Reducing Cardiovascular Mortality in Patients With Type 2 Diabetes Mellitus - Episode 8

Why Recent Clinical Trials Make This a "Very Exciting Time" in Diabetes Care

Dennis P. Scanlon, PhD: Let’s talk about adding therapy to improve cardiovascular outcomes. In recent years, the FDA has required long-term cardiovascular outcome trials for diabetes and obesity therapies to ensure safety, and there have been some new studies recently.

We’ve talked about the EMPA-REG OUTCOME trial, funded by Boehringer Ingelheim. There’s also been the LEADER trial from Novo Nordisk, and the Insulin Resistance Intervention after Stroke (IRIS) trial from Takeda. Could you talk a little bit about those trials? What do you think the evidence result is, and what does that mean when thinking about adding on therapy?

Zachary T. Bloomgarden, MD, MACE: This goes back about 8 years. In 2007, an inflammatory and incorrectly conducted meta-analysis was published in the New England Journal of Medicine, suggesting that the thiazolidinedione, rosiglitazone, was associated with increased [risk of] cardiovascular outcomes. That led to huge outcry and huge pressure on the FDA asking, “Why didn’t you stop this?”

Then, a year or 2 later, was the report of 3 large cardiovascular outcome trials which attempted to demonstrate that glycemic control actually improved cardiovascular disease. These were called ACCORD, ADVANCE, and the Veterans Administration Diabetes trials.

The ACCORD trial, which sort of threw the kitchen sink at everybody, said that hypoglycemia is not so important, and [rather, what’s important is] to just get the blood sugar down. [The trial] found about a 20% increase in mortality in intensively treated patients as opposed to the standard of care group.

Between these 2 body blows, the FDA said, “We are going to institute some changes, and we’re going to require that all new drugs have proof, not of cardiovascular benefit, but have proof that there couldn’t be as much as a 5% chance that there would be a 30% increase in cardiovascular events with this drug.” That started off with total cardiovascular events. It looks like from their latest announcements, the FDA might now be leaning to specific endpoints like heart failure.

As a consequence, the pharmaceutical industry has carried out these very expensive—hundreds of millions of dollars per trial—cardiovascular safety trials with a variety of drugs to try to show that people who have cardiovascular disease can take these drugs without as much as a 5% chance of increased risk. We’re not trying to show that there’s not a statistically significant chance. We’re trying to show that there’s a statistically significant non-chance. It’s a very different paradigm.

So, in this very complicated and messy situation, we’ve had 3 recent trials that really are earth-shattering. First of all, in a relatively small trial of empagliflozin and a SGLT2 (sodium-glucose co-transporter 2) inhibitor in 6000 people—2000 on usual care and 4000 receiving various doses of empagliflozin—there was a reduction in cardiovascular death. In addition, reduction in hospitalization for heart failure was reported as a secondary endpoint.

Then, as just published officially in the New England Journal of Medicine, yesterday, but available online about a month or 2 earlier, a trial was carried out after pioglitazone became generic. We’ve learned that in a long-term trial of pioglitazone, in individuals who did not have diabetes but who had had a stroke and had increased levels of insulin resistance, those individuals have a reduction both in stroke and heart attack when treated with pioglitazone. It was a complicated trial done the right way. They were careful to avoid heart failure, which is a known complication of this drug, and they showed very appreciable reductions in these 2 major macrovascular outcomes.

Just recently, over the past month, we’ve learned from Novo Nordisk that their LEADER trial with liraglutide shows a reduction in major adverse cardiovascular events (MACE)—myocardial infarction, stroke, and cardiovascular mortality. All components were reduced and the total MACE endpoint was significantly reduced.

Now, we have a GLP-1 (glucagon-like peptide-1) drug, a thiazolidinedione, and an SGLT2 inhibitor. It’s very exciting for the diabetes community because we can say that diabetes treatment in people at high risk may actually have unique benefit, and we can talk about potential mechanisms. We don’t know why, but it’s pretty good.

Dennis P. Scanlon, PhD: Any thoughts on this mechanism?

Michael Gardner, MD: Yeah. In the EMPA-REG Outcome trial, we don’t know why the cardiovascular risk decreased because the actual number of events of heart attack and stroke didn’t really significantly decrease. It’s basically the same between the 2 groups. There’s a lot of speculation out there. It certainly wasn’t the glycemia.

That’s something very important to recognize in all of these trials, and particularly in EMPA-REG, that the divergence of the 2 groups was too early for it to have been the glucose. It appears to have accelerated over time. Whether you are a believer that, particularly with EMPA-REG, it was the natriuresis, the blood pressure, or some combination of natriuresis, blood pressure, and endothelial function, it’s a very exciting time.

Robert Gabbay, MD, PhD, FACP: It sort of changes the way we think about choice of medications. We have that list of [considerations]. Does it cause weight gain or not? Does it cause hypoglycemia or not?

And now we have an expanded number of drugs that [lead us to question] if they also lower cardiovascular risk beyond glucose effects. Obviously, that’s critically important because the number 1 reason why people with diabetes die is heart disease. For anything that’s going to lower that number, particularly in people at high risk, it’s hard not to consider it as a really important factor when weighing the different factors in terms of choice.

Zachary T. Bloomgarden, MD, MACE: With the thiazolidinediones, I’m thinking back to the studies that showed that people who’ve had PTCA (percutaneous transluminal coronary angioplasty) with and without diabetes and were randomized to a thiazolidinedione or not, had reduction in restenosis if they were on either rosiglitazone or pioglitazone.

The findings of PROactive, which was a big trial of pioglitazone, showed a 50% reduction in stroke if you had a history of stroke. That was actually the rationale for the IRIS trial. That leads us to say, “Well, for people with diabetes who’ve had strokes, if we can be very careful about the known complications of these drugs, should they all have a thiazolidinedione?” And then, [we need to ask] what dose is right? Should we aim for lower doses to avoid complications? There’s so much more left to learn.

Dennis P. Scanlon, PhD: John, getting back to formulary decisions, your staff is keeping busy, I assume, given these results. This is an example where new evidence probably has to be considered pretty quickly and pretty carefully?

John A. Johnson, MD, MBA: Absolutely. So, where there’s precedence and where there’s evidence that suggest that these medications need to be made available to our members, we definitely want to consider that as we design our drug formularies. [We must] realize that in some instances, it’s not really a class effect. As in several of the studies you referenced, it was 1 agent in a class as opposed to all the agents in a class.

Zachary T. Bloomgarden, MD, MACE: So another GLP-1 drug, lixisenatide, which is going to be approved soon and will be much cheaper than liraglutide, did not show [benefits in terms of] cardiovascular events.

John A. Johnson, MD, MBA: Did not show. Exactly.

Zachary T. Bloomgarden, MD, MACE: So often, when I try to prescribe liraglutide, I get a nasty note back—not from you guys of course, but some other unnamed companies.

John A. Johnson, MD, MBA: Other companies.

Zachary T. Bloomgarden, MD, MACE: Right. They say, “Well, don’t use that. Use this—which is on our formulary.” And unfortunately, the most expensive of the GLP-1 drugs, and it probably shouldn’t be, is this Novo Nordisk drug. But, that other one may really have benefits.

John A. Johnson, MD, MBA: I think, again, as we design our formulary, we take information from the various medical societies—the FDA, the CDC (Centers for Disease Control and Prevention), and all the available information from the experts. Within that environment, we look at what the most affordable, cost-effective agents are to make available to our members. Not just those with diabetes, but all of our members.