Presented by:
Vanita R. Aroda, MD
University of Washington, Seattle, WA, USA Richard E. Pratley, MD
University Hospital Aachen, Aachen, Germany Stephen C. Bain, MA, MD, FRCP
University of Texas Southwestern Medical Center, Dallas, TX, USA Mansoor Husain, MD, FRCPC
Würzburg University Clinic, Würzburg, Germany John B. Buse, MD, PhD
Monash University, Melbourne, Australia Vivian Fonseca, MD
Tulane University, New Orleans, LA, USA
The PIONEER clinical development program consists of 8 clinical trials that compared the efficacy and safety of semaglutide to placebo, a SGLT2 inhibitor, another GLP1-RA, a DPP-4 inhibitor, and as add-on to insulin.
The program also investigated the efficacy and safety of semaglutide in patients with moderate renal impairment and its cardiovascular safety.
Semaglutide is the first tablet formulation of a glucagon-like peptide-1 receptor agonist (GLP1-RA). The PIONEER series of trials evaluated its efficacy and safety in several patient populations and vs. several other classes of therapies.
PIONEER 1: monotherapy vs. placebo.
PIONEER 2: vs. empagliflozin.
PIONEER 3: vs. sitagliptin.
PIONEER 4: vs. liraglutide.
PIONEER 5: moderate renal impairment.
PIONEER 6: cardiovascular outcomes trial.
PIONEER 7: flexible dose adjustment vs. sitagliptin.
Semaglutide significantly reduced HbA1c (placebo-adjusted treatment differences at week 26: treatment policy estimand (i.e., the treatment effect in the target population regardless of trial product discontinuation or use of rescue medication) –0.6% (3 mg), –0.9% (7 mg), –1.1% (14 mg); P <0.001 for all).
Semaglutide reduced body weight (treatment policy estimand: –0.1 kg (3 mg), –0.9 kg (7 mg), –2.3 kg (14 mg; P <0.001)).
Conclusion
Oral semaglutide monotherapy demonstrated superior and clinically relevant improvements in HbA1c (all doses) and body weight loss (14 mg dose) vs. placebo, with a safety profile consistent with other GLP-1 RAs.
To compare the efficacy and safety of oral semaglutide vs. empagliflozin in patients with type 2 diabetes.
52-week, open-label trial.
816 patients randomized to oral semaglutide 14 mg or empagliflozin 25 mg.
Results
HbA1c was reduced by 1.4% at 26 weeks and 1.3% at 52 weeks compared to 0.9% and 0.8% with 25 mg empagliflozin at 26 and 52 weeks, respectively.
The 14 mg dose of oral semaglutide demonstrated weight loss of 4.2 kg at 26 weeks and 4.7 kg at 52 weeks versus 3.8 kg with 25 mg empagliflozin at both 26 weeks and 52 weeks.
The increased weight loss with oral semaglutide was statistically significant compared to empagliflozin at the 52-week time point.
Conclusion
Semaglutide is superior to empagliflozin in reducing HbA1c, with less clear comparative effects on weight loss.
To compare the efficacy and long-term adverse event profiles of oral semaglutide vs. sitagliptin added on to metformin with or without a sulfonylurea in patients with type 2 diabetes.
1864 adults with type 2 diabetes uncontrolled with metformin, with or without a sulfonylurea, were randomized to receive once-daily oral semaglutide, 3 mg (n=466), 7 mg (n=466), or 14 mg (n=465), or sitagliptin, 100 mg (n=467).
Results
Semaglutide, 7 and 14 mg/day, compared with sitagliptin, significantly reduced HbA1c (differences, –0.3% (95% CI –0.4% to –0.1%) and –0.5% (95% CI –0.6% to –0.4%), respectively; P <0.001 for both) and body weight (differences, –1.6 kg (95% CI –2.0 to –1.1 kg) and –2.5 kg (95% CI –3.0 to –2.0 kg), respectively; P <0.001 for both) from baseline to week 26.
Conclusion
Oral semaglutide, 7 mg/day and 14 mg/day, compared with sitagliptin, resulted in significantly greater reductions in HbA1c over 26 weeks, but there was no significant benefit with the 3 mg/day dosage.
To compare the efficacy and long-term adverse event profiles of oral semaglutide with subcutaneous liraglutide and placebo in patients with type 2 diabetes.
711 adults with type 2 diabetes were randomized to receive oral semaglutide (n=285), subcutaneous liraglutide (n=284), or placebo (n=142).
Results
Mean change from baseline in HbA1c at week 26 was –1.2% (SE 0.1) with oral semaglutide, –1.1% (SE 0.1) with subcutaneous liraglutide, and –0.2% (SE 0.1) with placebo.
Oral semaglutide was non-inferior to subcutaneous liraglutide in decreasing HbA1c (estimated treatment difference (ETD) –0.1%, 95% CI –0.3 to 0.0; P <0.0001) and superior to placebo (ETD –1.1%, 95% CI –1.2 to –0.9; P <0.0001) by use of the treatment policy estimand.
Semaglutide resulted in superior weight loss (–4.4 kg (SE 0.2)) compared with liraglutide (–3.1 kg (SE 0.2); ETD –1.2 kg, 95% CI –1.9 to –0.6; P=0.0003) and placebo (–0.5 kg (SE 0.3); ETD –3.8 kg, 95% CI –4.7 to –3.0; P <0.0001) at week 26.
Adverse events were more frequent with oral semaglutide (n=229 (80%)) and subcutaneous liraglutide (n=211 (74%)) than with placebo (n=95 (67%)).
Conclusion
Semaglutide was non-inferior to subcutaneous liraglutide and superior to placebo in decreasing HbA1c, and superior in decreasing body weight compared with both liraglutide and placebo at week 26.
Safety and tolerability of oral semaglutide were similar to subcutaneous liraglutide.
To investigate the efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment.
26-week, randomized, double-blind, trial.
324 patients were assigned to oral semaglutide (n=163) or placebo (n=161).
Renal inclusion criteria was an estimated glomerular filtration rate of 30-59 mL/min/1.73 m2.
Results
Semaglutide was superior to placebo in decreasing HbA1c (estimated mean change of –1.0 percentage point (SE 0.1; –11 mmol/mol (SE 0.8)) vs. –0.2 percentage points (SE 0.1; –2 mmol/mol (SE 0.8)); ETD: –0.8 percentage points, 95% CI –1.0 to –0.6; P <0.0001) and body weight (estimated mean change of –3.4 kg (SE 0.3) vs. –0.9 kg (SE 0.3); ETD, –2.5, 95% CI –3.2 to –1.8; P <0.0001) by the treatment policy estimand.
Safety, including renal safety, was consistent with the GLP-1 RA class.
Conclusion
Semaglutide was effective in patients with type 2 diabetes and moderate renal impairment, potentially providing a new treatment option for this population.
To investigate CV outcomes of once-daily semaglutide in an event-driven, randomized, double-blind, placebo-controlled trial.
CV inclusion criteria were presence of high CV risk (age of ≥50 years with established CV or chronic kidney disease, or age of ≥60 years with CV risk factors only).
3,183 patients were randomly assigned to receive oral semaglutide or placebo.
The primary outcome in a time-to-event analysis was the first occurrence of a major adverse CV event (death from CV causes, nonfatal myocardial infarction, or nonfatal stroke).
Results
Median time in the trial was 15.9 months.
Major adverse CV events occurred in 61 of 1,591 patients (3.8%) in the oral semaglutide group and 76 of 1,592 (4.8%) in the placebo group (HR 0.79; 95% CI, 0.57 to 1.11; P <0.001 for noninferiority).
Results for components of the primary outcome were as follows: death from CV causes 15 of 1,591 patients (0.9%) in the semaglutide group and 30 of 1,592 (1.9%) in the placebo group (HR 0.49; 95% CI, 0.27 to 0.92); nonfatal myocardial infarction, 37 of 1,591 patients (2.3%) and 31 of 1,592 (1.9%), respectively (HR 1.18; 95% CI, 0.73 to 1.90); and nonfatal stroke, 12 of 1,591 patients (0.8%) and 16 of 1,592 (1.0%), respectively (HR 0.74; 95% CI, 0.35 to 1.57).
Conclusion
The CV risk profile of oral semaglutide was not inferior to that of placebo.
504 patients were assigned to oral semaglutide (n=253) or sitagliptin (n=251).
Results
From a mean baseline HbA1c of 8·3% (SD 0.6%; 67 mmol/mol (SD 6.4)), a greater proportion of participants achieved an HbA1c of less than 7% with oral semaglutide than did with sitagliptin (treatment policy estimand: 58% (134 of 230) vs. 25% (60 of 238); and trial product estimand (i.e., the treatment effect in the target population had all patients remained on trial product and did not use rescue medication): 63% (123 of 196) vs. 28% (52 of 184)).
The odds of achieving an HbA1c of less than 7% were significantly higher with semaglutide than sitagliptin (treatment policy estimand: odds ratio (OR) 4.40, 95% CI 2.89-6.70, P <0.0001; and trial product estimand: 5.54, 95% CI 3.54-8.68, P <0.0001).
The odds of decreasing mean body weight from baseline to week 52 were higher with semaglutide than with sitagliptin (estimated mean change in body weight, treatment policy estimand: –2.6 kg (SE 0.3) vs. –0.7 kg (SE 0.2), ETD –1.9 kg, 95% CI –2.6 to –1.2; P <0.0001; and trial product estimand: –2.9 kg (SE 0.3) vs. –0.8 kg (SE 0.3), ETD –2.2 kg, 95% CI –2.9 to -1.5; P <0.0001).
The safety profile was consistent with subcutaneous GLP-1 RAs.
Conclusion
Oral semaglutide, with flexible dose adjustment, based on efficacy and tolerability, provided superior glycemic control and weight loss compared with sitagliptin.
52-week trial investigating the efficacy and safety of 3, 7, and 14 mg oral semaglutide compared with placebo in 731 people with type 2 diabetes treated with insulin and an average duration of diabetes of 15 years.
During the first 26-week treatment period, the total daily insulin dose was not allowed to be increased above baseline followed by a 26-week period where the insulin treatment was adjusted without restrictions.
Results
From a mean baseline of 8.2%, 3, 7, and 14 mg oral semaglutide achieved reductions in HbA1c of 0.6%, 1.0% and 1.4% respectively, compared to no reduction (0.0%) in people treated with placebo, all in addition to insulin, at week 26, and 0.5%, 0.8%, and 1.2% respectively, compared with 0.0% at week 52.
From a mean baseline body weight of 85.9 kg, people treated with 3, 7 and 14 mg semaglutide experienced a weight loss of 1.0 kg, 2.9 kg, and 4.3 kg, respectively, compared to a weight increase of 0.6 kg in people treated with placebo at week 52, all in addition to insulin.
The total insulin dose at week 52 was increased by 2 units/day, reduced by 6 units/day and reduced by 7 units/day for people treated with 3, 7, and 14 mg semaglutide respectively, compared to an increase of 10 units/day for people treated with placebo.
Conclusion
Oral semaglutide improved HbA1c in patients with a long duration of diabetes and already treated with insulin, with the benefit of clinically meaningful weight reduction, and without increasing the risk of hypoglycemia.
Key Messages/Clinical Perspectives
The PIONEER program confirms the efficacy of oral GLP-1 RA technology for reduction of HbA1c.
Oral semaglutide has the potential to replace all injectable GLP-1 RAs.
Pieber TR, Bode B, Mertens A, et al. Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicentre, open-label, randomised, phase 3a trial. Lancet Diabetes Endocrinol. 2019 Jun 6. pii: S2213-8587(19)30194-9.
Rosenstock J, Allison D, Birkenfeld AL, et al. Effect of Additional Oral Semaglutide vs. Sitagliptin on Glycated Hemoglobin in Adults With Type 2 Diabetes Uncontrolled With Metformin Alone or With Sulfonylurea: The PIONEER 3 Randomized Clinical Trial. JAMA. 2019 Mar 23. doi: 10.1001/jama.2019.2942.
VBain SC, Mosenzon O, Arechavaleta R, et al. Cardiovascular safety of oral semaglutide in patients with type 2 diabetes: Rationale, design and patient baseline characteristics for the PIONEER 6 trial. Diabetes ObesMetab. 2019 Mar;21(3):499-508. doi: 10.1111/dom.13553.
Present disclosure: J.B. Buse: Neurimmune, ADOCIA, AstraZeneca, Dance Biopharm, Eli Lilly, MannKind, NovaTarg, Novo Nordisk, Senseonics, vTv Therapeutics, Zafgen, AstraZeneca, National Center for Advancing Translational Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, Novo Nordisk, Sanofi, vTv Therapeutics, Mellitus Health, PhaseBio Pharmaceuticals’, Stability Health. V.R. Aroda: ADOCIA, AstraZeneca, Becton, Dickinson and Company, Novo Nordisk, Sanofi, Zafgen, Merck, Calibra, Eisai, Janssen, Novo Nordisk, Sanofi, Theracos. R.E. Pratley: Sanofi, AstraZeneca, Eli Lilly, GlaxoSmithKline, Janssen, Lexicon, Ligand, Merck Sharp & Dome, Mundipharma, Novo Nordisk, Pfizer, Sanofi, Takeda, Center Americas. S.C. Bain: AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dome, Mylan, NAPP, Novo Nordisk. M. Husain: AstraZeneca, Boehringer Ingelheim, Janssen, Merck, Novo Nordisk. O. Mosenzons: AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dome, Novo Nordisk.
Jose C. Florez, MD, PhD
Chair, ADA Scientific Sessions Meeting Planning Committee
The 79th American Diabetes Association’s Scientific Sessions were held in San Francisco, California from June 7-11, 2019. The meeting was attended by over 15,000 professional attendees from 115 countries, … [ Read all ]
Presented by: Kimberly L. Drews, MD, PhD; Lorraine E. Levy Katz, MD; Petter Bjornstad, MD; Neil H. White, MD; Jeanie B. Tryggestad, MD; Ruth S. Weinstock, MD, PhD; for the TODAY2 Study Group
Presented by: Gilles R. Dagenais, MD; Rafael Diaz, MD; Matthew C. Riddle, MD; Hertzel C. Gerstein, MD, MSc; Helen Colhoun, MD; Jeffrey L. Probstfield, MD; Hertzel C. Gerstein, MD, MSc
Presented by: Vanita R. Aroda, MD; Richard E. Pratley, MD; Stephen C. Bain, MA, MD, FRCP; Mansoor Husain, MD, FRCPC; John B. Buse, MD, PhD; Vivian Fonseca, MD
Presented by: Alison B. Evert, MD; Janice MacLeod, MA, RDN, CDE; William S. Yancy, Jr., MD, MHS; W. Timothy Garvey, MD; Ka Hei Karen Lau, MS, RD, LDN, CDE; Christopher D. Gardner, PhD; Kelly M. Rawlings, MS
OFFICIAL HIGHLIGHTS
中文
Español
Italiano
Australia
Argentina
Brazil
Lebanon
Switzerland