Michelle L. O'Donoghue, MD, MPH; Marc S. Sabatine, MD, MPH


December 14, 2015

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Diabetes Trial Under The Radar

Michelle L. O'Donoghue, MD, MPH: I'm Dr Michelle O'Donoghue, coming to you from the 2015 American Heart Association (AHA) annual meeting in Orlando, Florida. With me today is Dr Marc Sabatine, chair of the TIMI study group, professor of medicine at Harvard Medical School, and cardiologist at Brigham and Women's Hospital. Thanks for joining me today, Marc.

There are other trials to discuss. What are your feelings about the EMPA-REG OUTCOME trial[1] and the additional data that we saw during the meeting?[2]

Marc S. Sabatine, MD, MPH: That's a topic near and dear to our hearts, and TIMI is doing the Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58 study, a very large trial with dapagliflozin, another member of this drug class. I think it's a fascinating story, especially when you consider that for other drugs, like dipeptidyl peptidase-4 (DPP-4) inhibitors, there was hope for an effect on cardiovascular outcomes through a series of molecular mechanisms and some early phase 2 and phase 3 studies[3] that seemed to be supportive, with relatively smaller numbers of events. However, DPP-4 inhibitors were stone-cold neutral for vascular events.[4]Heart failure is a more complex story.[5]

For the sodium glucose cotransporter 2 (SGLT2) inhibitors, there is a much simpler story at first. SGLT2 inhibitors cause more excretion of glucose, and blood pressure will be a little bit lower. You'll get rid of the calories that way. There's a bit of a diuretic effect with that, a natriuretic effect that should help heart failure, and maybe there will be some benefit for that. It's certainly what we had hypothesized, as had the EMPA-REG OUTCOME investigators.

The reduction in mortality was really quite surprising. The effects on major adverse cardiovascular events were roughly what we and other groups had estimated, around a 15% reduction. The effects on heart failure, we would expect them to be good, and they're in line with the phase 2 and phase 3 data. The cardiovascular death endpoint is really quite robust. We're still trying to figure out why that's the case. If you thought giving these drugs was just the blood pressure reduction and the diuretic effect, like giving a thiazide, you would not expect that benefit over that time course. There's something else going on, and people are investigating it.

Not only is it a great treatment for patients with diabetes that now actually reduces cardiovascular outcomes, but I think it is a validation of doing these large trials. We've learned for some of the DPP-4 inhibitors that there appears to be a signal for increased heart failure that may be drug specific or may be a class effect, and that needs to be teased out more. However, there's now benefit for this other class that we never would have known had we just relied on small trials.

Dr O'Donoghue: I couldn't agree more. I've really been struck by the tremendous benefit that we've now seen with an oral hypoglycemic. What a breakthrough. I've been surprised that there hasn't been more discussion about the results of EMPA-REG OUTCOME because it really is just a practice-changing finding.

Dr Sabatine: They should have featured it in the heart failure late-breaking trial session. Those were some of the most impressive results for heart failure of anything we've studied recently.

PCSK9 Inhibitors: What's New?

Dr O'Donoghue: Now moving on to a topic that's near and dear to your heart, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. What did we learn during AHA about these agents, and where are we going?

Dr Sabatine: There have been additional studies coming out at AHA, rounding out our knowledge of the class. I think the biggest thing for clinicians is not so much the data coming out at this meeting but knowing that the drugs are now available.

There are genetic data that the people who've lost a function variance appear to do better. The low-density lipoprotein cholesterol (LDL-C) reduction with these drugs is great, and that is why they are approved in addition to appearing to be safe. But, of course, these are in relatively short-term trials.

The labels include indications for both patients with familial hypercholesterolemia as well as patients with atherosclerotic disease. I think each clinician is going to need to grapple with when they should reach for one of these drugs for their patients. I have to say that I think even lower LDL-C is better. Hopefully the guidelines will re-embrace that notion. The Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) showed that adding a medication onto a statin—in that case, ezetimibe—reduced events.[6] I would extrapolate from that an LDL-C mid-50 mg/dL is better than 70 mg/dL. For my high-risk patients, that's where I want them. If I can't get them there with the statin and ezetimibe, I would reach for a PCSK9 inhibitor.

However, that's why we do the big outcomes trials. You don't know until you study it. We'll have several of these trials reporting data in the next 1 or 2 years. But in that interim, clinicians will need to think about when they'll reach for a PCSK9 inhibitor. Whether payers will allow them to reach for it is another layer of complexity.

Clinical Research Going Forward

Dr O'Donoghue: No doubt. Now just to wrap up, and because we have you as the chair of the TIMI study group, do you have any thoughts on the direction of clinical trials in general? Is this something that's going to be changing in the future? What are your thoughts?

Dr Sabatine: It's a great question. I think there are opposing forces out there. On one hand, there is the notion of doing a large, simple trial. Against that is the intense review that happens in regulatory agencies and the demands in the review process that force sponsors to invest a colossal amount of resources in recording details that probably don't affect the validity of the trial in any way. There's a notion of doing adaptive design, which the US Food and Drug Administration has embraced in position papers, but in a practice, having those shifts as new data come out are harder to do.

And with the wealth of information out there, how can we leverage that? I'm a little more cautious about that. For all observational data, you have to view it as potentially confounded. That's why we do randomized trials. These "real world" observations are hypothesis generating but oftentimes can be quite confounded.

In terms of the wholesale gathering of information, it's great what you can do on a large scale. The question is the fidelity and accuracy of that information. It will be great if we can leverage that, so that people who want to use these electronic devices remain enthusiastic over the typical horizon of a trial of a half decade. But if we do it, it does open the door for gathering data in a way that we couldn't before. It's exciting if it can be implemented well.

Dr O'Donoghue: Thank you so much for joining me today, Marc. This has been great.

Dr Sabatine: Thanks for having me.


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