GLP-1 Agonists for the Treatment of Type 2 Diabetes - Episode 9
John B. Buse, MD, PhD: The 1 fly in the ointment with regard to this story of GLP-1 [glucagon-like peptide-1] receptor agonists and cardiovascular disease is the fact that in the LEADER trial, SUSTAIN 6 trial, the EXSCEL [exenatide study of cardiovascular event lowering] trial, and the topline result from the dulaglutide trial that hasn’t been published yet, it seems that there’s evidence for benefit in patients with clinical cardiovascular disease, generally patients who’ve had a heart attack, a stroke, or peripheral vascular disease that’s been revascularized, or where there’s greater than 50% lesions. So for a broad swath of people with atherosclerotic cardiovascular disease, there has been benefit.
But in those patients who didn’t have clinical cardiovascular disease who were recruited in these studies—generally older patients with risk factors—we’ve not shown any hint of benefit with regard to cardiovascular outcome. The standard story is that it’s because those populations were at lower risk, so there were fewer events, and we just didn’t have the power to demonstrate the benefit. That said, it’s been a consistent finding across 3 trials, for sure, with the fourth one—if you read between the line in the press release—suggesting that’s true as well.
So it’s a bit of a conundrum why we haven’t shown any benefit in that setting. The ADA/EASD [American Diabetes Association and European Association for the Study of Diabetes] guidelines are quite clear. If patients have clinical cardiovascular disease, using a GLP-1 receptor agonist is recommended. And the same story is true for SGLT2 [sodium-glucose cotransporter-2] inhibitors. It’s a good idea to prevent cardiovascular events. But if people don’t have clinical cardiovascular disease, there really isn’t benefit for preventing cardiovascular disease; or primary prevention is something for which we don’t have proof of a role with a GLP-1 receptor agonist or an SGLT2 inhibitor.
John Anderson, MD: As I go forward, and I’m looking at my patients with type 2 diabetes, again, it’s about individualizing therapy. If these patients don’t have cardiovascular disease, or I think there’s sort of a lower risk for cardiovascular disease, I don’t have to think about that when I’m making a decision about medical therapy.
However, after diet and lifestyle, metformin is still the No 1 recommended agent. The No 1 next recommend agent, or the second class of agents, or if you can’t tolerate metformin, which many people can’t, is the GLP-1 receptor agonist. And behind that are the SGLT2 inhibitors. I think this is where the field is going. I think it’s looking at how much efficacy you need. We know the GLP-1 receptor agonist class is the most potent of all the classes out there. Is there cardiovascular disease? Is there chronic kidney disease? Is there heart failure? And that’s what the ADA and EASD have now said. You have to think about these individual factors. So for this woman, as I said before, not only does she need pretty potent glycemic lowering, but she’s had a cardiac event.
If I can get her down to goal with a GLP-1 receptor agonist and, at the same time, reduce her cardiovascular risk while doing so, then that is exactly what I’m going to pick for her. If, however, she had come in with kidney disease, or if she’d come in with heart failure where the SGLT2 class might be a preferred agent, that’s where I would be going. And there are 2 agents now preferred for cardiovascular risk reduction in the SGLT2 class.
Vanita Aroda, MD: What is our experience using these agents in patients who have established cardiovascular disease? What I’ve seen most directly is that patients really appreciate the education and the potential for improving their long-term outcomes. When you talk to patients about what’s important for them, it’s important for them to get to goal and for them to not have adverse effects. But a lot of times, patients want to see that they are doing what’s best for them in the long run, and that they’ll be there and with high-quality health spans and a good quality of living so that they can be there for their kids, and their grandkids, etc, etc. But what patients like to see is that when we’re giving them a new medication, we’re not just thinking about their short-term effect and what’s in the number but also what we’re doing for their overall health.
So in diabetes, and especially in what we’re seeing now with GLP-receptor agonists, we’re able to treat not just the glucose, not just the number, but the patient as a whole.
Transcript edited for clarity.