Oral Semaglutide Meets CV Safety Mark, Reduces Events in High-Risk T2D Patients

Oral semaglutide, the first glucagon-like peptide 1 (GLP-1) receptor agonist in a pill, met safety benchmarks and reduced major cardiovascular (CV) events for high-risk patients with type 2 diabetes (T2D) in PIONEER 6, a CV outcomes trial presented Tuesday at the 79th Scientific Sessions of the American Diabetes Association in San Francisco, California.

Oral semaglutide, given in a once-daily 14 mg dose, has been widely anticipated as a means to bring the GLP-1 class to patients reluctant to use injectable drugs and to physicians wary of prescribing them. This class offers more powerful glycemic control and superior weight loss effects than other newer T2D agents.

Novo Nordisk, the maker of both oral semaglutide and the once-weekly injectable formulation, sold as Ozempic, is seeking approval through the priority review process, which could bring news from FDA by September. The company also seeks CV indications for both formulations.

However, PIONEER 6 did not achieve superiority, even though Tuesday’s results show that oral semaglutide reduced first major CV events by 21%, and reduced CV death and all-cause mortality by nearly 50% after a follow-up of 15.9 months. Results simultaneously published in the New England Journal of Medicine note that despite the trial’s shorter duration, the hazard ratio (HR) was similar to SUSTAIN-6, the CV outcomes trial for injectable semaglutide, which “may suggest the cardiovascular effect of semaglutide is independent of the rout of administration.”

Cardiovascular outcomes trials, or CVOTs, were required by the FDA after 2008 to show that newer glucose-lowering therapies did not cause heart attacks, strokes or cardiovascular death. Trials must meet a basic standard of robustness for noninferiority, meaning the drug is safe, and a higher standard for superiority, which means the drug offers a clear benefit. The unexpected benefits of some drugs have prompted some companies to see additional indications from the FDA. SUSTAIN-6 attained the standard for superiority, but this measure was not included in that study’s conclusion.

In commenting on the results during Tuesday’s symposium, Vivian Fonseca, MD, of Tulane University, said of PIONEER 6, “I would have expected the results to be more robust.”

Another GLP-1 receptor agonist sold by Novo Nordisk, liraglutide (Victoza) demonstrated a cardiovascular benefit (superiority) in the LEADER trial in 2016; that trial randomized 9340 patients and lasted 3.8 years. PIONEER 6 had 3183 patients randomized. Liraglutide has since received FDA approval for an indication to reduce the risk of major adverse cardiovascular events.

Primary results for the trial were as follows:

• First major adverse cardiovascular events (non-fatal myocardial infarction, stroke, and cardiovascular death): 61 out of 1591 patients (3.8%) in the oral semaglutide group, compared with 76 out of 1592 (4.8%) in the placebo group (HR, 0.79; 95% CI, 0.57-1.11; P <.001 for noninferiority).
• Death from cardiovascular events: 15 events (0.9%) in the oral semaglutide group, compared with 30 events (1.9%) in the placebo group; (HR 0.49; 95% CI, 0.35-1.57).
• Death from any cause: 23 events (1.4%) in the oral semaglutide group and 45 events (2.8%) in the placebo group (HR 0.51; 95% CI, 0.31-0.84).
• Gastrointestinal adverse events were more common in the oral semaglutide group and were consistent with the GLP-1 class.

The authors note no differences among subgroups, including patients with established CV disease or chronic kidney disease, compared with those who have CV risk factors only. However, they note that after randomization, more patients in the placebo group received treatment with sodium glucose co-transporter 2 (SGLT2) inhibitors, a class with demonstrated CV benefits. They write, that “few patients initiated SGLT2 inhibitors in the current trial,” and that this makes “an influence on the primary outcome unlikely in our view.”

During a briefing on the results, The American Journal of Managed Care^® asked the study’s lead author, Mansoor Husain, MD, how the results would be presented to regulators to achieve a CV indication. Husain said possibly results from both cardiovascular safety trials would be pooled. “That would be my conjecture,” he said.

Indeed, during the presentation, John Buse, MD, PhD, said the combined data from PIONEER 6 and SUSTAIN 6 reach nearly 400 events, with an HR of 0.76 (95% CI 0.62-0.92) to the first major CV event, for a 24% reduction in events.

Reference

Husain M, Birkenfeld AL, Donsmark M et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes [published online June 11, 2019]. N Engl J Med. doi:10.1056/NEJMoa1901118.