PIONEER 1: Randomized ClinicalTrial of the Efficacy and Safety ofOral Semaglutide Monotherapy inComparison With Placebo inPatients With Type 2 DiabetesDiabetes Care 2019;42:1724–1732 | https://doi.org/10.2337/dc19-0749

OBJECTIVE

This trial compared the efficacy and safety of the first oral glucagon-like peptide1 (GLP-1) receptor agonist, oral semaglutide, as monotherapy with placebo inpatients with type 2 diabetes managed by diet and exercise alone. Two estimandsaddressed two efficacy-related questions: a treatment policy estimand (regardlessof trial product discontinuation or rescue medication use) and a trial productestimand (on trial product without rescue medication use) in all randomizedpatients.

RESEARCH DESIGN AND METHODS

This was a 26-week, phase 3a, randomized, double-blind, placebo-controlled,parallel-group trial conducted in 93 sites in nine countries. Adults with type 2diabetes insufficiently controlled with diet and exercise were randomized (1:1:1:1)to once-daily oral semaglutide 3mg, 7mg, 14mg, or placebo. The primary end pointwas change from baseline to week 26 in HbA1c. The confirmatory secondary endpoint was change from baseline to week 26 in body weight.

RESULTS

In the 703 patients randomized (mean age 55 years, 50.8%male, andmean baselineHbA1c 8.0% [64 mmol/mol]), oral semaglutide reduced HbA1c (placebo-adjustedtreatment differences at week 26: treatment policy estimand,20.6% [3 mg],20.9%[7 mg], and 21.1% [14 mg]; trial product estimand,20.7% [3 mg], 21.2% [7 mg],and21.4% [14 mg]; P < 0.001 for all) and body weight (treatment policy,20.1 kg[3 mg], 20.9 kg [7 mg], and 22.3 kg [14 mg, P < 0.001]; trial product, 20.2 kg[3mg],21.0 kg [7mg, P = 0.01], and22.6 kg [14mg, P < 0.001]). Mild-to-moderatetransient gastrointestinal events were the most common adverse events with oralsemaglutide. Trial product discontinuations occurred in 2.3–7.4% with oral sem-aglutide and 2.2% with placebo.

CONCLUSIONS

In patients with type 2 diabetes, oral semaglutide monotherapy demonstratedsuperior and clinically relevant improvements in HbA1c (all doses) and body weightloss (14 mg dose) versus placebo, with a safety profile consistent with other GLP-1receptor agonists.

1Brigham and Women’s Hospital, Harvard Med-ical School, Boston, MA2MedStar Health Research Institute, Hyattsville,MD3DallasDiabetesResearchCenter atMedical City,Dallas, TX4Yokohama City University, Yokohama, Japan5Division of EndocrinologyMetabolismDiabetes,Department of Internal Medicine, Sisli HamidiyeEtfal Teaching and Research Hospital, Universityof Health Sciences, Istanbul, Turkey6Clinic for Endocrinology, Diabetes and Meta-bolic Diseases, Faculty of Medicine, Universityof Belgrade, Belgrade, Serbia7Cardiometabolic Research Center, Aguasca-lientes, Mexico8Novo Nordisk A/S, Søborg, Denmark9Institute for Clinical and Experimental Medicineand Institute for Endocrinology, Prague, CzechRepublic

Corresponding author: Vanita R. Aroda, varoda@bwh.harvard.edu

Received 15 April 2019 and accepted 7 June 2019

Clinical trial reg. no. NCT02906930, clinicaltrials.gov

This article contains Supplementary Data onlineat http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc19-0749/-/DC1.

This article is featured in a podcast available athttp://www.diabetesjournals.org/content/diabetes-core-update-podcasts.

*A complete list of investigators in the PeptideInnovation for Early Diabetes Treatment 1 (PIO-NEER 1) trial is provided in the SupplementaryData online.

© 2019 by the American Diabetes Association.Readers may use this article as long as the workis properly cited, the use is educational and notfor profit, and the work is not altered. More infor-mation is available at http://www.diabetesjournals.org/content/license.

Vanita R. Aroda,1,2 Julio Rosenstock,3

Yasuo Terauchi,4 Yuksel Altuntas,5

Nebojsa M. Lalic,6

Enrique C. Morales Villegas,7

Ole K. Jeppesen,8 Erik Christiansen,8

Christin L. Hertz,8 and Martin Haluzı́k,9 forthe PIONEER 1 Investigators*

1724 Diabetes Care Volume 42, September 2019

EMER

GINGTH

ERAPIES:

DRUGSANDREG

IMEN

S

Glucagon-like peptide 1 (GLP-1) receptoragonists are effective treatment optionsfor achieving glycemic control in patientswith type 2 diabetes but so far have onlybeen available as subcutaneous injec-tions (1,2). The GLP-1 analog semaglu-tide, administered subcutaneously onceweekly, has been shown to effectivelyreduce glycated hemoglobin (HbA1c) andinduce body weight loss in patients withtype 2 diabetes (3) and reduce the risk ofcardiovascular events in those with es-tablished cardiovascular disease or highcardiovascular risk (4).Peptide-based drugs, including GLP-1

receptor agonists, typically have very lowbioavailability when administered orallydue to extensive degradation by proteo-lytic enzymes and poor absorption acrossthe gastrointestinal mucosa (5,6). Oralsemaglutide is developed as a tablet,coformulated with the absorption en-hancer sodium N-(8-[2-hydroxylbenzoyl]amino) caprylate (SNAC) (7). SNAC exertsmultiple actions to enhance absorption,including facilitating the passage ofsemaglutide across the gastric epithe-lium via a transcellular mechanism, aswell as providing a localized increase in pHto protect semaglutide from proteolyticdegradation (8). The pharmacokinetics oforal semaglutide have been establishedin healthy subjects and subjects withtype 2 diabetes and support once-dailydosing (9). Based on the results of thedose-finding phase 2 trial (7), three dosesof oral semaglutide (3, 7, and 14mg)wereselected for the phase 3 program. Here,we present the results of the first com-pleted phase 3 trial with oral semaglutide,which assessed the efficacy and safety oforal semaglutide monotherapy in patientswith type 2 diabetes managed only withdiet and exercise.

RESEARCH DESIGN AND METHODS

The trial protocol was approved by rele-vant local independent ethics committeesand institutional reviewboards at each siteand conducted in accordance with theDeclaration of Helsinki and InternationalCouncil for Harmonisation of TechnicalRequirements for Pharmaceuticals forHuman Use (ICH) (10,11). All patientsprovided written, informed consent priorto commencement of trial-related activities.

Trial DesignThiswas a 26-week, randomized, double-blind, placebo-controlled, parallel-group

trial conducted at 93 sites across ninecountries (Algeria, Bulgaria, Czech Re-public, Japan, Mexico, Russia, Serbia,Turkey, and the U.S.) from September2016 to December 2017. The trial wasregistered with ClinicalTrials.gov (identi-fier NCT02906930 [trial registered 15September 2016 and initiated 20 Septem-ber 2016]). Randomization of patientswas stratified by Japanese and non-Japanese patients. Patients and investiga-tors were blinded to treatment throughthe use of visually identical tablets andpackaging for trial products and the useof a trial-specific interactive web/voicesystem that assigned treatment codes.

Two different scientific questions re-lated to the efficacy objectives wereaddressed through the definition of twoestimands (“treatment policy” and “trialproduct”). Both estimands were definedbased on interactions with regulatoryagencies (12).

The treatment policy estimand eval-uates the treatment effect for all ran-domized patients regardless of trialproduct discontinuation and use of res-cue medication. This estimand reflectsthe intention-to-treat principle as de-fined in ICH E9 (R1) (13). The estimandreflects the effect of initiating treat-ment with oral semaglutide comparedwith initiating treatment with placebo,both potentially followed by discontin-uation of trial product and/or additionof or switch to another glucose-loweringdrug.

The trial product estimand evaluatesthe treatment effect for all randomizedpatients under the assumption that allpatients remained on trial product for theentire planned duration of the trial anddid not use rescue medication. This es-timand aims at reflecting the effect oforal semaglutide comparedwith placebowithout the confounding effect of rescuemedication. The statistical analysis thatwas applied to estimate this estimand issimilar to how many phase 3a diabetestrials have previously been evaluated,and results from such analyses are cur-rently included in many product labels(prescribing information, U.S., and sum-mary of product characteristics [SmPC],European Union) for glucose-loweringdrugs (e.g., Ozempic SmPC) (14).

Trial product discontinuation and ini-tiation of rescue medication are ac-counted for by the treatment policystrategy for the treatment policy estimand

and by the hypothetical strategy for thetrial product estimand as defined in draftICH E9 (R1) (13). Further details on theestimands can be found in SupplementaryAppendix 2.

Patient PopulationAdult patients with type 2 diabetes wereeligible if they had HbA1c in the range of7.0–9.5% (53–80 mmol/mol) with man-agement only by diet and exercise. Keyexclusion criteria included treatment withany antidiabetes medication within90 days before screening, proliferativeretinopathy or maculopathy requiringacute treatment, personal or familyhistory of medullary thyroid carcinomaor multiple endocrine neoplasia syn-drome type 2, estimated glomerularfiltration rate ,60 mL/min/1.73 m2,or a history of pancreatitis. See Supple-mentary Table 1 for more details oneligibility criteria.

Drug AdministrationPatients were randomized 1:1:1:1 toreceive 3, 7, or 14 mg oral semaglutideor placebo. All patients randomized tooral semaglutide initiated treatmentwith 3 mg once daily with dose escala-tions every 4 weeks until the randomizedmaintenance dose was achieved. Therewas a 5-week follow-up period after the26-week treatment period (Supplemen-tary Fig. 1).

Since food intake can decrease thebioavailability of semaglutide adminis-tered in the oral formulation (15), pa-tients were instructed to administer trialproduct in the morning in a fasting state,with up to half a glass of water (;120 mLor 4 fluid ounces), and wait at least 30 minbefore the first meal of the day and/ortaking other oral medication.

Rescue medication criteria for persis-tent hyperglycemia were confirmedfasting blood glucose.240 mg/dL (13.3mmol/L) from weeks 8213 or .200mg/dL (11.1 mmol/L) from week 14 on-ward. Rescuemedication was prescribedat the investigator’s discretion accordingto American Diabetes Association andEuropean Association for the Study ofDiabetes guidelines (2) (excluding GLP-1receptor agonists, dipeptidyl peptidase 4inhibitors, and amylin analogs). Patientscontinued in the trial after receivingrescue medication and also if discontin-uing trial product and receiving otherglucose-lowering medications.

care.diabetesjournals.org Aroda and Associates 1725

Study End Points and AssessmentsThe primary end point was change inHbA1c from baseline to week 26. Theconfirmatory secondary end point waschange from baseline to week 26 in bodyweight. Supportive secondary end pointsincluded changes in measures of glucosecontrol (including fasting plasma glucose,C-peptide, insulin, proinsulin, glucagon,self-monitored blood glucose [SMBG]profile, and achievement of an HbA1ctarget of ,7% [53 mmol/mol] or#6.5% [48mmol/mol]) andachievementof weight loss of at least 5% or 10%, aswell as C-reactive protein and fasting lipidlevelsdall from baseline to week 26.Prespecified composite end points in-cluded the following: 1) HbA1c ,7%(53 mmol/mol) without severe (16) orblood glucose–confirmed (,56 mg/dL[3.1 mmol/L]) symptomatic hypoglyce-mia and noweight gain, and 2) at least anabsolute reduction in HbA1c of 1% (11mmol/mol) and body weight loss of 3%or more. Blood samples were drawn atbaseline and 4, 8, 14, 20, and 26 weeksand analyzed at a central laboratory toassess HbA1c and fasting plasma glucose(all visits) and other efficacy parameters(baseline and week 26 only). Patientswere provided with a blood glucosemeter to perform a 7-point SMBG profileat baseline and week 26 and to confirmhypoglycemic symptoms.Safety end points were number of

adverse events and number of severeor blood glucose–confirmed symptom-atic hypoglycemic episodes until week31. Other safety measurements includedchanges in vital signs and laboratoryvariables. A treatment-blinded indepen-dent external adjudication committee(EAC) validated prespecified categoriesof adverse events (including deaths,cardiovascular events, malignant neo-plasms, acute kidney injury, acute pan-creatitis, and lactic acidosis).

Statistical AnalysisThe primary end point and the confirma-tory secondary end point were planned tobe tested for superiority of oral semaglu-tide 3 mg, 7 mg, and 14 mg versusplacebo, with a sample size calculation(n = 704) to ensure a power of at least90% to jointly confirm HbA1c superiorityof oral semaglutide versus placebo ateach dose level.The confirmation of efficacy of oral

semaglutide on change in HbA1c and in

body weight both from baseline to week26 was based on a weighted Bonferroniclosed-testing strategy (17) to control theoverall type 1 error for the hypothesesevaluated by the treatment policy esti-mand (see Supplementary Appendix 3for details of statistical considerations).The treatment policy was controlled formultiplicity to claim superiority, and allother P values are descriptive.

The treatment policy estimand wasestimated by a pattern mixture modelusing multiple imputation to handle miss-ing week-26 data for both confirmatoryend points. Data collected at week 26 irre-spective of premature discontinuation oftrial product and initiation of rescue med-ication were included in the statisticalanalysis. Imputation was done withingroups defined by trial product and treat-ment status at week 26. Both the impu-tation and the analysis were based onANCOVA models. The results were com-bined by use of Rubin’s rules (18).

The trial product estimand was esti-mated by a mixed model for repeatedmeasurements (MMRM) that used datacollected prior to premature trial productdiscontinuation or initiation of rescuemedication from all randomized patients.

Further details on the statistical anal-yses can be found in the SupplementaryAppendix 3

All analyses were performed usingSAS, version 9.4M2.

Data AvailabilityData will be shared with bona fide re-searchers submitting a research proposalapproved by the independent reviewboard. Access request proposals canbe found at novonordisk-trials.com. Datawill be made available after researchcompletion, approval of the product,and product use in the European Unionand U.S. Individual participant data willbe shared in data sets in a deidentified/anonymized format using a specializedSAS data platform.

RESULTS

Patient Disposition and BaselineCharacteristicsA total of 1,006 patients were screenedand 703 patients were randomized(Supplementary Fig. 2). All randomizedpatients were exposed to trial productand included in the full and safety anal-ysis sets. Forty randomized patients did

not complete the trial: 6 (3.4%) withoral semaglutide 3 mg, 14 (8.0%) withoral semaglutide 7 mg, 12 (6.9%)with oral semaglutide 14 mg, and8 (4.5%) with placebo (SupplementaryFig. 2). Baseline demographics and dis-ease characteristics were similar be-tween treatment groups (Table 1).Approximately 50% of randomized pa-tients were female, and mean age was55 years, diabetes duration 3.5 years,BMI 31.8 kg/m2, and HbA1c 8.0%[64 mmol/mol].

In total, 46 (6.5%) patients receivedrescue medication, predominantly in theplacebo group: 27 (15.2%) with placeboand 13 (7.4%), 4 (2.3%), and 2 (1.1%)withoral semaglutide 3, 7, and 14 mg, re-spectively (Supplementary Table 2). Ad-ditional glucose-lowering medication(rescuemedication or the use of glucose-lowering medication for patients dis-continuing trial product but remainingin the trial) was received by 16 (9.1%),8 (4.6%), and 7 (4.0%) with oral semaglu-tide 3, 7, and 14 mg, respectively, and35 (19.7%) with placebo (SupplementaryTable 2).

Glycemic ControlAll three doses of oral semaglutide re-sulted in clinically meaningful and supe-rior reductions in HbA1c compared withplacebo for the treatment policy esti-mand (regardless of rescue medicationuse and trial product discontinuation)and statistically significant reductionsfor the trial product estimand (on treat-ment without the use of rescue med-ication) (Fig. 1). Placebo-adjustedestimated treatment differences atweek 26 for oral semaglutide 3, 7, and14mg, respectively, were as follows (P,0.001 for all): 20.6% (95% CI 20.8 to20.4) (–6 mmol/mol [95% CI –9 to –4]),20.9% (21.1 to 20.6) (–9 mmol/mol[–12 to –7]), and 21.1% (21.3 to 20.9)(–12 mmol/mol [–15 to –9]) for thetreatment policy estimand and 20.7%(20.9 to20.5) (–7mmol/mol [–10 to –5]),21.2% (21.5 to 21.0) (–14 mmol/mol[–16 to –11]), and 21.4% (21.7 to 21.2)(–16 mmol/mol [–18 to –13]) for thetrial product estimand.

The observed proportion of patientsachieving the HbA1c targets (,7.0% [53mmol/mol] and #6.5% [48 mmol/mol])were greater with oral semaglutide com-pared with placebo. The odds of achi-eving each target were statistically

1726 Oral Semaglutide Monotherapy in Type 2 Diabetes Diabetes Care Volume 42, September 2019

significantly greater with oral semaglu-tide than with placebo (P, 0.001 for alldoses) (Table 2). Oral semaglutide alsoreduced fasting plasma glucose signifi-cantly more than placebo (P, 0.001 forthe trial product estimand) (Table 2).

Body WeightOral semaglutide (14 mg only) providedsuperior reductions in body weight com-pared with placebo when evaluated bythe treatment policy estimand. Accord-ing to the trial product estimand, oralsemaglutide (7 and 14 mg) providedstatistically significant reductions inbody weight compared with placebo(Fig. 1). Placebo-adjusted estimatedtreatment differences at week 26 fororal semaglutide 3, 7, and 14 mg, re-spectively, were20.1 kg (95% CI20.9 to0.8) (P = 0.87),20.9 kg (21.9 to 0.1) (P =0.09), and 22.3 kg (23.1 to 21.5) (P ,0.001) for the treatment policy estimandand20.2 kg (21.0 to0.6) (P=0.71),21.0kg (21.8 to20.2) (P = 0.01), and22.6 kg(23.4 to 21.8) (P , 0.001) for the trialproduct estimand. Significantly morepatients achieved body weight lossof at least 5% with oral semaglutide at7 mg and 14 mg compared with placebo(Table 2).

Other OutcomesThe observed proportion of patients whoachieved the triple composite end pointof HbA1c ,7% (53 mmol/mol) without

severe or blood glucose–confirmed symp-tomatic hypoglycemia or weight gain washigher with oral semaglutide (all doses)versus placebo (Table 2). The observedproportion of patients who achievedthe composite end point of an HbA1creduction of 1% (11 mmol/mol) or moreand body weight loss of 3% or more wasalso higher with oral semaglutide versusplacebo (trial product estimand; Table 2).Results for fasting lipid levels and variousparameters of glucose metabolism areincluded in Supplementary Table 3.

SafetyOverall, the incidence of adverse eventsand serious adverse events was similarfor oral semaglutide compared with pla-cebo. The most frequent adverse eventswere nausea and diarrhea (Table 3). Nau-sea was reported by a low proportion ofpatients across groups (5.1% to 16%)(Table 3 and Supplementary Fig. 3), andevents were generally mild to moderateand transient. The majority of adverseevents weremild tomoderate in severity(Table 3). More patients prematurelydiscontinued trial product due to adverseevents with oral semaglutide 7 and14 mg, and these were predominantlygastrointestinal disorders (Table 3 andSupplementary Table 4). No deaths oc-curred while on trial product (Table 3 andSupplementary Table 5). One patientassigned to the oral semaglutide14 mg group died due to cardiogenic

shock on trial day 138, 42 days after trialproduct discontinuation.

The proportion of subjects with at leastone severe or blood glucose–confirmedsymptomatic hypoglycemic episodeevent was low (5 [2.9%], 2 [1.1%], and1 [0.6%] patients with oral semaglutide 3,7, and 14 mg, respectively, and 1 [0.6%]with placebo) (Table 3), and only onesevere hypoglycemic episode (oral sem-aglutide 7 mg) was reported. Diabeticretinopathy–related adverse eventswere also infrequent across groups(1 [0.6%], 6 [3.4%], and 2 [1.1%] patientswith oral semaglutide 3, 7, and 14 mg,respectively, and 3 [1.7%] with placebo)(Supplementary Table 6).

There were significant increases inmean levels of lipase (13% to 34%)with oral semaglutide compared withplacebo (Supplementary Table 7); in-creases greater than three times theupper limit of normal occurred in 1.7%to 3.4% with oral semaglutide and 1.7%with placebo. Therewere no instances ofEAC-confirmed acute pancreatitis; theprevalence of other EAC-confirmedevents is reported in SupplementaryTable 7. At week 26, mean pulse rateincreased significantly with oral semaglu-tide 14 mg (3 bpm; P = 0.003), but notwith 3 or 7 mg, compared with placebo(Supplementary Table 7). There wereno clinically relevant changes in bloodpressure or other safety laboratoryassessments.

Table 1—Baseline characteristics and demographics

Oral semaglutide3 mg (n = 175)

Oral semaglutide7 mg (n = 175)

Oral semaglutide14 mg (n = 175)

Placebo(n = 178)

Total(N = 703)

Men, n (%) 89 (50.9) 93 (53.1) 86 (49.1) 89 (50.0) 357 (50.8)

Age, years 55 6 11 56 6 11 54 6 11 54 6 11 55 6 11

Race, n (%)White 135 (77.1) 131 (74.9) 130 (74.3) 132 (74.2) 528 (75.1)Black or African American 6 (3.4) 11 (6.3) 10 (5.7) 10 (5.6) 37 (5.3)Asian 31 (17.7) 30 (17.1) 29 (16.6) 31 (17.4) 121 (17.2)Other 3 (1.7) 3 (1.7) 6 (3.4) 5 (2.8) 17 (2.4)

Hispanic or Latino ethnicity, n (%) 52 (29.7) 31 (17.7) 46 (26.3) 51 (28.7) 180 (25.6)

Diabetes duration, years 3.8 6 5.3 3.6 6 5.1 3.4 6 4.4 3.4 6 4.6 3.5 6 4.9

Body weight, kg 86.9 6 21.0 89.0 6 21.8 88.1 6 22.1 88.6 6 23.4 88.1 6 22.1

BMI, kg/m2 31.8 6 6.3 31.6 6 6.4 31.7 6 6.6 32.2 6 6.9 31.8 6 6.6

HbA1c, % 7.9 6 0.7 8.0 6 0.6 8.0 6 0.7 7.9 6 0.7 8.0 6 0.7

HbA1c, mmol/mol 63 6 8 64 6 7 64 6 8 63 6 7 63 6 8

Fasting plasma glucose, mg/dL 158 6 42 162 6 42 158 6 39 160 6 39 160 6 41

Fasting plasma glucose, mmol/L 8.78 6 2.35 8.98 6 2.34 8.77 6 2.17 8.88 6 2.16 8.85 6 2.25

Estimated glomerular filtration rate, mL/min/1.73 m2* 99 6 14 95 6 16 97 6 16 100 6 15 98 6 15

Data aremeans6 SD unless otherwise indicated. *Glomerular filtration ratewas estimated by the Chronic Kidney Disease Epidemiology Collaboration(CKD-EPI) formula.

care.diabetesjournals.org Aroda and Associates 1727

Figure 1—Change in HbA1c (primary end point) and body weight (confirmatory secondary end point) from baseline to 26 weeks. Observed absolutemean values (6SEM) for HbA1c by the treatment policy estimand (A) and the trial product estimand (B) and estimatedmean change from baseline forHbA1cby the treatmentpolicyestimand (C) and the trial productestimand(D) atweek26.Observedchange frombaseline inbodyweight (6SEM) for thetreatment policy estimand (E) and trial product estimand (F) andmean estimated change from baseline for the treatment policy estimand (G) and thetrial product estimand (H). Data in the bar charts also show estimated treatment differences (ETDs)with 95%CIs. Treatment policy estimand (C andG):ANCOVA using data irrespective of discontinuation of trial product and initiation of rescue medication. Missing values were imputed by a patternmixture model using multiple imputation. Patterns were defined by use of trial product and rescue medication. Trial product estimand (D and H):MMRM. Data collected after discontinuation of trial product and initiation of rescue medication are excluded.

1728 Oral Semaglutide Monotherapy in Type 2 Diabetes Diabetes Care Volume 42, September 2019

Table

2—Se

condary

endpoints

atweek26

Treatmen

tpolicy

estimand

Trialproduct

estimand

Oralsem

aglutid

e3mg

(n=175)

Oralsem

aglutid

e7mg

(n=175)

Oralsem

aglutid

e14

mg

(n=175)

Placebo

(n=178)

Oralsem

aglutid

e3mg

(n=175)

Oralsem

aglutid

e7mg

(n=175)

Oralsem

aglutid

e14

mg

(n=175)

Placebo

(n=178)

%ach

ievingHbA1c,7%

(53mmol/m

ol)

55.168.8

76.931.0

59.171.9

80.333.8

OR(95%

CI)vs.

placeb

o3.09

(1.91–4.99)

5.79(3.50

–9.59)8.36

(4.86–14.41)

d3.37

(2.05–5.55)

8.65(5.04

–14.83)13.35

(7.49–23.83)

d

Pvalu

e,0.001

,0.001

,0.001

d,0.001

,0.001

,0.001

d

%ach

ievingHbA1c#6.5%

(48mmol/m

ol)

35.947.5

63.817.9

38.950.0

68.021.1

OR(95%

CI)vs.

placeb

o2.83

(1.66–4.83)

5.10(2.97

–8.76)9.06

(5.20–15.78)

d2.86

(1.65–4.96)

6.30(3.60

–11.02)12.06

(6.75–21.55)

d

Pvalu

e,0.001

,0.001

,0.001

d,0.001

,0.001

,0.001

d

%ach

ievingbodyweigh

tloss

$5%

19.626.9

41.314.9

21.328.7

44.315.7

OR(95%

CI)vs.

placeb

o1.30

(0.73–2.33)

2.05(1.16

–3.63)3.74

(2.18–6.41)

d1.27

(0.70–2.31)

1.92(1.08

–3.42)4.17

(2.38–7.29)

d

Pvalu

e0.37

0.01,0.001

d0.43

0.03,0.001

d

%ach

ievingcomposite:

HbA1c,7%

(53mmol/m

ol)with

out

hypoglycem

ia*andnoweigh

tgain

37.156.9

68.823.2

41.659.6

72.827.1

OR(95%

CI)vs.

placeb

o1.98

(1.21–3.24)

4.49(2.74

–7.36)7.13

(4.28–11.89)

d2.20

(1.33–3.64)

5.29(3.17

–8.83)10.08

(5.87–17.32)

d

Pvalu

e0.007

,0.001

,0.001

d0.002

,0.001

,0.001

d

%ach

ievingcomposite:

HbA1cred

uctio

n$1%

(11mmol/m

ol)andbody

weigh

tloss

$3%

18.036.9

50.610.7

20.139.0

54.411.3

OR(95%

CI)vs.

placeb

o1.71

(0.90–3.26)

4.51(2.47

–8.22)7.96

(4.40–14.42)

d2.11

(1.07–4.13)

5.90(3.12

–11.17)11.66

(6.15–22.11)

d

Pvalu

e0.10

,0.001

,0.001

d0.03

,0.001

,0.001

d

Fastingplasm

aglu

cose,

mg/d

LEstim

atedmean

143.4131.7

126.7156.3

147.0132.6

122.8163.5

Mean

change

from

baselin

e216.2

227.9

232.9

23.2

212.5

227.0

236.7

4.0Estim

atedtreatm

entdifferen

cevs.

placeb

o(95%

CI)

212.9

(–21.4to

–4.5)224.6

(–35.1to

–14.2)229.6

(–38.3to

–21.0)d

216.5

(–24.2to

–8.8)230.9

(–38.7to

–23.2)240.7

(–48.5to

–33.0)d

Pvalu

e0.003

,0.001

,0.001

d,0.001

,0.001

,0.001

d

7-pointSM

BGmean

,mg/d

LEstim

atedmean

153.2147.8

143.2175.9

148.8141.9

138.4174.5

Mean

change

from

baselin

e230.1

235.5

240.1

27.5

230.9

237.8

241.3

25.2

Estimated

treatmen

tdifferen

cevs.

placeb

o(95%

CI)

222.7

(–31.0to

–14.4)228.1

(–37.4to

–18.7)232.6

(–41.8to

–23.5)d

225.7

(–33.5to

–17.9)232.6

(–40.4to

–24.8)236.1

(–43.9to

–28.3)d

Pvalu

e,0.001

,0.001

,0.001

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care.diabetesjournals.org Aroda and Associates 1729

CONCLUSIONSOral semaglutide represents the first oralGLP-1 receptor agonist to be studied inphase 3 clinical trials for the treatment oftype 2 diabetes. In the Peptide Innova-tion for Early Diabetes Treatment 1(PIONEER 1) trial, the superiority of allthree doses of oral semaglutide givenonce daily for 26 weeks in reducing HbA1cwas confirmed versus placebo. The high-est dose of oral semaglutide studied(14 mg daily) resulted in a mean reduc-tion of 1.5%, from a baseline HbA1c of8.0% (64 mmol/mol) to a final HbA1c of6.5% (47 mmol/mol), and a body weightreduction of 4.1 kg, with 80% of patientsachieving an HbA1c target of ,7%(53 mmol/mol) (trial product estimand).These data are comparable with thoseobserved with subcutaneous semaglu-tide in a similar population in the SUS-TAIN 1 trial (19). Similar to the phase2 trial of oral semaglutide (7), dose-dependent weight loss was observed,with a statistically significant effect of

oral semaglutide on body weight versusplacebo seen at higher doses (trial prod-uct estimand). The findings from thecurrent study are also consistent withthe dose-dependent reductions frombaseline in HbA1c and body weight ob-served in the PIONEER 3 trial, which com-pared oral semaglutide with sitagliptinin adult patients with type 2 diabetesfor up to 78 weeks (20). Notably, thepatients included in PIONEER 3 had moreadvanced diabetes than those in PIONEER1ddiabetes was of longer duration atbaseline (8.6 vs. 3.5 years, respectively)and uncontrolled with metformin aloneor with sulfonylurea at trial entry (20).

The safety profile of oral semaglutidewas generally consistent with that re-ported for subcutaneous semaglutide (19)and the GLP-1 receptor agonist class(21–25). As expected, the most frequentadverse events were gastrointestinal, inparticular mild-to-moderate nausea. Asfewer nausea events were observedwith initiation of oral semaglutide at lower

doses in the phase 2 study (7), a doseescalation was used in the present trialto help mitigate adverse gastrointestinaleffects. Consequently, the proportion ofpatients reporting gastrointestinal eventsand the number of trial product discon-tinuations due to adverse events wereboth low. Similarly, and consistent withtheGLP-1 receptor agonist class, PIONEER3 also identified gastrointestinal adverseevents, including transient nausea, as themost common adverse events reportedby patients using oral semaglutide (20).

The present trial has several consid-erations that may influence the interpre-tation and generalizability of the data.Our trial enrolled patients whose diabe-tes was being managed only with dietand exercise at trial entry, and the meanduration of diabetes was only 3.5 years.Also, oral semaglutide was given as first-line monotherapy, while metformin isusually recommended as first-line phar-macotherapy in the management oftype 2 diabetes (1,2). However, the study

Table 3—On-treatment adverse events

Oral semaglutide3 mg (n = 175)

Oral semaglutide7 mg (n = 175)

Oral semaglutide14 mg (n = 175)

Placebo(n = 178)

Any adverse event 101 (57.7) 93 (53.1) 99 (56.6) 99 (55.6)

SeveritySevere 8 (4.6) 1 (0.6) 3 (1.7) 5 (2.8)Moderate 40 (22.9) 29 (16.6) 34 (19.4) 47 (26.4)Mild 89 (50.9) 84 (48.0) 81 (46.3) 81 (45.5)

Severe or blood glucose–confirmed symptomatichypoglycemic episode*†‡ 5 (2.9) 2 (1.1) 1 (0.6) 1 (0.6)

Severe hypoglycemic episodes*† 0 1 (0.6) 0 0

Most frequent adverse events.5% in any group (preferredterm)

Nausea 14 (8.0) 9 (5.1) 28 (16.0) 10 (5.6)Diarrhea 15 (8.6) 9 (5.1) 9 (5.1) 4 (2.2)Vomiting 5 (2.9) 8 (4.6) 12 (6.9) 4 (2.2)Nasopharyngitis 10 (5.7) 11 (6.3) 3 (1.7) 6 (3.4)Influenza 9 (5.1) 5 (2.9) 4 (2.3) 2 (1.1)Headache 6 (3.4) 10 (5.7) 9 (5.1) 9 (5.1)Decreased appetite 2 (1.1) 3 (1.7) 9 (5.1) 1 (0.6)

Serious adverse events 5 (2.9) 3 (1.7) 2 (1.1) 8 (4.5)

Adverse events leading to premature trial productdiscontinuation 4 (2.3) 7 (4.0) 13 (7.4) 4 (2.2)

Adverse events leading to premature trial productdiscontinuation (.3% in any system organ class)§

Gastrointestinal disorders 3 (1.7) 4 (2.3) 9 (5.1) 1 (0.6)

Deaths 0 0 0| 0

Data are n (%). SI conversion factor: to convert glucose to mmol/L, multiply by 0.055494. “On-treatment”: the period when the patient is consideredtreated with trial product. *Hypoglycemic episodes were reported on a form separate from that used for adverse events. †Severe hypoglycemiawas defined according to the American Diabetes Association classification (16) (requiring assistance of another person to actively administercarbohydrateor glucagonor takeother correctiveactions). Therewasone caseof severenocturnal hypoglycemia,whichoccurred in apatient in theoralsemaglutide 7 mg group. ‡Blood glucose confirmation of symptomatic hypoglycemia was based on a blood glucose value,56 mg/dL with symptomsconsistent with hypoglycemia. §There were no more than n = 3 (1.7%) adverse events leading to premature trial product discontinuation by any onepreferred term in any treatment group. |One patient died (cardiogenic shock with onset 42 days after discontinuing treatment due to other adverseevents [decreased appetite and weight loss]).

1730 Oral Semaglutide Monotherapy in Type 2 Diabetes Diabetes Care Volume 42, September 2019

of oral semaglutide as monotherapy, asrequired by regulatory agencies, allows aclearer clinical interpretation of its effi-cacy and safety. Longer-duration trialsare needed to determine the durability ofthe effect of oral semaglutide; such trialsare part of the PIONEER program andinclude testing versus active compara-tors and also examining the efficacy andsafetyof oral semaglutide in combinationwith other glucose-lowering medica-tions, including metformin. At present,the efficacy and safety of oral semaglu-tide compared with sitagliptin have beenreported in patients with type 2 diabetesuncontrolled with metformin, alone orwith sulfonylureas, in thePIONEER3 trial,whichdemonstrated significantly greaterHbA1c reductions for the oral semaglu-tide 7 and 14 mg once-daily doses com-pared with sitagliptin (20).Thedesignof thepresent trial included

estimands, as recommended by recentregulatory guidelines (13), to addressdifferent scientific questions of interestand to prespecify how intercurrentevents and missing data were to behandled. The treatment policy estimand,which evaluates effect regardless of ad-herence to randomized treatment, maybe relevant for understanding overallpopulation-level effects, accounting fortreatment effect, risks, adherence, andthe addition of “rescue”medication. Thisis complemented by the trial productestimand, which here estimates treat-ment effect for those who remain ontreatment without rescuemedication, tosupport clinical decision-making by de-scribing theanticipated treatment effect.A numerically greater HbA1c reductionwas observed with placebo for the treat-ment policy estimand comparedwith thetrial product estimand,which is likely dueto the inclusion of patients receivingrescue medication. However, in general,efficacy results were broadly consistentwhether based on the treatment policyor trial product estimand, likely reflectiveof a high proportion of patients com-pleting the trial with the vast majoritycompleting on treatment (12).

ConclusionPIONEER 1 demonstrates the efficacyand safety of the novel oral GLP-1 re-ceptor agonist, semaglutide, in patientswith type 2 diabetes. Oral semaglutideachieved clinically meaningful and supe-rior glucose lowering (all dose levels) and

weight loss (14 mg dose) when usedas monotherapy in patients with type 2diabetes. Treatment with oral semaglu-tide was well tolerated, with a safetyand tolerability profile consistent with theGLP-1 receptor agonist class. Ongoingadditional studies in the PIONEER pro-gram will further define its effect whenused in combination with other glucose-lowering therapies and in other popula-tions (e.g., in thosewithhighcardiovascularrisk or renal impairment) of interest.

Acknowledgments. Emisphere Technologies isacknowledged for providing a license to EligenTechnology, the SNAC component of oral sem-aglutide. The authors thank the patients partici-pating in this trial, the investigators, all trial sitestaff, and all Novo Nordisk A/S employees in-volved in the trial. The authors also thank HelleLynggaard (Novo Nordisk A/S) for her contribu-tion to developing the manuscript, Brian BekkerHansen of Novo Nordisk for critically reviewingthe manuscript, and Graham Allcock and EmmaMarshman (Spirit Medical CommunicationsGroup Ltd.) for medical writing and editorialassistance.Duality of Interest. This trial was funded byNovo Nordisk A/S. Novo Nordisk A/S designedthe trial, monitored sites, and collected andanalyzed the data. Editorial support was fundedby Novo Nordisk A/S and provided by indepen-dent medical writers under the guidance of theauthors. V.R.A. reports receiving consultancyfees fromAdocia, AstraZeneca, BD,NovoNordiskA/S, Sanofi, and Zafgen and research grantsupport (to institution) from AstraZeneca/Bristol-Myers Squibb (BMS), Calibra, Eisai, Janssen,Novo Nordisk A/S, Sanofi, and Theracos. J.R.reports serving on scientific advisory boardsand receiving honoraria or consulting feesfrom Eli Lilly, Novo Nordisk A/S, Sanofi, Janssen,Boehringer Ingelheim, and Intarcia Therapeuticsand receiving grants/research support fromMerck, Pfizer, Sanofi, Novo Nordisk A/S, BMS,Eli Lilly, GlaxoSmithKline, AstraZeneca, Janssen,Genentech, Boehringer Ingelheim, Intarcia Ther-apeutics, and Lexicon. Y.T. reports receivinghonoraria for serving on advisory boards forMerck Sharp & Dohme (MSD), Boehringer In-gelheim, Mitsubishi Tanabe Pharma, DaiichiSankyo, Novo Nordisk A/S, Eli Lilly, Sanofi,Astellas Pharma, AstraZeneca, and Teijin; receivingspeakers fees from MSD, Ono Pharmaceutical Co.Ltd., Boehringer Ingelheim, Takeda, MitsubishiTanabe Pharma, Daiichi Sankyo, Sanwa KagakuKenkyusho, Novo Nordisk A/S, Eli Lilly, Sanofi,Sumitomo Dainippon Pharma, Shionogi, BayerYakuhin, Astellas Pharma, and AstraZeneca; andresearch support from MSD, Ono PharmaceuticalCo. Ltd., Boehringer Ingelheim, Novartis, Takeda,Daiichi Sankyo, Sanwa Kagaku Kenkyusho, NovoNordiskA/S, Eli Lilly, Sanofi, SumitomoDainipponPharma, Shionogi, Astellas Pharma, and Astra-Zeneca. Y.A. reports receiving personal fees fromNovo Nordisk A/S. E.C.M.V. reports receivingresearch honoraria from Novo Nordisk A/S asPrincipal Investigator in the PIONEER 1 trial.

O.K.J. reports being an employee and stock-holder of Novo Nordisk A/S. E.C. reports beingan employee and stockholder of Novo NordiskA/S. C.L.H. reports being an employee of NovoNordisk A/S. M.H. reports receiving consultancyfees from Novo Nordisk A/S, Eli Lilly, Sanofi,AstraZeneca, and Novatin; grants from Eli Lilly,BMS, and AstraZeneca; and lecture or other feesfrom Novo Nordisk A/S, Eli Lilly, Novartis, Sanofi,Johnson & Johnson, AstraZeneca, Novatin, Med-tronic, and Mundipharma.Author Contributions. V.R.A. and M.H. servedas global signatory investigators on the study.V.R.A., J.R., Y.T., Y.A., N.M.L., E.C.M.V., O.K.J.,E.C., C.L.H., and M.H. were responsible for theacquisition, analysis, or interpretation of dataand drafting of or critical revision of the man-uscript for important intellectual content.O.K.J. was responsible for the statistical analysis.E.C. and C.L.H. were involved in the concept anddesign of the study. V.R.A. and C.L.H. are theguarantors of this work and, as such, had fullaccess to all the data in the study and takeresponsibility for the integrity of the data andthe accuracy of the data analysis.Prior Presentation. Parts of this study werepresented in abstract form at the 78th ScientificSessions of the American Diabetes Association,Orlando, FL, 22–26 June 2018, and at the 54thAnnual Meeting of the European Association forthe Study of Diabetes, Berlin, Germany, 1–5October 2018.

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1732 Oral Semaglutide Monotherapy in Type 2 Diabetes Diabetes Care Volume 42, September 2019