Aus Alzaid, MD; Bernard Zinman, MD


September 28, 2015

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Game-Changing Results

Aus Alzaid, MD: Welcome to Medscape. I'm here today to talk to Dr Bernard Zinman, who is very much in the spotlight because of his work on the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) study, which was presented yesterday and published in the New England Journal of Medicine.[1] I was there, with the excitement and the drama unfolding. Now, the day after, can you tell us about the study and its after-effects in terms of the comments you received and discussions you have had?

Bernard Zinman, MD: It's a pleasure to talk to you today. Indeed, at the European Association for the Study of Diabetes annual meeting, there was a great deal of excitement about the EMPA-REG OUTCOME study results. The reason there was all this excitement is because, as is appropriate, we've had several studies now look at the safety of diabetes therapies. It's really important to make sure that new diabetes therapies don't cause any cardiovascular harm.

Previous studies, mostly with dipeptidyl peptidase 4 (DPP-4) inhibitors and one with a glucagon-like peptide 1 (GLP-1) receptor agonist, have been sort of neutral; they've shown good safety. There was an indication that one DPP-4 inhibitor may increase hospitalization for heart failure. I think it is very important to show safety.

Now, EMPA-REG OUTCOME is clearly different because not only did it show safety, but it showed a dramatic benefit of empagliflozin, a sodium/glucose cotransporter 2 (SGLT-2) inhibitor, specifically in reducing cardiovascular death. The composite major adverse cardiovascular event outcome was reduced by 14%, but remarkably, cardiovascular death, all-cause mortality, and hospitalization for heart failure were all reduced by over 30%.

When we presented these data, there was literally applause in the audience. People were anxious for a diabetes therapy that does more than just glucose-lowering. Here we have a diabetes therapy that lowers glucose effectively, but also has some added value. The added value is a reduction in cardiovascular death, hospitalization for heart failure, and all-cause mortality.

Will It Affect Treatment Guidelines?

Dr Alzaid: It was a breathtaking scene of the survival curves separating. It was clear-cut; it was distinctive. We've learned for years to accept that "no news is good news," like no effect on cardiovascular outcomes being good news. But now, good news is truly good news in terms of improving cardiovascular outcomes.

Do you think we should translate these results into restructuring the [diabetes treatment] guidelines? People would say it was a game-changer last night, with the outcome of the study and the clear-cut difference in cardiovascular mortality.

Dr Zinman: People who are involved in guideline development do it in a very systematic way, and one of the things that is very important in the development of guidelines is looking at the evidence. The EMPA-REG OUTCOME study is evidence, and I am certain that the guidelines committees will look at this evidence in the context of determining recommendations for therapy for patients with type 2 diabetes. Because this is the first diabetes therapy that has had this quite dramatic benefit on cardiovascular outcomes, I would imagine that it will be elevated in the context of the algorithm for using different diabetes therapies.

I might add that personally, I think that combination therapies are required for diabetes management. I see empagliflozin being used in combination as opposed to replacing anything, such as in combination with metformin or with a DPP-4 inhibitor. I think we're making really good progress, and hopefully it will change the outcome for many patients with type 2 diabetes.

Dr Alzaid: What about side effects? Were there any cases of diabetic ketoacidosis?

Dr Zinman: As you know, diabetic ketoacidosis has been reported with SGLT-2 inhibitors. In EMPA-REG OUTCOME, we did not see any difference in the rates of diabetic ketoacidosis between placebo and active treatment. Indeed, the rates were very low.

Applying These Results in Practice

Dr Zinman: One of the things I should mention as far as an outcome study like EMPA-REG OUTCOME is that you can translate the findings in the study to patients in your clinical practice who are similar to the ones studied, such as patients with type 2 diabetes who have cardiovascular disease, and patients who have had diabetes for more than 10 years.

Once you have an outcome study like this, you can say to yourself that patients who have the same profile as those studied should benefit to the same degree; however, extrapolating to other patients with type 2 diabetes is still a little more difficult.

Dr Alzaid: I liked your comment last night about how we shouldn't "cut and paste" conclusions. But how much can we generalize the findings to the masses of diabetic patients that you and I see on a regular basis?

Dr Zinman: At the end of the day, for people with diabetes, our aim is to improve their glucose control early on in the course of diabetes to prevent both microvascular and macrovascular complications. We now know that if you have cardiovascular disease, this particular strategy is very beneficial as far as very clinically relevant outcomes, such as cardiovascular death. For people who don't yet have cardiovascular disease, we don't know the magnitude of the benefit, but there may very well be benefit as well.

Dr Alzaid: Can we generalize [these results] to other agents in the drug class? Can we spread the benefit here?

Dr Zinman: Generally speaking, if you look historically at angiotensin-converting enzyme (ACE) inhibitors or DPP-4 inhibitors, agents in the same class don't necessarily have similar effects. There are examples where there is a difference in outcomes for the same class.

For instance, with DPP-4 inhibitors, one study showed an increase in heart failure admissions, whereas another study did not. It's very, very difficult to be sure that it's a class effect. What we are certain of is that empagliflozin gives you this result. If we have another SGLT-2 inhibitor with a similar finding, then I would be more confident in saying this is a class effect.

Sorting Out Mechanisms, Cost/Benefit

Dr Alzaid: One thing that caught my attention talking to people after your presentation was the stunning separation [in the curves tracking effects] so early on—within 3 months. It's fantastic to see a difference so early. Generally, you'd expect a longer time before seeing a difference. What is your take on this?

Dr Zinman: The fact that the empagliflozin group benefited very early in the course of this study to me indicates that we're not dealing with an effect that's related to hyperglycemia or atherosclerosis, or even blood pressure. Rather, it's a hemodynamic effect. We know that there are hemodynamic changes that occur with SGLT-2 inhibitors. So, is this an effect on cardiac function, on diastolic or systolic function? Certainly, there's a diuretic effect. It looks like the benefits occur very early and are probably a consequence of hemodynamic changes.

Dr Alzaid: Let's talk a little bit about the future. Cost vs benefit? In the context of the rising prices of diabetes medications, are we expecting to see a cost/benefit analysis in the future?

Dr Zinman: I think when you reduce hospital admissions for heart failure and when you reduce mortality, this is very valuable in the context of cost. I haven't done a quality-adjusted life-year assessment, but I'm sure that will be done. However, on the basis of the magnitude of the response, I would think it would be very favorable.

Dr Alzaid: Fantastic. The feeling I had last night was that it was a great day for diabetes, diabetes patients, and all those who care about diabetes. It was like the diabetes community had won the lottery last night. Thank you very much.


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