The PIONEER 6 trial: semaglutide in type 2 diabetic patients does not increase cardiovascular risk

1. Over a median period of almost 16 months, type 2 diabetic (T2DM) patients randomized to oral semaglutide for experienced a similar rate of cardiovascular (CV) events compared to placebo treated patients.

2. Discontinuation of therapy due to gastrointestinal issues occurred more often in the semaglutide group.

Evidence Rating Level: 1 (Excellent)  

Study Rundown: Patients with T2DM experience high rates of CV disease and death due to CV events is a leading cause of mortality. Glucagon-like peptide-1 (GLP-1) receptor agonists such as semaglutide are used to lower glucose levels in T2DM patients. All presently approved GLP-1 receptor agonists are administered subcutaneously, so an oral option may provide convenience and adherence benefits for many patients. The phase 3 Peptide Innovation for Early Diabetes Treatment (PIONEER) 6 trial evaluated oral semaglutide compared to placebo in T2DM patients and showed noninferior rates of major cardiovascular events in the treatment group. Death from any cause or from a CV event occurred less frequently in semaglutide treated patients. More patients in the treatment group discontinued therapy due to gastrointestinal issues.

This study provides strong support for the CV safety with oral use of semaglutide in T2DM patients. Strengths of the study include the randomized design, large trial size, and evaluation of various secondary CV outcomes. The trial is limited by its evaluation of non-CV adverse events.

Click to read the study in NEJM

Relevant Reading: Semaglutide, reduction in glycated haemoglobin and the risk of diabetic retinopathy

In-Depth [randomized controlled trial]: This phase 3, international, randomized, placebo-controlled trial enrolled patients in 2017. Eligible patients had T2DM, 50 years of age or older, had CV or kidney disease, and did not have extensive or high severity CV or kidney disease. Patients were randomized in a 1:1 ratio to receive a target dose of 14mg semaglutide daily (n=1591) or a placebo (n=1592). Patients were instructed on how to take the semaglutide to reduce gastrointestinal symptoms and followed for a median period of 15.9 months. The primary study outcome of a first major CV event occurred in 3.8% of semaglutide patients and 4.8% of placebo patients (hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.57 to 1.11; P<0.001 for noninferiority; P = 0.17 for superiority). For individual components of the composite outcome, treatment patients experienced fewer deaths from CV causes (0.9% vs 1.9%; HR, 0.49; 95% CI, 0.27 to 0.92). Nonfatal myocardial infarction and nonfatal stroke both occurred at similar rates in the treatment and placebo groups. Glycated hemoglobin, systolic blood pressure, and body weight decreased more during the trial in the semaglutide group. Serious adverse events occurred in 18.9% and 22.5% of semaglutide and placebo patients, respectfully. Patients discontinued semaglutide at a higher rate compared to placebo, mostly due to a higher rate of gastrointestinal adverse events (6.8% vs 1.6% of treatment and placebo patients, respectfully). Severe hypoglycemia occurred in 1.4% of treated and 0.8% of placebo patients.

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