Severe hypoglycemia defined as per American Diabetes Association classification (requiring assistance of another person to actively administer carbohydrates, glucagon, or take other correc-
tive actions) [92], except for PIONEER 6, in which severe hypoglycemia was identified through a search of Medical Dictionary for Regulatory Activities terms (version 20.1)
c
Confirmed based on BG < 56 mg/dL (< 3.1 mmol/L) with symptoms consistent with hypoglycemia
d
Including metformin, SU, SGLT2i, or TZD
e
Oral semaglutide was initiated at 3 mg once daily; dose adjustment was performed every 8 weeks, with doses increased (to 7 mg and then 14 mg) if H
bA1c was ≥7.0% (≥53 mmol/mol), main-
A Pharmacological and Clinical Overview of Oral Semaglutide for the Treatment of Type 2 Diabetes
tained if HbA1c was < 7.0% (< 53 mmol/mol), and reduced (minimum dose of 3 mg) if moderate-to-severe nausea or vomiting was reported in the 3 days within the week prior to the dose-
adjustment assessment (regardless of H bA1c level)
f
Including SU, glinide, TZD, alpha-glucosidase inhibitor, or SGLT2i
g
Estimated glomerular filtration rate 30–59 mL/min/1.73 m2
h
Patients were eligible if they were 50 years or older and had established CV disease or chronic kidney disease, or 60 years or older and had CV risk factors
1021
1022 A. Andersen et al.
5.1.3 Other Adverse Events of Special Interest oral semaglutide treatment [HR 0.49 (95% CI 0.27–0.92)];
however, no significant differences were observed for other
Post-marketing case reports and retrospective analyses of MACE components [51]. The authors of this study con-
AEs have raised a possible association between pancreatitis cluded that the CV risk profile of oral semaglutide was
and GLP-1RA therapy [63]. Cases of acute pancreatitis have noninferior to that of placebo [51]. Interestingly, the obser-
been reported in the PIONEER clinical studies; however, the vations from PIONEER 6 are also broadly consistent with
incidence of adjudication committee-confirmed pancreatitis those of the SUSTAIN 6 CV outcomes trial for s.c. sema-
with oral semaglutide was low, with no events observed in glutide, including the HR for the primary MACE endpoint,
seven studies and the rate being generally similar to com- which was 0.74 (95% CI 0.58–0.95) with s.c. semaglutide
parators in the other trials [46–50, 52–55]. In the CV out- compared with placebo [5, 51]. A recent patient-level analy-
comes trial, the frequency of acute pancreatitis was 0.1% for sis of data from PIONEER 6 and SUSTAIN 6 combined
semaglutide and 0.2% for placebo [51]. showed consistent effects on MACE incidence across the
The incidence of malignant neoplasms reported for oral two formulations, with an overall HR of 0.76 (95% CI
semaglutide was also low and broadly similar to that of com- 0.62–0.92) for combined semaglutide data (s.c. and oral)
parators [46–50, 52–55]. versus placebo [65]. These observations suggest that the CV
In a 2-year study of s.c. semaglutide in patients consid- profile of oral semaglutide is likely to be similar to that of
ered at high CV risk, a treatment difference was observed s.c. semaglutide [51, 65].
between groups with respect to diabetic retinopathy compli-
cations, i.e., 3.0% of patients in the s.c. semaglutide group 5.3 Tolerability of Oral Semaglutide in Special
experienced these complications compared with 1.8% of Patient Populations
patients in the placebo group. This treatment difference
appeared early and persisted throughout the trial [5]. In In patients with T2D and moderate renal impairment (PIO-
clinical trials of oral semaglutide of up to 18 months’ dura- NEER 5), no unexpected safety concerns were observed for
tion and involving 6352 patients with T2D, AEs related to oral semaglutide [50] (Table 4). Pharmacokinetic studies in
diabetic retinopathy were reported in similar proportions in patients with renal impairment (mild, moderate, or severe, or
patients treated with oral semaglutide (4.2%) and compara- ESRD) and hepatic impairment (mild, moderate, or severe)
tors (3.8%) [29]. indicated no impact of such impairment on either oral sema-
It should be noted, however, that patients with a history of glutide pharmacokinetics or safety [36, 37].
pancreatitis, with proliferative retinopathy or maculopathy
requiring acute treatment, or a history of malignant neoplasms
in the previous 5 years were excluded from the phase III 6 Subgroup Analyses
studies with oral semaglutide.
Subgroup analyses have been conducted to examine whether
5.2 Cardiovascular Safety the efficacy of oral semaglutide is consistent across differ-
ent patient groups within the PIONEER 1−5, 7, and 8 tri-
As CV disease is the leading cause of death among patients als (N = 5657 patients). An exploratory analysis of these
with T2D, establishing the CV safety of new glucose- PIONEER trials evaluated the efficacy of once-daily oral
lowering therapies is of prime importance and required by semaglutide (3, 7, and 14 mg) versus comparators by dia-
regulatory authorities. PIONEER 6 was an event-driven CV betes duration at baseline. Patients were grouped according
outcomes trial conducted to establish the CV safety of oral to diabetes duration (< 5, 5 to < 10, and ≥10 years). The
semaglutide (14 mg) compared with placebo in patients con- results showed that oral semaglutide (7 and 14 mg) improved
sidered at high CV risk [51]. Patients were followed up for a glycemic control versus comparators in all groups, irrespec-
median of 15.9 months. Observations for key CV endpoints tive of disease duration subgroup [66].
are summarized in Table 5. The primary composite endpoint The impact of age at baseline on the efficacy and safety
of major adverse CV events (MACE) was reported in 3.8% of oral semaglutide was also examined in an exploratory
of patients in the oral semaglutide group versus 4.8% in the analysis, and this showed that there were greater effects of
placebo group [hazard ratio (HR) 0.79; 95% CI 0.57–1.11]. oral semaglutide versus comparators on HbA1c and body
These data confirmed the noninferiority (p < 0.001), but not weight in patients with T2D regardless of age group (< 45,
superiority (p = 0.17), of oral semaglutide to placebo in this ≥ 45–< 65, or ≥ 65 years). For the < 65 and ≥ 65 age
study [51]. However, the study was not sufficiently powered groups, the safety profile of oral semaglutide was in line
to demonstrate superiority [64]. An analysis of individual with that of other GLP-1RAs. In general, there was a higher
MACE components revealed a nominally statistically sig- discontinuation rate with oral semaglutide in older patients,
nificant reduction in the risk of death from CV causes with although this was also true for many comparators [67].
A Pharmacological and Clinical Overview of Oral Semaglutide for the Treatment of Type 2 Diabetes 1023
Table 5 Observations for oral semaglutide 14 mg once daily in the PIONEER 6 cardiovascular outcomes trial [51]
Outcomea Oral semaglutide (14 mg) Placebo Hazard ratio (95% CI)
(N = 1591) (N = 1592)
No. (%) No./100 No. (%) No./100
person-yr person-yr
CI confidence interval, CV cardiovascular, MACE major adverse cardiovascular event, MI myocardial infarction
a
Outcomes are first events that were positively adjudicated by the external adjudication committee. Data are for the full analysis set during the
in-trial observation period (from randomization to the final follow-up visit). Deaths from CV causes included deaths for which the cause was
undetermined.
b
The primary outcome was a composite of death from CV causes, nonfatal MI, or nonfatal stroke
c
p < 0.001 for noninferiority, p = 0.17 for superiority. The primary outcome analysis was controlled for multiple comparisons. CIs for other
analyses have not been adjusted for multiple comparisons
d
The expanded composite outcome consisted of death from CV causes, nonfatal MI, nonfatal stroke, unstable angina resulting in hospitalization,
or heart failure resulting in hospitalization
The impact of race was also examined in a subgroup anal- compared with sitagliptin in all groups, except for oral sema-
ysis of the same studies. This analysis revealed that there glutide 7 mg in the HbA1c ≤ 8.0% group [70].
was a significant interaction between treatment and race in The potential impact of background therapy in the PIO-
PIONEER 1, 4, and 8, with greater HbA1c reductions and NEER trials is an important consideration. An exploratory
ETDs in Asian patients than in other race subgroups. How- subgroup analysis of five PIONEER trials (3−5, 7, and 8)
ever, a treatment interaction by race was not observed in assessed the potential impact of different background medi-
the PIONEER 2, 3, 5, and 7 studies [68], and the prescrib- cations (metformin, SU, SGLT2i, insulin, or combinations)
ing information notes that the efficacy of semaglutide is not on the efficacy and safety of oral semaglutide and compara-
impacted by race [29]. tors [71]. Reductions in H bA1c and body weight were greater
Meier et al. conducted an exploratory analysis to examine for oral semaglutide versus comparators (except liraglutide
the effect of baseline HbA1c on overall H bA1c and body- 1.8 mg, which gave similar reductions in H bA1c), regard-
weight reductions achieved during each trial [69]. Patients less of background medication. In general, there were no
were grouped by trial and according to baseline H bA1c statistically significant treatment interactions found between
(≤ 8.0%, > 8.0–≤ 9.0%, and > 9.0%). H bA1c reductions treatment and subgroups [71]. In PIONEER 4, the glycemic
were greater with higher baseline HbA1c, but there was no effects of oral semaglutide and comparators were investi-
consistent relationship between change in body weight and gated in patients with and without SGLT2i as background
baseline HbA1c. Reductions in HbA1c were greater with oral therapy. This subgroup analysis showed that both changes
semaglutide (7 and 14 mg) versus placebo and versus active in HbA1c and body weight were similar in patients receiving
comparator in all H bA1c subgroups [69]. A subgroup analy- oral semaglutide or s.c. liraglutide with or without SGLT2i
sis of the PIONEER 3 study explored the glycemic effects background medication, as were the occurrence of gastroin-
of oral semaglutide (3, 7, and 14 mg) versus sitagliptin testinal AEs [72]. An exploratory sub-analysis of the PIO-
(100 mg) by baseline H bA 1c and also by background NEER 8 study evaluated the impact of background insulin
oral glucose-lowering therapy [70]. In this analy- (basal, premixed, or basal-bolus) with or without metformin
sis, HbA1c was reduced across all baseline H bA 1c and on the efficacy and safety of oral semaglutide. Reductions in
background oral glucose-lowering therapy groups both HbA1c and body weight were similar across all back-
in all treatment arms; reductions were greater with ground insulin groups. Most of the hypoglycemic episodes
higher baseline H bA 1c . H bA 1c reductions were sig- (six out of nine) were observed in the basal-bolus insulin
nificantly greater with oral semaglutide (7 and 14 mg) subgroup. Fewer patients had severe or symptomatic blood
1024 A. Andersen et al.
of different background medications [47–50, 52, 53, 55], semaglutide (14 mg) are not significantly different com-
including diet and exercise [46, 54]. Moreover, oral sema- pared with s.c. GLP-1RAs [82]. Studies in Japanese patients
glutide appears to offer advantages over some commonly found that constipation was observed with oral semaglutide
used oral therapies in terms of glycemic efficacy and/or more frequently than nausea, vomiting, or diarrhea [54, 55].
reductions in body weight, and therefore represents a valu- Studies with other GLP-1RAs have also observed a pro-
able option for intensifying glycemic control when an oral pensity towards constipation as a gastrointestinal AE with
therapy is preferred. these agents in Japanese patients [84–86], and this could
Oral semaglutide may also represent a useful option in be a result of differences in diet and patient behavior [86].
patients without a preference for oral administration. Direct Although gastrointestinal AEs with GLP-1RAs can be trou-
comparisons of oral semaglutide with s.c. GLP-1RAs are blesome, they are generally transient and decrease over a
somewhat limited, as two of the studies were conducted in period of weeks or months. More gradual dose titration can
Japanese patients and consequently used maintenance doses help reduce their frequency and intensity for patients [3]. A
of liraglutide and dulaglutide that are smaller than those potential risk to patients for gastrointestinal AEs is dehydra-
commonly used elsewhere. When compared with the usual tion and, as such, patients taking oral semaglutide should
dose of s.c. liraglutide (1.8 mg), oral semaglutide appeared take precautions to avoid fluid depletion [29].
to provide greater body-weight loss and improved glycemic Hypoglycemia is an important consideration for any
control in the longer term (52 weeks) [49]. Interestingly, a glucose-lowering therapy, and severe hypoglycemic epi-
recent systematic review and network meta-analysis of ran- sodes were found to be rare with oral semaglutide. The
domized controlled trials with GLP-1RAs also suggested incidence of other AEs of special interest, including acute
that oral semaglutide (14 mg) was associated with HbA1c pancreatitis, malignant neoplasms, and diabetic retin-
and body-weight reductions that were at least as great, if not opathy, was also low and was broadly similar between
greater, than seen with most approved s.c. GLP-1RAs, with oral semaglutide and comparators [46–55]. Perhaps
the exception of once-weekly s.c. semaglutide (1 mg) [82]. In most importantly, given the link between CV complica-
this meta-analysis, the glycemic efficacy of once-weekly s.c. tions and T2D, the CV risk profile of oral semaglutide
semaglutide 0.5 mg was similar to that seen with once-daily was also found to be noninferior to that of placebo [51].
oral semaglutide 14 mg. The efficacy of once-weekly sub- However, unlike the observations for once-weekly s.c.
cutaneous semaglutide 1 mg appeared to be slightly greater semaglutide in the SUSTAIN 6 trial, a significant CV ben-
than that seen with once-daily oral semaglutide 14 mg, efit was not observed with oral semaglutide [5, 51]. While
although the differences in H bA1c [0.21% (95% credible the HR for the primary MACE endpoint in PIONEER 6
intervals: − 0.03 to 0.46)] and body weight (0.63 kg [95% was similar in magnitude to that seen with once-weekly s.c.
credible interval: − 0.28 to 1.52)] did not achieve statistical semaglutide in SUSTAIN 6 [5, 51], the PIONEER 6 trial
significance [82]. However, it should be noted that the meta- was likely underpowered to demonstrate superiority versus
analysis is subject to various limitations, such as heterogene- placebo for oral semaglutide [64]. CV outcomes trials for
ity in populations between trials and differing time points GLP-1RAs were compared in a recent network meta-analy-
used between trials, and therefore the comparative efficacy sis using a binomial likelihood logit link model for outcomes
of once-daily oral semaglutide 14 mg versus once-weekly including CV death, myocardial infarction (MI), stroke, and
subcutaneous semaglutide 1 mg needs to be confirmed in death from any cause [87]. Seven GLP-1RA CV outcomes
prospective clinical trials. trials were included in this analysis after screening, and the
The safety and tolerability of the GLP-1RA class is well results showed that oral semaglutide was statistically better
established [3, 63], with evidence available from a large than lixisenatide (HR 0.43; CI 0.19−0.92), albiglutide (HR
number of clinical trials and from routine use in daily clini- 0.45; CI 0.19−0.97), dulaglutide (HR 0.46; CI 0.20−0.97),
cal practice. It is widely accepted that the most frequently and exenatide (HR 0.47; CI 0.21−0.99) in reducing CV
encountered AEs with GLP-1RAs are gastrointestinal dis- deaths. No significant differences were detected between
orders, in particular nausea, vomiting, and diarrhea [3, 83]. most of the treatments regarding reducing all-cause death,
In the PIONEER trials, oral semaglutide was shown to be MI, and stroke events. Ranking results showed that oral
well tolerated, including in patients with renal impairment semaglutide had the highest probability to be ranked first
or at high CV risk [50, 51], and the safety and tolerability (> 90%) in reducing CV death and death from any cause,
profile was consistent with the GLP-1RA class [49, 54, 55]. while once-weekly s.c. semaglutide had the highest prob-
As expected for a GLP-1RA, gastrointestinal disorders such ability to be ranked first in reducing MI and stroke events
as nausea, vomiting, and diarrhea were the most prevalent [87]. Further clinical studies are required to confirm if the
AEs seen with oral semaglutide [46–50, 52–55]. However, CV benefit seen with s.c. semaglutide will translate to oral
a systematic review and network meta-analysis suggested semaglutide, and a phase III study (SOUL; clinicaltrials.gov
that the odds of experiencing gastrointestinal AEs with oral
1026 A. Andersen et al.
NCT03914326 [88]) is underway to investigate the effect of 14 mg, liraglutide 0.9 mg, and dulaglutide 0.75 mg, based
oral semaglutide treatment on CV outcomes. on the results from the PIONEER 9 and 10 trials. Of note,
A potential limitation of oral semaglutide is the need the doses of liraglutide and dulaglutide used in these trials
to dose patients in a fasted state upon waking and 30 min are the highest doses approved in Japan. Overall, 88–91%
before consuming food, drink, or other oral medications. For of patients preferred the profile of oral semaglutide versus
some patients this may not be practical, and currently there dulaglutide [91]. Cost-effectiveness must also be taken into
are no data regarding the efficacy of oral semaglutide with account in addition to these clinical attributes. Studies have
dosing conditions (e.g., different times or fasting periods) demonstrated oral semaglutide to be cost-effective versus
other than those used in the PIONEER trials. A recent online both injectable GLP-1RAs and some oral agents; however,
survey presented seven hypothetical, blinded drug profiles this varies by setting and healthcare system [74–76]. To date,
to 553 respondents in order to evaluate patient preferences there are no real-world studies assessing adherence rates
towards various oral glucose-lowering therapies. In this sur- with oral semaglutide and the injectable GLP-1RAs, or the
vey, more patients said that they would prefer a treatment impact that nonadherence has on outcomes; this is another
with a profile similar to empagliflozin (41%) or sitagliptin important area for future research.
(31%) than to oral semaglutide (11%), with factors such as With both oral and subcutaneous formulations of sema-
the need for fasting and potential for adverse gastrointestinal glutide being available, physicians may be faced with a
effects influencing their decisions [89]. However, it should decision over which treatment to prescribe. As mentioned,
be noted that patients may evaluate drugs differently during a shared decision-making approach may help physicians
actual treatment, and the impact of these various factors in understand which treatment would best fit a patient’s pref-
practice may be less than patients anticipate. Indeed, it is erences and lifestyle. If it is clear that there is a fear of nee-
interesting to note that, despite the dosing conditions and dles, or if good injection technique may be an issue (e.g.,
potential for gastrointestinal effects with oral semaglutide, due to limitations with manual dexterity or lack of injection
satisfaction and convenience of treatment was reported to training opportunities), then oral semaglutide would seem a
be comparable with sitagliptin [52]. This may suggest that reasonable approach. Alternatively, if the dosing conditions
the dosing conditions of oral semaglutide are manageable of oral semaglutide are not suitable, whether it be due to
by most patients. a patient preference to avoid the fasting period or patients
In recent years, the management of T2D has been evolv- receiving other medications with potentially conflicting
ing, with a more patient-centric and individualized approach dosing conditions, then the once-weekly s.c. formulation of
being recommended by organizations [1, 58]. Shared deci- semaglutide may be the preferred option. Finally, if patients
sion-making to address the needs and preferences of each have no clear preference regarding injectable therapy and a
patient, and the individual characteristics that influence the little more efficacy is desirable, then once-weekly s.c. sema-
risks and benefits of therapy for each patient are an impor- glutide should be considered.
tant consideration [58]. Patient preferences for oral versus In conclusion, GLP-1RAs provide effective glycemic
injectable GLP-1RAs need to be further explored in this control and body weight reductions with a low risk of hypo-
context. In a recent online survey, N = 600 patients with glycemia. However, until very recently, these agents were
T2D were asked to provide their treatment preferences only available as s.c injections, which may not be the most
regarding a once-daily oral GLP-1RA compared with a desirable mode of delivery for some patients [90]. Oral
once-weekly injectable GLP-1RA. Initially, the majority of semaglutide is the first GLP-1RA available in a tablet form,
patients favored the use of a once-daily oral versus a once- and therefore could be important in facilitating treatment
weekly injectable GLP-1RA (76.5% vs. 23.5%). However, intensification with GLP-1RAs and providing an alterna-
when patients were then presented with a video detailing the tive option for patients with a preference for oral glucose-
dosing conditions required with oral semaglutide and those lowering therapy to achieve better glycemic control.
with once-weekly injectable dulaglutide, 52.5% indicated
a preference for oral semaglutide [90]. This study assessed Supplementary file1 (DOCX 2,342 kb)Supplementary Information The
online version contains supplementary material available at https://d oi.
patient preferences based only on the dosing conditions, but org/10.1007/s40265-021-01499-w.
a wide range of treatment-related factors may be considered
when selecting a GLP-1RA, including the expected efficacy Acknowledgments Under the direction of the authors, medical writing
and safety. A subsequent Japanese survey (N = 500) also and editorial support, including the literature search, were provided by
assessed the willingness of patients with T2D to initiate Graham Allcock of Axis, a division of Spirit Medical Communications
Group Limited (funded by Novo Nordisk A/S).
different GLP-1RA therapies based on unbranded therapy
profiles. These outlined the mode and frequency of admin-
istration, as well as the changes in HbA1c, body weight,
and risk of nausea, expected with oral semaglutide 7 and
A Pharmacological and Clinical Overview of Oral Semaglutide for the Treatment of Type 2 Diabetes 1027
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been part of speakers’ bureaus for, served as a consultant to, and/or trolled trial. Lancet. 2019;394(10193):121–30.
received research support from Amgen, AstraZeneca, Bayer, Boehring- 8. Hernandez AF, Green JB, Janmohamed S, D’Agostino RB Sr,
er Ingelheim, Carmot Therapeutics, Eli Lilly, Gubra, MedImmune, Granger CB, Jones NP, et al. Albiglutide and cardiovascular out-
MSD/Merck, Mundipharma, Norgine, Novo Nordisk, Sanofi, and Zea- comes in patients with type 2 diabetes and cardiovascular disease
land Pharma. Tina Vilsbøll has served on scientific advisory panels, (Harmony Outcomes): a double-blind, randomised placebo-con-
been part of speakers’ bureaus for, served as a consultant to, and/or trolled trial. Lancet. 2018;392(10157):1519–29.
received research support from Amgen, AstraZeneca, Boehringer In- 9. American Diabetes Association. 9 Pharmacologic approaches to
gelheim, Eli Lilly, Gilead, Mundipharma, MSD/Merck, Novo Nordisk, glycemic treatment: standards of medical care in diabetes—2020.
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