Director, USC Clinical Diabetes Program
Professor of Clinical Medicine
Keck School of Medicine of USC
Los Angeles, California
Anne Peters, MD, has disclosed that she has received consulting fees from Abbott Diabetes Care, Boehringer Ingelheim, Lilly, Livongo, MannKind, Merck, Novo Nordisk, Pendulum, and Sanofi; has received funds for research support from Dexcom and vTv Therapeutics; and has ownership interest in Livongo, Mellitus Health, Omada Health, Pendulum Therapeutics, and Stability Health.
In my practice, I regularly rely on the GLP-1 receptor agonists to help patients with diabetes achieve control of their blood glucose. And when selecting among these GLP-1 receptor agonists for patients who also have established cardiovascular disease (CVD), my choice is first guided by which has an indication for reducing cardiovascular events. We are fortunate to have several GLP-1 receptor agonists with an indication for reducing the risk of major adverse cardiovascular events (MACE): liraglutide, dulaglutide, and injected semaglutide. These indications were authorized based on results from cardiovascular outcomes trials for each agent, giving us confidence that treatment can not only help lower blood glucose levels, but can also protect at-risk patients from serious cardiovascular complications.
In fact, in an online decision support tool developed by a panel consisting of me and 4 other diabetes experts, when presented with a patient with T2D and CVD, the panel was unanimous in choosing one of the 3 GLP-1 receptor agonists indicated for reducing the risk of MACE—either liraglutide, dulaglutide, or semaglutide. None of us chose exenatide for such a patient, likely because it does not have this indication.
Next, I consider ease of administration, which can be subjective depending on patient preference. Among the 3 agents with an indication for reducing the risk of MACE, I give patients the choice and generally they choose dulaglutide or semaglutide because they prefer a once-weekly injection, whereas liraglutide requires daily injections. However, some patients prefer a daily injection because they find the daily reminder encourages them to adhere to lifestyle recommendations.
Ease of Injection
Although the idea of any injection can be a barrier for some practitioners and patients, in my practice I find that injections are easy to implement.
With dulaglutide, the pen is preloaded, simple, and easy to use because patients do not have to install the pen needle.
By contrast, liraglutide and semaglutide are administered with a pen that requires some teaching—patients need to attach the needle before injecting and they must be taught to prime the pen the first time they use it but not thereafter. But an advantage of this pen is that I can dose the liraglutide or semaglutide in “clicks,” which is an off-label approach to reducing the starting dose, and I find it tends to mitigate the gastrointestinal adverse events. I generally start with 4 clicks and increase weekly based on gastrointestinal adverse events.
For patients who strongly prefer to avoid injections, semaglutide is also now available as an oral formulation. Although the oral formulation has not been studied in a cardiovascular outcomes trial and thus does not have an indication for reducing the risk of MACE, I suspect it will have a cardiovascular benefit just like its subcutaneous formulation. If you reach circulating levels of the compound in your body, I believe it should have comparable benefits whether you inject it or ingest it.
Another consideration when choosing treatment is the impact on weight loss. In patients with a compelling need for weight loss, I tend to prefer injected semaglutide because it has the best weight loss and the best A1C lowering properties. Although weight loss is not an indication for using these agents, if that helps patients in an ancillary way, I like that benefit.
An exception would be a patient with very high A1C who may have retinopathy. Data from the cardiovascular outcomes trial for semaglutide showed that retinopathy seems to worsen in patients with preexisting retinopathy, long-standing diabetes, and higher A1C. I suspect those outcomes are due to the rapid fall of glucose levels observed in patients who start on semaglutide. So in those individuals, I would choose dulaglutide or liraglutide (depending on patient preference around dosing interval).
Overall, I think it is important to focus on what benefits antidiabetes agents offer and why we are using them. Ever since the LEADER trial demonstrated cardiovascular benefits with liraglutide use, my thinking has changed—the notion that I can further reduce cardiovascular events in high-risk patients really matters to me. A drug that offers multiple benefits is always better than a drug that offers one. Fortunately, GLP-1 receptor agonists have many benefits, including A1C reduction, cardiovascular risk reduction, and weight loss. That’s pretty great.
How do you choose among GLP-1 receptor agonists for patients with diabetes and established CVD? Answer the polling question and join the discussion by posting a comment below. And for more support on selecting the ideal GLP-1 receptor agonist, I encourage you to visit the online decision support tool, Choosing Among GLP-1 Receptor Agonists for Patients With Type 2 Diabetes, which I developed with my colleagues, Martin J. Abrahamson, MD, FACP; Zachary T. Bloomgarden, MD, MACE; Richard E. Pratley, MD; and Robert S. Zimmerman, MD. In this decision support tool, you can enter the details of your patient and learn how 5 experts would proceed.