Journal of Diabetes and Its Complications 34 (2020) 107520

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Journal of Diabetes and Its Complications

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Oral semaglutide in type 2 diabetes

Sarah L. Anderson, Trevor R. Beutel, Jennifer M. Trujillo ⁎
University of Colorado Skaggs School of Pharmacy & Pharmaceutical Sciences, Department of Clinical Pharmacy, 12850 E. Montview Blvd., Aurora, CO 80045, United States of America

a r t i c l e i n f o a b s t r a c t

Article history: Background: Previously, the only available glucagon-like peptide-1 receptor agonists (GLP-1 RA) were injectable.
Received 16 October 2019 Approval of oral semaglutide (Rybelsus®) represents the first orally available GLP-1 RA.
Received in revised form 12 November 2019 Objective: To review the literature and describe pharmacologic, pharmacokinetic, and pharmacodynamics prop-
Accepted 30 December 2019 erties; clinical safety; and efficacy of oral semaglutide, a newly approved oral GLP-1 RA.
Available online 8 January 2020
Methods: A MEDLINE (1995-October 2019) and ClinicalTrials.gov search was conducted using the terms oral
semaglutide, semaglutide, PIONEER, and a combination of those terms. Reference citations from publications iden-
Keywords:
Oral semaglutide
tified were also reviewed. All English-language studies, including abstracts, evaluating oral semaglutide use in
Rybelsus humans were included in this review.
Glucagon-like peptide-1 receptor agonist Conclusions: The approval of oral semaglutide (Rybelsus®) represents a paradigm shift in the management of
Type 2 diabetes T2D as this is the first FDA-approved oral GLP-1 RA. Oral semaglutide may be an attractive option for patients
with T2D who require improved glycemic control, would like to lose weight, and who are not interested in inject-
able therapy. However, the lack of positive cardiovascular (CV) and renal data are significant limitations to its use.
© 2020 Elsevier Inc. All rights reserved.

1. Introduction proved by the Food and Drug Administration (FDA) under the brand
name Rybelsus® for the treatment of adults with T2D (Fig. 1).8 Oral
The broad treatment armamentarium for type 2 diabetes (T2D) allows semaglutide is available in 3 mg (starting dose), 7 mg, and 14 mg tab-
for a patient-centered approach to achieving and maintaining glycemic lets. This review discusses the pharmacology, efficacy, safety, and
control. Following metformin and lifestyle modifications, there are a vari- place in therapy of the first oral GLP-1 RA, oral semaglutide.
ety of second-line treatment options available [ADA 2019]. Selection of a
second-line agent is based on a combination of patient-specific factors, in- 2. Data sources
cluding presence of comorbid conditions, weight, hypoglycemia risk, cost,
and patient preference.1 Glucagon-like peptide-1 receptor agonists (GLP- A MEDLINE search (1995–October 2019) was conducted using the
1 RA) are one such treatment option that have a wealth of data supporting search terms oral semaglutide, semaglutide, PIONEER, and a combination
their glucose-lowering efficacy, favorable safety profile, and in the case of of those terms. Review of the references listed in the articles identified
some agents, improvement in CV outcomes.2–4 was also performed. The oral semaglutide prescribing information was
A limitation to the use of currently available GLP-1 RAs is that they reviewed, as well as abstracts from scientific meetings and ongoing clin-
are administered via subcutaneous injection in order to avoid enzymatic ical trial data.
and pH degradation of the peptide in the gastrointestinal (GI) tract. Pa-
tients with T2D often have difficulty with adherence to and persistence 3. Pharmacology
with injectable medications, with “injection concerns” being one of the
most frequently cited barriers.5–7 In order to overcome this barrier, an Semaglutide is a 31-amino acid peptide that mimics native GLP-1
oral formulation of the GLP-1 RA semaglutide has been developed with two key structural modifications: substitution of alanine at posi-
through co-formulation with an absorption enhancer. Oral semaglutide tion 8 with α-aminoisobutyric acid and addition of a spacer to conjugate
was studied in the PIONEER clinical trial program and was recently ap- the C18 fatty diacid to the position 26 lysine. These modifications allow
for resistance of drug degradation by dipeptidyl peptidase-4 (DPP-4)
and reduced renal clearance of the drug respectively, resulting in
Conflict of Interest Statement: The authors have no conflicts of interest to declare.
⁎ Corresponding author.
prolonged plasma half-life.9,10 Successful oral delivery of native GLP-1
E-mail addresses: sarah.anderson@cuanschutz.edu (S.L. Anderson), co-formulated with the absorption enhancer SNAC (sodium N-[8-(2-
Trevor.2.Beutel@cuanschutz.edu (T.R. Beutel), Jennifer.Trujillo@cuanschutz.edu hydroxybenzoyl)amino] caprylate) has been previously demonstrated.
(J.M. Trujillo). SNAC is a hydrophobic molecule that noncovalently binds to GLP-1

https://doi.org/10.1016/j.jdiacomp.2019.107520
1056-8727/© 2020 Elsevier Inc. All rights reserved.
2 S.L. Anderson et al. / Journal of Diabetes and Its Complications 34 (2020) 107520

GLP-1 RA Concurrent Japanese

Monotherapy OAD
and/or insulin disease states pa ents

9. Monotherapy
1. Monotherapy 2. SGLT-2 inhibitor 4. GLP-1 RA 5. Renal
vs. placebo and
vs. Placebo comparator comparator impairment
GLP-1 RA

10. OAD
3. DPP-4 inhibitor 8. Add-on to
6. CVOT vs.
comparator insulin vs. placebo
GLP-1 RA

7. Flexible dose vs.

DPP-4 inhibitor
comparator

Fig. 1. PIONEER clinical trial series.

and other related peptides, resulting in increased lipophilicity of the Because oral semaglutide can delay gastric emptying, this has the po-
peptide molecule(s). Oral administration of GLP-1 co-formulated with tential to affect absorption of other oral medications.
SNAC results in increased GLP-1 transport across intestinal epithelium.
The noncovalent bonds between SNAC and GLP-1 are readily broken 5. Dose ranging studies
upon exposure to the bloodstream, allowing for circulation of unbound
GLP-1.11 Safety and tolerability of single oral semaglutide doses ranging from
Semaglutide is a GLP-1 RA that decreases blood glucose via the pri- 2 mg to 20 mg co-formulated with SNAC were demonstrated in a phase
mary mechanisms of increasing insulin secretion and decreasing gluca- II trial.20 The trial analyzed the effect of varying doses of SNAC when co-
gon secretion, both in a glucose-dependent manner.12 Gastric emptying formulated with fixed doses of oral semaglutide. Two pairs of co-
is delayed in the early post-prandial phase. Semaglutide decreases both formulations were analyzed: 5 mg oral semaglutide/300 mg SNAC vs.
fasting and post-prandial blood glucose levels as well as body weight. 5 mg oral semaglutide/150 mg SNAC and 10 mg oral semaglutide/
300 mg SNAC vs. 10 mg oral semaglutide/600 mg SNAC. The formula-
4. Pharmacokinetics and pharmacodynamics tion with 300 mg SNAC resulted in significantly greater semaglutide
plasma concentrations than the comparator co-formulation in both
Oral semaglutide undergoes gastric absorption, which is different analyses. A linear relationship was observed in semaglutide plasma con-
from all other available GLP-1 RAs.13 Gastric absorption is also different centrations between oral semaglutide doses of 2 mg, 5 mg, and 10 mg
from most other oral medications, which are more commonly absorbed when co-formulated with 300 mg SNAC. The authors concluded that
in the intestines. Oral administration of semaglutide in the fasted state 300 mg SNAC is the optimal dosage for co-formulation with oral
with up to 120 mL of water followed by a 30-min post-dosing fast re- semaglutide.
sults in maximal systemic absorption.14 This is because SNAC protects Dose ranges and escalations of oral semaglutide for the treatment of
semaglutide from pH-dependent degradation and food consumption T2D were studied in a phase II randomized controlled trial.21 Once daily
increases the gastric pH.13 Oral semaglutide is less bioavailable and oral semaglutide doses of 2.5 mg, 5 mg, 10 mg, 20 mg, and 40 mg were
has more absorption variability from patient-to-patient than injectable studied and all doses showed significantly greater glycosylated hemo-
semaglutide, which is why a higher dose is needed for the oral globin A1C (A1C) reduction than placebo and were dose-dependent.
formulation.15 Research has shown safety and tolerability of oral There was no statistically significant difference in A1C reduction ob-
semaglutide dosed once daily for ten weeks in both healthy volunteers served in the 20 mg and 40 mg oral semaglutide groups compared to
and patients with T2D.16 The use of oral semaglutide has been studied in the 1 mg injectable semaglutide once weekly group. The most common
patients with varying degrees of hepatic or renal impairment. There adverse events observed with oral semaglutide were mild to moderate
were no differences in area under the curve (AUC), maximum concen- nausea and less frequently, vomiting and diarrhea. These events oc-
tration (Cmax), or half-life (t1/2) in patients with mild, moderate, or se- curred at similar rates in both the oral and injectable semaglutide
vere hepatic impairment as compared to patients with normal hepatic arms. Serious adverse events were rare with no differences in event
function; therefore, no hepatic dose adjustments are recommended.17 rates between groups. These data suggest that once daily doses of oral
In patients with mild, moderate, or severe renal impairment and those semaglutide ranging from 2.5 mg to 40 mg are well tolerated and effica-
with end-stage renal disease on hemodialysis (ESRD-HD), there was cious for the treatment of T2D. Oral semaglutide doses of 3 mg, 7 mg,
no significant difference in AUC or t1/2 as compared to patients with nor- and 14 mg were studied in Phase III clinical trials.
mal renal function.15 Researchers concluded there were no clinically rel-
evant differences in pharmacokinetics (PK) based on degree of renal 6. Efficacy: summary of phase III clinical trials
impairment; therefore, no renal dosing adjustments are required.
Several studies examined the presence and severity of drug-drug in- The PIONEER trial program, evaluating the efficacy and safety of oral
teractions with oral semaglutide and other commonly prescribed med- semaglutide, is one of the first clinical trial programs in T2D to use
ications. No clinically relevant drug-drug interactions have been estimands. This is due to the US FDA recommending against the use of
observed with oral semaglutide co-administered with omeprazole, last observation carried forward (LOCF) because it is a flawed approach
lisinopril, warfarin, metformin, or digoxin.18,19 Despite the lack of data for handling missing data.22 At its simplest, an estimand is that which is
regarding drug-drug interactions, the prescribing information recom- being estimated. In a clinical trial, estimands may be included in order to
mends waiting 30 min before taking other medications after the admin- align the trial objective, design, conduct, and data analysis. Most clinical
istration of oral semaglutide to ensure optimal semaglutide absorption. trials report statistical endpoints that incorporate the population of
 S.L. Anderson et al. / Journal of Diabetes and Its Complications 34 (2020) 107520 3

interest (e.g., adults with T2D), the endpoint of interest (e.g., A1C at was statistically significantly greater than placebo at weeks 26 (ETD
52 weeks), and a population level summary (e.g., mean difference be- −0.9 to −3.3 kg; p b 0.05 for all oral semaglutide vs. placebo differences)
tween treatment group and placebo). However, most clinical trials do and 52 (ETD −1.3 to −4.3 kg compared to placebo; p b 0.05 for all oral
not have a robust way to report out intercurrent events, such as use of semaglutide vs. placebo comparisons). At 52 weeks, all groups of oral
a rescue medication and premature study discontinuation. semaglutide had significantly lower doses of basal insulin compared to
The PIONEER trial program used two estimands – a “treatment pol- placebo (−8 units for 3 mg [p b 0.05], −16 units for 7 mg [pb 0.001],
icy estimand” and a “trial product estimand.” The treatment policy and −17 units for 14 mg [pb0.001]). There was no difference in rates
estimand aimed to describe the treatment effect in patients with T2D of hypoglycemia between oral semaglutide and placebo. The most fre-
regardless of trial product (oral semaglutide) discontinuation or use of quent adverse effect related to oral semaglutide was nausea (11.4 to
rescue medication while the trial product estimand aimed to describe 23.2% vs. 7.1% with placebo). The authors concluded that oral
the treatment effect in patients with T2D if all patients had continued semaglutide was an effective add-on to insulin ± metformin and has a
use of the trial product (oral semaglutide) and did not use rescue side effect profile consistent with injectable GLP-1 RAs.
medication.23 The treatment policy estimand is the more conservative
of the two given that it focuses on an intent-to-treat population and in- 9. Active comparators – sodium glucose co-transporter 2 (SGLT-2)
cludes all patients' data. inhibitors
For purposes of this manuscript, we have reported out both the
treatment policy and trial product estimand data in Table 1, which fo- The PIONEER 2 study was a 52-week, open label trial in which 821
cuses on results from the primary endpoint timeframe only and pro- patients with T2D were randomized to receive semaglutide 14 mg or
vides actual change from baseline in each group. When describing empagliflozin 25 mg, on a background of metformin therapy.26 At base-
endpoints in the text we have focused on the treatment policy line, the mean age was 57 years, mean A1C was 8.1%. At week 26, the
estimand, placebo-adjusted results and includes information on multi- mean A1C reduction was −1.3% with oral semaglutide compared with
ple time points if applicable to the study. −0.9% with empagliflozin. These differences were statistically signifi-
cant for demonstrating superiority of semaglutide over empagliflozin
7. Placebo comparators: use as monotherapy and were maintained at week 52. Body weight loss was similar between
groups; at week 52, oral semaglutide-treated patients had lost a mean of
In the PIONEER 1 study, 703 patients with T2D who had not achieved 3.8 kg compared with 3.7 kg for the empagliflozin group (p=0.05). The
their A1C goal despite diet and exercise were randomized to receive oral authors concluded that oral semaglutide 14 mg produced superior A1C
semaglutide or placebo.24 The primary endpoint was change in A1C from lowering compared to empagliflozin 25 mg at weeks 26 and 52. Body
baseline to week 26 and a secondary endpoint was change in body weight weight reduction was not statistically different at week 26 but oral
during the same timeframe. At baseline, the mean A1C was 8.0%, mean semaglutide demonstrated superior weight reduction at week 52 by
age was 55 years, and 50.8% of patients were male. Patients were random- trial product estimand.
ized 1:1:1:1 to oral semaglutide 3 mg, 7 mg, 14 mg, or placebo. Rescue
medication was prescribed at the investigators' discretion if fasting 10. Active comparators – dipeptidyl peptidase 4 (DPP-4) inhibitors
plasma glucose (FPG) was N240 mg/dl from weeks 8 through 13 or
N200 mg/dl from week 14 onwards. All doses of oral semaglutide resulted Oral semaglutide was compared with sitagliptin in 1864 patients
in reductions in A1C. The placebo-adjusted treatment differences in A1C with T2D receiving background therapy with metformin, with or with-
at week 26 were: −0.6% (−0.8 to −0.4) for 3 mg, −0.9% (−1.1 to out a sulfonylurea, in the PIONEER 3 study.27 At baseline, the mean age
−0.6) for 7 mg, and − 1.1% (−1.3 to −0.9) for 14 mg (all p b 0.001). was 58 years, mean A1C was 8.3%, and 47.2% of patients were female.
The 14 mg dose of oral semaglutide provided superior reductions in Patients were randomized 1:1:1:1 to receive oral semaglutide 3 mg,
body weight compared to placebo and both the 7 mg and 14 mg provided 7 mg, or 14 mg or sitagliptin 100 mg daily for 78 weeks. All patients ran-
statistically significant weight reduction. The placebo-adjusted treatment domized to oral semaglutide started at a dose of 3 mg and the dose was
differences in body weight at week 26 were: −0.1 kg (−0.9 to 0.8) for escalated every 4 weeks until the randomized dosage was achieved. Re-
3 mg (p=0.87), −0.9 kg (−1.9 to 0.1) for 7 mg (p=0.09), and − 2.3 kg sults were reported out at week 26. The changes in A1C at week 26 were
(−3.1 to −1.5) for 14 mg (p b 0.001). The authors concluded that oral −0.6%, −1.0%, and −1.3% for oral semaglutide 3 mg, 7 mg, and 14 mg,
semaglutide, used as monotherapy in patients with T2D, was more effec- respectively, and −0.8% for sitagliptin 100 mg. The 7 mg and 14 mg
tive than placebo and commented that the effects observed in this study doses of oral semaglutide were superior to sitagliptin with regard to
were similar to those seen with other GLP-1 RA monotherapy, placebo- A1C reduction (p b 0.001 for both). Mean changes in body weight at
comparator studies. week 26 were −1.2 kg, −2.2 kg, and −3.1 kg for oral semaglutide
3 mg, 7 mg, and 14 mg, respectively, and −0.6 kg for sitagliptin
8. Placebo comparators: use as combination therapy 100 mg. Again, the 7 mg and 14 mg doses of oral semaglutide were su-
perior to sitagliptin with regard to weight reduction (p b 0.001 for
PIONEER 8 was a randomized trial of 731 patients with T2D uncon- both). At week 78, the A1C reductions continued to be significantly
trolled on basal insulin with or without metformin who were assigned greater with the oral semaglutide 7 mg (trial product estimand only)
1:1:1:1 to received oral semaglutide 3 mg, 7 mg, or 14 mg or placebo and 14 mg doses compared with sitagliptin. For all doses of oral
for 52 weeks.25 Randomization was stratified by country of origin semaglutide, weight reductions were superior to sitagliptin by both
(Japanese and non-Japanese). Compared to other PIONEER studies, this estimands. Study authors concluded that oral semaglutide 7 mg and
trial enrolled older patients (mean age 61 years) who had had diabetes 14 mg doses were superior in efficacy compared to sitagliptin for both
for a mean of 15 years. Patients' insulin dose was pre-emptively reduced A1C and body weight reduction.
by 20% and maintained until week 8 unless an increase was necessary. The PIONEER 7 trial also compared oral semaglutide with sitagliptin,
Insulin dosing was able to be altered during weeks 8 to 26 without ex- but with a flexible dosing strategy.28 Over 500 patients were random-
ceeding the pre-randomization dose. For the second 26 weeks, insulin ized to flexibly-dosed oral semaglutide or sitagliptin 100 mg daily.
dose adjustments were freely allowed. At weeks 26 and 52 oral Oral semaglutide was started at 3 mg daily and the dose was adjusted
semaglutide demonstrated significantly greater decreases in A1C than at week 8 and every 8 weeks after based on A1C measured by point-
placebo (estimated treatment difference [ETD] -0.5 to −1.2% at week of-care device and/or based on tolerability of the study drug. The
26 and −0.4 to −0.9% at week 52; p b 0.001 for all oral semaglutide mean age at baseline was 57.4 years, mean A1C was 8.3%, and 57% of pa-
vs. placebo differences). Similarly, weight loss with oral semaglutide tients were male. At week 8, 73% of patients in the oral semaglutide
4 S.L. Anderson et al. / Journal of Diabetes and Its Complications 34 (2020) 107520

Table 1
Summary of published phase 3 randomized controlled trials of oral semaglutide in type 2 diabetes.

Citation Design Baseline characteristics Background Randomly Change in A1C from Change in weight
treatment assigned baseline, % from baseline, kg
treatment
Treatment Trial Treatment Trial
policy product policy product
estimand estimand estimand estimand

PIONEER 1 Randomized, double-blind, Mean age, 55 years; A1C, None Semaglutide 3 mg −0.9⁎ −0.8⁎ −1.5 −1.7
placebo-controlled, 26 weeks, 8.0%; BMI, 31.8 kg/m2; Semaglutide 7 mg −1.2⁎ −1.3⁎ −2.3 −2.5⁎
n = 703 duration of diabetes, Semaglutide 14 mg −1.4⁎ −1.5⁎ −3.7⁎ −4.1⁎
3.5 years Placebo −0.3 −0.1 −1.4 −1.5
PIONEER 2 Randomized, open-label, Mean age, 58 years; A1C, Metformin Semaglutide 14 mg −1.3⁎ −1.4⁎ −3.8 −4.2
active-controlled, 8.1%; BMI 32.9 kg/m2; Empagliflozin 25 mg −0.9 −0.9 −3.7 −3.8
parallel-group, duration of diabetes,
52 weeks, 7.4 years
n = 822
PIONEER 3 Randomized, double-blind, Mean age, 58 years; A1C, Metformin ± SU Semaglutide 3 mg −0.6 −0.5 −1.2⁎ −1.2⁎
double-dummy, 8.3%; BMI, 32.5 kg/m2; Semaglutide 7 mg −1.0⁎ −1.1⁎ −2.2⁎ −2.2⁎
parallel-group, 78 weeks, duration of diabetes, Semaglutide 14 mg −1.3⁎ −1.4⁎ −3.1⁎ −3.3⁎
n = 1864 8.6 years Sitagliptin 100 mg −0.8 −0.8 −0.6 −0.7
PIONEER 4 Randomized, double-blind, Mean age, 56 years; Metformin ± SGLT-2 Semaglutide 14 mg −1.2 −1.3⁎ −4.4⁎ −4.7⁎
double-dummy, 52 weeks, A1C, inhibitor Liraglutide 1.8 mg −1.1 −1.1 −3.1 −3.2
n = 711 8.0%; BMI, 33.0 kg/m2; Placebo −0.2 −0.1 −0.5 −0.7
duration of diabetes,
7.6 years
PIONEER 5 Randomized, double-blind, Mean age, 70 years; Metformin or SU Semaglutide 14 mg −1.0⁎ −1.1⁎ −3.4⁎ −3.7⁎
26 weeks, n = 324 A1C, or both or basal Placebo −0.2 −0.01 −0.9 −1.1
8.0%; BMI 32.4 kg/m2; insulin ± metformin
duration of diabetes,
14 years; eGFR
30–59 mL/min/1.73m2
PIONEER 7 Randomized, open-label, Mean age, 57.4 years; 1–2 oral diabetes Semaglutide flexible −1.3⁎ −1.4⁎ −2.6⁎ −2.9⁎
52 weeks, n = 504 A1C, 8.3%; agents dose
BMI 31.5 kg/m2; Sitagliptin 100 mg −0.8 −0.7 −0.7 −0.8
duration of diabetes,
8.8 years
PIONEER 8 Randomized, open-label Mean age, 61 years; A1C Insulin (basal, basal/bolus, Semaglutide 3 mg −0.6⁎ −0.8⁎ −1.4⁎ −1.3⁎
26 weeks, n = 731 8.2%; BMI 31 kg/m2; or pre-mixed) ± Semaglutide 7 mg −0.9⁎ −1.0⁎ −2.4⁎ −3.0⁎
duration of metformin Semaglutide 14 mg −1.3⁎ −1.4⁎ −3.7⁎ −4.1⁎
diabetes 15 years Placebo −0.1 −0.0 −0.4 −0.4

Abbreviations: AC, active comparator; A1C, glycosylated hemoglobin; BL, baseline; BMI, body mass index; NR, not reported; SGLT-2, sodium glucose co-transporter 2; SU, sulfonylurea.
⁎ Statistically significantly superior to comparator.

group were dose-increased to 7 mg. By week 52, 9% of patients in the statistically significantly greater than both liraglutide and placebo at
oral semaglutide group were receiving 3 mg, 30% were receiving weeks 26 (ETD for liraglutide −1.2 kg; p=0.0003 and ETD for placebo
7 mg, and 59% were receiving 14 mg. Twice as many patients in the −3.8 kg; p b 0.0001) and 52 (ETD for liraglutide −1.3 kg; p=0.0019
sitagliptin group received additional glucose-lowering drugs compared and ETD for placebo −3.3 kg; p b 0.0001). Using treatment policy
to patients in the oral semaglutide group. Oral semaglutide resulted in estimands, oral semaglutide was non-inferior to liraglutide and superior
significantly greater decreases in A1C than sitagliptin (ETD -0.5%; 95% to placebo in decreasing A1C. Oral semaglutide was superior to both
CI -0.7 to −0.4; p b 0.0001). At week 52, 58% of patients in the oral liraglutide and placebo in decreasing body weight. The authors con-
semaglutide group achieved an A1C of b7% compared to 25% in the cluded that oral semaglutide offers a comparable option to an injectable
sitagliptin group (p b 0.0001). Oral semaglutide also resulted in signifi- GLP-1 RA in patients who are reluctant to initiate or intensify injectable
cantly greater weight loss than sitagliptin (ETD −1.9 kg; 95% CI −2.6 to GLP-1 RA therapy.
−1.2; p b 0.0001). The authors concluded that flexibly-dosed oral
semaglutide was superior to sitagliptin with respect to A1C and body 12. Other PIONEER trials
weight reductions and achieved these outcomes despite having fewer
add-on medications for glucose lowering. There are 10 trials in the PIONEER trial series; PIONEER 9 and 10
have not yet been published. However, there are preliminary results
11. Active comparators – injectable GLP-1 RA available for each.
PIONEER 9 compared the use of oral semaglutide 3 mg, 7 mg, and
Oral semaglutide was compared to liraglutide in a 52-week clinical 14 mg vs. liraglutide 0.9 mg (maximum allowable dose in Japan) and
trial.29 Patients with T2D were randomly assigned in 2:2:1 fashion to re- vs. placebo in 243 Japanese adults with T2D.30 All doses of oral
ceive oral semaglutide (dose-escalated to 14 mg), liraglutide (dose-es- semaglutide resulted in a statistically significant reduction from base-
calated to 1.8 mg), or placebo. At baseline, the mean age was 56 years, line A1C at 26 weeks compared to placebo. Oral semaglutide 14 mg
mean A1C was 8.0%, and 48% of patients were female. At week 26, oral achieved a statistically significant reduction in A1C compared to
semaglutide demonstrated significantly greater decreases in A1C com- liraglutide 0.9 mg (−1.7% vs. −1.4%) at week 26. At 52 weeks, all
pared to both liraglutide (ETD −0.2%; 95% CI −0.3 to −0.1; p= doses of oral semaglutide maintained a statistically significant reduction
0.0056) and placebo (ETD −1.2%; 95% CI −1.4 to −1.0; p b 0.0001), in A1C, but the 14 mg dose was no longer superior to liraglutide. Also at
which was also seen at 52 weeks (ETD for liraglutide −0.3%; 95% CI 52 weeks, use of oral semaglutide 14 mg resulted in statistically signifi-
-0.5 to −0.1; p=0.0002 and ETD for placebo −1.0%; 95% CI −1.2 to cantly greater weight loss (−2.8 kg) compared to either placebo
−0.8; p b 0.0001). Similarly, weight loss with oral semaglutide was (−1.0 kg) or liraglutide (+0.4 kg).
 S.L. Anderson et al. / Journal of Diabetes and Its Complications 34 (2020) 107520 5

PIONEER 10 was a randomized, open label trial in 44 Japanese patients semaglutide studied. 24,26–29 The incidence of nausea appears to be
with uncontrolled T2D on one oral antidiabetic agent.31 Patients were dose-related. The PIONEER 7 trial allowed for a flexible oral semaglutide
randomized to oral semaglutide 3 mg, 7 mg, or 14 mg or dulaglutide dosing protocol, but this did not mitigate the incidence of nausea (21%
0.75 mg. Oral semaglutide 14 mg had a statistically significant reduction incidence).28 A recent systematic review and meta-analysis of oral
in A1C compared to dulaglutide at 52 weeks (−1.8% vs. −1.3%). Similarly, semaglutide trials confirmed that the incidence of nausea, vomiting,
weight loss with oral semaglutide 14 mg was statistically significant com- and diarrhea were increased with oral semaglutide compared to pla-
pared to dulaglutide at 52 weeks (−1.9 kg vs. −1.1 kg). cebo and were dose-related.33 Importantly, there were no differences
in the incidence of hypoglycemia, renal adverse effects, or pancreatitis
13. Efficacy in special populations between oral semaglutide and placebo or oral semaglutide and active
comparator (Table 2).
There is one placebo-controlled, active comparator study evaluating As with injectable GLP-1 RAs, oral semaglutide carries a black box
oral semaglutide in patients with T2D and renal dysfunction. The warning stating that it should not be used in patients with a personal
PIONEER 5 study compared oral semaglutide to placebo in 324 patients or family history of medullary thyroid carcinoma (MTC) or multiple en-
with T2D who had been receiving a stable dose of metformin or sulfo- docrine neoplasia syndrome type 2 (MEN 2). Oral semaglutide should
nylurea or both, or basal insulin with or without metformin use.32 Pa- not be used in patients with a history of pancreatitis and if signs and
tients also had to have an estimated glomerular filtration rate (eGFR) symptoms of pancreatitis arise while on treatment, oral semaglutide
of 30 to 59 mL/min/1.73m2. At baseline, the mean A1C was 8.0%, mean should be discontinued. Oral semaglutide should not be used in preg-
age was 70 years, mean eGFR was 48 mL/min/1.73m2, and 52% of pa- nant women. Females who are contemplating pregnancy should dis-
tients were female. Patients were randomized 1:1 to oral semaglutide continue oral semaglutide 2 months prior to attempting conception.8
or placebo in addition to their current background therapy. The dose
of oral semaglutide was initiated at 3 mg, then increased to 7 mg at 15. Special populations
4 weeks and further increased to 14 mg at 8 weeks. Oral semaglutide
was superior to placebo in decreasing A1C and body weight over Similar to the other PIONEER trials, the main adverse effect noted by
26 weeks. At week 26, the mean change in A1C from baseline was patients enrolled in PIONEER 5 (which evaluated oral semaglutide in
−1.0% for oral semaglutide and − 0.2% for placebo (ETD -0.8%; 95% CI patients with T2D and renal dysfunction) was nausea, at a rate of 19%
-1.0 to −0.6; p b 0.0001). The mean change in body weight at week for those who received oral semaglutide.32 The primary reason for
26 was −3.4 kg for oral semaglutide and −0.9 kg for placebo (ETD study discontinuation in both the oral semaglutide and placebo groups
−2.5 kg; 95% CI −3.2 to −1.8; p b 0.0001). Changes in A1C and body was GI disorders (12% and 3%, respectively). Renal function remained
weight were similar to the results of PIONEER 1, demonstrating consis- constant throughout the study in both CKD patient subgroups from
tent results as monotherapy across a range of renal function. The au- week 31 follow-up to baseline. The authors noted the overall safety pro-
thors concluded that these results are important in demonstrating file within this population was consistent with the safety profile of in-
that oral semaglutide is a safe option when other oral agents jectable GLP-1 RAs.
(e.g., metformin) are not an option based on the patient's renal function.
16. Cardiovascular outcomes trial
14. Key safety considerations
The cardiovascular (CV) safety of oral semaglutide in high CV risk
14.1. General patients was analyzed in the PIONEER 6 study.34 The primary outcome
was the first occurrence of a major adverse cardiovascular event
The primary adverse effect reported in the PIONEER clinical trial se- (MACE; death from CV causes, nonfatal myocardial infarction [MI], or
ries were GI related.24,26–29 Nausea in the oral semaglutide groups was nonfatal stroke). Patients were eligible for inclusion if they were deter-
the most frequently reported GI adverse event, at a rate of approxi- mined to be at high CV risk, which was defined as age ≥50 years with
mately 5 to 20% within the trial series across all doses of oral established CV disease (CVD) or CKD, or age ≥60 years with CV risk

Table 2
Adverse events across phase 3 randomized controlled trials of oral semaglutide in type 2 diabetes.

Study Randomly Assigned Nausea, No. Vomiting, No. Diarrhea, No. Severe or confirmed symptomatic Discontinuation because
Treatment (%) (%) (%) hypoglycemia, No. (%) of an AE, No. (%)

PIONEER 1 Semaglutide 3 mg 14 (8) 5 (2.9) 15 (8.6) 5 (2.9) 4 (2.3)

Semaglutide 7 mg 9 (5.1) 8 (4.6) 9 (5.1) 2 (1.1) 7 (4.0)
Semaglutide 14 mg 28 (16) 12 (6.9) 9 (5.1) 1 (0.6) 13 (7.4)
Placebo 10 (5.6) 4 (2.2) 4 (2.2) 1 (0.6) 4 (2.2)
PIONEER 2 Semaglutide 14 mg 81 (19.8) 30 (7.3) 38 (9.3) 7 (1.7) 44 (10.7)
Empagliflozin 25 mg 10 (2.4) 7 (1.7) 13 (3.2) 8 (2.0) 18 (4.4)
PIONEER 3 Semaglutide 3 mg 34 (7.3) 13 (2.8) 45 (9.7) 23 (4.9) 26 (5.6)
Semaglutide 7 mg 62 (13.4) 28 (6.0) 53 (11.4) 24 (5.2) 27 (5.8)
Semaglutide 14 mg 70 (15.1) 42 (9.0) 57 (12.3) 36 (7.7) 54 (11.6)
Sitagliptin 100 mg 32 (6.9) 19 (4.1) 37 (7.9) 39 (8.4) 24 (5.2)
POINEER 4 Semaglutide 56 (20) 25 (9) 43 (15) 2 (1) 31 (11)
Liraglutide 51 (18) 13 (5) 31 (11) 7 (2) 22 (8)
Placebo 5 (4) 3 (2) 11 (8) 3 (2) 15 (11)
PIONEER 5 Semaglutide 31 (19) 19 (12) 17 (10) 9 (6) 24 (15)
Placebo 12 (7) 2 (1) 6 (4) 3 (2) 8 (5)
PIONEER 7 Semaglutide 53 (21) 14 (6) 22 (9) 14 (5.5) 22 (9)
Sitagliptin 6 (2) 2 (1) 8 (3) 14 (5.6) 8 (3)
PIONEER 8 Semaglutide 3 mg 3 (1.6) 2 (1.1) 2 (1.1) 52 (28.3) 13 (7.1)
Semaglutide 7 mg 5 (2.8) 2 (1.1) 5 (2.8) 47 (26) 16 (8.8)
Semaglutide 14 mg 11 (6.1) 5 (2.8) 3 (1.7) 48 (26.5) 24 (13.3)
Placebo 0 (0) 0 (0) 1 (0.5) 54 (29.3) 5 (2.7)

Abbreviations: AE, adverse event.

6 S.L. Anderson et al. / Journal of Diabetes and Its Complications 34 (2020) 107520

factors, which mirrored SUSTAIN-6 inclusion criteria.2,34 Because inject- to approximately 64 weeks) and had more CV events occur. PIONEER
able semaglutide was associated with a higher risk of diabetic retinopa- 6 included more patients with established CVD (84.7%) compared to
thy in SUSTAIN-6, patients with proliferative retinopathy or SUSTAIN-6 (80.3%). SUSTAIN-6 showed a statistically significant de-
maculopathy requiring active treatment were excluded from PIONEER crease in nonfatal stroke (HR 0.61; 95% CI, 0.38–0.99; p=0.04) whereas
6.2,34 A total of 3183 patients were randomized in a 1:1 ratio to receive PIONEER 6 showed a significant reduction in CV deaths (Table 3).2,34 It is
either once daily oral semaglutide (n = 1591) dose-escalated to target possible that while oral and injectable semaglutide demonstrate similar
dose 14 mg, or once daily oral placebo (n = 1592). The trial was glycemic effects, their effects on the CV system may be different.
prespecified to continue until at least 122 primary outcome events oc- PIONEER 6 was powered to show non-inferiority of oral semaglutide
curred. Median time in the trial was 15.9 months, which was shorter compared to placebo in the primary composite MACE outcome. Non-
than previous cardiovascular outcomes trials (CVOTs) for other inferiority was demonstrated; however, further randomized controlled
antihyperglycemic agents, including the ELIXA (25 months), LEADER trials are needed to determine if oral semaglutide is superior to placebo
(45.6 months), SUSTAIN-6 (25.2 months), EXSCEL (38.4 months), and and if there are differences in the incidence of MACE with the use of oral
EMPA-REG OUTCOME (37.2 months) trials.2,3,35–37 The trial was com- versus injectable semaglutide. PIONEER 6 was the first trial to demon-
pleted by 1347 of 1591 patients (84.7%) in the oral semaglutide group strate CV safety of an oral GLP-1 RA with no increase in incidence of di-
and 1435 of 1592 patients (90.1%) in the placebo group. More patients abetic retinopathy during the trial.
in the oral semaglutide group (11.6%) discontinued treatment than
the placebo group (6.5%) due to adverse events, which was driven by 17. Place in therapy
the increased frequency of GI events in the oral semaglutide group.34
The primary MACE outcome occurred in 61 of 1591 patients (3.8%) The American Diabetes Association (ADA) Standards of Medical Care
in the oral semaglutide group and 76 of 1592 patients (4.8%) in the pla- in Diabetes recommend that in the absence of contraindications, met-
cebo group (HR, 0.79; 95% CI, 0.57 to 1.11; Pb0.001 for non-inferiority). formin is the preferred initial pharmacologic option for the treatment
The reduction in the primary composite MACE outcome observed in the of T2D.1 The choice of which agent to add second depends on patient-
oral semaglutide group was largely driven by the 51% reduction in CV specific factors. The guidelines currently advocate for the use of GLP-1
mortality. However, the 21% reduction in the primary endpoint with RAs that have demonstrated CV benefit in patients with T2D and
oral semaglutide was non-statistically significant. The trial investigators established atherosclerotic cardiovascular disease (ASCVD) and the
concluded that oral semaglutide was non-inferior to placebo.34 use of GLP-1 RAs that have demonstrated reduction in CKD progression,
Secondary outcomes included CV death, nonfatal MI, nonfatal stroke, CV events, or both patients with T2D and CKD. Lastly, GLP-1 RAs are rec-
unstable angina requiring hospitalization, heart failure (HF) requiring ommended in patients who desire weight loss, an agent with a low risk
hospitalization, all-cause mortality, and composite outcomes of these of hypoglycemia, and who need greater glucose lowering with an inject-
secondary events. There was a significant decrease in CV deaths in the able agent.1 It is unclear, however, how the ADA will approach recom-
oral semaglutide group (15 of 1591 patients, 0.9%) compared with the mendations regarding oral semaglutide. The PIONEER 6 trial
placebo group (30 of 1592 patients, 1.9%; HR 0.49; 95% CI 0.27–0.92). demonstrated non-inferior CV safety of oral semaglutide compared to
All-cause mortality occurred in 23 of 1591 patients (1.4%) in the oral placebo, but not superiority, in patients with T2D and CVD. This makes
semaglutide group and 45 of 1592 patients (2.8%) in the placebo oral semaglutide less favorable than other GLP-1 RAs that have demon-
group (HR, 0.51; 95% CI, 0.31 to 0.84). All-cause mortality was largely strated superiority in CV risk reduction in similar patients. The Heart
driven by CV mortality in both groups.34 Disease Study of Semaglutide in Patients with T2D (SOUL) is still under-
In the SUSTAIN-6 trial, there were significantly fewer CV events for way and should provide additional insight into the role of oral
patients at high CV risk treated with injectable semaglutide compared semaglutide in patients with T2D and heart disease.38 The PIONEER 5
with placebo. SUSTAIN-6 demonstrated superiority of injectable trial demonstrated efficacy and safety of oral semaglutide in patients
semaglutide in comparison to placebo for the same composite MACE with T2D and moderate renal impairment, but not delay of CKD pro-
outcome described in the PIONEER 6 trial (HR 0.74; 95% CI, 0.58– gression as has been demonstrated with some sodium glucose co-
0.95). Secondary outcome analyses showed no difference between the transporter-2 (SGLT2) inhibitors.32,39
two groups for CV death and all-cause mortality.2 Compared to Cost-effectiveness analyses of oral semaglutide have demonstrated
PIONEER 6, SUSTAIN-6 was longer in duration (104 weeks compared that the 14 mg dose is more cost effective than its comparators in the

Table 3
Comparison of PIONEER 6 and SUSTAIN-6.

Citation Design Numbers of CV Risk Profile Baseline Primary Primary Primary Hazard
Patients characteristics Outcome outcome: outcome: Ratio (95% CI)
Composite Oral Placebo, n
Semaglutide, (%)
n (%)

PIONEER 6 Event-driven, n = 1591 oral Age ≥ 50 years with Mean age, 66 years; First 61 (3.8) 76 (4.8) 0.79 (0.57–1.1)⁎
double-blind, semaglutide established CVD or A1C, 8.2%; weight 91 occurrence
placebo-controlled, CKD or ≥ 60 years kg; of MACE: death
63.6 weeks n = 1592 placebo with CV risk factors duration of diabetes, from CV causes,
15 years nonfatal MI,
nonfatal stroke
SUSTAIN-6 Randomized, n = 1648 Age ≥ 50 years with Mean age, 65 years; A1C, First 108 (6.6) 146 (8.9) 0.74 (0.58–0.95)§
double-blind, injectable established CVD or 8.7%; weight 92 kg; occurrence
placebo-controlled, semaglutide CKD or ≥ 60 years duration of diabetes, of MACE: death
parallel group trial, with CV risk 13.9 years from CV causes,
104 weeks n = 1649 placebo factors nonfatal MI,
nonfatal stroke

Abbreviations: A1C, glycosylated hemoglobin; CKD, chronic kidney disease; CI, confidence interval; CV, cardiovascular; CVD, cardiovascular disease; MACE, major adverse cardiovascular
event.
⁎ pb0.001 for noninferiority, p=0.17 for superiority.
§
pb0.001 for noninferiority, p=0.02 for superiority.
 S.L. Anderson et al. / Journal of Diabetes and Its Complications 34 (2020) 107520 7

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Funding
25. Zinman B, Aroda VR, Buse JB, et al. Efficacy, safety, and tolerability of oral semaglutide
versus placebo added to insulin ± metformin in patients with type 2 diabetes: the
This research did not receive any specific grant from funding agen- PIONEER 8 trial. Diabetes Care 2019 Sept 17. https://doi.org/10.2337/dc19-0898
[Epub ahead of print].
cies in the public, commercial, or not-for-profit sectors.
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