Semaglutide Added to Basal Insulin in Type 2 Diabetes (SUSTAIN 5): A Randomized, Controlled Trial
J Clin Endocrinol Metab, June
Semaglutide Added to Basal Insulin in Type 2 Diabetes (SUSTAIN 5): A Randomized, Controlled Trial
Helena W. Rodbard 0
Ildiko Lingvay 1
John Reed 2
Raymond de la Rosa 3
Ludger Rose 4
Danny Sugimoto 5
Eiichi Araki 6
Pei-Ling Chu 7
Nelun Wijayasinghe 8
Paul Norwood 9
0 Endocrine and Metabolic Consultants , Rockville, Maryland 20852 , USA
1 Department of Internal Medicine, University of Texas Southwestern Medical Center , Dallas, Texas 75390 , USA
2 Endocrine Research Solutions, Inc. , Roswell, Georgia 30076 , USA
3 Four Rivers Clinical Research , Paducah, Kentucky 42003 , USA
4 Institute of Diabetes Research , 48145 M u ?nster , Germany
5 Cedar-Crosse Research Center , Chicago, Illinois 60607 , USA
6 Department of Metabolic Medicine, Kumamoto University , Kumamoto, 860-8555 Japan
7 Novo Nordisk Inc. , Plainsboro, New Jersey 08536 , USA
8 Novo Nordisk A/S , 2860 S?borg , Denmark
9 University of California at San Francisco , Fresno, California 93730 , USA
Context: Combination therapy with insulin and glucagon-like peptide-1 receptor agonists (GLP1RAs) is important for treating type 2 diabetes (T2D). This trial assesses the efficacy and safety of semaglutide, a GLP-1RA, as an add-on to basal insulin. Objective: To demonstrate the superiority of semaglutide vs placebo on glycemic control as an addon to basal insulin in patients with T2D. Design: Phase 3a, double-blind, placebo-controlled, 30-week trial. Setting: This study included 90 sites in five countries. Patients: We studied 397 patients with uncontrolled T2D receiving stable therapy with basal insulin with or without metformin. Interventions: Subcutaneous semaglutide 0.5 or 1.0 mg once weekly or volume-matched placebo. Main Outcome Measures: Primary endpoint was change in glycated Hb (HbA1c) from baseline to week 30. Confirmatory secondary endpoint was change in body weight from baseline to week 30. Results: At week 30, mean HbA1c reductions [mean baseline value, 8.4% (67.9 mmol/mol)] with semaglutide 0.5 and 1.0 mg were 1.4% (15.8 mmol/mol) and 1.8% (20.2 mmol/mol) vs 0.1% (1.0 mmol/ mol) with placebo [estimated treatment difference (ETD) vs placebo, -1.35 (14.8 mmol/mol); 95% CI, -1.61 to -1.10 and ETD, -1.75% (19.2 mmol/mol); 95% CI, -2.01 to -1.50; both P , 0.0001]. Severe or blood glucose-confirmed hypoglycemic episodes were reported in 11 patients (17 events) and 14 patients (25 events) with semaglutide 0.5 and 1.0 mg, respectively, vs seven patients (13 events) with placebo (estimated rate ratio vs placebo, 2.08; 95% CI, 0.67 to 6.51 and estimated rate ratio vs placebo, 2.41; 95% CI, 0.84 to 6.96 for 0.5 and 1.0 mg; both P = nonsignificant). Mean body weight decreased with semaglutide 0.5 and 1.0 mg vs placebo from baseline to end of treatment: 3.7, 6.4, and 1.4 kg (ETD, -2.31; 95% CI, -3.33 to -1.29 and ETD, -5.06; 95% CI, -6.08 to -4.04 kg; both P , 0.0001). Premature treatment discontinuation due to adverse events was higher for semaglutide 0.5 and 1.0 mg vs placebo (4.5%, 6.1%, and 0.8%), mainly due to gastrointestinal disorders.
Abbreviations: ADA, American Diabetes Association; AE, adverse event; bpm, beats per
minute; DR, diabetic retinopathy; EAC, Event Adjudication Committee; ETD, estimated
treatment difference; FPG, fasting plasma glucose; GI, gastrointestinal; GLP-1RA,
glucagon-like peptide-1 receptor agonist; HbA1c, glycated Hb; SF-36v2, 36-Item Short
Form; SMBG, self-measured blood glucose; SUSTAIN, Semaglutide Unabated
Sustainability in Treatment of Type 2 Diabetes; T2D, type 2 diabetes.
Conclusions: Semaglutide, added to basal insulin, significantly reduced HbA1c and body weight in
patients with uncontrolled T2D vs placebo. (J Clin Endocrinol Metab 103: 2291?2301, 2018)
Tquires individualized treatment strategies. Because of
ype 2 diabetes (T2D) is a complex disorder that
reits progressive nature, many individuals receiving basal
insulin require intensification of therapy to maintain
optimal glycemic control and to reduce the risk of
). Although increasing the basal insulin dose
and/or adding mealtime insulin is often effective, this
approach can increase the risk of hypoglycemia and lead
to weight gain in an often overweight population (
Glucagon-like peptide-1 receptor agonists
(GLP1RAs) reduce blood glucose levels, with a low risk of
hypoglycemia, and decrease body weight through
reduced appetite and energy intake (
GLP-1RAs in combination with basal insulin have been
shown to reduce glycated Hb (HbA1c) and body weight,
with a relatively low risk of hypoglycemia (
improve treatment adherence and health-related quality
of life for patients, recent efforts have focused on the
development of once-weekly GLP-1RAs (
Semaglutide is a GLP-1 analog for the treatment of
T2D. It has 94% amino acid sequence homology with
native GLP-1 and is structurally similar to liraglutide (
). Its minor structural modifications make it less
susceptible to degradation by dipeptidyl peptidase-4 and
improve binding to albumin (15). These modifications
result in a half-life of ;1 week (
onceweekly subcutaneous administration (
The objective of this phase 3a, Semaglutide
Unabated Sustainability in Treatment of Type 2 Diabetes
(SUSTAIN) 5 trial was to demonstrate the superiority of
once-weekly semaglutide (0.5 and 1.0 mg) vs placebo on
glycemic control in patients with uncontrolled T2D on
basal insulin therapy.
Materials and Methods
This 30-week, randomized, double-blind, placebo-controlled,
parallel-group, multinational, multicenter, four-armed trial
(NCT02305381; Supplemental Fig. 1) recruited patients from
90 sites in Germany, Japan, Serbia, Slovakia, and the United
States. The trial was conducted in compliance with the
International Conference on Harmonization Good Clinical
Practice guidelines (
) and the Declaration of Helsinki (
The protocol, which is available online, was approved by the
relevant institutional review boards.
Eligible patients were $18 years of age (or $20 years of age
in Japan) and diagnosed with T2D. All patients were receiving
stable basal insulin therapy (minimum of 0.25 IU/kg/d and/or
20 IU/d of insulin glargine, insulin detemir, insulin degludec,
and/or neutral protamine Hagedorn insulin) alone or in
combination with metformin for 90 days prior to screening, with
an HbA1c level of 7.0% to 10.0% (53.0 to 85.8 mmol/mol).
Key exclusion criteria included treatment with any
glucoselowering agent other than those listed herein in the 90 days
prior to screening (excepting short-term bolus insulin therapy
of #7 days); history of pancreatitis (acute or chronic); family
history of medullary thyroid carcinoma or multiple endocrine
neoplasia type 2; severe renal impairment (estimated glomerular
filtration rate ,30 mL/min/1.73 m2 according to the
Modification of Diet in Renal Disease formula); more than three
episodes of severe hypoglycemia within the 6 months prior to
screening; known proliferative retinopathy or maculopathy
requiring acute treatment; or being pregnant, breastfeeding, or
intending to become pregnant. Full inclusion and exclusion
criteria are listed in Supplemental Table 1. Written informed
consent was obtained from all patients before trial-related
Randomization and masking
Patients were randomized using an interactive
voice/webresponse system in a 2:2:1:1 ratio to receive once-weekly
semaglutide (0.5 or 1.0 mg subcutaneously) or placebo
administered subcutaneously as an add-on to pretrial background
medication. Semaglutide and placebo treatments were, as far as
possible, visually identical and packaged in a way so that study
patients and investigators would not be able to distinguish
between trial products. Furthermore, semaglutide and placebo
were volume-matched during treatment to ensure blinding
within dose level. The randomization was stratified according
to HbA1c level at screening (#8.0% or .8.0%) and use of
metformin (yes or no).
Background medication and basal insulin titration
Patients with HbA1c #8.0% (63.9 mmol/mol) at screening
had their background basal insulin dose reduced by 20% at the
start-of-trial medication to limit the potential risk of
hypoglycemia. For these patients the insulin dose could be uptitrated
from week 10 to week 16 (for further details, please see the
titration protocol in the Supplemental Material). Increasing
basal insulin dose before week 10 or after week 16 was avoided
unless required to control acute hyperglycemia or prevent acute
For all patients, insulin titrations were based on the lowest of
three consecutive fasting self-measured blood glucose (SMBG)
values according to a prespecified titration protocol
(Supplemental Table 2). As far as possible, doses of basal insulin and
metformin were to remain stable throughout the trial, with the
exception of (
) dose reduction due to hypoglycemia or (
confirmatory fasting plasma glucose (FPG) exceeding
predefined limits per protocol, where the patient was offered
intensification of therapy (rescue medication). Basal insulin dose
increase was the first choice of rescue medication
(Supplemental Material), which was initiated at the discretion of the
investigator and in accordance with the American Diabetes
Association (ADA)/European Association for the Study of
Diabetes recommendations (
Patients received semaglutide (0.5 or 1.0 mg subcutaneously)
or volume-matched placebo once weekly for 30 weeks followed
by a 5-week follow-up period. Study medication was
administered following a fixed dose-escalation regimen. For 0.5 mg, the
maintenance dose was reached after 4 weeks of 0.25 mg
semaglutide or matching placebo once weekly. For 1.0 mg, the
maintenance dose was reached after 4 weeks of 0.25 mg,
followed by 4 weeks of 0.5 mg semaglutide or matching placebo
once weekly. Trial products were manufactured and supplied by
Novo Nordisk A/S (Bagsvaerd, Denmark).
The primary outcome was the change in HbA1c from
baseline to week 30. The confirmatory secondary endpoint was
the change in body weight from baseline to week 30. Secondary
efficacy endpoints included the proportion of patients who
achieved HbA1c ,7.0% (53 mmol/mol) (
) or #6.5%
(48 mmol/mol) (
) by end of treatment; HbA1c ,7.0%
without severe or blood glucose?confirmed symptomatic
hypoglycemic episodes [plasma glucose level ,3.1 mmol/L
(56 mg/dL)] and no weight gain at week 30; change from
baseline to week 30 in FPG; SMBG seven-point profiles and
postprandial increments (mean over all meals); insulin dose;
body mass index; waist circumference; proportion of patients
who achieved weight loss of $5% and $10% at week 30; and
change from baseline to week 30 of systolic and diastolic blood
pressure, fasting lipids, and patient-reported outcomes [36-Item
Short Form (SF-36v2) Health Survey and Diabetes Treatment
Safety outcomes after 30 weeks of therapy included the
number of treatment-emergent adverse events (AEs), severe or
blood glucose?confirmed symptomatic hypoglycemic episodes
(according to the ADA classification or blood glucose?confirmed
by a plasma glucose value ,3.1 mmol/L with symptoms
consistent with hypoglycemia), and pulse rate. Hypoglycemia was
assessed as a secondary safety endpoint. When a hypoglycemic
episode was suspected, the blood glucose level at the time of the
event was recorded as well as additional information relating to
the circumstances of the patient. A hypoglycemic episode form
was completed for each hypoglycemic episode; if the episode
fulfilled the criteria for a serious AE, then an AE form and a safety
information form were also completed. Hypoglycemic episodes
were classified according to the Novo Nordisk A/S classification
and ADA classification guidelines.
An external Event Adjudication Committee (EAC) validated
predefined events of special interest [including those
associated with GLP-1RA therapy: acute pancreatitis, neoplasm
(excluding thyroid), and thyroid disease (including neoplasms)]
in an independent, blinded manner (Supplemental Material).
The trial was designed to establish superiority jointly for
both doses of semaglutide vs pooled placebo (hereafter referred
to as ?placebo?) for the change in HbA1c and body weight at
week 30 with a one-sided a of 2.5%, assuming treatment
differences vs placebo of 0.45% and 2.25 kg for each
semaglutide dose level, and SDs of 1.1% and 4.0 kg. The type I error
probability was controlled at 2.5% (one-sided) across the four
confirmatory superior hypotheses in a hierarchical testing
strategy. For HbA1c, the superiority of semaglutide vs placebo
was tested first, starting with the highest semaglutide dose level,
followed by body weight superiority vs placebo in the same dose
order. Based on these assumptions and on a target sample size of
390 patients in total, the overall power to simultaneously
demonstrate superiority on change in HbA1c and body weight
for the two dose levels of semaglutide vs placebo was 82% (full
details are in Supplemental Material).
HbA1c, body weight, and other continuous endpoints
assessed over time were analyzed using a mixed model for
repeated measurements, with treatment, country, and
stratification variables [HbA1c level at screening (#8.0% or .8.0%)
crossed with use of metformin (yes or no)] as fixed factors and
baseline value as covariate, all nested within visit (full details are
in Supplemental Material). Efficacy evaluations were based on
the full analysis set, comprising all randomized patients exposed
to at least one dose of trial product. The primary analyses used
data collected before initiation of any rescue medication or
before premature treatment discontinuation. The robustness of
the analyses of HbA1c and body weight was assessed by
handling missing data in various ways, including a placebo-based
multiple imputation model, in which missing data points were
imputed as if the patient was receiving placebo. Details of the
sensitivity analyses are included in Supplemental Material.
Patient disposition and baseline characteristics
In total, 397 patients were randomized to receive
semaglutide or placebo from 1 December 2014 through
21 November 2015; 396 patients were exposed to
treatment, and 380 patients completed the trial
(Supplemental Fig. 2). A total of 23 patients required rescue
medication: three in the semaglutide 0.5 mg group, one
in the semaglutide 1.0 mg group, and 19 in the placebo
group. Baseline characteristics were similar between
treatment groups (Table 1). The mean duration of
diabetes prior to trial entry was 13.3 years (range, 0.4 to
39.6 years). The majority of patients were receiving
insulin glargine therapy at baseline (Table 1).
Mean HbA1c [baseline 8.4%; SD, 0.83 (67.9 mmol/mol;
SD, 9.04)] levels decreased over time (Fig. 1A; Supplemental
Fig. 3A). At week 30, mean HbA1c values with semaglutide
0.5 and 1.0 mg were 6.9% and 6.5%, vs 8.3% with placebo,
corresponding to reductions of 1.4% and 1.8% vs 0.1%
with placebo [estimated treatment difference (ETD) vs
placebo, ?1.35%; 95% CI, ?1.61 to ?1.10 and ETD, ?1.75%;
95% CI, ?2.01 to ?1.50; both P , 0.0001]. The changes
from baseline in HbA1c in patients with HbA1c #8% at
screening were ?0.88% (SD, 0.94), ?1.32% (SD, 0.71), and
?0.04% (SD, 0.98) with semaglutide 0.5 mg, semaglutide
1.0 mg, and placebo, respectively, whereas in patients with
HbA1c .8% the changes were ?1.83% (SD, 1.00), ?2.19%
(SD, 0.86), and ?0.28% (SD, 1.12), respectively.
Baseline Characteristics of the Study Population
aRandomization was stratified according to HbA1c level at screening (#8.0% or .8.0%) and use of metformin (yes or no).
bHbA1c may be outside the range specified in the inclusion criteria because baseline measurement was conducted at randomization visit.
cThis patient was randomized in error and consequently excluded from the trial.
Significantly more patients achieved an HbA1c target
of ,7.0% with semaglutide 0.5 mg and 1.0 mg than
with placebo (61%, 79%, and 11%) (Fig. 2A) and an
HbA1c target #6.5% with semaglutide 0.5 and 1.0 mg
vs placebo (41%, 61%, and 5%) (Supplemental Fig.
4A). Significantly more patients achieved a composite
endpoint of ,7.0% without severe or blood glucose?
confirmed symptomatic hypoglycemia and with no
weight gain with semaglutide 0.5 and 1.0 mg compared
with placebo (54%, 67%, and 7%) (Fig. 3).
At week 30, mean FPG values with semaglutide 0.5
and 1.0 mg were 7.0 and 6.3 mmol/L, vs 8.2 mmol/L
with placebo, corresponding to decreases of 1.6 and
2.4 mmol/L, compared with 0.5 mmol/L with placebo
(ETD, ?1.14; 95% CI, ?17.5 to ?0.54 and ETD, ?1.88;
95% CI, ?2.48 to ?1.28; both P , 0.001) (Fig. 1B;
Supplemental Table 3). Both incremental and mean
seven-point SMBG decreased significantly with
semaglutide 0.5 mg (by 0.8 and 2.5 mmol/L; both P , 0.004)
and 1.0 mg (by 1.2 and 3.0 mmol/L; P , 0.0001 for both)
vs placebo (reductions of 0.2 and 0.8 mmol/L) (Fig. 4;
Supplemental Table 3).
Severe or blood glucose?confirmed hypoglycemic
episodes were reported in 11 (8.3%) patients (17 events)
in the semaglutide 0.5 mg group, in 14 (10.7%) patients
(25 events) in the semaglutide 1.0 mg group, and in
7 (5.3%) patients (13 events) in the placebo group. The
estimated rate ratio for events of severe or blood glucose?
confirmed hypoglycemia was 2.08 (95% CI, 0.67 to 6.51;
P = 0.2071) for semaglutide 0.5 mg vs placebo and 2.41
(95% CI, 0.84 to 6.96; P = 0.1030) for semaglutide 1.0 mg vs
placebo. Among patients with HbA1c #8.0% at screening,
semaglutide 1.0 mg, and placebo was
0.90, 0.85, and 0.96 (estimated
treatment ratio for semaglutide 0.5 mg and
1.0 mg vs placebo, 0.94; 95% CI, 0.90
to 0.98 and estimated treatment ratio,
0.88; 95% CI, 0.84 to 0.92; P = 0.0046
and P , 0.0001). The largest overall
decrease in insulin dose was in patients
with baseline HbA1c ,8.0%. These
patients reduced their insulin dose by
20% at randomization, in accordance
with protocol (Supplemental Fig. 5).
Body weight and related endpoints
At week 30, mean body weight
decreased with semaglutide 0.5 and 1.0 mg
vs placebo by 3.7, 6.4, and 1.4 kg (ETD
for semaglutide 0.5 mg and 1.0 mg vs
placebo, ?2.31; 95% CI, ?3.33 to ?1.29
and ETD, ?5.06; 95% CI, ?6.08 to ?4.04;
both P , 0.0001) (Fig. 1C; Supplemental
Fig. 3B). Body weight reductions of $5%
were achieved in the semaglutide 0.5 mg,
semaglutide 1.0 mg, and placebo groups
by 42%, 66%, and 11% of patients and
reductions of $10% by 9%, 26%, and
3% (Fig. 2B; Supplemental Fig. 4B).
the proportion of patients reporting these events was higher
in both semaglutide groups vs the placebo group and highest
in the higher-dose semaglutide group (15.7, 46.5, and 9.9
events per 100 patient-years of exposure for semaglutide
0.5 mg, semaglutide 1.0 mg, and placebo, respectively). In
subjects with HbA1c .8%, the rates of ?severe or
BGconfirmed symptomatic? hypoglycemic episodes were
comparable among the three groups (22.9, 21.2, and 18.6 events
per 100 patient-years of exposure for semaglutide 0.5 mg,
semaglutide 1.0 mg, and placebo, respectively) (Fig. 1D;
Supplemental Table 5; Supplemental Fig. 8).
Insulin dose decreased from baseline to week 30 with
semaglutide 0.5 mg, semaglutide 1.0 mg, and placebo
(geometric means from 39.3 to 35.4, from 37.4 to 31.5,
and from 36.6 to 35.2 IU). The end-of-treatment to
baseline ratio for insulin dose with semaglutide 0.5 mg,
Other efficacy endpoints
Improvements in other efficacy
endpoints, including lipid profile and
systolic blood pressure, were observed
with semaglutide vs placebo
(Supplemental Tables 3 and 4). At week 30,
mean systolic blood pressure values
were 130.5 and 127.5 mm Hg for
semaglutide 0.5 mg and 1.0 mg vs 133.8 mm Hg for
placebo (ETD, ?3.31; 95% CI, ?6.92 to 0.31 and ETD,
?6.29; 95% CI, ?9.91 to ?2.66; P = 0.0728 and P =
0.0007). Overall treatment satisfaction (measured by the
Diabetes Treatment Satisfaction Questionnaire, status
version) significantly improved with both semaglutide
doses vs placebo (0.5 mg: ETD, 1.48; 95% CI, 0.14 to
2.82 and 1.0 mg: ETD, 2.22; 95% CI, 0.87 to 3.56)
(Supplemental Fig. 6). No significant changes were
evident from the SF-36v2 Health Survey questionnaire with
either semaglutide dose compared with placebo.
Safety and tolerability
The proportions of patients with AEs and serious AEs
for semaglutide 0.5 and 1.0 mg vs placebo were 68.9%,
64.1%, and 57.9% and 6.1%, 9.2%, and 6.8%
(Table 2). Rates of premature treatment discontinuation
due to AEs were generally low but were higher with
semaglutide 0.5 and 1.0 mg vs placebo (4.5% and 6.1%
compared with 0.8% in the placebo group) and were
primarily due to gastrointestinal (GI) AEs (Table 2).
No fatalities were reported during the trial. One
patient receiving semaglutide 0.5 mg became pregnant
during the trial and discontinued treatment after 106 days
(fetal exposure was ;9 weeks). A healthy baby was born
with no known congenital abnormalities.
The most frequent AEs with semaglutide were GI AEs
(Table 2). Nausea was reported in 11.4% of patients
treated with semaglutide 0.5 mg and in 16.8% treated with
semaglutide 1.0 mg compared with 4.5% receiving
placebo. In general, the prevalence of nausea events over time
with semaglutide treatment was ;3% to 5% throughout
the study (Supplemental Fig. 7A). The proportions of
patients reporting vomiting were 6.1%, 11.5%, and 3.0%
(the prevalence of vomiting events over time is shown in
Supplemental Fig. 7B), and the proportions reporting
diarrhea were 4.5%, 6.9%, and 1.5%. All GI AEs were mild
to moderate in severity. Pulse rate increased from baseline
by 1 beat per minute (bpm) with semaglutide 0.5 mg and
by 4 bpm with semaglutide 1.0 mg, vs a decrease of 1 bpm
with placebo (for semaglutide 1.0 mg vs placebo, P , 0.0001;
Supplemental Table 3). The proportion of patients with
diabetic retinopathy (DR) events was 3.0% with
semaglutide 0.5 mg and 0.8% with semaglutide 1.0 mg; there
were no patients with DR events on placebo.
Gallbladder-related AEs were reported in four
semaglutide-treated patients. With semaglutide 0.5 mg,
cholelithiasis, gallbladder disorder, and blood alkaline
phosphatase were reported in three patients; with
semaglutide 1.0 mg, acute cholecystitis was reported in one
patient (Table 2). Mean lipase and amylase activity
increased significantly from baseline to end of
treatment with both semaglutide doses compared with placebo
(P , 0.0001 for all) (Supplemental Table 6; Supplemental
Fig. 9), although no pancreatitis events were confirmed by
the EAC. Two investigator-reported events were sent for
Adverse Events Overview
Abbreviations: AE, adverse event; BG, blood glucose; EAC, Event Adjudication Committee; GI, gastrointestinal.
aSevere, considerable interference with the subject?s daily activities, unacceptable; moderate, marked symptoms, moderate interference with the
subject?s daily activities; mild, no or transient symptoms, no interference with the subject?s daily activities.
bThere were five events in four patients with semaglutide 0.5 mg.
adjudication: one patient (female, age 47 years)
receiving semaglutide 0.5 mg reported acute pancreatitis, which
led to premature treatment discontinuation (reported on
study day 152, concurrent mild vomiting); the second
patient (male, age 55 years) receiving semaglutide 1.0 mg
reported elevated lipase but had an elevated level prior
to administration of trial product (reported on study day
1, concurrent mild vomiting).
Neoplasms were confirmed by the EAC in four
patients treated with semaglutide 0.5 mg and in one patient
receiving placebo (Table 2). One malignant neoplasm
(basal cell carcinoma) was reported in a patient treated
with semaglutide 1.0 mg. Additionally, one patient
treated with semaglutide 1.0 mg had confirmed
metastatic pancreatic cancer with an onset date of 65 days
after the end of treatment. There were no confirmed
In patients with T2D inadequately controlled with basal
insulin, semaglutide provided superior improvements in mean
HbA1c, FPG, and SMBG and superior weight loss compared
with placebo. There was a low rate of hypoglycemic episodes
across the trial. Compared with placebo, severe or blood
glucose?confirmed symptomatic episodes were more
frequent with semaglutide in patients with HbA1c #8.0%
at screening, which might be expected given the
improvements in HbA1c in these patients vs placebo. A
greater pre-emptive insulin dose reduction, greater than
the 20% mandated by the protocol in this trial, may
be appropriate when titrating from 0.5 to 1.0 mg in
In this study population with a mean diabetes
duration of .13 years, the majority of patients in both
semaglutide-treatment groups attained an HbA1c target
of ,7.0%. In addition, significant weight loss was
observed with both doses of semaglutide vs placebo. The
improvements (weight reductions of 2.3 to 5.1 kg) with
semaglutide appear to be greater in magnitude than those
previously reported for other long-acting GLP-1RAs
added to basal insulin (weight reductions of 1.0 to
1.6 kg), although these are cross-trial observations and
therefore are not directly comparable (
A significantly larger proportion of patients
receiving semaglutide achieved the composite endpoint of
HbA1c ,7.0% without severe or blood glucose?confirmed
symptomatic hypoglycemia (plasma glucose level below
3.1 mmol/L) and without weight gain compared with
placebo. This finding is clinically meaningful and especially
promising in a population where hypoglycemia and weight
gain impede insulin titration and glycemic control.
Semaglutide was well tolerated in this trial, with an AE
profile similar to that of other GLP-1RAs. GI symptoms
were the most common AEs with semaglutide and were
responsible for the higher proportion of patients
discontinuing treatment prematurely compared with
placebo. This effect has been noted previously with
GLP1RAs, and GI AEs commonly occur early in the course of
treatment and subside over time (
). Accordingly, in this
study, nausea events in the semaglutide groups occurred
mainly in the first 8 to 9 weeks of treatment, generally
coinciding with the dose-escalation steps, and declined
gradually thereafter until the end of the trial. Although
the proportion of patients experiencing an event at least
once was ;11% to 17% with semaglutide, the actual
prevalence was ;3% to 5% on any given week. The
prevalence of vomiting over time remained #2.5% in
both semaglutide groups, and the majority of events
occurred before week 18 of the study.
Similarly, the significant increase in pulse rate observed
with semaglutide 1.0 mg compared with placebo has been
previously reported in patients treated with GLP-1RAs
); however, the reasons for this hemodynamic effect
are unclear (33). DR AEs in SUSTAIN 5 are discussed in a
publication that analyzes DR in the SUSTAIN clinical
program. An analysis of DR AEs in SUSTAIN 1?5 and the
Japanese trials showed no evidence of increased DR AEs
with semaglutide vs placebo or active comparators (
One malignant neoplasm (basal cell carcinoma) was
reported in the study in a patient treated with semaglutide
1.0 mg. In the same treatment group, one patient had
metastatic pancreatic cancer, although the recorded date
of onset was 65 days after the end of treatment. In
published data from the SUSTAIN program, the overall
incidence of malignant neoplasms was similarly low, with
no evident imbalances between semaglutide dose groups
or between semaglutide and comparators (
pancreatitis events were confirmed by the EAC, a finding
that aligns with a recent meta-analysis of incretin-based
medications and the reported risk of such events (
the analysis, which included results from the SUSTAIN 6
), the relative risk of both acute pancreatitis and
pancreatic carcinoma was reduced for semaglutide and the
GLP-1RA class overall (
Semaglutide treatment was associated with
improvements in treatment satisfaction compared with placebo.
However, despite the double-blind study design, the
substantial differences in efficacy (e.g., weight loss) and
safety (e.g., GI AEs) between semaglutide and placebo
may have unblinded the study in many patients by week
30, thereby affecting the patient?s evaluation of the
treatment. Nevertheless, therapies demonstrating
increased treatment satisfaction in T2D could be beneficial,
particularly because insulin therapy for diabetes is
associated with a high treatment burden and compliance
The strengths of this study include its randomized,
double-blind, placebo-controlled design, which adds
validity to the evaluation of outcomes. The trial was
conducted in patients with long-standing T2D who were
receiving basal insulin, and, although the majority was
receiving insulin glargine therapy at baseline, a diverse
range of insulin types was used, reflecting the
international nature of the trial sites in this study.
This was not a treat-to-target study; thus, titration was
carried out at the investigators? discretion, with the
exception of the mandatory dose decrease in patients with
HbA1c #8%. The lack of dose uptitration in the placebo
arm may have been partially responsible for HbA1c and
FPG levels remaining elevated in this treatment group.
Furthermore, because basal insulin was not titrated to
target and because the placebo arm had no active
intervention, the comparison of hypoglycemia rates
between the arms and the applicability of the study findings
to clinical practice should be interpreted according to
The relatively short study length was a limitation, and
the blinding aspect of the trial may have been partially
lost due to the incidence of GI AEs and the improved
fasting glucose levels over placebo. Because of the
reduced insulin dose in the cohort with HbA1c #8% and
the subsequent delay before uptitration could be
commenced, the results relating to weight loss and reduced
insulin requirements should be interpreted in this
context. In addition, the observed decrease in insulin dose
and in body weight in the placebo group was
unexpected, and the reasons for these anomalous effects
In summary, semaglutide, administered
subcutaneously once weekly, provided superior glycemic control
and body weight reductions compared with placebo in
patients with T2D receiving basal insulin therapy. No
unexpected safety issues were identified. Semaglutide was
well tolerated, with a safety profile similar to that of
We thank the patients, investigators, and trial-site staff who were
involved in the trial; Louise Faerch, Uffe Ploug, and Desire?e
Thielke (all Novo Nordisk employees) for their review of and
input to the manuscript; and Madeleine Nowak (AXON
Communications) for medical writing and editorial assistance. Key
findings from this study were presented in abstract form at the
52nd EASD Annual Meeting, Munich, Germany, 12?16
Financial Support: This study was funded by Novo
Clinical Trial Information: SUSTAIN 5 ClinicalTrials.gov
no. NCT02305381 (registered 28 November 2014).
Author Contributions: All authors were site investigators,
except those employed by Novo Nordisk, and took part in the
conduct of the trial and the data collection. The data were
analyzed by the statistical group. H.W.R. served as a Principal
Investigator, researched the data, reviewed and edited the
manuscript, and contributed to the discussion. I.L. researched the
data, reviewed and edited the manuscript, and contributed to
the discussion. J.R. reviewed and edited the manuscript and
contributed to the discussion. R.d.l.R. reviewed and edited the
manuscript and contributed to the discussion. L.R. reviewed and
edited the manuscript and contributed to the discussion. D.S.
researched the data and reviewed and edited the manuscript. E.A.
reviewed and edited the manuscript and contributed to the
discussion. P.-L.C. researched the data, reviewed and edited the
manuscript, and contributed to the discussion. N.W. researched
the data, wrote the manuscript, reviewed and edited the
manuscript, and contributed to the discussion. P.N. researched the data,
reviewed and edited the manuscript, and contributed to the
discussion. All the authors have read the report critically and
approved the submitted version, and all authors take responsibility
for the contents of the article.
Correspondence and Reprint Requests: Helena W. Rodbard,
MD, 3200 Tower Oaks Boulevard, Suite 250, Rockville,
Maryland 20852. E-mail: .
Disclosure Summary: H.W.R. has received grant support
and fees for consultancy from AstraZeneca, Boehringer Ingelheim,
Janssen, Lilly, Novo Nordisk and Sanofi. I.L. has received grant
support from GI Dynamics, Merck, Novartis, Novo Nordisk,
and Pfizer; travel and editorial support from Novo Nordisk; and
editorial support from AstraZeneca, Boehringer Ingelheim, and
Sanofi. J.R. has received research support from Novo Nordisk;
Eli Lilly; Sanofi; Takeda; Bristol Myers Squibb; Diasome; Gann
& Lee; Kowa; Calibra Medical, Inc.; Amylin, Medtronic; EISAI;
Biodel; Johnson & Johnson; Amgen; Wyeth; Novartis; Dexcom;
and Pfizer. R.d.l.R. has received grant support, speaker fees, and
medical writing support from Novo Nordisk; grant support and
speaker fees from Sanofi Aventis; speaker fees from Boehringer
Ingelheim; and grant support from Amylin, Elcelyx Therapeutics,
GlaxoSmithKline, Intarcia Therapeutics, Merck, and Theracos.
D.S. has received grants from AstraZeneca, Boehringer Ingelheim,
Bristol-Myers Squibb, Elcelyx Therapeutics, Ligand
Pharmaceuticals, Merck, Novo Nordisk, Roche, Sanofi, and Takeda and
has received medical writing support from Novo Nordisk and
Sanofi. L.R. has received grants and personal fees from
AstraZeneca, Lilly, and Novo Nordisk. E.A. has received research
support or grants and/or personal fees for lecturing and
consulting on advisory boards and has received editorial support
from Arkray, Inc.; Astellas Pharma, Inc.; AstraZeneca KK; Bayer
Yakuhin Ltd; Bunkodo Co. Ltd; Daido Gakkan; Daiichi Sankyo;
Eli Lilly Japan KK; Kissei Pharmaceutical Co.; Kowa
Pharmaceutical Co. Ltd; Kyowa Hakko Kirin Co. Ltd; Kyowa Kikaku
Ltd; Medical Review Co. Ltd; Mochida Pharmaceutical Co. Ltd.;
Mitsubishi Tanabe Pharma Corporation; MSD; Nankodo Co.
Ltd; Nippon Boehringer Ingelheim; Novartis Pharma KK; Novo
Nordisk; Ono Pharmaceutical; Sanofi KK; Sanwa Kagaku
Kenkyusho Co.; Shionogi & Co. Ltd; Sumitomo Dainippon
Pharma Co.; Taisho Toyama Pharmaceutical Co. Ltd.; Takeda
Pharmaceutical Company; T-Pec Corporation; and Wiley
Publishing Japan Co. Ltd. P.-L.C. reports being an employee of Novo
Nordisk Inc. while the trial was conducted. N.W. reports being an
employee of Novo Nordisk A/S. P.N. reports receiving research
support from Novo Nordisk.
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