Sustaine 10
Sustaine 10
Sustaine 10
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Original article
A R T I C L E I N F O A B S T R A C T
Article history: Aims. – SUSTAIN 10 compared the efficacy and safety of the anticipated most frequent semaglutide dose
Received 14 June 2019 (1.0 mg) with the current most frequently prescribed liraglutide dose in Europe (1.2 mg), reflecting
Received in revised form 28 August 2019 clinical practice.
Accepted 1st September 2019
Methods. – In this phase 3b, open-label trial, 577 adults with type 2 diabetes (HbA1c 7.0–11.0%) on 1–3
Available online xxx
oral antidiabetic drugs were randomized 1:1 to subcutaneous once-weekly semaglutide 1.0 mg or
subcutaneous once-daily liraglutide 1.2 mg. Primary and confirmatory secondary endpoints were
Keywords:
changes in HbA1c and body weight from baseline to week 30, respectively.
Glycaemic control
Glucagon-like peptide-1 receptor agonist
Results. – Mean HbA1c (baseline 8.2%) decreased by 1.7% with semaglutide and 1.0% with liraglutide
Liraglutide (estimated treatment difference [ETD] –0.69%; 95% confidence interval [CI] 0.82 to 0.56, P < 0.0001).
Semaglutide Mean body weight (baseline 96.9 kg) decreased by 5.8 kg with semaglutide and 1.9 kg with liraglutide
Type 2 diabetes (ETD 3.83 kg; 95% CI 4.57 to 3.09, P < 0.0001). The proportions of subjects achieving glycaemic
SUSTAIN targets of < 7.0% and 6.5%, weight loss of 5% and 10%, and a composite endpoint of HbA1c < 7.0%
without severe or blood glucose-confirmed symptomatic hypoglycaemia and no weight gain were
greater with semaglutide vs liraglutide (all P < 0.0001). Both treatments had similar safety profiles,
except for more frequent gastrointestinal disorders (the most common adverse events [AEs]) and AEs
leading to premature treatment discontinuation with semaglutide vs liraglutide (43.9% vs 38.3% and
11.4% vs 6.6%, respectively).
Conclusion. – Semaglutide was superior to liraglutide in reducing HbA1c and body weight. Safety profiles
were generally similar, except for higher rates of gastrointestinal AEs with semaglutide vs liraglutide.
C 2019 Published by Elsevier Masson SAS.
Abbreviations: AACE, American Association of Clinical Endocrinologists; ADA, American Diabetes Association; AE, adverse event; BG, blood glucose; BMI, body mass index;
bpm, beats per minute; CI, confidence interval; CKD-EPI, The Chronic Kidney Disease Epidemiology Collaboration; CoV, coefficient of variation; CV, cardiovascular
DPP-4i, dipeptidyl peptidase-4 inhibitor; DTSQs, Diabetes Treatment Satisfaction Questionnaire status version; E, number of events; EASD, European Association for the Study
of Diabetes; eGFR, estimated glomerular filtration rate; exenatide ER, exenatide extended release; ETD, estimated treatment difference; ETR, estimated treatment ratio; FAS,
full analysis set; FPG, fasting plasma glucose; GI, gastrointestinal; GLP-1, glucagon-like peptide-1; GLP-1RA, glucagon-like peptide-1 receptor agonist; KDIGO, Kidney Disease
Improving Global Outcomes; max., maximum; MedDRA, Medical Dictionary for Regulatory Activities; MET, metformin; min., minimum; MTD, maximum tolerated dose; n,
number of subjects; N, total number of subjects; OAD, oral antidiabetic drug; OD, once daily; OR, odds ratio; OW, once weekly; PRO, patient-reported outcome; R, event rate
per 100 exposure-years; SAS, safety analysis set; s.c., subcutaneous; SD, standard deviation; SE, standard error; SGLT-2i, sodium–glucose cotransporter-2 inhibitor; SF-36v21,
Short-Form 36 Health Survey version 21; SMBG, self-measured blood glucose; SU, sulfonylurea; SUSTAIN, Semaglutide Unabated Sustainability in Treatment of Type
2 Diabetes; TEAE, treatment-emergent adverse event; T2D, type 2 diabetes.
* Corresponding author. Rotherham Institute for Obesity (RIO), Clifton Medical Centre, The Health Village, Doncaster Gate, Rotherham S65 1DA, UK.
E-mail address: [email protected] (M.S. Capehorn).
https://doi.org/10.1016/j.diabet.2019.101117
1262-3636/ C 2019 Published by Elsevier Masson SAS.
Please cite this article in press as: Capehorn MS, et al. Efficacy and safety of once-weekly semaglutide 1.0 mg vs once-daily liraglutide
1.2 mg as add-on to 1–3 oral antidiabetic drugs in subjects with type 2 diabetes (SUSTAIN 10). Diabetes Metab (2019), https://doi.org/
10.1016/j.diabet.2019.101117
G Model
DIABET-101117; No. of Pages 10
Please cite this article in press as: Capehorn MS, et al. Efficacy and safety of once-weekly semaglutide 1.0 mg vs once-daily liraglutide
1.2 mg as add-on to 1–3 oral antidiabetic drugs in subjects with type 2 diabetes (SUSTAIN 10). Diabetes Metab (2019), https://doi.org/
10.1016/j.diabet.2019.101117
G Model
DIABET-101117; No. of Pages 10
Endpoints The Type-I error rate for testing the three confirmatory
hypotheses relating to HbA1c and body weight was preserved at
The primary endpoint was change in HbA1c (%-point, hereafter an overall one-sided alpha (a) level of 2.5%. A sample size of
referred to as ‘%’) from baseline to week 30. The confirmatory 288 subjects was needed in each of the semaglutide and
secondary endpoint was change in body weight (kg) from baseline liraglutide groups (total planned randomized: 576 subjects), to
to week 30. Other pre-specified supportive secondary efficacy provide at least 90% power to reject all three confirmatory
endpoints included changes from baseline to week 30 in: FPG; hypotheses and, thus, confirm HbA1c superiority and body
mean postprandial increment across all meals and mean 7-point weight superiority of semaglutide vs liraglutide across efficacy
profile based on self-measured blood glucose (SMBG); fasting and in-trial assumptions.
blood lipids (total cholesterol, low-density lipoprotein-cholesterol, The primary analysis addressed the primary estimand, which
high-density lipoprotein-cholesterol, and triglycerides); body was based on the FAS using measurements up to and including
mass index (BMI); waist circumference; and systolic and diastolic week 30 from the ‘on-treatment without rescue medication’
blood pressure. observation period.
Pre-specified clinical treatment targets included subjects In the primary analysis, imputation of missing data was
who, after 30 weeks of treatment, achieved HbA1c < 7.0% (ADA) handled using multiple imputation assuming that missing
[24] or 6.5% (American Association of Clinical Endocrinolo- data were missing at random. Missing data were imputed as
gists) [25]. In addition, the proportions of subjects achieving intermittent values using a Markov Chain Monte Carlo method to
HbA1c reduction 1%; weight loss 3%, 5%, or 10%; a obtain a monotone missing data pattern. This imputation was done
composite endpoint of HbA1c < 7.0% without severe (ADA for each treatment group separately and 500 copies of the dataset
classification) [26] or blood glucose (BG)-confirmed symptom- were generated. A sequential regression approach for imputing
atic hypoglycaemic episodes and no weight gain; and composite monotonely missing values at planned visits was implemented
endpoints of HbA1c reduction of 1% and weight loss starting with the first visit after baseline and sequentially
of 3%, 5%, or 10%. Supportive secondary endpoints for continued to the last planned visit (week 30). A linear model
patient-reported outcomes (PROs) included changes from was applied to each treatment group. This model used
baseline to week 30 in Short-Form 36 Health Survey version the background medication stratification factor (SU MET,
21 (SF-36v21) and Diabetes Treatment Satisfaction Question- SGLT-2i MET, SU and SGLT-2i MET, and MET monotherapy) as
naire status version (DTSQs) scores [27,28]. a categorical effect, and baseline and post-baseline HbA1c values
Safety endpoints included the number of treatment-emergent (observed and imputed) prior to the visit in question as covariates. An
adverse events (TEAEs, classified as events that had an onset date, analysis of covariance with treatment and background medication
or increase in severity, during the ‘on-treatment’ observation stratification factor as categorical effects and baseline HbA1c as a
period) and the number of treatment-emergent severe or BG- covariate were used to analyze HbA1c at week 30 for each of the
confirmed symptomatic hypoglycaemic episodes. Other safety 500 data sets generated as part of the imputation of missing values.
endpoints included change from baseline to week 30 in haema- Rubin’s rule was used to combine the analysis results in order to draw
tology, biochemistry, calcitonin, pulse rate, electrocardiogram inference. Sensitivity analyses (tipping-point, retrieved drop-out
category, physical examination category, and eye examination [superiority only], and per-protocol [non-inferiority only] analyses)
category. All AEs were coded using the most recent version of the were conducted on the primary analysis, see Table S3 (see
Medical Dictionary for Regulatory Activities (MedDRA). supplementary materials associated with this article on line) for
details.
Statistical analysis The secondary confirmatory endpoint of change from baseline
to week 30 in body weight was analyzed in the same way as the
The primary estimand was defined as the treatment difference primary endpoint, but using baseline and post-baseline body
between semaglutide and liraglutide at week 30 for all randomized weight measurements as covariates (instead of HbA1c). Sensitivity
subjects if all subjects completed treatment and did not initiate analyses (tipping-point and retrieved drop-out analyses) were also
rescue medication. This estimand was considered clinically conducted on the secondary confirmatory endpoint, see Table S3
relevant as it assessed the glycaemic benefit a subject with T2D (see supplementary materials associated with this article on line)
was expected to achieve if they initiated and continued treatment for details.
with semaglutide vs liraglutide. Continuous endpoints were analyzed separately using a similar
Efficacy endpoints were evaluated based on the full analysis set model approach as for the primary endpoint, with associated
(FAS, which included all randomized subjects) from the ‘on-treatment baseline values as covariates (instead of HbA1c). The binary
without rescue medication’ observation period; safety endpoints were endpoints were analyzed using a logistic regression model with
analyzed using the safety analysis set (SAS, which included data from treatment and stratification factor as fixed factors and baseline
all subjects exposed to at least one dose of trial product) from the values as covariates. Before analysis, missing data for individual
‘on-treatment’ or ‘in-trial’ observation periods. See Table S3 and components were imputed separately using the same approach as
protocol (see supplementary materials associated with this article on for continuous endpoints and subsequently dichotomized. The
line) for the definitions of the observation periods. PRO questionnaires (SF-36v21 and DTSQs) were used to evaluate
Three confirmatory hypotheses were tested using the following quality of life and treatment satisfaction; see Table S3 (see
hierarchical testing procedure [29]: supplementary materials associated with this article on line) for
further details on the PRO questionnaires.
1 HbA1c non-inferiority of semaglutide 1.0 mg vs liraglutide Safety outcomes were summarized descriptively based on the
1.2 mg (non-inferiority margin of 0.3); SAS using data the from ‘on-treatment’ observation period,
2 Body weight superiority of semaglutide 1.0 mg vs liraglutide except neoplasms and diabetic retinopathy, which were
1.2 mg; reported using data from the ‘in-trial’ observation period.
3 HbA1c superiority of semaglutide 1.0 mg vs liraglutide 1.2 mg Summaries of treatment-emergent hypoglycaemic episodes
[Figure S2 (see supplementary materials associated with this were presented as an overview, including all episodes and
article on line)]. episodes by severity.
Please cite this article in press as: Capehorn MS, et al. Efficacy and safety of once-weekly semaglutide 1.0 mg vs once-daily liraglutide
1.2 mg as add-on to 1–3 oral antidiabetic drugs in subjects with type 2 diabetes (SUSTAIN 10). Diabetes Metab (2019), https://doi.org/
10.1016/j.diabet.2019.101117
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DIABET-101117; No. of Pages 10
Fig. 1. Subject disposition. One subject receiving liraglutide 1.2 mg discontinued treatment prematurely, the primary reason for which was a non-treatment-emergent
adverse event. *Screened subjects who withdrew consent before randomization; yincludes only exposed subjects; zsubjects who completed the trial according to the end-of-
trial form; §subjects who completed treatment according to the end-of-treatment form; ôone extra subject in the liraglutide group received rescue medication but did not
complete treatment.
Please cite this article in press as: Capehorn MS, et al. Efficacy and safety of once-weekly semaglutide 1.0 mg vs once-daily liraglutide
1.2 mg as add-on to 1–3 oral antidiabetic drugs in subjects with type 2 diabetes (SUSTAIN 10). Diabetes Metab (2019), https://doi.org/
10.1016/j.diabet.2019.101117
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DIABET-101117; No. of Pages 10
Table 1
Baseline characteristics – full analysis set.
Data are mean (SD) or n (%) for the full analysis set (FAS), unless otherwise stated. Baseline information is defined as the measurement at the latest assessment before dosing.
Body mass index is calculated based on baseline measurement of body weight and height.
%: percentage of subjects; CKD-EPI: The Chronic Kidney Disease Epidemiology Collaboration; CoV: coefficient of variation; DPP-4i: dipeptidyl peptidase-4 inhibitor;
eGFR: estimated glomerular filtration rate; max.: maximum; min.: minimum; n: number of subjects; N: total number of subjects; SD: standard deviation; SGLT-2i:
sodium–glucose cotransporter-2 inhibitor.
a
The renal function categories are based on the eGFR using CKD-EPI. No subjects had an eGFR < 30 mL/min/1.73 m2.
b
The two subjects on DPP-4is and repaglinide were randomized in error and discontinued treatment.
semaglutide vs liraglutide (76% vs 37% respectively, estimated OR line]). There were no significant differences in any other DTSQs
6.07 [95% CI 4.02 to 9.15], P < 0.0001; Fig. 4a). scales or SF-36v21 domains [Table S7 (see supplementary
A greater proportion of subjects treated with semaglutide vs materials associated with this article on line)].
liraglutide also achieved composite endpoints of HbA1c In total, 70.6% (n = 204) subjects experienced TEAEs in the
reduction 1% and different weight-loss responses of 3%, semaglutide group, and 66.2% (n = 190) in the liraglutide group
5%, and 10% body weight: 62% vs 21% (estimated OR (Table 2). TEAEs were mainly mild to moderate in severity. A
6.63 [95% CI 4.44 to 9.91], P < 0.0001; Figure S4a [see supplemen- slightly higher number of subjects experienced serious TEAEs with
tary materials associated with this article on line]), 50% vs 12% liraglutide (n = 22, 7.7%) than with semaglutide (n = 17, 5.9%).
(estimated OR 7.55 [95% CI 4.80 to 11.88], P < 0.0001; Figure S4b There were no deaths in either treatment group. A higher
[see supplementary materials associated with this article on line]), proportion of subjects reported TEAEs leading to premature
and 17% vs 4% (estimated OR 5.26 [95% CI 2.58 to 10.73], treatment discontinuation with semaglutide (n = 33, 11.4%) vs
P < 0.0001; Fig. 4b), respectively. liraglutide (n = 19, 6.6%); this was primarily driven by GI AEs (7.6%
The change from baseline (136.4 mmHg) to week 30 in systolic with semaglutide vs 3.8% with liraglutide).
blood pressure was moderate with both semaglutide (4.5 mmHg The most commonly reported AEs were GI disorders, reported
[standard error (SE) 0.7]) and liraglutide (3.5 [0.7]), and the ETD in 127 (43.9%) subjects with semaglutide and 110 (38.3%) subjects
between the treatment arms was not significant (1.0 [95% CI 3.0 with liraglutide. The onset of GI AEs was typically during the initial
to 1.1] Table S5 [see supplementary materials associated with this 12 weeks of the trial. GI AEs were most prevalent during the dose-
article on line]). Similarly, there was no significant difference in escalation period (liraglutide) or within the first 12 weeks of
diastolic blood pressure between treatments [Table S5 (see treatment (semaglutide); events were generally mild in severity.
supplementary materials associated with this article on line)]. Nausea was the most frequently reported GI AE, reported by 63
Changes from baseline to week 30 for lipid levels were modest (21.8%) vs 45 (15.7%) subjects with semaglutide vs liraglutide
for both treatments, but the semaglutide group showed signifi- (Table 2). Other frequently reported GI AEs with semaglutide and
cantly greater improvements vs the liraglutide group for total liraglutide were: diarrhea (15.6% and 12.2%), vomiting (10.4% and
cholesterol and triglycerides [Table S6 (see supplementary 8.0%), constipation (5.9% and 3.5%), and abdominal pain (5.2% and
materials associated with this article on line)]. 2.1%). A list of the AEs reported in 5% of subjects in either
Improvements in PRO scores were reported with both treatment arm is shown in Table S8 (see supplementary materials
treatment arms. The DTSQs showed a significant difference associated with this article on line).
between treatment groups in ‘Feeling of unacceptably high blood Severe or BG-confirmed symptomatic hypoglycaemia was
sugars’, with this aspect of treatment satisfaction favouring experienced by 1.7% of subjects (n = 5; 8 events) in the semaglutide
semaglutide (ETD 0.55 [95% CI 0.83 to 0.27], P = 0.0001; group and 2.4% of subjects (n = 7; 8 events) in the liraglutide group;
Table S7 [see supplementary materials associated with this article no subject in either group experienced severe hypoglycaemic
on line]). The SF-36v21 questionnaire showed significant diffe- episodes (ADA definition; data not shown). Of the 16 episodes of
rences between the two treatment groups in two components of severe or BG-confirmed symptomatic hypoglycaemia, 15 were in
health-related quality of life, with the results favouring sema- subjects receiving background SU.
glutide: vitality (ETD 1.68 [95% CI 0.45 to 2.92], P = 0.0076) and Pancreatitis TEAEs (pre-defined MedDRA search) were reported
mental health (ETD 1.30 [95% CI 0.06; 2.53], P = 0.0396; Table S7 in two (0.7%) subjects receiving liraglutide and no subjects.
[see supplementary materials associated with this article on Neoplasms (benign, malignant, and unspecified) were reported in
Please cite this article in press as: Capehorn MS, et al. Efficacy and safety of once-weekly semaglutide 1.0 mg vs once-daily liraglutide
1.2 mg as add-on to 1–3 oral antidiabetic drugs in subjects with type 2 diabetes (SUSTAIN 10). Diabetes Metab (2019), https://doi.org/
10.1016/j.diabet.2019.101117
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DIABET-101117; No. of Pages 10
Fig. 2. Glycaemic endpoints with semaglutide 1.0 mg and liraglutide 1.2 mg. Estimated change in HbA1c by week (a); estimated change in HbA1c from overall baseline mean to
week 30 (b); estimated change in FPG over time (c); observed mean 7-point SMBG profile at baseline and at week 30 (d); mean 7-point SMBG profile change from baseline to
week 30 (e); proportion of subjects achieving HbA1c < 7.0% (f) and 6.5% (g) at week 30. *P < 0.0001 vs liraglutide 1.2 mg. All figures based on the full analysis set, using
‘on-treatment without rescue medication’ data. Figures a–c and e: mean estimates are from an analysis of covariance, where missing data were accounted for using multiple
imputation (data from subjects within the same group defined by randomized treatment) using a regression model including stratification factor as categorical effect and data
from baseline and all previous post-baseline visits as covariates. Error bars are standard errors of the means. Dashed grey lines indicate the overall mean values at baseline.
Values in square brackets are 95% CIs. Figure d: dashed lines indicate baseline values; solid lines indicate week 30 data. SMBG assessed with glucose meter as plasma equivalent
values of capillary whole blood glucose. Figures f, g: missing HbA1c data were accounted for using multiple imputation (data from subjects within the same group defined by
randomized treatment) using a regression model including stratification factor as categorical effect and data from baseline and all previous post-baseline visits as covariates. After
imputation, continuous data were dichotomized. AACE: American Association of Clinical Endocrinologists; ADA: American Diabetes Association; CI: confidence interval;
ETD: estimated treatment difference; FPG: fasting plasma glucose; SMBG: self-measured blood glucose.
Please cite this article in press as: Capehorn MS, et al. Efficacy and safety of once-weekly semaglutide 1.0 mg vs once-daily liraglutide
1.2 mg as add-on to 1–3 oral antidiabetic drugs in subjects with type 2 diabetes (SUSTAIN 10). Diabetes Metab (2019), https://doi.org/
10.1016/j.diabet.2019.101117
G Model
DIABET-101117; No. of Pages 10
Fig. 3. Body weight outcomes with semaglutide 1.0 mg and liraglutide 1.2 mg. Estimated change in body weight over time (a); body weight change from baseline to week 30
(b); proportion of subjects achieving weight loss 5% (c) and 10% (d) at week 30. * P < 0.0001 vs liraglutide 1.2 mg. All figures based on the full analysis set, using ‘on-
treatment without rescue medication’ data. Figure a, b: mean estimates are from an analysis of covariance, where missing data were accounted for using multiple imputation
(data from subjects within the same group defined by randomized treatment) using a regression model including stratification factor as categorical effect and data from
baseline and all previous post-baseline visits as covariates. Error bars are standard errors of the means. Dashed grey line indicates the overall mean value at baseline. Values in
square brackets are 95% CIs. Figure c, d: missing body weight (kg) data were accounted for using multiple imputation (data from subjects within the same group defined by
randomized treatment) using a regression model including stratification factor as categorical effect and data from baseline and all previous post-baseline visits as covariates. After
imputation, continuous data were dichotomized. All site visits, except screening visits, were to be completed in a fasting state. CI: confidence interval; ETD: estimated treatment
difference.
Fig. 4. Composite endpoints with semaglutide 1.0 mg and liraglutide 1.2 mg at week 30. Proportion of subjects achieving HbA1c < 7.0% without severe or BG-confirmed
symptomatic hypoglycaemia and without weight gain (a); and proportion of subjects achieving HbA1c reduction 1% and weight loss 10% (b). *P < 0.0001 vs. liraglutide
1.2 mg. Full analysis set and ‘on-treatment without rescue medication’ data with missing HbA1c (%) and body weight (kg) data accounted for using multiple imputation
(individual components imputed separately for composite endpoints; data from subjects within the same group defined by randomized treatment) using a regression model
including stratification factor as categorical effect and data from baseline and all previous post-baseline visits as covariates. After imputation continuous data were
dichotomized. All site visits, except screening visit, were completed in the fasting state. BG: blood glucose.
nine (3.1%) subjects receiving semaglutide and four (1.4%) subjects There was no change in eGFR (geometric mean) from baseline
receiving liraglutide during the ‘in-trial’ period; no clustering of to week 30 with semaglutide or liraglutide (ratios to baseline at
neoplasms was reported. ‘In-trial’ AEs related to diabetic week 30 were 0.99 and 1.00, respectively). Mean pulse rate
retinopathy (pre-defined MedDRA search) were reported in three increased from baseline (74.3 bpm) to week 30 with both
(1.0%) subjects receiving semaglutide and four (1.4%) subjects semaglutide (2.5 bpm [SE 0.5]) and liraglutide (3.9 bpm [0.5]);
receiving liraglutide. All seven events were non-serious, and all but the difference was not significantly different (ETD–1.36 [95%
one were mild in severity (one event with liraglutide was recorded CI – 2.75 to 0.03], P = 0.0556; Table S5 [see supplementary
as moderate severity). materials associated with this article on line]). There were no
Please cite this article in press as: Capehorn MS, et al. Efficacy and safety of once-weekly semaglutide 1.0 mg vs once-daily liraglutide
1.2 mg as add-on to 1–3 oral antidiabetic drugs in subjects with type 2 diabetes (SUSTAIN 10). Diabetes Metab (2019), https://doi.org/
10.1016/j.diabet.2019.101117
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Table 2
Treatment-emergent adverse events.
n (%) E R n (%) E R
All TEAEs 204 (70.6) 758 418.5 190 (66.2) 691 377.6
Severity of TEAEs
Mild 175 (60.6) 564 311.4 168 (58.5) 512 279.8
Moderate 84 (29.1) 168 92.8 83 (28.9) 152 83.1
Severe 17 (5.9) 26 14.4 15 (5.2) 27 14.8
Serious TEAEs 17 (5.9) 22 12.1 22 (7.7) 31 16.9
TEAEs leading to premature treatment discontinuation 33 (11.4) 54 29.8 19 (6.6) 26 14.2
Gastrointestinal AEs leading to premature treatment discontinuation 22 (7.6) 34 18.8 11 (3.8) 13 7.1
Gastrointestinal disorders 127 (43.9) 315 173.9 110 (38.3) 219 119.7
Nauseaa 63 (21.8) 89 49.1 45 (15.7) 54 29.5
Diarrheaa 45 (15.6) 56 30.9 35 (12.2) 44 24.0
Vomitinga 30 (10.4) 44 24.3 23 (8.0) 33 18.0
Constipationa 17 (5.9) 17 9.4 10 (3.5) 13 7.1
Abdominal paina 15 (5.2) 18 9.9 6 (2.1) 6 3.3
clinically relevant changes in other safety laboratory assessments, (OD liraglutide, OW dulaglutide, twice-daily exenatide, OW
physical examinations category, or electrocardiogram category exenatide, OD lixisenatide, and OW albiglutide) in subjects with
(data not shown). T2D previously receiving basal insulin or 1–2 OADs [31,32]. In
these analyses, OW semaglutide 1.0 mg was associated with
greater reductions in HbA1c and body weight vs all GLP-1RA
Discussion comparators and was generally well tolerated.
Other clinical trials have studied the effects of OW GLP-1RAs
The SUSTAIN 10 trial showed that OW semaglutide 1.0 mg was (dulaglutide 1.5 mg [AWARD-6] [33], exenatide ER 2.0 mg
superior to OD liraglutide 1.2 mg in reducing HbA1c and body [DURATION-6] [34]) vs OD liraglutide 1.85 mg (a higher dose
weight after 30 weeks of treatment in subjects with T2D than in SUSTAIN 10) in subjects with T2D. Whereas in AWARD-6
uncontrolled on 1–3 OADs, few of whom received rescue dulaglutide was non-inferior to liraglutide in reducing HbA1c, in
medication. A greater proportion of subjects achieved HbA1c DURATION-6 liraglutide demonstrated superiority vs exenatide
targets of < 7.0% and 6.5% and weight-loss responses of 5% ER.
and 10% with semaglutide vs liraglutide. The observed The SUSTAIN 10 trial was the first Europe-based head-to-head
differences in efficacy between the two medications could be trial to compare s.c. OW semaglutide vs s.c. OD liraglutide, and had
due to minor but clinically relevant differences in their molecular relatively broad inclusion criteria in terms of the range of
structure: compared with liraglutide, which has an alanine at background medications and baseline characteristics. SUSTAIN
position 8 and a C-16 fatty acid chain with a gamma glutamate 10 is, thus, both representative of patients that physicians are
(gGlu) linker at position 26, semaglutide has an alanine to alpha- likely to consider for treatment with a GLP-1RA and reflective of
aminoisobutyric acid amino acid substitution at position 8 and a discussions that physicians may have with patients regarding
C-18 fatty diacid side chain with a gGlu-2xOEG linker at position dosing regimen preferences. These factors make the findings of
26 [30]. SUSTAIN 10 particularly relevant for real-world clinical practice.
Both semaglutide 1.0 mg and liraglutide 1.2 mg were generally The trial design also aimed to reflect real-world clinical practice, as
well tolerated. As expected, GI events were the most commonly it compared the most commonly prescribed dose for OD liraglutide
reported, with a higher proportion of subjects experiencing them (1.2 mg) with the anticipated most frequent dose for OW
with semaglutide vs liraglutide. GI AEs, which generally occurred semaglutide (1.0 mg) in Europe. These features of the trial increase
in the first 12 weeks of treatment, were typically mild in severity the relevance of the results for physicians and also for medicine
and transient in duration. Conversely, a slightly higher proportion management teams, who are responsible for planning formularies
of subjects reported serious TEAEs with liraglutide vs semaglutide. in a crowded diabetes treatment arena.
While it may be anticipated that patient preference and The limitations of the SUSTAIN 10 trial include its open-label
treatment satisfaction could be influenced by dosing frequency, design, which was necessitated by the different dosing frequen-
SUSTAIN 10 showed similar improvements in patient-reported cies of semaglutide and liraglutide. The relatively short trial
treatment satisfaction with both the OW (semaglutide) and OD duration is also a limitation; the change over time curves for
(liraglutide) treatments. This may be a result of the already good HbA1c and body weight indicate that the effects, at least with
glycaemic and body weight control observed with liraglutide, and/ semaglutide, had not yet plateaued – a longer trial duration would
or other factors affecting treatment satisfaction. It should be noted, have enabled the full extent of any treatment differences to be
however, that SUSTAIN 10 was not powered to reveal differences in revealed. Furthermore, the trial only included two of the four
treatment satisfaction and/or effect of dosing frequency. potential treatment doses, as semaglutide 0.5 mg and liraglutide
The results from SUSTAIN 10 are consistent with those from the 1.8 mg were not investigated, although this was based on the
SUSTAIN 3 and 7 trials, which also compared OW semaglutide with rationale to assess the most commonly prescribed and anticipated
other GLP-1RAs (exenatide ER and dulaglutide, both OW), and most commonly prescribed doses of the two GLP-1RAs, and
with those from a systematic literature review and network provide a basis for clinical decision-making when choosing
meta-analysis comparing OW semaglutide with other GLP-1RAs treatment.
Please cite this article in press as: Capehorn MS, et al. Efficacy and safety of once-weekly semaglutide 1.0 mg vs once-daily liraglutide
1.2 mg as add-on to 1–3 oral antidiabetic drugs in subjects with type 2 diabetes (SUSTAIN 10). Diabetes Metab (2019), https://doi.org/
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