EBM Focus articles provide concise summaries of clinical trials most likely to inform clinical practice curated by the DynaMed® editorial team.

Due to the increased risk of cardiovascular disease-related death in patients with type 2 diabetes, new glucose-lowering medications must be shown not to contribute to this risk before they can be considered for use in this patient group. Glucagon-like peptide-1 (GLP-1) receptor agonists such as semaglutide are recommended as second-line glucose-lowering medications for adults with type 2 diabetes and many have been shown to be cardiovascularly safe or beneficial. However, all currently available GLP-1 receptor agonists must be administered subcutaneously, which can reduce patient comfort and adherence. This new oral formulation of semaglutide was previously shown to be effective for glycemic control and weight loss in the Pioneer 5 trial. If it is also safe, it could offer an additional option to those patients who would like to avoid the needle.

The PIONEER 6 trial, a recent double-blind randomized noninferiority trial, examined cardiovascular outcomes following daily treatment with oral semaglutide or placebo in addition to standard care in 3,183 patients with type 2 diabetes aged at least 50 years with cardiovascular or chronic kidney disease (84.7 percent) or aged at least 60 years with cardiovascular risk factors only (15.3 percent). Patients were followed for a median of 15.9 months, with 84.7 percent of patients assigned to oral semaglutide and 90.1 percent of patients assigned to placebo completing the trial. Data were analyzed using an intention-to-treat rather than a per-protocol analysis (typically preferred for a noninferiority trial) because the protocol allowed for dose adjustment (3, 7, or 14 mg per day) and treatment pauses due to adverse events.

The primary outcome was the first occurrence of a major adverse cardiovascular event, including cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. With noninferiority of oral semaglutide defined by a hazard ratio (HR) of 1.8 compared to placebo, 3.8 percent of the semaglutide group experienced a major adverse cardiovascular event compared with 4.8 percent of the placebo group (HR 0.79, 95% CI 0.57-1.11, p < 0.001 for noninferiority, p = 0.17 for superiority). Examining specific adverse cardiovascular events individually, the study found that death from cardiovascular causes occurred in 0.9 percent with semaglutide vs. 1.9 percent with placebo (NNT 100), nonfatal myocardial infarction in 2.3 percent with semaglutide vs. 1.9 percent with placebo, and nonfatal stroke in 0.8 percent with semaglutide vs. 1 percent with placebo. Patients taking semaglutide had lower all-cause mortality compared to patients taking placebo (NNT 72). There were no significant differences between the two groups in unstable angina or heart failure resulting in hospitalization.

What this trial can tell us is that patients with diabetes at high risk of cardiovascular death taking oral semaglutide do not appear to be more likely to die or have cardiovascular complications than patients not taking the drug. Not surprisingly, this trial was sponsored by a pharmaceutical company with a vested interest in getting this new drug approved as quickly as possible. The company had significant influence on all aspects of the trial, including data analysis and writing, leading to a conflict of interest statement almost as long as the article itself. Moreover, many aspects of this trial are designed with event rates in mind, and the lack of per-protocol analysis threatens the validity of these findings.

Finally, since this was a noninferiority trial, we view the reported better mortality outcomes as interesting but unproven. This is not to say that oral semaglutide may not help patients with diabetes live better or longer, we just can’t conclude any of that from this trial’s data. However, given further testing, oral semaglutide may be a viable option for patients with type 2 diabetes seeking to avoid injections. Finally, of note, the FDA approved oral semaglutide on September 20, 2019, so expect to see a lot of marketing soon.

For more information, see the topic Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists in DynaMed.

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