Efficacy and Safety of Oral Semaglutide Versus Empagliflozin in Subjects With Type 2 Diabetes Mellitus (PIONEER 2)

This trial is conducted globally. The aim of this trial is to investigate Efficacy and Safety of Oral Semaglutide versus Empagliflozin in Subjects with Type 2 Diabetes Mellitus.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2; Diabetes
• Intervention / Treatment: Drug: semaglutide; Drug: empagliflozin

• Study Type: Interventional
• Enrollment (Actual): 822
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Caba, Argentina, C1417EYG
    • Novo Nordisk Investigational Site
  • Capital Federal, Argentina, 1405
    • Novo Nordisk Investigational Site
  • Córdoba, Argentina, X5006IKK
    • Novo Nordisk Investigational Site
  • Córdoba, Argentina, X5016KEH
    • Novo Nordisk Investigational Site
• Brazil
  • Porto Alegre, Brazil, 90035-170
    • Novo Nordisk Investigational Site
  • Sao Paulo, Brazil, 05437-010
    • Novo Nordisk Investigational Site
  • Sao Paulo
    • São Paulo, Sao Paulo, Brazil, 01228-000
      • Novo Nordisk Investigational Site
• Croatia
  • Karlovac, Croatia, 47000
    • Novo Nordisk Investigational Site
  • Krapinske Toplice, Croatia, 49217
    • Novo Nordisk Investigational Site
  • Pula, Croatia, 52100
    • Novo Nordisk Investigational Site
  • Virovitica, Croatia, 33000
    • Novo Nordisk Investigational Site
  • Zagreb, Croatia, 10 000
    • Novo Nordisk Investigational Site
  • Zagreb, Croatia, 10000
    • Novo Nordisk Investigational Site
• Greece
  • Athens, Greece, 115 25
    • Novo Nordisk Investigational Site
  • Athens, Greece, GR-10552
    • Novo Nordisk Investigational Site
  • Thessaloniki, Greece, GR-54636
    • Novo Nordisk Investigational Site
  • Thessaloniki, Greece, GR-57010
    • Novo Nordisk Investigational Site
  • Thessaloniki, Greece, GR-57001
    • Novo Nordisk Investigational Site
  • Thessaloniki, Greece, GR-54642
    • Novo Nordisk Investigational Site
  • Thessaloniki, Greece, GR-54643
    • Novo Nordisk Investigational Site
• Hungary
  • Budapest, Hungary, 1152
    • Novo Nordisk Investigational Site
  • Budapest, Hungary, 1139
    • Novo Nordisk Investigational Site
  • Cegléd, Hungary, 2700
    • Novo Nordisk Investigational Site
  • Nyíregyhaza, Hungary, 4400
    • Novo Nordisk Investigational Site
  • Salgótarján, Hungary, 3100
    • Novo Nordisk Investigational Site
  • Szekszárd, Hungary, 7100
    • Novo Nordisk Investigational Site
• Italy
  • Bologna, Italy, 40138
    • Novo Nordisk Investigational Site
  • Lucca, Italy, 55100
    • Novo Nordisk Investigational Site
  • Palermo, Italy, 90127
    • Novo Nordisk Investigational Site
  • Roma, Italy, 00161
    • Novo Nordisk Investigational Site
  • Roma, Italy, 00133
    • Novo Nordisk Investigational Site
  • Siena, Italy, 53100
    • Novo Nordisk Investigational Site
• Poland
  • Bialystok, Poland, 15-435
    • Novo Nordisk Investigational Site
  • Lublin, Poland, 20-538
    • Novo Nordisk Investigational Site
  • Pulawy, Poland, 24-100
    • Novo Nordisk Investigational Site
  • Warszawa, Poland, 00-911
    • Novo Nordisk Investigational Site
  • Wroclaw, Poland, 50-127
    • Novo Nordisk Investigational Site
  • Zabrze, Poland, 41-800
    • Novo Nordisk Investigational Site
• Russian Federation
  • Kazan, Russian Federation, 420012
    • Novo Nordisk Investigational Site
  • Moscow, Russian Federation, 117292
    • Novo Nordisk Investigational Site
  • Saint Petersburg, Russian Federation, 194291
    • Novo Nordisk Investigational Site
  • Saint-Petersburg, Russian Federation, 194356
    • Novo Nordisk Investigational Site
  • Saratov, Russian Federation, 410053
    • Novo Nordisk Investigational Site
  • Tumen, Russian Federation, 625023
    • Novo Nordisk Investigational Site
• Serbia
  • Kragujevac, Serbia, 34000
    • Novo Nordisk Investigational Site
  • Nis, Serbia, 18000
    • Novo Nordisk Investigational Site
  • Novi Sad, Serbia, 21000
    • Novo Nordisk Investigational Site
• Spain
  • Almería, Spain, 04001
    • Novo Nordisk Investigational Site
  • Centelles (Barcelona), Spain, 08540
    • Novo Nordisk Investigational Site
  • Hospitalet de Llobregat, Spain, 08907
    • Novo Nordisk Investigational Site
  • La Roca del Vallés, Spain, 08430
    • Novo Nordisk Investigational Site
  • Pozuelo de Alarcon, Spain, 28223
    • Novo Nordisk Investigational Site
  • Sevilla, Spain, 41010
    • Novo Nordisk Investigational Site
  • Sevilla, Spain, 41009
    • Novo Nordisk Investigational Site
  • Valencia, Spain, 46010
    • Novo Nordisk Investigational Site
  • Vic (Barcelona), Spain, 08500
    • Novo Nordisk Investigational Site
• Thailand
  • Bangkok, Thailand, 10400
    • Novo Nordisk Investigational Site
  • Bangkoknoi, Bangkok, Thailand, 10700
    • Novo Nordisk Investigational Site
• United States
  • Alabama
    • Tuscumbia, Alabama, United States, 35674
      • Novo Nordisk Investigational Site
  • California
    • Encino, California, United States, 91436
      • Novo Nordisk Investigational Site
    • La Mesa, California, United States, 91942
      • Novo Nordisk Investigational Site
    • Northridge, California, United States, 91325
      • Novo Nordisk Investigational Site
    • Palm Springs, California, United States, 92262-6972
      • Novo Nordisk Investigational Site
    • Poway, California, United States, 92064
      • Novo Nordisk Investigational Site
    • Riverside, California, United States, 92506
      • Novo Nordisk Investigational Site
    • Spring Valley, California, United States, 91978
      • Novo Nordisk Investigational Site
  • Florida
    • Bradenton, Florida, United States, 34201
      • Novo Nordisk Investigational Site
    • Jacksonville, Florida, United States, 32216
      • Novo Nordisk Investigational Site
    • Jacksonville, Florida, United States, 32256
      • Novo Nordisk Investigational Site
    • Jacksonville, Florida, United States, 32277
      • Novo Nordisk Investigational Site
    • Miami, Florida, United States, 33143
      • Novo Nordisk Investigational Site
    • Miami Lakes, Florida, United States, 33014
      • Novo Nordisk Investigational Site
    • Orlando, Florida, United States, 32801
      • Novo Nordisk Investigational Site
    • Oviedo, Florida, United States, 32765
      • Novo Nordisk Investigational Site
  • Georgia
    • Atlanta, Georgia, United States, 30328
      • Novo Nordisk Investigational Site
    • Perry, Georgia, United States, 31069
      • Novo Nordisk Investigational Site
  • Idaho
    • Meridian, Idaho, United States, 83646
      • Novo Nordisk Investigational Site
  • Illinois
    • Peoria, Illinois, United States, 61603
      • Novo Nordisk Investigational Site
  • Indiana
    • Evansville, Indiana, United States, 47713
      • Novo Nordisk Investigational Site
    • Indianapolis, Indiana, United States, 46254
      • Novo Nordisk Investigational Site
  • Kentucky
    • Lexington, Kentucky, United States, 40503
      • Novo Nordisk Investigational Site
    • Lexington, Kentucky, United States, 40502
      • Novo Nordisk Investigational Site
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70808-4124
      • Novo Nordisk Investigational Site
  • Maryland
    • Rockville, Maryland, United States, 20852
      • Novo Nordisk Investigational Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Novo Nordisk Investigational Site
  • Michigan
    • Buckley, Michigan, United States, 49620
      • Novo Nordisk Investigational Site
    • Kalamazoo, Michigan, United States, 49009
      • Novo Nordisk Investigational Site
  • Montana
    • Butte, Montana, United States, 59701
      • Novo Nordisk Investigational Site
  • New York
    • Albany, New York, United States, 12203
      • Novo Nordisk Investigational Site
    • Northport, New York, United States, 11768
      • Novo Nordisk Investigational Site
  • North Carolina
    • Wilmington, North Carolina, United States, 28401
      • Novo Nordisk Investigational Site
  • Ohio
    • Cincinnati, Ohio, United States, 45245
      • Novo Nordisk Investigational Site
    • Mason, Ohio, United States, 45040-6815
      • Novo Nordisk Investigational Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19140
      • Novo Nordisk Investigational Site
  • South Carolina
    • Greer, South Carolina, United States, 29651
      • Novo Nordisk Investigational Site
  • Tennessee
    • Humboldt, Tennessee, United States, 38343
      • Novo Nordisk Investigational Site
    • Kingsport, Tennessee, United States, 37660
      • Novo Nordisk Investigational Site
  • Texas
    • Arlington, Texas, United States, 76012-4637
      • Novo Nordisk Investigational Site
    • Dallas, Texas, United States, 75230
      • Novo Nordisk Investigational Site
    • Houston, Texas, United States, 77074
      • Novo Nordisk Investigational Site
    • Houston, Texas, United States, 77004
      • Novo Nordisk Investigational Site
    • Katy, Texas, United States, 77450
      • Novo Nordisk Investigational Site
    • San Antonio, Texas, United States, 78209
      • Novo Nordisk Investigational Site
    • San Antonio, Texas, United States, 78258
      • Novo Nordisk Investigational Site
    • San Antonio, Texas, United States, 78228-3419
      • Novo Nordisk Investigational Site
  • Virginia
    • Richmond, Virginia, United States, 23219
      • Novo Nordisk Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Informed consent obtained before any trial-related activities. Trial-related activities are any procedures that are carried out as part of the trial, including activities to determine suitability for the trial
• Male or female, age above or equal to 18 years at the time of signing informed consent
• Diagnosed with type 2 diabetes mellitus at least 90 days prior to day of screening
• HbA1c (glycosylated haemoglobin) of 7.0-10.5 % (53-91 mmol/mol) (both inclusive)
• Stable daily dose of metformin (at least 1500 mg or maximum tolerated dose as documented in the subject medical record) at least 90 days prior to the day of screening

Exclusion Criteria:

• Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing potential and not using an adequate contraceptive method (adequate contraceptive measure as required by local regulation or practice).For certain specific countries: Additional specific requirements apply
• Any disorder, which in the investigator's opinion might jeopardise subject's safety or compliance with the protocol
• Family or personal history of Multiple Endocrine Neoplasia Type 2 or Medullary Thyroid Carcinoma
• History of pancreatitis (acute or chronic)
• History of major surgical procedures involving the stomach potentially affecting absorption of trial product (e.g. subtotal and total gastrectomy, sleeve gastrectomy, gastric bypass surgery)
• Any of the following: myocardial infarction, stroke or hospitalisation for unstable angina or transient ischaemic attack within the past 180 days prior to the day of screening
• Subjects presently classified as being in New York Heart Association Class IV
• Planned coronary, carotid or peripheral artery revascularisation known on the day of screening
• Subjects with ALT (alanine aminotransferase) above 2.5 x upper normal limit
• Renal impairment defined as Estimated Glomerular Filtration Rate below 60 mL/min/1.73 m^2 as per Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI)
• Treatment with any medication for the indication of diabetes or obesity other than stated in the inclusion criteria in a period of 90 days before the day of screening. An exception is short-term insulin treatment for acute illness for a total of below or equal to 14 days
• Proliferative retinopathy or maculopathy requiring acute treatment. Verified by fundus photography or dilated fundoscopy performed within 90 days prior to randomisation
• History or presence of malignant neoplasms within the last 5 years (except basal and squamous cell skin cancer and carcinoma in situ)
• History of diabetic ketoacidosis

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 14 mg oral semaglutide	Drug: semaglutide; Oral administration once-daily.
ACTIVE_COMPARATOR: 25 mg empagliflozin	Drug: empagliflozin; Oral administration once-daily.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in HbA1c	Change from baseline (week 0) in glycosylated haemoglobin (HbA1c) was evaluated at week 26. The endpoint was evaluated based on data from the in-trial observation period which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product. The endpoint was also evaluated based on the data from the on-treatment without rescue medication observation period which was the time period when a participant was on treatment with trial product, excluding any period after initiation of rescue medication.	Week 0, week 26

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Body Weight (Kg)	Change from baseline (week 0) in body weight was evaluated at week 26. The endpoint was evaluated based on data from the in-trial observation period which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product. The endpoint was also evaluated based on the data from the on-treatment without rescue medication observation period which was the time period when a participant was on treatment with trial product, excluding any period after initiation of rescue medication.	Week 0, week 26
Change in HbA1c (%)	Change from baseline (week 0) in HbA1c was evaluated at week 52. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 0, week 52
Change in Body Weight (kg)	Change from baseline (week 0) in body weight was evaluated at week 52. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 0, week 52
Change in Fasting Plasma Glucose	Change from baseline (week 0) in fasting plasma glucose was evaluated at week 26 and week 52. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 0, week 26, week 52
Change in SMPG : Mean of the 7-point Profile	Change from baseline (week 0) in mean of the 7-point self-measured plasma glucose (SMPG) (i.e. before and after breakfast, lunch and dinner, and at bedtime) profile was evaluated at week 26 and week 52. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 0, week 26 and week 52
Change in SMPG : Mean Postprandial Increment Over All Meals	Change from baseline (week 0) in mean postprandial glucose increment was evaluated at week 26 and week 52. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 0, week 26 and week 52
Change in Fasting C-peptide (Ratio to Baseline)	Change from baseline (week 0) in fasting C-peptide (Nanomoles per liter [nmol/L]) at week 26 and week 52 is presented as ratio to baseline. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 0, week 26 and week 52
Change in Fasting Insulin (Ratio to Baseline)	Change from baseline (week 0) in fasting insulin (picomoles per liter [pmol/L]) at week 26 and week 52 is presented as ratio to baseline. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 0, week 26 and week 52
Change in Fasting Pro-insulin (Ratio to Baseline)	Change from baseline (week 0) in fasting pro-insulin (pmol/L) at week 26 and week 52 is presented as ratio to baseline. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 0, week 26 and week 52
Change in Fasting Glucagon (Ratio to Baseline)	Change from baseline (week 0) in fasting glucagon (picograms per milliliter [pg/mL]) at week 26 and week 52 is presented as ratio to baseline. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 0, week 26 and week 52
Change in HOMA-IR (Ratio to Baseline)	Change from baseline (week 0) in homeostatic model assessment index of insulin resistance (HOMA-IR) (%) at week 26 and week 52 is presented as ratio to baseline. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 0, week 26 and week 52
Change in HOMA-B (Ratio to Baseline)	Change from baseline (week 0) in homeostatic model assessment index of beta-cell function (HOMA-B) (%) at week 26 and week 52 is presented as ratio to baseline. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 0, week 26 and week 52
Change in C-reactive Protein (Ratio to Baseline)	Change from baseline (week 0) in C-reactive protein (milligrams per liter [mg/L]) at week 26 and week 52 is presented as ratio to baseline. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 0, week 26 and week 52
Change in Body Weight (%)	Relative change from baseline (week 0) in body weight (kg) was evaluated at week 26 and week 52. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 0, week 26, week 52
Change in Body Mass Index	Change from baseline (week 0) in body mass index (BMI) was evaluated at week 26 and week 52. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 0, week 26, week 52
Change in Waist Circumference	Change from baseline (week 0) in waist circumference was evaluated at week 26 and week 52. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 0, week 26, week 52
Change in Fasting Total Cholesterol (Ratio to Baseline)	Change from baseline (week 0) in fasting total cholesterol (mmol/L) at week 26 and week 52 is presented as ratio to baseline. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 0, week 26 and week 52
Change in Fasting LDL Cholesterol (Ratio to Baseline)	Change from baseline (week 0) in fasting low density lipoprotein (LDL) cholesterol (mmol/L) at week 26 and week 52 is presented as ratio to baseline. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 0, week 26 and week 52
Change in Fasting HDL Cholesterol (Ratio to Baseline)	Change from baseline (week 0) in fasting high density lipoprotein (HDL) cholesterol (mmol/L) at week 26 and week 52 is presented as ratio to baseline. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 0, week 26 and week 52
Change in Fasting VLDL Cholesterol (Ratio to Baseline)	Change from baseline (week 0) in fasting very low density lipoprotein (VLDL) cholesterol (mmol/L) at week 26 and week 52 is presented as ratio to baseline. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 0, week 26 and week 52
Change in Fasting Free Fatty Acids (Ratio to Baseline)	Change from baseline (week 0) in fasting free fatty acids (FFA) (mmol/L) at week 26 and week 52 is presented as ratio to baseline. The results are based on the data from the in-trial observation period. Because of an issue with the handling of the blood samples for FFA, all FFA data are considered invalid for this trial; thus, no conclusion with regards to FFA levels can be made based on the FFA data. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 0, week 26 and week 52
Change in Fasting Triglycerides (Ratio to Baseline)	Change from baseline (week 0) in fasting triglycerides (mmol/L) at week 26 and week 52 is presented as ratio to baseline. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 0, week 26 and week 52
Participants Who Achieve HbA1c <7.0 % (53 mmol/Mol) ADA Target (Yes/no)	Participants who achieved HbA1c <7.0% (53 mmol/mol) (American Diabetes Association (ADA) target) at week 26 and week 52. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 26 and week 52
Participants Who Achieve HbA1c ≤6.5% (48 mmol/Mol), AACE Target (Yes/no)	Participants who achieved HbA1c ≤6.5% (48 mmol/mol) (American Association of Clinical Endocrinologists (AACE) target) at week 26 and week 52. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 26 and week 52
Participants Who Achieve Weight Loss ≥5% (Yes/no)	Participants who achieved weight loss of ≥5% at week 26 and week 52. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 26 and week 52
Participants Who Achieve Weight Loss ≥10% (Yes/no)	Participants who achieved weight loss of ≥10% at week 26 and week 52. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 26 and week 52
Participants Who Achieve HbA1c <7.0 % (53 mmol/Mol) Without Hypoglycaemia (Severe or BG Confirmed Symptomatic Hypoglycaemia) and no Weight Gain (Yes/no)	Participants who achieved HbA1c <7.0% (53 mmol/mol) without severe or blood glucose (BG) confirmed symptomatic hypoglycaemia and without weight gain at week 26 and week 52. Severe or BG-confirmed symptomatic hypoglycaemia: an episode, that is severe according to the ADA classification or BG-confirmed by a plasma glucose value <3.1 mmol/L with symptoms consistent with hypoglycaemia. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 26 and week 52
Participants Who Achieve HbA1c Reduction ≥1% (10.9 mmol/Mol) and Weight Loss ≥3% (Yes/no)	Participants who achieved HbA1c reduction ≥1%-point and weight loss of ≥3% at week 26 and week 52. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 26 and week 52
Time to Additional Anti-diabetic Medication	Presented results are the number of participants who had taken additional anti-diabetic medication anytime during the periods, from week 0 to week 26 and week 0 to week 52. Additional anti-diabetic medication: use of new anti-diabetic medication for more than 21 days with the initiation at or after randomisation (week 0) and before (planned) end-of-treatment (week 26/week 52), and/or intensification of anti-diabetic medication (a more than 20% increase in dose relative to baseline) for more than 21 days with the intensification at or after randomisation and before (planned) end-of-treatment. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Weeks 0-52
Time to Rescue Medication	Presented results are the number of participants who had taken rescue medication anytime during the periods, from week 0 to week 26 and week 0 to week 52. Rescue medication: use of new antidiabetic medication as add-on to trial product and used for more than 21 days with the initiation at or after randomisation (week 0) and before last day on trial product, and/or intensification of anti-diabetic medication (a more than 20% increase in dose relative to baseline for more than 21 days with the intensification at or after randomisation and before last day on trial product. Results are based on the data from the on-treatment without rescue medication observation period. On-treatment without rescue medication observation period: the time period when a participant was on treatment with trial product, excluding any period after initiation of rescue medication.	Weeks 0-52
Number of Treatment-emergent Adverse Events (TEAE)	A treatment-emergent adverse event (TEAE) is defined as an adverse event (AE) with onset in the on-treatment observation period (the time period where participants are considered treated with trial product) and was assessed up to approximately 57 weeks (52-week treatment period plus the 5-week follow-up period).	Weeks 0-57
Change in Amylase (Ratio to Baseline)	Change from baseline (week 0) in amylase (units per liter [U/L]) at week 26 and week 52 is presented as ratio to baseline. Results are based on the data from the on-treatment observation period. On-treatment observation period: the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication.	Week 0, week 26, week 52
Change in Lipase (Ratio to Baseline)	Change from baseline (week 0) in lipase (U/L) at week 26 and week 52 is presented as ratio to baseline. Results are based on the data from the on-treatment observation period. On-treatment observation period: the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication.	Week 0, week 26, week 52
Change in Pulse Rate	Change from baseline (week 0) in pulse rate was evaluated at week 26 and week 52. Results are based on the data from the on-treatment observation period. On-treatment observation period: the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication.	Week 0, week 26, week 52
Change in Blood Pressure (Systolic and Diastolic Blood Pressure)	Change from baseline (week 0) in systolic blood pressure (SBP) and diastolic blood pressure (DBP) was evaluated at week 26 and week 52. Results are based on the data from the on-treatment observation period. On-treatment observation period: the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication.	Week 0, week 26, week 52
Change in ECG	Change from baseline (week 0) in electrocardiogram (ECG) was evaluated at week 26 and week 52. Change from baseline results are presented as shift in findings (normal, abnormal and not clinically significant (NCS), and abnormal and clinically significant (CS)) from week 0 to week 26 and week 52. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 0, week 26, week 52
Change in Physical Examination	The physical examination findings (normal, abnormal NCS and abnormal CS) of the participants at week -2 and week 52 are presented for the following examinations: Cardiovascular system, Nervous system (central and peripheral); Gastrointestinal system, incl. mouth; General appearance; Head (ears, eyes, nose), throat, neck; Lymph node palpation; Musculoskeletal system; Respiratory system; Skin; Thyroid gland. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week -2, week 52
Change in Eye Examination	The eye examination findings (normal, abnormal NCS and abnormal CS) of the participants at baseline (week -2) and week 52 are presented. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week -2, week 52
Occurrence of Anti-semaglutide Binding Antibodies (Yes/no)	This outcome measure is only applicable for the oral semaglutide 14 mg treatment arm. Number of participants who measured with anti-semaglutide binding antibodies anytime during post-baseline visits (week 0 to week 57) are presented. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Weeks 0-57
Occurrence of Anti-semaglutide Neutralising Antibodies (Yes/no)	This outcome measure is only applicable for the oral semaglutide 14 mg treatment arm. Number of participants who measured with anti-semaglutide neutralising antibodies anytime during post-baseline visits (week 0 to week 57) are presented. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Weeks 0-57
Occurrence of Anti-semaglutide Binding Antibodies Cross Reacting With Native GLP-1 (Yes/no)	This outcome measure is only applicable for the oral semaglutide 14 mg treatment arm. Number of participants who measured with anti-semaglutide binding antibodies cross reacting with native glucagon-like peptide-1 (GLP-1) anytime during post-baseline visits (week 0 to week 57) are presented. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Weeks 0-57
Occurrence of Anti-semaglutide Neutralising Antibodies Cross Reacting With Native GLP-1 (Yes/no)	This outcome measure is only applicable for the oral semaglutide 14 mg treatment arm. Number of participants who measured with anti-semaglutide neutralising antibodies cross reacting with native GLP-1 anytime during post-baseline visits (week 0 to week 57) are presented. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Weeks 0-57
Anti-semaglutide Binding Antibody Levels	This outcome measure is only applicable for the oral semaglutide 14 mg treatment arm. It is based on the data from participants who were measured with anti-semaglutide antibodies anytime during post-baseline visits (week 0 to week 57). Results are presented as percentage of bound radioactivity-labelled semaglutide /total added radioactivity-labelled semaglutide (%B/T). The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Weeks 0-57
Number of Treatment-emergent Severe or Blood Glucose-confirmed Symptomatic Hypoglycaemic Episodes	Treatment-emergent hypoglycaemia is an episode with onset in the on-treatment observation period (the time period where participants are considered treated with trial product) and was assessed up to approximately 57 weeks (52-week treatment period plus the 5-week follow-up period). Severe or BG-confirmed symptomatic hypoglycaemia is an episode that is severe according to the American Diabetes Association classification or blood glucose-confirmed by a plasma glucose value <3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia. Results are based on the data from the on-treatment observation period. On-treatment observation period: the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication.	Weeks 0-57
Participants With Treatment-emergent Severe or BG-confirmed Symptomatic Hypoglycaemic Episodes (Yes/no)	Number of participants with treatment-emergent severe or BG-confirmed symptomatic hypoglycaemic episodes was recorded during week 0-57. Results are based on the data from the on-treatment observation period. On-treatment observation period: the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication.	Weeks 0-57
Semaglutide Plasma Concentrations for Population PK Analyses	Semaglutide plasma concentrations were measured after 25 minutes post-dose at week 4, 26 and 52. Results are based on the data from the on-treatment observation period. On-treatment observation period: the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication.	Weeks 0-52
SNAC Plasma Concentrations	This outcome measure is only applicable for the oral semaglutide 14 mg treatment arm. Sodium N-[8-(2-hydroxybenzoyl) amino]caprylate (SNAC) plasma concentrations were measured after 25 and 40 minutes post-dose at week 4, 26 and 52. Results are based on the data from the on-treatment observation period. On-treatment observation period: the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication.	Weeks 0-52
Change in Short Form Health Survey Version 2.0 (SF-36v2™, Acute Version) Health Survey: Scores From the 8 Domains and Summaries of the Physical Component Score (PCS) and the Mental Component Score (MCS)	SF-36 is a 36-item patient-reported survey of patient health that measures the participant's overall health-related quality of life (HRQoL). SF-36v2™ (acute version) questionnaire measured eight domains of functional health and well-being as well as two component summary scores (physical component summary (PCS) and mental component summary (MCS)). The 0-100 scale scores (where higher scores indicated a better HRQoL) from the SF-36 were converted to norm-based scores to enable a direct interpretation in relation to the distribution of the scores in the 2009 U.S. general population. In the metric of norm-based scores, 50 and 10 corresponds to the mean and standard deviation respectively of the 2009 U.S. general population. Change from baseline (week 0) in the domain scores and component summary (PCS and MCS) scores were evaluated at weeks 26 and 52. A positive change score indicates an improvement since baseline. Results are based on the data from the in-trial observation period.	Week 0, week 26, week 52
Change in CoEQ: Scores From the 4 Domains and the 19 Items	Change from baseline (week 0) in Control of Eating Questionnaire (CoEQ) was evaluated at weeks 26 and 52. The CoEQ comprised 19 items to assess the intensity and type of food cravings, as well as subjective sensation of appetite and mood, with the 4 domains: 'craving control' (items 9-12, 19), 'positive mood' (items 5-8), 'craving for savoury' (items 4, 16-18) and 'craving for sweet' (items 3, 13-15). The 19 items were scored on an 11-point graded response scale ranging from 10 to 0, with items relating to each of the 4 domains being averaged to create a final score. A low score in the domains 'craving for sweet and 'craving for savoury' represents a low level of craving; whereas a high score in the domains 'craving control' and 'positive mood' represents good control and a good mood, respectively. Results are based on the data from the in-trial observation period.	Week 0, week 26, week 52

Collaborators and Investigators

• Sponsor: Novo Nordisk A/S

Publications and helpful links

General Publications

• Aroda VR, Bauer R, Christiansen E, Haluzik M, Kallenbach K, Montanya E, Rosenstock J, Meier JJ. Efficacy and safety of oral semaglutide by subgroups of patient characteristics in the PIONEER phase 3 programme. Diabetes Obes Metab. 2022 Jul;24(7):1338-1350. doi: 10.1111/dom.14710. Epub 2022 May 9.
• Thethi TK, Pratley R, Meier JJ. Efficacy, safety and cardiovascular outcomes of once-daily oral semaglutide in patients with type 2 diabetes: The PIONEER programme. Diabetes Obes Metab. 2020 Aug;22(8):1263-1277. doi: 10.1111/dom.14054. Epub 2020 May 13.
• Husain M, Bain SC, Jeppesen OK, Lingvay I, Sorrig R, Treppendahl MB, Vilsboll T. Semaglutide (SUSTAIN and PIONEER) reduces cardiovascular events in type 2 diabetes across varying cardiovascular risk. Diabetes Obes Metab. 2020 Mar;22(3):442-451. doi: 10.1111/dom.13955. Epub 2020 Feb 5.
• Rodbard HW, Rosenstock J, Canani LH, Deerochanawong C, Gumprecht J, Lindberg SO, Lingvay I, Sondergaard AL, Treppendahl MB, Montanya E; PIONEER 2 Investigators. Oral Semaglutide Versus Empagliflozin in Patients With Type 2 Diabetes Uncontrolled on Metformin: The PIONEER 2 Trial. Diabetes Care. 2019 Dec;42(12):2272-2281. doi: 10.2337/dc19-0883. Epub 2019 Sep 17.
• Eliasson B, Ericsson A, Fridhammar A, Nilsson A, Persson S, Chubb B. Long-Term Cost Effectiveness of Oral Semaglutide Versus Empagliflozin and Sitagliptin for the Treatment of Type 2 Diabetes in the Swedish Setting. Pharmacoecon Open. 2022 May;6(3):343-354. doi: 10.1007/s41669-021-00317-z. Epub 2022 Jan 21.
• Mosenzon O, Capehorn MS, De Remigis A, Rasmussen S, Weimers P, Rosenstock J. Impact of semaglutide on high-sensitivity C-reactive protein: exploratory patient-level analyses of SUSTAIN and PIONEER randomized clinical trials. Cardiovasc Diabetol. 2022 Sep 2;21(1):172. doi: 10.1186/s12933-022-01585-7.
• Lingvay I, Capehorn MS, Catarig AM, Johansen P, Lawson J, Sandberg A, Shaw R, Paine A. Efficacy of Once-Weekly Semaglutide vs Empagliflozin Added to Metformin in Type 2 Diabetes: Patient-Level Meta-analysis. J Clin Endocrinol Metab. 2020 Dec 1;105(12):e4593-604. doi: 10.1210/clinem/dgaa577.

Helpful Links

• Clinical Trials at Novo Nordisk

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 10, 2016
• Primary Completion (ACTUAL): August 1, 2017
• Study Completion (ACTUAL): March 8, 2018

Study Registration Dates

• First Submitted: August 8, 2016
• First Submitted That Met QC Criteria: August 8, 2016
• First Posted (ESTIMATE): August 11, 2016

Study Record Updates

• Last Update Posted (ACTUAL): July 20, 2022
• Last Update Submitted That Met QC Criteria: July 11, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Empagliflozin
• Other Study ID Numbers: NN9924-4223; 2015-005209-36 (EUDRACT_NUMBER); U1111-1176-6006 (OTHER: World Health Organization (WHO))