Cardiovascular Safety of Oral Semaglutide in Patients with Type 2 Diabetes

By Heather Nelson Cortes, PhD and Kevin C Maki, PhD

Cardiovascular disease (CVD) is the leading cause of mortality in patients with type 2 diabetes (T2D), therefore it is required that all new glucose-lowering therapies demonstrate no increase in cardiovascular risk with treatment.1  Glucagon-like-peptide-1 (GLP-1) receptor agonists have shown cardiovascular safety and in some cases, such as for semaglutide, benefit.2,3  The GLP-1 receptor agonists approved to date are administered subcutaneously, but a new oral semaglutide was recently developed, and the Peptide Innovation for Early Diabetes Treatment (PIONEER) 6 trial was conducted to rule out an excess in cardiovascular risk among patients with T2D treated with this product.4

PIONEER 6 was an event-driven, randomized, double-blind trial in which 3,183 patients with high CVD risk (≥50 y of age with established CVD or chronic kidney disease or ≥60 y of age with CVD risk factors only) were treated with 14 mg/day oral semaglutide or placebo.4  The primary outcome was the first occurrence of a major cardiovascular event (e.g., death from CVD, nonfatal myocardial infarction [MI], nonfatal stroke).

The mean age of the subjects was 66 y.  Subjects that were ≥50 y of age with either CVD or chronic kidney disease accounted for 2,695 (84.7%) of the subjects. The median time in the trial was 15.9 months with 61 of 1591 patients (3.8%) in the semaglutide and 76 of 1592 patients (4.8%) in the placebo group experiencing a major cardiovascular event.  Consistent with previous GLP-1 receptor agonist cardiovascular outcomes trials, this study demonstrated that oral semaglutide was non-inferior to placebo for the primary outcome (hazard ratio [HR] 0.79; 95% confidence interval [CI], 0.57-1.11) thus confirming that there is no excess CVD risk with oral semaglutide treatment.  The results for the individual components of the primary outcome and deaths from any cause are shown in the table below.

Table:  Major CVD outcomes in patients with high CVD risk receiving either oral semaglutide or placebo.

Primary Outcomes

Oral Semaglutide (n = 1591)


 (n = 1592)

HR (95% CI)



                                            n (%)


Death from cardiovascular causes

15 (0.9%)

30 (1.9%)

0.49 (0.27-0.92)

Nonfatal MI

37 (2.3%)

31 (1.9%)

1.18 (0.73-1.90)

Nonfatal stroke

12 (0.8%)

16 (1.0%)

0.74 (0.35-1.57)

Death from any cause

23 (1.4%)

45 (2.8%)

0.51 (0.31-0.84)


Glycated hemoglobin was decreased with semaglutide compared to placebo (mean change from baseline to end of the trial, -1.0 vs. -0.3, respectively).  Body weight was also decreased from baseline to the end of the study by 4.2 kg with semaglutide compared to 0.8 kg with placebo.  Systolic blood pressure was also lower with semaglutide, compared to placebo, and there was a modest lowering of low-density lipoprotein cholesterol and triglycerides with semaglutide.

Comment.  These results showed that oral semaglutide has a similar cardiovascular safety profile to the subcutaneous form of semaglutide, and that the cardiovascular risk profile of oral semaglutide is not inferior to the cardiovascular risk profile of placebo.  It is notable that there were statistically significant reductions in secondary outcomes of cardiovascular and total mortality.  Because some patients may be reluctant to take an injectable medication, an orally administered GLP-1 receptor agonist may be an attractive alternative for patients with T2D.  Additional research is warranted to further investigate potential cardiovascular and mortality benefits of this agent.



  1. American Diabetes Association. Cardiovascular disease and risk management: Standards of Medical Care in Diabetes – 2019. Diabetes Care. 2019;42(Suppl 1):S103-S123.


  1. Bethel MA, Patel RA, Merrill P, et al. Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis. Lancet Diabetes Endocrinol. 2018;6:105-113.


  1. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcome sin patients with type 2 diabetes. N Engl J Med. 2016;375:1834-1844.


  1. Husain M, Birkenfeld AL, Donsmark M, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2019; Epub ahead of print.


Photo by Tbel Abuseridze

Leave a Comment