Will Oral Semaglutide PIONEER the Way to Lower Cardiovascular Risk?

Author(s)
Sally Earl, PharmD, BCPS
Megan Supple, PharmD, BCACP

Reviewed By
Kristin Rieser, PharmD, BCACP
Elizabeth A. Cook, PharmD, BCACP

Citation
Husain M, Birkenfeld A, Donsmark M, et al. Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes (PIONEER 6). N Engl J Med 2019; 381: 841-51.

The Problem

 

Until recently, glucagon-like-peptide-1 (GLP-1) receptor agonists were only available as injectable products. Some clinicians and patients are reluctant to use injectable agents because they require additional patient education and can be intimidating.  If a GLP-1 receptor agonist were available in an oral dose form, it would be welcomed treatment option. But would the cardiovascular safety and benefits of oral GLP-1 receptor agonists be better, similar, or worse than their injectable siblings?  Over 65% of patients with diabetes over the age of 65 die of cardiovascular disease; therefore, it is vital to identify therapies that can improve cardiovascular outcomes, not just lower blood glucose.¹

 

What’s Known

 

Six GLP-1 receptor agonists are currently available in the United States, all of which are available as subcutaneous injections. Semaglutide is the first in its class to be available in an oral dosage form. On September 20, 2019, oral semaglutide was FDA approved under the brand name Rybelsus.²

 

Since 2008, antidiabetic medications have been required to been required to demonstrate cardiovascular safety after negative cardiovascular outcomes were associated with the use of rosiglitazone.³ Over the past 5 years, multiple medications have shown not only cardiovascular safety, but some have cardiovascular benefits.  Medications with positive CVOT (cardiovascular outcome trials) include liraglutide, semaglutide, dulaglutide, and albiglutide, and as well as the oral sodium-glucose cotransporter 2 (SGLT2) inhibitors empagliflozin, canagliflozin, and dapagliflozin.  See Table 1.

 

Table 1: Summary of Cardiovascular Outcomes Trials

Trial Name (study drug)	Overall Study Outcome	Primary Composite MACE Adjusted HR (95% CI)
ELIXA4 (lixisenatide)	CV neutral	1.02 (0.89–1.17) Noninferiority met
EXSCEL5 (exenatide)	CV neutral	0.91 (0.83−1.00) Noninferiority met
LEADER6 (liraglutide)	CV benefit	0.87 (0.78–0.97) Superiority met
SUSTAIN-67 (semaglutide)	CV benefit	0.74 (0.58–0.95) Superiority met
REWIND8 (dulaglutide)	CV benefit	0.88 (0.79–0.99) Superiority met
HARMONY Outcomes9 (albiglutide)	CV benefit	0.78 (0.68–0.90) Superiority met
EMPA-REG Outcomes10 (empagliflozin)	CV benefit	0.86 (0.74-0.99) Superiority met
CANVAS Program11 (canagliflozin)	CV benefit	0.86 (0.75-0.97) Superiority met
DECLARE-TIMI 5812 (dapagliflozin)	CV neutral	0.93 (0.84-1.03) Noninferiority met
VERTIS CV (ertugliflozin)	Results pending	Results pending

 

 

The American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) released a consensus report in 2018 with updates for second line medication therapy recommendations after metformin in patients with type 2 diabetes. Second line therapy recommendations include utilizing a GLP-1 receptor agonist or SGLT2 inhibitor  with proven CVD benefit in patients with atherosclerotic cardiovascular disease (ASCVD).¹³

 

What’s New

 

The PIONEER 6 trial evaluated the cardiovascular safety of oral semaglutide in patients with type 2 diabetes.  PIONEER 6 was an international, event-driven, randomized, double-blinded trial designed to rule out an increase in cardiovascular risk with oral semaglutide.  This phase 3 trial, sponsored by Novo Nordisk, included patients who were at least 50 years old and had established atherosclerotic cardiovascular disease or chronic kidney disease, or were at least 60 years old and had cardiovascular risk factors,  including microalbuminuria or proteinuria, hypertension and left ventricular hypertrophy, left ventricular systolic or diastolic dysfunction, or ankle-brachial index <0.9.  Exclusion criteria included use of an injectable GLP-1 receptor agonist, DDP4 inhibitor, or the amylinomimetic, pramlintide, within 90 days of screening; NYHA class IV heart failure; planned revascularization or MI, stroke/TIA, hospitalization for unstable angina within 60 days; GFR<30 mL/min/1.73m² or dialysis, or retinopathy or maculopathy.  Patients received oral semaglutide initiated at 3mg daily and titrated to a target dose of 14mg/day or matching placebo.  The primary outcome was the time to first occurrence of a major adverse cardiovascular event (MACE), defined as a composite of death from cardiovascular causes, nonfatal MI, or nonfatal stroke. 

 

A total of 3183 patients were enrolled and followed for a median of about 16 months.  Baseline characteristics were similar between the two groups.  The average age was 66 years, men out-numbered women 2 to 1, average duration of diabetes was about 15 years and mean baseline A1c was 8.1%.  Approximately 85% of the patients had established cardiovascular disease or CKD at the time of study enrollment. Most patients were taking metformin (77.4%) or insulin (60.6%), with a smaller percentage on sulfonylureas (32.3%) or SGLT2 inhibitors (9.6%). By the end of the trial, 82% of the patients in the semaglutide group were receiving the 14mg target dose. 

 

The primary outcome occurred in 3.8% of oral semaglutide patients versus 4.8% of patients receiving placebo (HR 0.7, CI 0.57-1.11, p<0.001) confirming non-inferiority to placebo but not superiority (p=0.17).  However, the composite outcome was driven by a significant reduction in the number of deaths from cardiovascular causes (HR 0.49, CI 0.27-0.92).  Similarly, there was a significant reduction in all-cause mortality (1.4% vs 2.8%; HR = 0.51, CI 0.31-0.84).  There was no statistical difference between oral semaglutide and placebo related to death from any cause, nonfatal MI, nonfatal stroke, unstable angina resulting in hospitalization or heart failure hospitalizations. Improvements in glycemic control (A1c = -1.0% vs -0.3%) and weight loss (-4.2 kg vs. -0.8kg) were significant greater in the oral semaglutide group compared to placebo.

 

Serious adverse events were numerically higher in the placebo group but a significantly higher number of patients discontinued semaglutide, most often due to gastrointestinal complaints.  Diabetic retinopathy occurred in 7.1% of the semaglutide group versus 6.3% in the placebo group.  No unexpected serious adverse events were reported.

 

Our Critical Appraisal

 

The PIONEER 6 trial was a well-designed multinational, randomized, placebo-controlled, double-blind trial. It was powered appropriately to detect an excess in cardiovascular risk associated with semaglutide. Furthermore, PIONEER 6 was well designed to address key safety endpoints. In particular, the incidence of diabetic retinopathy was monitored after higher rates were seen with the injectable semaglutide in a previous study. Although a slightly higher incidence of diabetic retinopathy was noted with oral semaglutide in this study, most cases were nonproliferative and over 75% did not result in new treatment. Finally, the efficacy and safety profiles of oral semaglutide were consistent with those of injectable semaglutide. This occurred despite higher initiation rates of SGLT2 inhibitor therapy in the placebo arm that may have narrowed the difference in the primary outcome observed in the two groups. This reinforces semaglutide as a safe and effective, first-in-class oral option for GLP-1 receptor agonist therapy.

 

The mean follow-up in PIONEER 6 was only 1.3 years, which was significantly shorter than other GLP-1 receptor agonist outcome trials; patients receiving subcutaneous semaglutide were followed for 2.1 years in SUSTAIN-6 and patients receiving liraglutide were followed for 3.8 years in the LEADER trial. Fewer patients were also enrolled in PIONEER 6 than other GLP-1 receptor agonist trials.  Although the non-inferiority of oral semaglutide was confirmed and resulted in a lower event rate in the primary outcome (3.8% versus 4.8% for placebo), this was driven by lower rates of death. A longer trial duration or larger sample size could have led to higher event rates, which might have yielded statistically significant reductions in nonfatal MI, stroke, or hospitalization due to unstable angina or heart failure. But, at this point, we don’t know with certainty if oral semaglutide will reduce non-fatal events or hospitalizations.  The biggest confounder in this study is the use of SGLT2 inhibitors. Significantly more patients were started on SGLT2 inhibitor therapy in the placebo group than in the oral semaglutide group after randomization, and this may have narrowed the differences observed in the two groups. Finally, patients with planned coronary or peripheral revascularization or recent ASCVD events within 2 months prior to enrollment were excluded, limiting the generalizability of these findings to these patient populations.

 

The Bottom Line

 

The PIONEER 6 trial confirms the cardiovascular safety of semaglutide, the first oral GLP-1 receptor agonist.  Despite fewer events in PIONEER 6, the hazard ratios were similar to those seen in SUSTAIN 6, which suggest the two dosage forms have similar cardiovascular benefits. Oral semaglutide is an option for patients with type 2 diabetes who value the therapeutic benefits and cardiovascular safety associated with a GLP-1 receptor agonist but have an aversion to injections.

 

The Key Points

• ADA guidelines recommend second line treatment after metformin to include either a GLP-1 receptor agonist or SGLT2 inhibitor with known CVD benefits in patients with ASCVD.
• Similar to injectable semaglutide, oral semaglutide is safe and prevents major cardiovascular deaths.  Some endpoints remain inconclusive and a longer study duration is needed.
• Oral semaglutide is the only GLP-1 receptor agonist available in an oral dosage form. This formulation is an effective option to lower A1c and promote weight loss for patients (and clinicians) who’d prefer an oral formulation.

 

FINAL NOTE:  This program will be available for recertification credit through the American Pharmacists Association (APhA) Ambulatory Care Review and Recertification Program.  To learn more, visit https://www.pharmacist.com/ambulatory-care-review-and-recertification-activities.