Cardiovascular Outcomes With GLP-1 Receptor Agonists in Type 2 Diabetes

Dennis P. Scanlon, PhD: Another trial, Dr Bloomgarden, is the LEADER trial, which showed a cardiovascular benefit for the GLP-1 (glucagon-like peptide-1) receptor agonist, liraglutide. Can you talk about that trial and tell us what those results were?

Zachary Bloomgarden, MD: LEADER was fascinating, coming as it did, more or less immediately after the EMPA-REG OUTCOME trial. In LEADER, a very potent glucose lowering drug, liraglutide, was given in the same fashion that Dr Inzucchi described—either being added to the mix, or patients were receiving various other treatments. The strategy was a little bit different. The centers were asked to try to achieve good glycemic control in the patients in the control group and the patients in the liraglutide group so that there was an uptitration of non-liraglutide, non—GLP-1 receptor agonist therapies, in the control group. And what was found was kind of different from what was seen in EMPA-REG. The overall MACE (myocardial infarction [MI], stroke, and cardiovascular mortality) was decreased, but it did not show specific significant improvement in any of the individual endpoints.

And, indeed, if I remember correctly, heart failure, I don’t think, was actually impacted, so there was a very different effect. One of the differences is that the drugs that were used in the control group, such as sulfonylureas and insulin, certainly cause more hypoglycemia than liraglutide. We could look at this and say, “Well, maybe this is examining a very different aspect of diabetes treatment. Rather than it being cardiovascular benefit from liraglutide, it’s avoiding the cardiovascular harms of other treatments.” But we really don’t have an answer as to what the exact cause is of the benefit in this trial versus our related trials with a drug that hasn’t come out yet, semaglutide, which is very similar and also showed cardiovascular benefit. So, now we’re in a new world where maybe some drugs were associated with benefit.

Silvio Inzucchi, MD: It’s interesting. When you compare the components of MACE, as you talked about (cardiovascular death, nonfatal MI, non-fatal stroke), you’d think that if 2 GLP-1 receptor agonist trials were positive, that their footprint, if you will, would be the same. But that’s not what we saw. In LEADER, there was a reduction in cardiovascular death (which was the most prominent reduction), but there were non-significant reductions in nonfatal MI and nonfatal stroke. So, all the hazard ratios were moving in the good direction—in other words, to the left side of unity.

With SUSTAIN-6, which is the semaglutide study (this is a weekly GLP-1 that’s not yet available), it seemed that the most potent effect was actually on stroke, which was surprising because that’s not what you typically see with atherosclerosis trials. You typically see it on nonfatal MI and, maybe, cardiovascular mortality. There was a nonsignificant reduction in nonfatal MI, and also an improvement in cardiovascular mortality leading to a more potent reduction in MACE. I suspect that this may not reflect the inherent differences between these drugs, although I could be wrong. I suspect that it has to do more with the patient populations, some of the methodologies, and the duration of treatment. But I think it leads us to understand that you cannot appreciate, I think, the effects of these individual drug categories, until you get at least 3 or 4 trials under your belt so you can see the overall effect of the class.

Zachary Bloomgarden, MD: And there’s the play of chance here. Despite the fact that these are very large trials with thousands of participants, still, they’re not powered to look at individual endpoints unless there’s some unexpected benefit (as we think might be the case with heart failure with empagliflozin).

Dennis P. Scanlon, PhD: For practicing clinicians and for those who pay for these drugs, there are some real implications, I would imagine?

Robert Gabbay, MD, PhD, FACP: Absolutely. I think, first, it’s tremendously exciting that there are now 2 drugs. If you look at the history of diabetes, metformin was the only drug ever shown to decrease mortality in people with diabetes. It was the only diabetes medication. Now, we have 2 new ones in a relatively short period of time. I think the questions that remain are some of the things that are already highlighted. To what population does this refer to? Clearly, in those at very high risk for cardiovascular disease and established cardiovascular disease, were the groups that were studied. “Here, there’s benefit.” Does the benefit extend throughout the class? There’s evidence, pro and con, in each of these that need to be sorted out. But, regardless of all of that, I think the headline of thinking about these drugs in patients with cardiovascular disease and diabetes has now moved way up in the thinking of providers.

Kenneth Snow, MD, MBA: And certainly, one of the major driving forces for why we treat diabetes to begin with and why payers pay for the treatment of diabetes is not so much because we want to see a lower blood sugar, but because we want folks to live longer, healthier lives. And ultimately, these types of outcome trials, particularly if we are seeing reductions in major cardiovascular events, are exciting.

Zachary Bloomgarden, MD: There’s the dilemma, and what we’d like to do is say, “When you develop diabetes, if you’re treated in such and such a fashion, you will live longer and you’ll be healthier.” Doing such a trial would require 10 times as many patients, 3 times as long of a duration, and instead of costing a mere few hundred million dollars, it might cost several billion dollars. And no one has the resources to undertake those trials, certainly a pharmaceutical company. We have to see if we are going to go in the direction of actually championing this type of study so that we can answer the question of the insurance companies: “What’s really going to help our patients?”