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GLP-1 receptor agonists a ‘key building block’ for improving cardiovascular health
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CHICAGO — GLP-1 receptor agonists are a medication class that has exhibited many benefits, especially in the cardiovascular realm, since being introduced, and more recent evidence has only solidified this notion, but the mechanisms behind their success are still difficult to pin down, according to a speaker at the Cardiometabolic Health Congress.
“We’ve had decades of GLP-1 biology,” Daniel J. Drucker, MD, a professor of medicine at the Lunenfeld Tanenbaum Research Institute of Mt. Sinai Hospital and the University of Toronto, said during a presentation. “The overall profile of the GLP-1 receptor agonists is sufficient to make them a key building block as we build the molecules of the future to make them even better for our patients.”
Currently, the list of GLP-1 receptor agonists that have been introduced is lengthy and includes exenatide (Byetta, AstraZeneca), liraglutide (Victoza, Novo Nordisk), dulaglutide (Trulicity, Eli Lilly) and semaglutide (Ozempic, Novo Nordisk), among others, according to Drucker.
“There’s lots of these drugs now available and unlike the DPP-IV inhibitors, which are more similar than they are different in their ultimate pharmacodynamic properties, these drugs are all different,” Drucker said. “That’s annoying if you’re a busy clinician and you just want to learn one or two drugs to use regularly because there’s lots of them coming. It also behooves us to understand these differences, particularly if we want to make patients better.”
While DPP-IV inhibitors “are much easier to use in the primary care setting,” that doesn’t necessarily mean they are the best options, especially when it comes to CV outcomes, Drucker said.
“As we often describe the relationship between cardiovascular disease, obesity and diabetes, the common soil that underlies these disorders in many patients is inflammation,” Drucker said. “While glucose control is very well understood ... the inflammation story is not very well understood and it’s highly complex.”
Benefits of GLP - 1 receptor agonists
Drucker noted that despite the many options that exist for GLP-1 receptor agonists, there is a consistent reduction across many CV outcomes, including major adverse CV events, CV death, fatal or nonfatal stroke and even all-cause mortality.
“The best endpoint that engenders the least debate and requires the least adjudication is death,” Drucker said. “That’s why all-cause mortality is a really important endpoint, because if you reduce major adverse CV events but you have increased cancer or increased suicide or other issues, you’re not really producing clinical benefit.”
Drucker said that while he is not the biggest fan of comparing trials due to the “enormous differences” in design and methods, he noted that the fact that the majority of GLP-1 receptor agonist trials have produced very similar results is promising.
“Given the amazing biological complexity and trial heterogeneity, the fact that we’re getting a tremendous consistency I think is amazing and pretty reassuring for those of us who may have doubted the actions of the GLP-1 receptor agonists,” Drucker said.
Drucker said, however, that for all of their benefits, GLP-1 receptor agonists fall short in some areas, particularly when it comes to hospitalization for heart failure and renal outcomes, which are more effectively confronted by SGLT2 inhibitors.
“I would be cautious about using these drugs in someone who had markedly reduced ejection fraction, class IV heart failure or a history of hospitalization for heart failure,” Drucker said. “The person who’s struggling with heart failure, who’s going in and out of hospital with heart failure, I believe should not be treated with the GLP-1 receptor agonist.”
However, he said, failure to demonstrate benefit in certain areas doesn’t mean GLP-1 receptor agonists are necessarily dangerous.
“People are not getting worse. There’s no harm you’re going to see with these drugs,” Drucker said.
Identifying the means of action
The challenge that remains with GLP-1 receptor agonists is parsing together their mechanisms, according to Drucker. Research in both animal and human models have provided theories.
For example, Drucker noted that with albiglutide (Tanzeum, GlaxoSmithKline), major adverse CV event risk has been shown to be lowered effectively by the medication in the face of no real meaningful changes in glucose management or weight.
“Albiglutide teaches us that it’s absolutely not how the GLP-1 receptor agonists are working because this drug virtually does not substantially alter any of those classic endpoints,” Drucker said. “This was a humbling and highly informative trial result.”
Findings from the REWIND trial on the effect of dulaglutide have also been important, according to Drucker, who noted that the findings indicate that dulaglutide could be used in primary prevention, although more research may be necessary to confirm this notion.
“This has provided us with the opportunity to extend our understanding of how these drugs might work in a much lower-risk population with much better diabetes control, the majority of whom did not have preexisting cardiovascular disease,” Drucker said. “I think this is very instructive because again it teaches us something about the biology that may be independent of just having pre-existing cardiovascular disease ... This trial really advances the understanding of the cardiovascular potential of GLP-1 receptor agonists.”
Going beyond trials, looking at the molecular mechanisms will be critical, even if it isn’t particularly simple, according to Drucker.
“The detection of GLP-1 receptor expression is very difficult. That might sound a little trite but almost all of the papers you see published depicting with antibodies where the receptor is are wrong,” Drucker said, noting this makes it difficult to put together a concrete picture when it comes to how GLP-1 receptor agonists affect difference tissues in the body, including in the heart and kidneys.
As researchers continue to learn about GLP-1 receptor agonists, the future of these medications will evolve.
“There’s going to be a wave of innovation coming based on GLP-1,” Drucker said, noting investigations into tirzepatide (Eli Lilly) and multi-agonists are ongoing. Tirzepatide is of particular interest because it had “the best data for a diabetes drug in Phase 2 that we have ever seen, bar none,” Drucker said. – by Phil Neuffer
Reference:
Drucker DJ. GLP-1 agonists: investigating the pleiotropic effects for cardio renal protection; What are the potential mechanisms involved? Presented at: Cardiometabolic Health Congress; Oct. 10-13, 2019; Chicago.
Disclosures: Drucker reports that he has served as an advisor or consultant for Forkhead Biotherapeutics, Intarcia, Kallyope, Merck Research Laboratories, Novo Nordisk, Pfizer and Sanofi and has received research support from Merck, Novo Nordisk and Shire/Takeda.