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Cardiovascular Benefits of Oral GLP-1RA in High-Risk Patients with Type 2 Diabetes

Jul 6, 2019
Editor: David L. Joffe, BSPharm, CDE, FACA

Author: Adam Chalela, B.S. Doctor of Pharmacy Candidate USF College of Pharmacy

Results from the recently published PIONEER trial series demonstrate the overall diabetic benefits of oral semaglutide, a novel GLP-1 receptor agonist. 

Feeling overwhelmed with treatment options may be a common theme for patients with type 2 diabetes when considering add on second and third line therapies with their providers. Many different medication classes exist for patients with type 2 diabetes to achieve glycemic homeostasis and HbA1c values within goal. A newer class of medications called the glucagon like peptide-1 receptor agonists (GLP-1RAs) have gained increasing popularity as they offer substantial HbA1c lowering, body weight reduction, and overall cardiovascular benefits. Historically, GLP-1RAs have been available only as subcutaneous injections; however, the conclusion of recent phase 3 studies shows promising results for the future of the GLP-1RA medication class.


The PIONEER line of clinical trials investigates oral semaglutide, a novel GLP-1RA that is available to be taken as a once daily oral tablet. Announced for the first time at the 79th annual Scientific Sessions of the American Diabetes Association (ADA) were results from the PIONEER 4 and 6 trials. PIONEER 4 compared the safety and efficacy of two GLP-1RAs: oral semaglutide and subcutaneous liraglutide. The results from that study showed that oral semaglutide was non inferior to subcutaneous liraglutide in HbA1c lowering and provided superior body weight reductions.

PIONEER 6 was a multicentered, placebo controlled, double blinded study with an aim to determine the long term cardiovascular benefits of oral semaglutide. The primary endpoint observed in this study was composite incidence of the first occurrence of any cardiovascular death or nonfatal MI or stroke. Secondary endpoints such as time-to-event data and hospitalizations due to unstable angina or heart failure were also observed. Safety endpoints of specific adverse events causing discontinuation of study medication as well as overall adverse event profile were also observed. Analysis of the primary outcome was reported using a stratified Cox proportional hazard model and respective hazard ratios.

Patients were enrolled into the PIONEER 6 study if they were 50 years of age or older and had previous cardiovascular disease or chronic kidney disease (eGFR >30 mL/min/m2) or if they were 60 years of age or older and were at a high risk for cardiovascular disease. Patients with type 2 diabetes who had previously been treated with another GLP-1RA or DPP-4 inhibitor were excluded from this study, as well as patients with severe heart failure or recent cardiovascular event (MI, stroke, or hospitalization) within the past 60 days.

A total of 3183 patients were randomly assigned to take either 14 mg of oral semaglutide daily or placebo. The baseline characteristics of all patients enrolled into the study were generally homogenous between the two treatment arms. A majority (68.4%) of patients enrolled were male and had type 2 diabetes for an average of 14.9 years. Also, patients were an average of 66 years old with a mean body weight of 90.9 kg, BMI of 32.3 kg/m2, HbA1c of 8.2%, and eGFR of 74 mL/min/m2 . A total of 84.7% of all patients within the study had established cardiovascular disease or chronic kidney disease, representing a largely at risk population.

Patients enrolled into this study were on a variety of other medications for comorbid conditions, such as metformin, insulin, or sulfonylureas for glucose control, as well as antihypertensives, lipid-lowering agents, and antiplatelets. A significant portion of patients assigned to receive placebo required intensification of current diabetic medications or initiation of additional therapies compared to those assigned to receive oral semaglutide (7.0% vs 3.1%, respectively).

The primary outcome occurred in a total of 3.8% of patients randomized to receive oral semaglutide and 4.8% of patients randomized to receive placebo, demonstrating statistically significant non-inferiority as add-on diabetes therapy to the current standard of care (HR 0.79, 95% 0.57-1.11) after a median follow-up of 15.9 months. There were significant reductions in HbA1c (-1.0% vs -0.3%) and total body weight (-4.2 kg vs -0.8%) in patients randomized to oral semaglutide when compared to placebo, respectively. Serious adverse events occurred more in the placebo group than the oral semaglutide group (22.5% vs 18.9%, respectively). The results of this study demonstrate that oral semaglutide does not pose extra cardiovascular risks for patients with type 2 diabetes when compared to placebo.


Practice Pearls

  • Results from the PIONEER trial series demonstrate the risks and benefits of oral semaglutide, a novel GLP-1RA
  • Oral semaglutide does not increase the risk of adverse cardiovascular events in high risk patients with type 2 diabetes when compared to placebo
  • Once FDA approved, providers should strongly consider oral semaglutide for patients who require extra glucose control and wish to avoid injectable medications.


References: PIONEER trial series 

Pratley R, Amod A, Hoff ST, et al. Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER4): a randomized, double-blind, phase 3a trial. 2019; [Epub ahead of print]. DOI: 10.1016/S0140-6736(19)31271-1.

Husain M, Birkenfeld AL, Donsmark M, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. NEJM 2019; [Epub ahead of print]. DOI: 10.1056/NEJMoa1901118.


Adam Chalela B.S., PharmD Candidate, USF College of Pharmacy Class of 2020