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)).
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.
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).
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.
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.
711 adults with type 2 diabetes were randomized to receive oral semaglutide (n=285), subcutaneous liraglutide (n=284), or placebo (n=142).
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%)).
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.
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.
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).
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).
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).
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.
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.
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.
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.
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.
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: 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