Semaglutide Takes Successful Formula Further

On December 5, 2017, the FDA approved semaglutide (Ozempic, Novo Nordisk), a once-weekly 0.5 mg injection or 1 mg as an adjunct glycemic control therapy, for adults with type 2 diabetes (T2D). The approval was an example of strengthening a strength—marking the advancement of a formula that has already demonstrated success in more than 1 way.

The glucagonlike peptide 1 (GLP-1) receptor agonist is a similar, longer-acting formula to that of liraglutide, another successful therapy from Novo Nordisk that was recently approved for its second indication of lowering cardiovascular risk.

Eliot Brinton, MD, FAHA, FNLA, president of the Utah Lipid Center in Salt Lake City, Utah, told MD Magazine^Ò that the GLP-1 receptor agonist class is a “very interesting class for diabetes.” Brinton noted the cardiovascular outcome benefits of semaglutide and liraglutide, which are not always a given in drugs that treat glycemia.

Semaglutide was backed with a 16-0 vote (with 1 abstention) in favor of approval by the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee in October 2017.

It was approved based on results from the phase 3a clinical trial program SUSTAIN, consisting of 8 separate trials including 8000 adults with T2D and a 2-year cardiovascular outcomes trial that tested the drug’s safety in adults with T2D at high risk of cardiovascular events. The drug showed clinically meaningful and statistically significant reductions in glycated hemoglobin (A1C) versus placebo, sitagliptin, and exenatide extended-release.

Exenatide was considered a good choice for comparison by Brinton, especially since it shares the once-per-week dosing regimen. Exenatide also showed benefit for cardiovascular outcomes in trials, although that benefit is considered controversial because the trial was a test of superiority.

“Really our question here is, Was this that short of reaching statistical significance?” Brinton said. “The statisticians are going to say, ‘There’s no such thing as benefit with this agent.’ I think the clinicians among us will say, ‘This is probably a class effect, at least to the effect of these 3 agents.’”

He added, “It’s a very exciting time to be treating diabetes, as we’re now better empowered to address the question of how we not only reduce glucose and keep that under control but how we also reduce cardiovascular disease, which is the number one cause of both death and disability in patients with type 2 diabetes.”

In SUSTAIN 7, semaglutide was compared with dulaglutide (Trulicity) in low (0.5 mg semaglutide vs 0.75 mg dulaglutide) and high (1.0 semaglutide vs 1.5 mg dulaglutide) doses.

Dulaglutide, Brinton said, was another good choice for comparison based on the available data and its use clinically. However, investigators are still waiting for the cardiovascular outcomes data.

“It’s a little hard to know whether it will have a benefit or not, given [that] our results so far are mixed,” Brinton said.

Semaglutide cut the A1C of patients by 1.5% compared with 1.1% with dulaglutide at the low dose and 1.8% compared with 1.4% at the high dose.

In the semaglutide low-dose arm, 69% of patients met the ≤7% A1C target goal compared with 52% in the dulaglutide low-dose arm. At the higher dose, 79% of patients met the goal with semaglutide compared with 68% with dulaglutide.

“We have a very interesting class of agents for diabetes, and that’s this GLP-1 receptor agonist class,” Brinton said. “We have some recent data for liraglutide—a very, very interesting study, the LEADER study, with very good data showing a reduction of cardiovascular events that is statistically and, I think, clinically significant.”

Liraglutide, approved for that second indication in August 2017, was shown to reduce the risk of major adverse cardiovascular events, such as nonfatal stroke, nonfatal myocardial infarction, and cardiovascular death, by 13% in the LEADER trial. Results also showed a 22% reduction in cardiovascular morbidity, a 15% reduction in any morbidity, and a 22% reduction in diabetic kidney disease.

In August 2017, Steven Nissen, MD, chairman of Cardiovascular Medicine at the Cleveland Clinic, expressed concern to MD Magazine^Ò about diabetes as an “epidemic” that has its most important consequences in the cardiovascular realm.

“By some estimates, as [many] as 60% to 70% of [patients with diabetes] will die of heart disease,” Nissen said. “Having drugs now that help to control [both] the blood sugar [and] also the cardiovascular consequences of diabetes is a very big deal.”

“We have these 2 agents with some very promising, recent data showing clear benefit for cardiovascular outcomes,” Brinton said. “Everybody is aware of the fact that this is not a given. When we have a drug that treats glycemia, the question is, Does it also reduce cardiovascular disease? And the quick answer is that a majority of recent trials have failed to show cardiovascular benefit. So, the fact [that] we have data from these 2 trials with these 2 agents for cardiovascular disease reduction is very helpful.”

The drug class’s additional benefits in weight loss and glucose control have “created a lot of excitement in the field,” Brinton said. There’s motivation to prescribe the inhibitors with other agents to treat cardiovascular events in patients with T2D.

Semaglutide is indicated as an adjunct to diet and exercise and is suitable for once-weekly dosing at any time of day, according to the FDA. It will be launched in the United States in the first quarter of 2018, according to Novo Nordisk, and is currently under review by the European Medicines Agency and Japan’s Pharmaceuticals and Medical Devices Agency.

“We have some very exciting movement here [with] this class of drugs, which has a lot of appeal because of weight loss, very nice glucose control, and some other benefits,” Brinton said. “We now see cardiovascular intervention, and this has created a lot of excitement in the field because as we treat a patient with diabetes, we have 12 different classes of drugs that can lower glucose levels. And to find good evidence with 2 or 3 different agents in that class that actually show cardiovascular event reduction [is] very exciting and, I think, very motivating for us to prescribe these drugs [and] to use them along with other agents that also show benefit in cardiovascular disease or may not show, as the case may be.”