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Diabetes & Metabolism xxx (2019) 101117

Available online at

ScienceDirect
www.sciencedirect.com

Original article

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)
M.S. Capehorn a,*, A.-M. Catarig b, J.K. Furberg b, A. Janez c, H.C. Price d, S. Tadayon b,
B. Vergès e, M. Marre f
a
Rotherham Institute for Obesity, Clifton Medical Centre, S65 1DA Rotherham, South Yorkshire, UK
b
Novo Nordisk A/S, DK-2860 Søborg, Denmark
c
Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia
d
West Hampshire Community Diabetes Service, SO43 7NG Lyndhurst, UK
e
CHU, 21000 Dijon, France
f
Clinique Ambroise Paré, 27, boulevard Victor-Hugo, 92200 Neuilly-sur-Seine, France

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: mcapehorn@yahoo.co.uk (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
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2 M.S. Capehorn et al. / Diabetes & Metabolism xxx (2019) 101117

Introduction Practice guidelines [20], and the Declaration of Helsinki

[21]. Subjects provided consent before the commencement of
There are currently a variety of treatment options for type any trial-related activities. The protocol is available in the
2 diabetes (T2D); despite this, a large proportion of subjects do not Appendix (see supplementary materials associated with this
achieve HbA1c treatment targets [1]. Furthermore, optimal article on line).
treatment of T2D should involve patient-oriented treatment goals
extending beyond glycaemic control, to include minimizing Participants
unwanted effects like weight gain and hypoglycaemia, and
reducing the risk of complications such as cardiovascular (CV) Key inclusion criteria were age  18 years; T2D with HbA1c 7.0–
events [2,3]. 11.0%; and stable daily doses of any of the following antidiabetic
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have drug(s) or combination regimens 90 days prior to screening:
emerged as effective treatments for T2D and are incorporated into biguanides (MET  1500 mg or maximum tolerated dose [MTD]),
the clinical guidelines [2,3]. The 2018 American Diabetes Associa- sulfonylurea (SU) or SGLT-2i (for both SU and SGLT-2i:
tion (ADA)/European Association for the Study of Diabetes (EASD)  0.5 maximum approved dose according to local label or MTD
consensus report and the 2019 ADA Standards of Care treatment as documented in subject medical record). Key exclusion criteria
guidelines recommend preferred treatments, following metformin were renal impairment, measured as estimated glomerular
(MET), as either GLP-1RAs or sodium–glucose cotransporter-2 filtration rate (eGFR) < 30 mL/min/1.73 m2; presence of New York
inhibitors (SGLT-2is), particularly in adults with T2D and Heart Association Class IV heart failure; proliferative retinopathy
additional CV risk factors (e.g. GLP-1RAs or SGLT-2is for or maculopathy requiring acute treatment, verified by fundus
established atherosclerotic disease or SGLT-2is for chronic kidney photography or dilated fundoscopy within the 90 days prior
disease or heart failure) [2,3]. In addition to improving glycaemic to randomization; impaired liver function (alanine
control, some drugs in the GLP-1RA class also provide weight loss, aminotransferase  2.5 times upper limit of normal at screening);
have CV benefits, improve renal outcomes, and minimize hypo- and presence or history of malignant neoplasms within the past
glycaemic risk [2–7]. Several GLP-1RAs are currently available, 5 years prior to screening. Full trial eligibility criteria are listed in
both short- and long-acting, as once-daily (OD) or once-weekly Table S2 (see supplementary materials associated with this article
(OW) injections [8], with different molecular sizes and structures on line).
that result in varying efficacy and safety profiles [9,10].
Semaglutide (Novo Nordisk A/S) is a long-acting glucagon-like Randomization
peptide-1 (GLP-1) analog, approved for the treatment of T2D in a
subcutaneous (s.c.), OW formulation [11,12]. The efficacy and safety of Subjects with T2D inadequately controlled on 1–3 oral antidiabetic
semaglutide OW has been investigated in the Semaglutide Unabated drug(s) (OADs) were randomized 1:1 to treatment with either s.c. OW
Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) phase semaglutide 1.0 mg or s.c. OD liraglutide 1.2 mg (both supplied by
3 clinical trial program across the continuum of care in subjects with Novo Nordisk A/S, Bagsværd, Denmark). Subjects were stratified
T2D. In the SUSTAIN trials semaglutide consistently demonstrated based on background medication of SU and SGLT2-i (SU  MET;
superior reductions in HbA1c and body weight vs placebo and a range SGLT-2i  MET; SU and SGLT-2i  MET; MET monotherapy).
of active comparators, including other GLP-1RAs (exenatide extended
release [ER] and dulaglutide) and basal insulin glargine, with a safety Treatments
profile similar to that of other GLP-1RAs [4,13–18]. Furthermore, and
in line with findings with the GLP-1 analog liraglutide in the LEADER Following a 2-week screening period, the treatment period
trial [5], the SUSTAIN 6 trial demonstrated that semaglutide was 30 weeks, with a 5-week safety data collection follow-up to
significantly reduced the risk of major adverse CV events, compared accommodate for the long half-life of semaglutide. After
with placebo, in subjects with T2D and high CV risk [4]. randomization, all subjects followed a dose-escalation regimen.
The aim of the SUSTAIN 10 trial (NCT03191396) was to compare The semaglutide maintenance dose was reached after an 8-week
the efficacy and safety of OW semaglutide 1.0 mg with OD escalation period consisting of 4 weeks of 0.25 mg OW, followed
liraglutide 1.2 mg in adults with T2D. These doses were chosen to by 4 weeks of 0.5 mg OW. The liraglutide maintenance dose was
reflect clinical practice regarding use of GLP-1RAs in Europe: OW reached after 1 week of 0.6 mg OD. In the event of unacceptable
semaglutide 1.0 mg is expected to be the most frequently gastrointestinal (GI) adverse events (AEs) with liraglutide,
prescribed dose, whereas OD liraglutide 1.2 mg is currently the escalation from 0.6 mg to 1.2 mg could be extended over 2 weeks
most frequently prescribed dose [19]. at the discretion of the investigator. Both medications were
administered by injections to the thigh, abdomen, or upper arm, at
any time of day and irrespective of meals. Semaglutide injections
Methods were administered OW preferably on the same day, while
liraglutide injections were administered OD at the same time
Trial design every day. Subjects were intended to continue on stable, pre-trial
background medication dose(s) throughout treatment, unless
SUSTAIN 10 was a 30-week, randomized, multicentre, rescue criteria were met or a safety concern relating to the
multinational, active-controlled, parallel-group, open-label, background medication arose.
two-armed phase 3b trial conducted in 11 European countries Rescue medication (intensification of antidiabetic background
(Bulgaria, Czech Republic, Finland, France, Hungary, Italy, Poland, medication and/or initiation of new antidiabetic medication) was
Slovenia, Spain, Sweden, United Kingdom). The trial design is offered if subjects experienced persistent and unacceptable hyper-
shown in Figure S1 (see supplementary materials associated with glycaemia (fasting plasma glucose [FPG] levels  13.3 mmol/L from
this article on line) and a full list of trial investigators is shown in week 8 to the end of week 15, or  11.1 mmol/L from week 16 to the
Table S1 (see supplementary materials associated with this article end of treatment). Rescue medication was prescribed at the
on line). The trial was conducted in compliance with the investigators’ discretion according to ADA/EASD 2012 and
International Council on Harmonisation of Technical Requirements 2015 guidelines [22,23]; GLP-1RAs, dipeptidyl peptidase-4 inhibitors
for Registration of Pharmaceuticals for Human Use Good Clinical (DPP-4is), and amylin analogs were not permitted.

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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M.S. Capehorn et al. / Diabetes & Metabolism xxx (2019) 101117 3

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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4 M.S. Capehorn et al. / Diabetes & Metabolism xxx (2019) 101117

Results P < 0.0001). Reductions in the SMBG increment from baseline to

week 30 were also greater with semaglutide vs liraglutide (ETD
Between June and November 2017, 767 subjects were screened, 0.53 mmol/L [95% CI 0.77 to 0.28], P < 0.0001; data not
of whom 577 were randomized and 576 were exposed to shown).
treatment (Fig. 1). Of the FAS, a total of 287 (99.0%) subjects in The proportions of subjects achieving HbA1c < 7.0% and  6.5%
the OW semaglutide 1.0 mg arm and 282 (98.3%) subjects in the OD at week 30 were 80% vs 46% and 58% vs 25%, respectively, with
liraglutide 1.2 mg arm completed the trial; 249 (85.9%) and 261 semaglutide vs liraglutide (estimated odds ratio [OR] 5.98 [95% CI
(90.9%) completed treatment, respectively. 3.83 to 9.32] and 4.84 [95% CI 3.21 to 7.30], respectively,
Baseline characteristics and background medications were P < 0.0001; Fig. 2f and g). A greater proportion of subjects achieved
generally similar in each treatment group. The overall mean age HbA1c reduction  1% with semaglutide vs liraglutide (83% vs 48%
was 59.5 years, HbA1c 8.2%, body weight 96.9 kg, and diabetes respectively, estimated OR 7.24 [95% CI 4.55 to 11.50], P < 0.0001;
duration 9.3 years. Most subjects (94.8%) received biguanides; Figure S3a [see supplementary materials associated with this
46.8% of subjects received SU and 24.6% received SGLT-2i. Few article on line]).
subjects in either treatment arm required rescue medication Mean body weight (baseline 96.9 kg) decreased over time for
(4 subjects with semaglutide vs 12 subjects with liraglutide; all both treatment arms (Fig. 3a), and from baseline to week 30
subjects except one in the liraglutide group were treatment (Fig. 3b) by 5.8 kg vs 1.9 kg with semaglutide vs liraglutide (ETD
completers; Table 1; Fig. 1). Diabetes complications at screening 3.83 kg [95% CI 4.57 to 3.09], P < 0.0001). The results of the
are shown in Table S4 (see supplementary materials associated confirmatory analysis were supported by the sensitivity analyses.
with this article on line). The proportions of subjects achieving weight loss of  5%
Mean HbA1c (baseline 8.2%) decreased over time for both and  10% at week 30 were 56% vs 18% and 19% vs 4%, respectively,
treatment arms (Fig. 2a), and from baseline to week 30 (Fig. 2b) by with semaglutide vs liraglutide (estimated OR 5.89 [95% CI 3.93 to
1.7% with semaglutide and 1.0% with liraglutide (estimated 8.81] and 4.99 [95% CI 2.57 to 9.68], respectively, both P < 0.0001;
treatment difference (ETD) at week 30 0.69% [95% confidence Fig. 3c and d). Similarly, a greater proportion of subjects also
interval (CI) 0.82 to 0.56], P < 0.0001 for superiority). The achieved weight loss  3% with semaglutide vs liraglutide (73% vs
results of the primary analysis were supported by the sensitivity 34% respectively, estimated OR 5.22 [95% CI 3.57 to 7.62],
analyses. P < 0.0001); Figure S3b (see supplementary materials associated
FPG was reduced with both semaglutide and liraglutide from with this article on line).
baseline to week 30, but changes were significantly greater with Changes in BMI and waist circumference from baseline to week
semaglutide (ETD 1.24 mmol/L [95% CI 1.54 to 0.93], 30 were also significantly greater with semaglutide than with
P < 0.0001, Fig. 2c). Observed SMBG 7-point profile (at baseline liraglutide [Table S5 (see supplementary materials associated with
and week 30) and change in mean 7-point SMBG profile from this article on line)].
baseline to week 30 are shown in Fig. 2d and e, respectively; The composite endpoint of HbA1c < 7.0% without severe or
reductions in the mean profile were greater with semaglutide vs BG-confirmed symptomatic hypoglycaemia and without weight
liraglutide (ETD 0.89 mmol/L [95% CI 1.15 to 0.64], gain was achieved by a greater proportion of subjects treated with

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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M.S. Capehorn et al. / Diabetes & Metabolism xxx (2019) 101117 5

Table 1
Baseline characteristics – full analysis set.

Semaglutide 1.0 mg Liraglutide 1.2 mg Total

(n = 290) (n = 287) (N = 577)

Age, years 60.1 (10.5) 58.9 (10.0) 59.5 (10.2)

Sex, male 160 (55.2%) 167 (58.2%) 327 (56.7%)
Race, White 264 (91.0%) 268 (93.4%) 532 (92.2%)
HbA1c, % 8.2 (0.9) 8.3 (1.0) 8.2 (1.0)
Fasting plasma glucose, mmol/L 9.8 (2.3) 9.9 (2.5) 9.9 (2.4)
Diabetes duration, years 9.6 (6.1) 8.9 (5.7) 9.3 (5.9)
Body weight, kg 96.6 (21.0) 97.2 (21.7) 96.9 (21.3)
Body mass index, kg/m2 33.7 (6.6) 33.7 (7.0) 33.7 (6.8)
eGFR, mL/min/1.73 m2 geometric mean (CoV) 91.3 (20.3) 89.7 (23.1) 90.5 (21.7)
Renal function, mL/min/1.73 m2a
eGFR  90 190 (65.5%) 185 (64.5%) 375 (65.0%)
eGFR  60– < 90 86 (29.7%) 88 (30.7%) 174 (30.2%)
eGFR 30– < 60 14 (4.8%) 14 (4.9%) 28 (4.9%)
Antidiabetes medication at screening
Biguanides 279 (96.2%) 268 (93.4%) 547 (94.8%)
Sulfonylurea 136 (46.9%) 134 (46.7%) 270 (46.8%)
SGLT-2i 73 (25.2%) 69 (24.0%) 142 (24.6%)
DPP-4ib 0 1 (0.3%) 1 (0.2%)
Other blood glucose-lowering drugs, excluding insulinb 1 (0.3%) 0 1 (0.2%)

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/
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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.

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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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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

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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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Table 2
Treatment-emergent adverse events.

Semaglutide 1.0 mg Liraglutide 1.2 mg

(n = 289) (n = 287)

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

‘On-treatment’ data based on the safety analysis set.

%: percentage of subjects experiencing at least one event; AE: adverse event; E: number of events; n: number of subjects experiencing at least one event; R: event rate per
100 exposure-years; TEAE: treatment-emergent adverse event.
a
The gastrointestinal AEs listed here are those experienced by  5% of subjects in at least one of the treatment arms.

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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Overall, the results from the SUSTAIN 10 trial provide useful [3] Davies MJ, D’Alessio DA, Fradkin J, Kernan WN, Mathieu C, Mingrone G, et al.
Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report
information for physicians, medicine management teams, and by the American Diabetes Association (ADA) and the European Association for
patients, in their joint decision-making process to optimize T2D the Study of Diabetes (EASD). Diabetologia 2018;61:2461–98.
management. [4] Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, et al. Sema-
glutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J
Med 2016;375:1834–44.
Conclusions [5] Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA,
et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med
2016;375:311–22.
Semaglutide 1.0 mg OW was superior to liraglutide 1.2 mg OD [6] Mann JFE, Ørsted DD, Brown-Frandsen K, Marso SP, Poulter NR, Rasmussen S,
in improving glycaemic control and reducing body weight in et al. Liraglutide and renal outcomes in type 2 diabetes. N Engl J Med
subjects with T2D uncontrolled on 1–3 OADs. The safety profile of 2017;377:839–48.
[7] Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, et al.
both GLP-1RAs was similar, although a higher proportion of Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of
subjects prematurely discontinued treatment with semaglutide vs the REWIND randomised, placebo-controlled trial. Lancet 2019;394:131–8.
liraglutide, primarily due to GI AEs. [8] Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabe-
tes mellitus. Nat Rev Endocrinol 2012;8:728–42.
The efficacy and safety profile of semaglutide 1.0 mg was
[9] Kalra S, Baruah MP, Sahay RK, Unnikrishnan AG, Uppal S, Adetunji O. Glucagon-
consistent with that observed in the other phase 3 SUSTAIN trials. like peptide-1 receptor agonists in the treatment of type 2 diabetes: past,
Thus, the SUSTAIN 10 results support the favourable benefit–risk present, and future. Indian J Endocrinol Metab 2016;20:254–67.
[10] Scheen AJ. GLP-1 receptor agonists and cardiovascular protection: a class
profile of semaglutide, as established in the SUSTAIN phase 3a
effect or not? Diabetes Metab 2018;44:193–6.
clinical trial program. [11] Novo Nordisk. Ozempic1 (semaglutide) Summary of Product Characteristics;
2018 [Available at: https://www.medicines.org.uk/emc/product/9728/
Disclosure of interest smpc. Accessed June 2019].
[12] Novo Nordisk. Ozempic1 (semaglutide) Prescribing Information; 2017 [Avail-
MC reports being an unpaid board member of the Association for the able at: https://www.novo-pi.com/ozempic.pdf. Accessed June 2019].
Study of Obesity (ASO) and the Primary Care Academy of Diabetes [13] Sorli C, Harashima SI, Tsoukas GM, Unger J, Karsbøl JD, Hansen T, et al. Efficacy
Specialists (PCADS), an expert advisor to The National Institute for Health and safety of once-weekly semaglutide monotherapy versus placebo in
and Care Excellence (NICE), a part-time Medical Director at LighterLife (a patients with type 2 diabetes (SUSTAIN 1): a double-blind, randomised,
placebo-controlled, parallel-group, multinational, multicentre phase 3a trial.
commercial weight-loss company), a partner at Clifton Medical Centre, and
Lancet Diabetes Endocrinol 2017;5:251–60.
director at RIO Weight Management, Ltd; he also reports research income/ [14] Ahrén B, Masmiquel L, Kumar H, Sargin M, Karsbøl JD, Jacobsen SH, et al.
support from Novo Nordisk, Novartis, BI/Lilly, GSK, Leo, and Abbott; advisory Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin
board support from Novo Nordisk, BI/Lilly, Janssen, and MSD; and speaker as an add-on to metformin, thiazolidinediones, or both, in patients with type
fees from Novo Nordisk, BI/Lilly and Janssen. AMC is a Novo Nordisk 2 diabetes (SUSTAIN 2): a 56-week, double-blind, phase 3a, randomised trial.
employee, and his wife is an employee of Novo Nordisk Region Europe Lancet Diabetes Endocrinol 2017;5:341–54.
[15] Ahmann AJ, Capehorn M, Charpentier G, Dotta F, Henkel E, Lingvay I, et al.
Pharmaceuticals A/S. JKF is a Novo Nordisk employee and shareholder. ST is
Efficacy and safety of once-weekly semaglutide versus exenatide ER in sub-
a Novo Nordisk employee. AJ and BV declare that they have no competing jects with type 2 diabetes (SUSTAIN 3): a 56-week, open-label, randomized
interest. HP reports that her institute was a trial site for the SUSTAIN clinical trial. Diabetes Care 2018;41:258–66.
10 clinical trial (funded by Novo Nordisk); she also reports grants and [16] Aroda VR, Bain SC, Cariou B, Piletič M, Rose L, Axelsen M, et al. Efficacy and
personal fees from Novo Nordisk; and personal fees from Sanofi, Boehringer safety of once-weekly semaglutide versus once-daily insulin glargine as add-
on to metformin (with or without sulfonylureas) in insulin-naive patients
Ingelheim, MSD, Lilly, and AstraZeneca. MM reports personal fees from Novo
with type 2 diabetes (SUSTAIN 4): a randomised, open-label, parallel-group,
Nordisk, Servier, and Merck Sharp & Dohme; and grants from Sanofi and multicentre, multinational, phase 3a trial. Lancet Diabetes Endocrinol
Bayer; he also reports being the president of a not-for-profit institution 2017;5:355–66.
named Fondation Francophone pour la Recherche sur le Diabète (supported [17] Rodbard HW, Lingvay I, Reed J, de la Rosa R, Rose L, Sugimoto D, et al.
by grants from Novo Nordisk, Sanofi, Merck Sharp & Dohme, AstraZeneca, Semaglutide added to basal insulin in type 2 diabetes (SUSTAIN 5): a random-
ized, controlled trial. J Clin Endocrinol Metab 2018;103:2291–301.
Abbott, and Roche).
[18] Pratley RE, Aroda VR, Lingvay I, Lüdemann J, Andreassen C, Navarria A, et al.
Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes
Funding (SUSTAIN 7): a randomised, open-label, phase 3b trial. Lancet Diabetes Endo-
Novo Nordisk A/S. crinol 2018;6:275–86.
[19] Ostawal A, Mocevic E, Kragh N, Xu W. Clinical effectiveness of liraglutide in
type 2 diabetes treatment in the real-world setting: a systematic literature
Acknowledgements review. Diabetes Ther 2016;7:411–38.
[20] International Council For Harmonisation Of Technical Requirements For Phar-
maceuticals For Human Use. Integrated addendum to ICH E6(R1): guideline for
This study was funded by Novo Nordisk. We thank all the good clinical practice – E6(R2). [Available at: https://www.ich.org/fileadmin/
participants, investigators, and trial-site staff, as well as Anna Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/
E6_R2__Step_4_2016_1109.pdf. Accessed June 2019].
Sandberg from Novo Nordisk for her review and input to the
[21] World Medical Association. World Medical Association Declaration of
manuscript, and Flavia Sciota, PhD (AXON Communications) for Helsinki: ethical principles for medical research involving human subjects.
medical writing and editorial assistance (funded by Novo Nordisk). JAMA 2013;310:2191–4.
[22] Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al.
Management of hyperglycaemia in type 2 diabetes: a patient-centered ap-
proach. Position statement of the American Diabetes Association (ADA) and
Appendix A. Supplementary data the European Association for the Study of Diabetes (EASD). Diabetologia
2012;55:1577–96.
Supplementary data (Figures S1, S2, S3, S4, Tables S1, S2, S3, S4, [23] Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al.
Management of hyperglycaemia in type 2 diabetes, 2015: a patient-centred
S5, S6, S7, S8 and the Appendix) associated with this article can be approach. Update to a position statement of the American Diabetes
found, in the online version, at https://doi.org/10.1016/j.diabet. Association and the European Association for the Study of Diabetes. Diabe-
2019.101117. tologia 2015;58:429–42.
[24] American Diabetes Association. 6. Glycemic targets: standards of medical care
in diabetes – 2019. Diabetes Care 2019;42:S61–70.
References [25] Handelsman Y, Bloomgarden ZT, Grunberger G, Umpierrez G, Zimmerman RS,
Bailey TS, et al. American Association of Clinical Endocrinologists and
[1] Mauricio D, Meneghini L, Seufert J, Liao L, Wang H, Tong L, et al. Glycaemic American College of Endocrinology – clinical practice guidelines for develop-
control and hypoglycaemia burden in patients with type 2 diabetes initiating ing a diabetes mellitus comprehensive care plan – 2015. Endocrine Practice
basal insulin in Europe and the USA. Diabetes Obes Metab 2017;19:1155–64. 2015;21 (Suppl. 1):1–87.
[2] American Diabetes Association. 9. Pharmacologic approaches to glycemic [26] Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al.
treatment: standards of medical care in Diabetes – 2019. Diabetes Care Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes
2019;42 (Suppl. 1):S90–102. Association and the Endocrine Society. Diabetes Care 2013;36:1384–95.

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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

10 M.S. Capehorn et al. / Diabetes & Metabolism xxx (2019) 101117

[27] Bradley C, Gamsu DS. Guidelines for encouraging psychological well-being: with other GLP-1 receptor agonists in patients with type 2 diabetes previously
report of a Working Group of the World Health Organization Regional Office receiving basal insulin. Diabetes Ther 2018;9:1233–51.
for Europe and International Diabetes Federation European Region St Vincent [32] Witkowski M, Wilkinson L, Webb N, Weids A, Glah D, Vrazic H. A systematic
Declaration Action Programme for Diabetes. Diabet Med 1994;11:510–6. literature review and network meta-analysis comparing once-weekly sema-
[28] Optum. SF-36 v2 Health Survey. [Available at: https://www.optum.com/ glutide with other GLP-1 receptor agonists in patients with type 2 diabetes
solutions/life-sciences/answer-research/patient-insights/sf-health-surveys/ previously receiving 1–2 oral anti-diabetic drugs. Diabetes Ther
sf-36v2-health-survey.html. Accessed June 2019]. 2018;9:1149–67.
[29] Bretz F, Posch M, Glimm E, Klinglmueller F, Maurer W, Rohmeyer K. Graphical [33] Dungan KM, Povedano ST, Forst T, González JG, Atisso C, Sealls W, et al. Once-
approaches for multiple comparison procedures using weighted Bonferroni, weekly dulaglutide versus once-daily liraglutide in metformin-treated
Simes, or parametric tests. Biom J 2011;53:894–913. patients with type 2 diabetes (AWARD-6): a randomised, open-label,
[30] Lau J, Bloch P, Schäffer L, Pettersson I, Spetzler J, Kofoed J, et al. Discovery of the phase 3, non-inferiority trial. Lancet 2014;384:1349–57.
once-weekly glucagon-like peptide-1 (GLP-1) analogue semaglutide. J Med [34] Buse JB, Nauck M, Forst T, Sheu WH, Shenouda SK, Heilmann CR, et al.
Chem 2015;58:7370–80. Exenatide once weekly versus liraglutide once daily in patients with
[31] Witkowski M, Wilkinson L, Webb N, Weids A, Glah D, Vrazic H. A systematic type 2 diabetes (DURATION-6): a randomised, open-label study. Lancet
literature review and network meta-analysis comparing once-weekly semaglutide 2013;381:117–24.

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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