A Phase 2, Randomized,Dose-Finding Study of the NovelOnce-Weekly Human GLP-1Analog, Semaglutide, ComparedWith Placebo and Open-LabelLiraglutide in PatientsWith Type 2DiabetesDiabetes Care 2016;39:231–241 | DOI: 10.2337/dc15-0165

OBJECTIVE

To investigate the dose-response relationship of semaglutide versus placebo andopen-label liraglutide in terms of glycemic control in patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

This was a 12-week, randomized, double-blind phase 2 trial. Patients (n = 415)were randomized to receive a subcutaneous injection of semaglutide once weeklywithout dose escalation (0.1–0.8 mg) or with dose escalation (E) (0.4 mg steps to0.8 or 1.6mg E over 1–2weeks), open-label liraglutide once daily (1.2 or 1.8mg), orplacebo. The primary end point was change in HbA1c level from baseline. Second-ary end points included change in body weight, safety, and tolerability.

RESULTS

Semaglutide dose-dependently reduced the level of HbA1c from baseline (8.1 6

0.8%) to week 12 by up to21.7%, and body weight by up to24.8 kg (1.6 mg E, P <0.001 vs. placebo). Up to 81% of patients achieved an HbA1c level of <7%. HbA1c

level and weight reductions with semaglutide 1.6 mg E were greater than thosewith liraglutide 1.2 and 1.8mg (based on unadjusted CIs), but adverse events (AEs)and withdrawals occurred more frequently. The incidence of nausea, vomiting,and withdrawal due to gastrointestinal AEs increased with the semaglutide dose;most events were mild to moderate, transient, and ameliorated by dose escala-tion. There were no major episodes of hypoglycemia and few cases of injectionsite reactions.

CONCLUSIONS

After 12 weeks, semaglutide dose-dependently reduced HbA1c level and weight inpatients with type 2 diabetes. No unexpected safety or tolerability concerns wereidentified; gastrointestinal AEs typical of glucagon-like peptide 1 receptor agonistswere mitigated by dose escalation. On this basis, weekly semaglutide doses of 0.5and 1.0 mg with a 4-week dose escalation were selected for phase 3.

1Diabetes Centre, Bad Lauterberg, Harz,Germany2University of Glasgow, Glasgow, U.K.3University Magna Graecia, Catanzaro, Italy4Careggi Teaching Hospital, Florence, Italy5General Hospital, Narbonne, France6Novo Nordisk A/S, Søborg, Denmark7Weill Cornell Medical College Qatar, Doha,Qatar

Corresponding author: Michael A. Nauck,michael.nauck@rub.de.

Received 23 January 2015 and accepted 4 August2015.

Clinical trial reg. no. NCT00696657, clinicaltrials.gov.NN9535-1821 (Novo Nordisk study ID number),2007-003956-12 (EudraCT Number).

This article contains Supplementary Data onlineat http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc15-0165/-/DC1.

M.A.N. is currently affiliated with the Division ofDiabetology, St. Josef-Hospital, Ruhr-UniversitatBochum, Germany.

*A full list of Study 1821 Principal Investigators islocated in the Supplementary Data online.

© 2016 by the American Diabetes Association.Readersmayuse this article as longas thework isproperly cited, the use is educational and not forprofit, and the work is not altered.

Michael A. Nauck,1 John R. Petrie,2

Giorgio Sesti,3 Edoardo Mannucci,4

Jean-Pierre Courreges,5

Marie L. Lindegaard,6 Christine B. Jensen,6

and Stephen L. Atkin,7 for the Study 1821

Investigators*

Diabetes Care Volume 39, February 2016 231

CLIN

CARE/ED

UCATIO

N/N

UTR

ITION/PSYC

HOSO

CIAL

Native glucagon-like peptide 1 (GLP-1)is a gut-derived incretin hormone thatstimulates insulin secretion and sup-presses glucagon secretion in a glucose-dependent manner. It also delays gastricemptying, and reduces appetite andenergy intake (1–4). These actions im-prove glucose homeostasis and therebyreduce hyperglycemia, making GLP-1 avaluable therapeutic target for the man-agement of type 2 diabetes.Ongoing approaches to optimizing GLP-1

therapy aim to improve efficacy, tolerabil-ity, and convenience, with a focus on thefrequency and ease of administration. Re-cent developments have focusedmainly onlengthening the period between injections(5). Currently in phase 3 clinical develop-ment for the treatment of type 2 diabetes,semaglutide is a human GLP-1 analogwith a long duration of action, allowingonce-weekly administration.Semaglutide is structurally similar to

native human GLP-1-(7–37), with 94%homology (6). Three minor but impor-tant modifications make semaglutidesuitable for once-weekly clinical use:amino acid substitutions at position 8(alanine to a-aminoisobutyric acid) andposition 34 (lysine to arginine), and ac-ylation of the lysine in position 26 with aspacer and C-18 fatty diacid chain. Thefatty diacid and the spacer mediatestrong binding to albumin, thereby re-ducing renal clearance. The amino acidsubstitution at position 8 makes sema-glutide less susceptible to degradationby dipeptidyl peptidase-4. The half-lifeof semaglutide is 165–184 h (6,7) (i.e.,appropriate for once-weekly injection).The primary objective of this phase

2 study was to explore the dose-response relationship of once-weeklysemaglutide versus placebo in glycemiccontrol therapy in patients with type 2diabetes inadequately controlled withdiet and exercise, either alone or in com-bination with metformin, with the aimof establishing the optimum dose andregimen to be taken forward into phase3 clinical trials. The safety, tolerability,andefficacy/pharmacodynamics of sema-glutide compared with placebo andopen-label, once-daily liraglutide werealso investigated.

RESEARCH DESIGN AND METHODS

This was a 12-week, randomized, nine-armed, parallel-group, phase 2, dose-finding trial, which was double-blind for

semaglutide versus placebo and open-label for the active control (liraglutide).Its aim was to assess the dose-responserelationship of five doses of once-weeklysemaglutide compared with placebo(primary objective) and open-label lira-glutide (secondary objective) in terms ofglycemic control in patients with type 2diabetes. Participants were randomizedto receive semaglutide once weekly,open-label liraglutide once daily, or pla-cebo once weekly. Patients were en-rolled between June 2008 and February2009 at 80 centers in 14 countries(Austria, Bulgaria, Finland, France, Ger-many, Hungary, India, Italy, Serbia,South Africa, Spain, Switzerland, Turkey,and the U.K.). Written informed consentwas obtained from all participants beforeany study-related activities commenced.The study was registered at http://www.clinicaltrials.gov (clinical trial reg. no.NCT00696657).

Patients $18 years of age who hadreceived a diagnosis of type 2 diabe-tes and had been treated with eitherdiet and exercise alone or togetherwith a stable regimen of metforminmonotherapy ($1,500 mg) for at least3 months were enrolled, comprisingmen and women categorized as not ofchildbearing potential (i.e., perma-nently sterilized or postmenopausal).Eligible patients had an HbA1c level of7.0–10.0% (inclusive 53–86 mmol/mol)and a body weight of 60–110 kg. Keyexclusion criteria included treatmentwith antidiabetic agents other thanmetformin (except for short-termtreatment with insulin at the discretionof the investigator) within the preced-ing 3 months; impaired liver and/orrenal function (serum creatinine); clin-ically significant active cardiovasculardisease (including myocardial infarc-tion within 6 months and/or heartfailure [New York Heart Associationclass III–IV]); uncontrolled hyperten-sion (systolic blood pressure [SBP]$160 mmHg and/or diastolic bloodpressure [DBP] $100 mmHg); prolifer-ative retinopathy; and cancer (exceptbasal skin cancer or squamous cellskin cancer).

The study was approved by localethics committees and was conductedin accordance with the Declaration ofHelsinki (8) and the International Con-ference on Harmonisation Guidelinefor Good Clinical Practice (9).

Drug AdministrationPatients were randomly assigned usingan interactive voice/web response sys-tem with equal ratio to one of ninetreatment arms to receive once-weeklysemaglutide (0.1, 0.2, 0.4, or 0.8 mg),once-weekly semaglutide with dose es-calation (E) (0.8 or 1.6 mg E), once-dailyopen-label liraglutide (1.2 or 1.8 mg), oronce-weekly placebo (Fig. 1). Patientswere stratified according to their previ-ous treatment (diet and exercise ormetformin monotherapy). A fixed 1- to2-week dose-escalation period wasused for the two highest semaglutidedoses (from 0.4 to 0.8 mg E and from0.4 to 0.8 to 1.6 mg E, respectively), andfor both open-label liraglutide activecomparator arms (from 0.6 to 1.2 mgand from 0.6 to 1.2 to 1.8 mg). The 12-week treatment periodwas followed by a5-week follow-up period and a follow-upvisit (week 17).

All trial products were supplied byNovo Nordisk A/S (Søborg, Denmark).Semaglutide was supplied in 1.5-mL car-tridges for once-weekly subcutane-ous injection in preparations of 1 and10 mg/mL concentrations. Semaglutidevehicle was used as a placebo. The car-tridges containing semaglutide or placebowere blinded. Blinding of semaglutidetreatment was maintained by administer-ing matching volumes to patients ran-domized to receive semaglutide or placebo.Liraglutide was administered as open la-bel due to differences in liraglutide (oncedaily) and semaglutide (once weekly)administration.

Semaglutide or placebo was adminis-tered subcutaneously in the abdomen,thigh, or upper arm by use of theNordiPen injection device. For eachpatient, the injection was administeredon the same day of the week and, pref-erably, the same area for injectionused throughout the trial. Liraglutide(6.0 mg/mL, open label) was available asactive drug for once-daily subcutaneousinjection in the abdomen, upper arm, orthigh using a 3-mL pen-injector (FlexPen).

Study End Points and AssessmentsThe primary efficacy end point was thechange from baseline in HbA1c level af-ter 12 weeks of treatment. Secondaryefficacy measures included changesfrom baseline in fasting plasma glucose(FPG) and postprandial plasma glucose(PPG) area under the curve (AUC), and

232 Phase 2 Dose-Finding Study of Semaglutide Diabetes Care Volume 39, February 2016

additional glycemic control parameters(insulin, C-peptide, glucagon, HOMAindex of b-cell function, and HOMA ofinsulin resistance), insulin/proinsulinratio, body measurements (body weightand waist and hip circumference), andfasting lipid profile. The proportion of pa-tients achieving predefined HbA1c targets(American Diabetes Association [ADA]target,7% [53mmol/mol] andAmericanAssociation of Clinical Endocrinologists[AACE] target #6.5% [48 mmol/mol])was also assessed (10,11), as was theproportion of patients achieving $5%and $10% body weight loss (12,13).Meal tests were performed at base-

line (before the initiation of treatment)and at the end of treatment (week 12).After overnight fasting, subjects wereasked (but not forced) to consumewithin 15 min a standard breakfast mealof fixed energy content (2 MJ; further

details are provided in Supplementary Ta-ble 1). Samples for the measurement ofplasma glucose levels were collected10 min before and 15, 30, 45, 60, 90,120, 180, and 240min after themeal test.

Safety assessments included adverseevents (AEs), physical examination, vitalsigns (SBP, DBP, and pulse), electrocar-diogram, fundoscopy, hypoglycemicepisodes, and laboratory safety param-eters (hematology, biochemistry, calci-tonin, urinalysis, and semaglutideantibodies). The severity of AEs was de-fined as follows: mild (transient symp-toms, no interference with a patient’sdaily activities); moderate (markedsymptoms, moderate interferencewith a patient’s daily activities); and se-vere (considerable interference with apatient’s daily activities, unacceptable).Treatment-emergent AEs (TEAEs) weredefined as events that had an onset on

or after the first day of exposure to thestudy drug and no later than 5 weeksafter the last date on the study drug,or that had onset before the first date,and increased in severity during thetreatment period and no later than 5weeks after the last date. All seriousAEs were coded using the Medical Dic-tionary for Regulatory Activities Coding,version 11.1. The Food and Drug Admin-istration requirement to assess amylaseand lipase in clinical trials with GLP-1receptor agonists was introduced afterthe semaglutide 1821 trial was initiated,and hence no such assessments wereincluded in the protocol.

Statistical AnalysisThe enrollment of 40 patients in thesemaglutide 1.6 mg E arm and 42 pa-tients in the combined placebo arm pro-vided 90% power of detecting a 1.0%

Figure 1—Study design. *Open-label.

care.diabetesjournals.org Nauck and Associates 233

HbA1c difference between treatments,with a two-sided test at a 5% signifi-cance level, a common SD of 1.2%,and a dropout rate of 20%. The placeboarm of 42 patients consisted of sixgroups with seven patients in eachgroup, corresponding to the six sema-glutide regimens (doses and/or dose-escalation regimens). In line with thesample size calculation, data for all pa-tients randomized to receive placebowere pooled, analyzed, and reportedas one placebo group.All efficacy end points were assessed

for all randomized patients who wereexposed to at least one dose of investi-gational drug, and patients were ana-lyzed as randomized (full analysis set).The safety analysis set included all pa-tients who were exposed to at least onedose of trial drug, and patients were an-alyzed by the actual treatment received,regardless of the treatment to whichthey were randomized. The primary ef-ficacy analysis was assessed by ANOVA,with treatment, previousantidiabetic treat-ment (diet and exercise ormetformin), andcountry as fixed factors, and baselinevalue as the covariate. Missing valueswere imputed using the last-observation-carried-forward approach using post-baseline values.Data for continuous secondary effi-

cacy end points prespecified for statisti-cal analysis and the post hoc analyses offasting lipid parameters and three safetyend points (SBP, DBP, and pulse) wereanalyzed by a similar ANOVA, with thecorresponding baseline value as the co-variate. The AUC and maximum concen-tration (Cmax) derived from meal testprofiles were log-transformed and ana-lyzed. The categorical variable of pa-tients attaining the ADA HbA1c targetof ,7% (53 mmol/mol) and the AACEHbA1c target of #6.5% (48 mmol/mol)was analyzed separately using a logisticregression model based on the last ob-servation carried forward and with thesame covariates that were used for theprimary end point. To adjust for multi-plicity within an end point, the resultsfor the primary pairwise comparisons ofthe semaglutide doses (0.1, 0.2, 0.4, 0.8,and 0.8 mg E, and 1.6 mg E) versus thosefor the placebo arm were reported asprespecified using the Dunnett methodwith adjusted 95% CIs and P valuesfor two-sided testing of the null hy-pothesis (no difference at a = 0.05). As

prespecified, the estimated treatmentdifferences (ETDs) for the semaglutide-liraglutide and liraglutide-placebo com-parisons were presentedwith unadjusted95% CIs and without P values.

RESULTS

Patient DispositionOverall, 711 patients were screened; atotal of 415 patients were randomizedto receive treatment, and 411 patientswere exposed to an investigational drug.Two patients randomized to receivesemaglutide 0.8 mg were mistakenly al-located to dose escalation, so their ac-tual treatment was semaglutide 0.8 mgE. In two patients who were randomizedto semaglutide 0.8 mg E, a 1.6 mg E waserroneously used. Of all patients ran-domized, 341 (82.2%) completed the12-week treatment period (Supplemen-tary Fig. 1). The nine treatment armswere generally well matched in termsof demographic and baseline character-istics (Table 1). Themean age of patientswas 55 years, and baseline HbA1c valueswere comparable across treatmentarms (mean 8.1 6 0.8% [65 mmol/mol]).The mean duration of diabetes was2.6 6 3.1 years, with marked variation,ranging from 0.2 to 30.7 years. Themean weight was 87.5 kg, with a meanBMI of 30.9 kg/m2. The majority of pa-tients were white (75.7%) and male(65.0%).

Efficacy

Glycemic Control

HbA1c decreased dose dependently withsemaglutide 0.1–1.6 mg E from baselineto week 12 (range 20.6 to 21.7%; Fig.2A); the mean change in HbA1c by weekis also shown in Fig. 2A. The meanchange from baseline in HbA1c was sig-nificantly greater for semaglutide 0.2–1.6 mg E vs. placebo (P , 0.05), andwas greater for semaglutide 1.6 mg Evs. liraglutide 1.2 and 1.8 mg (Fig. 2Aand Table 2).

Dose-dependent increases in theproportion of patients reaching thepredefined ADA target (HbA1c ,7%[53 mmol/mol]) and AACE target(HbA1c #6.5% [48 mmol/mol]) for gly-cemic control were observed for sema-glutide (Fig. 2B). Up to 81% of patientsreached an HbA1c level of ,7% withsemaglutide (0.1–1.6 mg E) vs. 57%with 1.8 mg liraglutide and 15% withplacebo. Up to 63% of patientsachieved an HbA1c level of #6.5% with

semaglutide (0.1–1.6 mg E) vs. 36% with1.8 mg liraglutide and 4% with placebo.

FPG levels decreased dose depen-dently with semaglutide 0.1–1.6 mg Efrom baseline to week 12 (range 20.5to 22.6 mmol/L; Fig. 2C); the meanchange in FPG levels by week is alsoshown in Fig. 2C. The reduction in FPGlevels at week 12 was significantlygreater for semaglutide 0.4–1.6 mg Evs. placebo (P , 0.01), and was greaterfor semaglutide 0.8–1.6mgE vs. liraglutide1.2 mg (Fig. 2C and Table 2).

Reductions in FPG levels were appar-ent in all treatment groups as early asweek 1 and had stabilized within the first3 weeks of treatment (Fig. 2C). In the re-maining treatment period, the mean FPGlevel remained stable in all groups.

Fasting plasma glucagon levels de-creased dose dependently with sema-glutide 0.1–1.6 mg E (the change frombaseline ranged from 4.9 to215.0 ng/L);this reached statistical significance forsemaglutide 1.6 mg E vs. placebo atweek 12 (P , 0.05; SupplementaryTable 1). No treatment differences wereapparent between lower doses of sema-glutide and placebo, or between sema-glutide and liraglutide.

Data on fasting insulin levels, fastingC-peptide levels, HOMA index of b-cellfunction, HOMA of insulin resistance,and meal-related responses, includingfood consumption, PPG, gastric empty-ing, and sensation of appetite, thirst,well-being, and nausea, are included inthe data supplement.

Although identical standardizedmeals of 2 MJ in energy content wereserved, there was a reduction in foodconsumption of up to 39.8 g (203.5 kJ)in the semaglutide and liraglutidegroups (12.2 g [62.5 kJ] with placebo)at week 12 compared with baseline.

Treatmentwith semaglutide 0.2–1.6mgE was associated with a significant anddose-dependent reduction in PPG AUC,AUC0–240min, compared with placebo (upto 35% reduction vs. placebo; P, 0.05);this effect appeared to be of a magni-tude that was similar to the effect ofliraglutide 1.8 mg (27% reduction vs.placebo; Supplementary Table 1). In ad-dition, Cmax and incremental AUCs(iAUCs) for glucose during a standardbreakfast meal were reduced in thesemaglutide 0.4–1.6 mg E dose rangevs. placebo (by up to 30% and 56%, re-spectively, for Cmax and iAUC). There

234 Phase 2 Dose-Finding Study of Semaglutide Diabetes Care Volume 39, February 2016

was a more pronounced effect on theAUC for glucose and a trend for a morepronounced effect on iAUC for glucosewith semaglutide 1.6 mg E vs. liraglutide1.8 mg (Supplementary Table 1).

Body Weight

Body weight decreased dose depen-dently from baseline to week 12 withsemaglutide 0.1–1.6 mg E (Fig. 2D); themean change in body weight by week isalso shown in Fig. 2D. The reduction inbodyweight at week 12was significantlygreater for semaglutide 0.8–1.6 mg E(range23.4 to24.8 kg; P, 0.001) vs. pla-cebo (21.2 kg). The mean change in bodyweight from baseline to week 12 wasgreater for semaglutide 0.8 and 1.6 mgE vs. liraglutide 1.8 mg (22.6 kg), and forsemaglutide 0.8 mg, 0.8 mg E, and 1.6 mgE vs. liraglutide 1.2mg (21.9 kg) based onunadjusted CIs (Fig. 2D and Table 2).

The proportion of patients achievinga$5% weight reduction increased dosedependently after 12 weeks of treat-ment (2.1%, 7.0%, 13.0%, 37.5%, 51.2%,and63.6%with semaglutide0.1–1.6mgE).With liraglutide 1.2 and 1.8mg, 17.8% and14.3% of patients, respectively, achieved a$5% weight reduction, compared with13% of patients in the placebo group.The proportion of patients achieving a$10% weight reduction was 2.1%, 0%,0%, 2.5%, 4.7%, and 9.1% with semaglu-tide treatment (0.1–1.6 mg E), while nopatients achieved a 10% weight loss inthe liraglutide and placebo groups.Weight loss occurred independently ofwhether or not patients reported nauseaor vomiting during the trial (data notshown). Both hip and waist circumfer-ence were reduced between baselineand the end of treatment for all treat-ment groups (data not shown), in accor-dance with the observed weight loss.

Safety and TolerabilityIn total, 74 of the 415 randomized patients(17.8%) withdrew from the trial, of whom46 patients withdrew due to AEs (11% oftotal patients; 62% of all withdrawals).Across all treatment groups, the majorityof AE withdrawals were due to gastroin-testinal (GI) disorders (86.7%) in the firstmonth of randomized treatment. The pro-portion of patients withdrawing from thestudy due to TEAEs increased dose depen-dently up to 29.8% in the semaglutide1.6 mg E group, compared with 4.4% and10.0% in the liraglutide groups (1.2 and1.8 mg). The proportion of patients

Table

1—Demograp

hics

andbase

linech

aracte

ristics(sa

fety

analysis

set)

Placebo

Semaglu

tide

Liraglutid

e

0.1mg

0.2mg

0.4mg

0.8mg

0.8mgE

1.6mgE

1.2mg

1.8mg

Exposed

patien

ts,n46

4743

4842

4347

4550

Diet

andexercise/m

etform

in,%

22/7823/77

14/8623/77

19/8116/84

19/8118/82

24/76

Age,years

55.36

10.655.2

610.1

54.76

10.053.8

610.2

55.06

9.755.9

67.9

56.46

10.554.8

69.2

54.36

10.1

Women

/men

,%39/61

34/6630/70

23/7748/52

37/6345/55

31/6930/70

Diab

etesduratio

n,years

2.46

3.33.6

65.0

2.36

2.72.0

62.3

3.06

3.02.6

62.1

1.86

2.03.3

63.4

2.56

2.6

HbA1c ,%

(mmol/m

ol)

8.16

0.8(65)

8.26

0.9(66)

8.26

0.9(66)

8.16

0.9(65)

8.26

0.9(66)

8.06

0.8(64)

8.06

0.7(64)

8.06

0.8(64)

8.16

0.7(65)

FPG,m

mol/L

8.96

1.59.8

62.7

9.56

2.59.3

62.1

9.56

2.49.6

62.1

9.06

1.99.0

62.3

9.36

2.0

Bodyweigh

t,kg90.5

613.0

89.56

14.286.3

615.1

87.06

14.085.9

615.1

85.76

12.684.5

614.0

90.56

13.587.2

613.1

BMI,kg/m

231.7

63.8

31.56

4.630.4

63.9

29.76

4.530.7

64.5

31.26

4.230.9

64.7

31.06

4.630.9

64.6

Waist

circumferen

ce,cm106

611

1066

11104

69

1056

12101

611

1046

11103

611

1066

11102

612

Hip

circumferen

ce,cm111

610

1116

11107

68

1066

10107

610

1086

11108

610

1106

11106

613

Data

arerep

orted

asthemean

6SD

,unless

otherw

isestated

.

care.diabetesjournals.org Nauck and Associates 235

withdrawing from the study due to GI AEswas similar for semaglutide 0.8 mg withdose escalation and without dose escala-tion (18.6% for 0.8 mg E vs. 14.3% for

0.8 mg). No patients withdrew due to anAE in the placebo group.

A summary of TEAEs with a frequencyof$5% in one or more treatment arm is

provided in Table 3. The majority ofTEAEs in the semaglutide and liraglutidetreatment groups were mild or moder-ate in severity (Supplementary Table 2).

Figure 2—Glycemic control and change in body weight. A: Mean change in HbA1c (%) from baseline at week 12 and byweek. B: Patients reaching ADAand AACE criteria for glycemic control. C: Mean change in FPG level (mmol/L) from baseline at week 12 and by week. D: Mean change in body weight(kg) from baseline at week 12 and by week. All data are full analysis sets, last observation carried forward. Change from baseline data are reported asthe least squaresmean6 SEM. Time-course data are reported as the rawmean6 SEM. †Mean baseline value. *P, 0.05, **P, 0.01, ***P, 0.001,****P, 0.0001 vs. placebo (P values adjusted for multiple testing using the Dunnett method). #Mean change greater for semaglutide vs. liraglutidebased on the unadjusted CIdfor specific comparison between treatment arms, see ETDs and 95% CIs in Table 2.

236 Phase 2 Dose-Finding Study of Semaglutide Diabetes Care Volume 39, February 2016

The most commonly reported AEs wereGI disorders, mainly nausea, vomiting,diarrhea, and dyspepsia. Rates ofnausea,vomiting, and diarrhea appeared to bedose dependent (Table 3). The proportionof patients reporting nausea, vomiting, anddiarrhea was numerically lower for sema-glutide 0.8 mg with dose escalation thanwithout dose escalation (nausea 39.5%for 0.8 mg E vs. 59.5% for 0.8 mg; vomiting30.2% for 0.8 mg E vs. 40.5% for 0.8 mg;diarrhea 16.3% for 0.8 mg E vs. 19.0% for0.8 mg; Table 3).

Themajority of GI AEswere reported asmild or moderate in severity (Supplemen-tary Table 3). The proportion of patientsreportingGI AEswas numerically lower forsemaglutide 0.8 mg with E than without E(62.8% for 0.8 mg E vs. 78.6% for 0.8 mg;Table 3). Rates for abdominal pain werelow across treatment groups; in no casewas there a suspicion of pancreatitisbased on local laboratory monitoring.

Most GI AEs occurred within the first2 weeks after the first dose, and nauseaand vomiting were transient in nature,decreasing over time, for both thesemaglutide and liraglutide treatmentgroups. The proportion of patientswith nausea and vomiting by day isshown in Supplementary Fig. 2.

Overall, 10 treatment-emergent seri-ous AEs (TESAEs) and 2 non-TESAEswere reported by 10 patients (8 patientsreceived treatment with semaglutide:0.1 mg [n = 2], 0.2 mg [n = 1], 0.4 mg[n = 2], 0.8 mg E [n = 1], and 1.6 mg E [n =2]; 1 patient received treatment withliraglutide 1.8 mg; and 1 patient re-ceived treatment with placebo). TESAEsincluded cardiac disorders (four eventsreported by three patients: acute leftventricular failure [semaglutide 0.2 mg],acute myocardial infarction [sema-glutide 0.8 mg], coronary artery disease[semaglutide 0.8mg], and myocardial in-farction [semaglutide 0.4 mg]) and vas-cular disorders (two events reported bytwo patients: arterial occlusive disease[semaglutide 0.1 mg] and hypertension[semaglutide 0.4 mg]). No apparentdose or time dependency was observed.All TESAEs in semaglutide-treated pa-tients were judged by the investigatoras being unlikely to be related to the trialproduct; oneTESAE in the liraglutide1.8mggroupwas judgedasbeingpossibly/unlikelyrelated to the trial product.

There were no clinically relevant dif-ferences among the treatment groups in

Table

2—ETDsforse

maglutid

evs.

place

boandlira

glutid

eatweek12

(HbA1c ,FP

G,andbodyweight)

ETDs

Semaglu

tide

Liraglutid

e

0.1mg

0.2mg

0.4mg

0.8mg

0.8mgE

1.6mgE

1.2mg

1.8mg

HbA1c ,%(95%

CI)

vs.placeb

o20.1

(20.5,0.3)

20.4*

(20.8,2

0.0)20.6***

(21.0,2

0.2)21.0****

(21.4,2

0.6)21.0****

(21.3,2

0.6)21.2****

(21.6,2

0.8)20.7

(21.0,2

0.4)20.8

(21.1,2

0.6)vs.

liraglutid

e1.2

mg

0.6(0.3,0.9)

0.3(2

0.0,0.6)0.1

(20.2,0.4)

20.3

(20.6,0.0)

20.3

(20.6,0.0)

20.5

(20.8,2

0.2)vs.

liraglutid

e1.8

mg

0.8(0.5,1.0)

0.4(0.2,0.7)

0.2(2

0.1,0.5)20.1

(20.4,0.2)

20.1

(20.4,0.2)

20.4

(20.6,2

0.1)

FPG,m

mol/L

(95%CI)

vs.placeb

o20.1

(21.0,2

0.8)20.6

(21.5,2

0.3)21.2**

(22.1,2

0.3)22.0****

(22.9,2

1.0)22.0****

(22.9,2

1.1)22.1****

(23.0,2

1.2)21.2

(21.9,2

0.5)21.8

(22.4,2

1.1)vs.

liraglutid

e1.2

mg

1.1(0.5,1.8)

0.6(2

0.1,1.3)0.0

(20.7,0.7)

20.8

(21.5,2

0.1)20.8

(21.5,2

0.1)20.9

(21.6,2

0.2)vs.

liraglutid

e1.8

mg

1.7(1.1,2.4)

1.1(0.5,1.8)

0.6(2

0.1,1.2)20.2

(20.9,0.5)

20.2

(20.9,0.5)

20.3

(21.0,0.3)

Bodyweigh

t,kg(95%

CI)

vs.placeb

o0.4

(20.9,1.7)

0.1(2

1.2,1.5)20.8

(22.1,0.5)

22.2***

(23.5,2

0.9)22.4****

(23.7,2

1.1)23.6****

(25.0,2

2.3)20.7

(21.7,0.3)

21.4

(22.4,2

0.4)vs.

liraglutid

e1.2

mg

1.1(0.1,2.0)

0.8(2

0.2,1.8)20.2

(21.2,0.8)

21.5

(22.6,2

0.5)21.7

(22.8,2

0.7)23.0

(24.0,2

2.0)vs.

liraglutid

e1.8

mg

1.8(0.8,2.8)

1.6(0.6,2.5)

0.6(2

0.4,1.5)20.8

(21.8,0.2)

21.0

(22.0,2

0.0)22.2

(23.2,2

1.3)

Estimates

arefro

man

ANOVAmodelw

ithtreatm

ent,co

untry,an

dprevio

ustreatm

entas

fixed

effects,andbaselin

evalu

eas

thecovariate;C

Isfortreatm

entdifferen

cesvs.p

laceboare

based

ontheDunnett

meth

od(w

ith6compariso

ns);

CIsfortreatm

entdifferen

cesvs.

liraglutid

eare

notcorrected

formultip

letestin

g.*P

,0.05.

**P,

0.01.***P

,0.001.

****P,

0.0001.

care.diabetesjournals.org Nauck and Associates 237

regard to electrocardiogram changesfrom baseline to the end of treatment.The change in SBP, DBP, and pulse ratefrom baseline to the end of treatment isshown in Table 4. A modest reduction inSBP from baseline to week 12 was ob-served with treatment with semaglutide0.2–1.6 mg E, although the reductionwas not significantly different fromthat with placebo. No consistent changein DBP was observed. Pulse rate in-creased from baseline in all groups after12 weeks (Table 4). The increase in pulseappeared to be dose dependent in thesemaglutide group. The ETDs were notstatistically significantly different forsemaglutide versus placebo. No appar-ent differences were observed for the

semaglutide and liraglutide compari-sons for SBP, DBP, or pulse rate.

There were no major episodes of hy-poglycemia (classified as patients beingunable to treat the episode themselves),and the incidence of minor hypoglycemia(a plasma glucose level ,3.1 mmol/L)was low: eight patients reported 11 mi-nor hypoglycemia events; 11 patientsreported 16 events of symptoms-onlyhypoglycemia. The frequency of minorhypoglycemia was comparable acrossall nine treatment arms, and no dose-dependent trends were observed (range0–4.4%corresponding to0–0.205episodes/patient-year). No new development ofproliferative retinopathy was observedover the duration of the study.

There were few cases of injection sitereactions, as follows: two patients re-ceiving semaglutide (0.2 mg, one eventof edema; 0.4 mg, two events of irrita-tion); three patients receiving liraglutide1.2 mg (two events of hematoma, oneevent of pruritus); and two patients re-ceiving liraglutide 1.8 mg (one event oferythema, one event of site reaction),with no differences among treatmentgroups. A single patient in the semaglutide1.6 mg E treatment group developed low-titer anti-semaglutide antibodies, whichdid not cross-react with native GLP-1 andhad no neutralizing effect in vitro. Notreatment-related changes in hematologyor biochemistry, including blood calci-tonin levels, were observed; pancreatic

Table 3—TEAEs by system organ class and preferred term, with frequency ‡5% in one or more treatment arms (safety analysis set)

Placebo(n = 46)

Semaglutide Liraglutide

0.1 mg(n = 47)

0.2 mg(n = 43)

0.4 mg(n = 48)

0.8 mg(n = 42)

0.8 mg E(n = 43)

1.6 mg E(n = 47)

1.2 mg(n = 45)

1.8 mg(n = 50)

TEAEs, n (%) 20 (43.5) 28 (59.6) 24 (55.8) 35 (72.9) 36 (85.7) 31 (72.1) 44 (93.6) 25 (55.6) 31 (62.0)

GI disorders 5 (10.9) 16 (34.0) 9 (20.9) 22 (45.8) 33 (78.6) 27 (62.8) 35 (74.5) 15 (33.3) 15 (30.0)Nausea 2 (4.3) 4 (8.5) 5 (11.6) 13 (27.1) 25 (59.5) 17 (39.5) 27 (57.4) 11 (24.4) 4 (8.0)Vomiting 1 (2.2) 0 (0.0) 3 (7.0) 7 (14.6) 17 (40.5) 13 (30.2) 13 (27.7) 4 (8.9) 6 (12.0)Diarrhea 0 (0.0) 5 (10.6) 2 (4.7) 7 (14.6) 8 (19.0) 7 (16.3) 11 (23.4) 2 (4.4) 7 (14.0)Dyspepsia 1 (2.2) 5 (10.6) 0 (0.0) 4 (8.3) 4 (9.5) 4 (9.3) 6 (12.8) 5 (11.1) 4 (8.0)Constipation 0 (0.0) 0 (0.0) 2 (4.7) 2 (4.2) 1 (2.4) 3 (7.0) 3 (6.4) 3 (6.7) 1 (2.0)

Nervous system disorders 7 (15.2) 11 (23.4) 4 (9.3) 11 (22.9) 8 (19.0) 3 (7.0) 5 (10.6) 10 (22.2) 6 (12.0)Headache 3 (6.5) 7 (14.9) 3 (7.0) 4 (8.3) 5 (11.9) 1 (2.3) 3 (6.4) 4 (8.9) 2 (4.0)Dizziness 1 (2.2) 3 (6.4) 0 (0.0) 2 (4.2) 1 (2.4) 0 (0.0) 0 (0.0) 2 (4.4) 0 (0.0)Lethargy 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.1) 0 (0.0) 1 (2.3) 0 (0.0) 3 (6.7) 0 (0.0)

Infections/infestations 6 (13.0) 9 (19.1) 7 (16.3) 10 (20.8) 4 (9.5) 6 (14.0) 10 (21.3) 2 (4.4) 9 (18.0)Nasopharyngitis 4 (8.7) 6 (12.8) 0 (0.0) 4 (8.3) 2 (4.8) 2 (4.7) 3 (6.4) 1 (2.2) 2 (4.0)Gastroenteritis 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.1) 0 (0.0) 0 (0.0) 2 (4.3) 0 (0.0) 3 (6.0)Urinary tract infection 0 (0.0) 0 (0.0) 3 (7.0) 0 (0.0) 1 (2.4) 1 (2.3) 2 (4.3) 0 (0.0) 0 (0.0)

General disorders and administration siteconditions 1 (2.2) 1 (2.1) 2 (4.7) 7 (14.6) 4 (9.5) 4 (9.3) 11 (23.4) 3 (6.7) 5 (10.0)Fatigue 1 (2.2) 1 (2.1) 0 (0.0) 3 (6.3) 0 (0.0) 0 (0.0) 6 (12.8) 0 (0.0) 2 (4.0)Asthenia 0 (0.0) 0 (0.0) 0 (0.0) 2 (4.2) 3 (7.1) 3 (7.0) 5 (10.6) 0 (0.0) 0 (0.0)

Metabolism/nutrition disorders 1 (2.2) 2 (4.3) 3 (7.0) 4 (8.3) 10 (23.8) 10 (23.3) 23 (48.9) 6 (13.3) 6 (12.0)Anorexia 1 (2.2) 2 (4.3) 2 (4.7) 3 (6.3) 10 (23.8) 7 (16.3) 15 (31.9) 3 (6.7) 5 (10.0)Decreased appetite 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.1) 0 (0.0) 2 (4.7) 8 (17.0) 1 (2.2) 1 (2.0)

Musculoskeletal/connective tissue disorders 2 (4.3) 5 (10.6) 2 (4.7) 3 (6.3) 2 (4.8) 3 (7.0) 4 (8.5) 2 (4.4) 2 (4.0)

Investigations 1 (2.2) 1 (2.1) 1 (2.3) 1 (2.1) 0 (0.0) 3 (7.0) 2 (4.3) 1 (2.2) 3 (6.0)

Vascular disorders 4 (8.7) 2 (4.3) 0 (0.0) 2 (4.2) 1 (2.4) 1 (2.3) 2 (4.3) 2 (4.4) 3 (6.0)Hypertension 4 (8.7) 1 (2.1) 0 (0.0) 2 (4.2) 1 (2.4) 1 (2.3) 1 (2.1) 1 (2.2) 2 (4.0)

Injury/poisoning/procedural complications 4 (8.7) 1 (2.1) 2 (4.7) 2 (4.2) 0 (0.0) 1 (2.3) 4 (8.5) 1 (2.2) 0 (0.0)

Skin and subcutaneous disorders 0 (0.0) 3 (6.4) 1 (2.3) 3 (6.3) 1 (2.4) 0 (0.0) 1 (2.1) 2 (4.4) 2 (4.0)

Respiratory, thoracic, and mediastinal disorders 3 (6.5) 1 (2.1) 1 (2.3) 1 (2.1) 2 (4.8) 1 (2.3) 1 (2.1) 2 (4.4) 2 (4.0)

Eye disorders 3 (6.5) 1 (2.1) 0 (0.0) 1 (2.1) 1 (2.4) 0 (0.0) 1 (2.1) 3 (6.7) 4 (8.0)Diabetic retinopathy 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0) 3 (6.0)

Cardiac disorders 2 (4.3) 1 (2.1) 4 (9.3) 2 (4.2) 0 (0.0) 1 (2.3) 1 (2.1) 1 (2.2) 0 (0.0)

Psychiatric disorders 1 (2.2) 3 (6.4) 0 (0.0) 2 (4.2) 0 (0.0) 0 (0.0) 1 (2.1) 0 (0.0) 0 (0.0)

Blood/lymphatic system disorders 0 (0.0) 0 (0.0) 0 (0.0) 3 (6.3) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Data are reported as the number (n) of randomized patients exposed to at least one dose of trial product and the percentage (%) of patientsexperiencing at least one AE.

238 Phase 2 Dose-Finding Study of Semaglutide Diabetes Care Volume 39, February 2016

enzymes were not routinely monitored.There were no reports of pancreatitis orclinical thyroid AEs.

CONCLUSIONS

This 12-week dose-finding study eva-luated a wide range of semaglutidedoses versus placebo and open-labelliraglutide in patients with type 2 diabe-tes. The effect of a 1-week dose escala-tion was explored with semaglutide0.8 mg in order to establish whetherthis regimen would mitigate the knownGI side effects associated with this classof agents, and thus provide insight intoappropriate dosing for phase 3 trials.

Once-weekly semaglutide treatmentprovided clinically meaningful, dose-dependent improvements in HbA1c level(up to 21.7% vs. 20.5% with placebo)andweight loss (up to24.8 kg vs.21.2 kgwith placebo), without any major epi-sodes of hypoglycemia. Weight lossseemed to occur independently ofnausea or vomiting. Weight loss withliraglutide (up to 22.6 kg) was consis-tent with previous clinical trials (at dosesup to 1.8 mg added to metformin)(14). Based on this relatively short study,HbA1c and body weight reductions withsemaglutide 1.6 mg were numericallygreater than with liraglutide 1.8 mg.Nevertheless, the relatively short dose-escalation period of 1–2 weeks resultedin an unacceptable tolerability profile,certainly for semaglutide 1.6 mg. Thesimilarity of responses in FPG levels be-tween liraglutide and semaglutide anddifferences in HbA1c levels suggest thatsemaglutide may have a preferential im-pact on PPG levels, perhaps mediated bydifferences in gastric emptying.

No pancreatitis, thyroid AEs, ortreatment-related effects on blood calcito-nin levelswereobserved.A similar increasein pulse rate from baseline was seen withsemaglutide and liraglutide, althoughthese findings were not significantly differ-ent from placebo in this small study, andmodest decreases in mean SBP were ob-served. Four serious cardiovascular eventswere reported in three semaglutide-treated patients; however, no dose- ortime-dependency could be established.Very few cases of injection site reactionswere reported, and although low-titeranti-semaglutide antibodies developedin one patient, no in vitro neutralizing ef-fect or cross-reactivity to native GLP-1 wasobserved.

Table

4—Meanch

angein

SBP,DBP,andpulse

rate

from

base

lineto

week12

Placebo

Semaglu

tide

Liraglutid

e

0.1mg

0.2mg

0.4mg

0.8mg

0.8mgE

1.6mgE

1.2mg

1.8mg

SBP,m

mHg

Estimated

LSmean

change

from

baselin

e23.8

2.423.8

21.8

26.2

28.4

26.2

24.9

25.7

ETDvs.

placeb

o(95%

CI)

6.1*(0.1,12.1)

20.1

(26.2,6.0)

2.0(2

4.0,7.9)22.4

(28.6,3.8)

24.6

(210.7,1.5)

22.5

(28.5,3.6)

21.1

(25.8,3.5)

22.0

(26.4,2.5)

ETDvs.

liraglutid

e1.2

mg(95%

CI)

7.2(2.7,11.8)

1.1(2

3.6,5.8)3.1

(21.6,7.8)

21.3

(26.0,3.5)

23.5

(28.2,1.2)

21.3

(25.9,3.3)

ETDvs.

liraglutid

e1.8

mg(95%

CI)

8.1(3.6,12.5)

1.9(2

2.7,6.5)3.9

(20.5,8.4)

20.5

(25.1,4.2)

22.7

(27.3,1.9)

20.5

(25.0,3.9)

DBP,m

mHg

Estimated

LSmean

change

from

baselin

e21.9

1.90.3

0.40.0

21.6

21.9

21.0

0.1ETD

vs.placeb

o(95%

CI)

3.8(2

0.3,7.9)2.1

(22.1,6.3)

2.3(2

1.9,6.4)1.9

(22.4,6.2)

0.2(2

4.0,4.5)20.1

(24.3,4.1)

0.8(2

2.4,4.0)1.9

(21.2,5.0)

ETDvs.

liraglutid

e1.2

mg(95%

CI)

3.0(2

0.2,6.1)1.3

(22.0,4.5)

1.4(2

1.8,4.6)1.1

(22.2,4.4)

20.6

(23.8,2.6)

20.9

(24.1,2.3)

ETDvs.

liraglutid

e1.8

mg(95%

CI)

1.9(2

1.2,4.9)0.2

(23.0,3.4)

0.3(2

2.7,3.4)20.0

(23.3,3.2)

21.7

(24.9,1.5)

22.0

(25.1,1.1)

Pulse

rate,bpm

Estimated

LSmean

change

from

baselin

e0.4

0.91.2

2.72.6

4.14.2

4.83.3

ETDvs.

placeb

o(95%

CI)

0.6(2

4.5,5.6)0.8

(24.3,6.0)

2.4(2

2.6,7.4)2.2

(23.0,7.5)

3.7(2

1.4,8.9)3.9

(21.3,9.0)

4.5(0.6,8.3)

2.9(2

0.9,6.7)ETD

vs.liraglu

tide1.2

mg(95%

CI)

23.9

(27.8,2

0.0)23.6

(27.6,0.3)

22.1

(26.0,1.8)

22.2

(26.2,1.8)

20.7

(24.7,3.2)

20.6

(24.5,3.3)

ETDvs.

liraglutid

e1.8

mg(95%

CI)

22.4

(26.1,1.4)

22.1

(25.9,1.8)

20.6

(24.3,3.2)

20.7

(24.6,3.2)

0.8(2

3.0,4.7)0.9

(22.8,4.7)

LSmean,least

squaresmean.Estim

atesare

froman

ANOVAmodelw

ithtreatm

ent,country,andprevious

treatment

asfixed

effectsand

baselinevalue

asthe

covariate;CIsfor

treatment

differencesvs.placebo

arebased

onthe

Dunnettm

ethod(with

6com

parisons);CIsfor

treatmentdifferences

vs.liraglutideare

notcorrectedfor

multiple

testing.Allvalues

forSBP,D

BP,andpulse

rateare

means,safety

analysisset,lastobservation

carriedforw

ard.*P,

0.05.

care.diabetesjournals.org Nauck and Associates 239

A dose-dependent increase in GI AEs(mainly nausea and vomiting) and instudy withdrawals due to GI AEs wasobserved with semaglutide, which isconsistent with the known side effectsof the GLP-1 drug class (15). Most GI AEsoccurred within the first 2 weeks of thefirst dose. Nausea and vomiting weretransient, decreasing gradually overtime with both semaglutide and liraglutide,indicating the development of toler-ance. The observed dose-dependentincrease in the proportion of patientswith GI AEs, and the proportion of pa-tients reporting nausea and vomiting,was ameliorated by including a 1-weekdose escalation of semaglutide from 0.4to 0.8 mg (the second-highest semaglu-tide dose). This phase 2 dose-findingstudy was designed to explore thedose-response relationship of once-weekly semaglutide treatment. Whilethe overall GI side effects were not un-expected, the incidence of GI side effectsobserved with the highest dose ofsemaglutide were not considered ac-ceptable. Semaglutide 1.6 mg has not,therefore, been taken forward intophase 3. There was a notable reductionin GI AEs with semaglutide 0.8 mg fol-lowing a 1-week dose-escalation step.This, together with the mild/moderateand transient nature of the GI AEs, indi-cates that unwanted side effects may beameliorated with slower dose escalationwithout compromising efficacydthisstrategy is being further explored inphase 3 studies, using semaglutide 0.5and 1.0mgwith a 4-week dose-escalationstep from 0.25 to 0.5 mg and from 0.5to 1.0 mg.Indeed, findings from a recent phase

1 study of semaglutide (6) have pro-vided further insight into the most ap-propriate dose and regimen. This studyused a more gradual dose-escalationregimen involving once-weekly sema-glutide treatment at 0.25 mg for 4weeks, followed by 0.5 mg for 4 weeks,before increasing the dose to 1.0 mg for5 weeks (6). This regimen was well tol-erated, and substantially reduced theseverity of nausea and the incidence ofvomiting and study withdrawals due toGI AEs. However, this was a small phase1 study, and phase 3 trials are neededto confirm the appropriate use of sema-glutide in clinical practice. The ongoingcomprehensive semaglutide phase 3aclinical trial program, SUSTAIN, comprises

eight clinical trials and is expected to in-clude.8,000 patients with type 2 diabe-tes. The program includes a long-term,global cardiovascular outcomes study,SUSTAIN-6 (clinical trial reg. no.NCT01720446, clinicaltrials.gov), involv-ing .3,000 patients, which was initiatedpreapproval to address the requirementsoutlined in the Food and Drug Adminis-tration and European Medicines Agencyguidance on cardiovascular safety studiesfor new antidiabetic drugs. It is estimatedthat the SUSTAIN-6 study will be com-pleted in early 2016.

This phase 2 study has some limita-tions, including its relatively short dura-tion (12 weeks), which is too short toevaluate fully the impact of the highestsemaglutide doses on HbA1c and bodyweight. There are statistical limitationsto the efficacy and safety comparisonswith liraglutide, as this treatment armwas open-label and not blinded, andthere was no specific hypothesis testingfor semaglutide versus liraglutide com-parisons. A further limitation relates tothe paracetamol method for measuringgastric emptying, which is not ideal forobtaining details regarding GI motility,but rather provides an approximation(16). In addition, this study did not con-trol for or standardize what patientsconsumed during the meal test. Assuch, the reduction in food consump-tion in the semaglutide and liraglutidegroups compared with baseline mayconfound interpretation of the treat-ment effects on postprandial responses.

In summary, semaglutide adminis-tered once weekly provides clinicallymeaningful, dose-dependent reduc-tions in HbA1c and body weight,with a low risk of hypoglycemia andinjection-site reactions, in patientswith type 2 diabetes. Semaglutide poten-tially offers potent glucose-loweringefficacy with a similar overall safetyprofile compared with other availableGLP-1 receptor agonists, providing arobust basis for further investigation.Glucose-lowering medications admin-istered once weekly have the potentialto improve patient adherence and,therefore, may impact treatment out-comes and quality of life (17). How-ever, the relatively high incidence ofGI side effects seen in this study sup-ports the adoption of slower dose es-calation, with a view to optimizing thepotent clinical efficacy of semaglutide in

the phase 3 setting. The results of the on-going SUSTAIN phase 3 clinical trial pro-gram will provide further information onthe potential of semaglutide to improvethe management of type 2 diabetes.

Acknowledgments. The authors thank all theinvestigators and their staff for the conduct ofthis study. The authors also thank all patientswho took part in this study. In addition, theauthors thank Novo Nordisk A/S for their con-tribution to datamanagement and data analysis.Editorial assistance was provided by Katrina deSaram from AXON Communications, funded byNovo Nordisk.Funding. The study was funded by Novo NordiskA/S, the manufacturer of semaglutide. Editorial as-sistance, provided by Katrina de Saram from AXONCommunications, was funded by Novo Nordisk A/S.Duality of Interest. M.A.N. has received re-search grants while participating in this study(to his institution, the Diabeteszentrum BadLauterberg) from Berlin-Chemie AG/Menarini,Eli Lilly&Co.,Merck, Sharp&Dohme, andNovartisPharma AG for participation in monocentric oroligocentric studies and from AstraZeneca,Boehringer Ingelheim, GlaxoSmithKline, LillyDeutschland GmbH, MetaCure Inc., RochePharma AG, Novo Nordisk Pharma GmbH, andTolerx Inc. for participation in multicentric clini-cal trials. M.A.N. has received consulting feesand/or honoraria for membership in advisoryboards and/or honoraria for speaking for AmylinPharmaceuticals Inc., AstraZeneca, Berlin-Chemie AG/Menarini, Boehringer Ingelheim,Bristol-Myers Squibb EMEA, Diartis Pharmaceu-ticals, Inc., Eli Lilly & Co., F. Hoffmann-La RocheLtd., GlaxoSmithKline LLC, Intarcia Therapeutics,Inc., Lilly Deutschland GmbH, MannKind Corp.,Merck Sharp & Dohme GmbH, Merck Sharp &Dohme Corp., Novartis Pharma AG, Novo NordiskA/S, NovoNordisk PharmaGmbH, Sanofi Pharma,Takeda, Versartis, andWyeth Research, includingreimbursement for travel expenses in connectionwith the above-mentioned activities. M.A.N.owns no stock and is currently employed bySt. Josef-Hospital (Ruhr-Universitat Bochum),Germany. J.R.P. has acted in an advisory capacityfor GlaxoSmithKline, Novo Nordisk, Sanofi, EliLilly, and Alere and receives support-in-kindfor an investigator-led trial from Merck Group(Germany). G.S. has received consultancy feesfrom Merck, Novo Nordisk, Janssen, Servier,AstraZeneca, Boehringer Ingelheim, Eli Lilly,Intarcia, and Sanofi and speaking fees fromNovo Nordisk, Merck, Boehringer Ingelheim, EliLilly, Sanofi, Janssen, and Novartis. E.M. has re-ceived consultancy and speakinghonoraria, aswellas research grants, from Novo Nordisk. J.-P.C. hasreceived honoraria for participation in clinical trials,advisoryboards, symposia, and congress invitationsfrom AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Elli Lilly, Janssen, Merck Sharp &Dohme, Novo Nordisk, Sanofi, Bastide, DinnoSante, LifeScan, Medtronic, Menarini, and Roche.M.L.L. and C.B.J. are employees of Novo Nordiskand own stock in the company. S.L.A. has actedin an advisory capacity for Novo Nordisk and forSporomex Ltd UK. No other potential conflicts ofinterest relevant to this article were reported.

240 Phase 2 Dose-Finding Study of Semaglutide Diabetes Care Volume 39, February 2016

The investigators and representatives fromNovo Nordisk were responsible for the studydesign, protocol, statistical analysis plans, anal-ysis, and reporting of results. Final responsibilityfor the decision to submit the manuscript forpublication was made jointly by all authors.Author Contributions. M.A.N., J.R.P., G.S.,E.M., J.-P.C., M.L.L., and S.L.A. contributed tothe data interpretation and the preparation ofthe article. C.B.J. contributed to the design,execution, data interpretation, and preparationof thearticle.M.A.N. is theguarantorof thisworkand, as such, had full access to all the data in thestudy and takes responsibility for the integrity ofthe data and the accuracy of the data analysis.PriorPresentation.Keyfindings fromthis studywere presented in abstract form at the 48thEuropean Association for the Study of Diabetes(EASD) Annual Meeting, Berlin, Germany, 1–5October 2012.

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