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- [00:03]
A
Welcome to this special two part series of Diabetes Core Update where we will discuss what is arguably the most important advance in the care of people with diabetes since the discovery of insulin and that is the development of the cardiovascular outcome trials, the cvots. I'm your host, Dr. Neal Skolnick, professor of Family and Community Medicine at the Sidney Kimmel Medical College of Thomas Jefferson University. This special series of Diabetes Core Update is sponsored by Lilly. In the first of this two part series, we put the CVOTs into historical context with Dr. Steve Nissen and discuss the findings that led to the FDA mandate for the cvots. It is a fascinating story. If you didn't listen to that part, let me suggest. Take a listen. This story is amazing. Today we're going to discuss some of the trials that occurred as a result of that FDA mandate and the updated FDA guidance from 2020, as well as new aspects that are being included in current trials, including active comparators and imputed placebos. And then we'll talk about the Surpass CVOT which demonstrates the result of these new methodologies and provides us with new exciting information to discuss this. We are so privileged to have Dr. Darren McGuire joining us. Dr. McGu is the distinguished teaching professor Jerry H. Mitchell, MD, distinguished chair in Cardiovascular Science at the University of Texas Southwestern Medical center and Parkland Health System. He is the immediate past Deputy Editor of Circulation. He is the Senior Editor of Diabetes and Vascular Disease Research and editor of the textbook Diabetes Cardiology, A Companion to Bruno's Heart Disease. He is a former member of and present ad hoc consultant for the FDA Cardiovascular and Nephrology Drugs Advisory Committee. And as if that isn't enough, he's also has over 500 peer reviewed publications and if you read the author list of clinical trials as they come out, as I do, you'll notice that his name is on many of those trials, including the recently reported and soon to be published Surpass cvot. Darren, welcome to our podcast.
- [02:41]
B
Thanks Neil, always great to be with you. Thank you.
- [02:44]
A
It is. I so enjoy our conversations and I always learn when I'm talking to you. During the first part of this series, Steve Nissen gave us just a wonderful overview of the concerns that led to the FDA mandating the CVOTs as a part of new drug registration processes beginning in 2008. We have come a long way since then and let's take it from there forward. Over the next few years there were a number of trials, the DPP4 inhibitors that showed non inferiority for major adverse cardiac events, Mace and that was important to see. And then though, in September 2015, something really remarkable happened. Can you tell us about that?
- [03:36]
B
Yeah, it's been a great history and you know, many of us gotten interested in diabetes from a cardiovascular perspective back in the mid-90s when type 2 diabetes was just taking off. We were just beginning to understand the cardiovascular implications and we began to realize that the drugs we were using. And again, I don't know about you, but when I was a resident, we only had insulin insulfonureas. And so we really hadn't put to the test anti hyperglycemic therapies. And so a lot of things were moving And I'm sure Dr. Nissen reviewed much of that. But in 2008, the FDA changed the rules where we had now a plethora of new therapeutics coming online, coming to market, and we now had the luxury we could pause and test them. And to your point, so we started doing these cardiovascular outcomes trials, but as, as the guidance from the regulators, it was to prove safety, not even efficacy. We needed to know while we're treating hyperglycemia and we're modifying microvascular disease risk, at the very least we need not be harming cardiovascular risk. And there were a number of earlier signals from other therapeutics of cardiovascular risk problems. And so we started on these large scale outcomes trials. And the low hanging fruit at the time were the DPP4 inhibitors. They were just coming online once daily, tablets, well tolerated, almost no side effects. And so we were very enthusiastic that these drugs might at least take over Sulfony Rheas, to be honest. And, and, and, and going back in time and, and I don't know if you recall this, but we started with sitagliptin. We actually started the Tecos trial of sitagliptin for cardiovascular safety before the regulatory guidance was even put into place. And so we were actually doing these trials before the regulators required them. And then subsequently three additional DPP four inhibitor inhibitors have been tested. And you know, I kind of make a joke about it at some points, but we proved over these four trials that the DPP4 inhibitors are the perfect placebo for cardiovascular outcomes.
- [05:45]
A
Oh, gosh.
- [05:45]
B
And, and we started getting criticism in the field that we're wasting our money, we're not moving the needle forward, but realized this was the first class of medicines where we had rigorously proven their safety from a cardiovascular perspective. Now, as you mentioned, In September of 2015, the momentum changed because we started getting efficacy outcomes for other therapeutics. But that was the big first step forward is that we had Large prospectively designed trials to evaluate the safety of these drugs. And we proved the safety. Now we found, I was on the executive committee of the DECLARE trial where we found saxagliptin increased risk for heart failure. We would have never seen that had we not been doing the large scale randomized trials. We're actually gleaning important information even though we're not moving the primary outcome of cardiovascular death, MI and stroke, which is our gold standard in the atherosclerosis cardiovascular research domain. We had a class of medicines that looked safe from a cardiovascular perspective because of the heart failure signal from saxagliptin. I was on the executive committee of the, of the TECOS trial and on the, I chaired the Carmelina trial. Those were ongoing when we saw the heart failure signal from saxagliptin. So we were able prospectively to, to develop a statistical analysis plan and file it with the regulators before we unblinded our data for heart failure and prove that linagliptin and sitagliptin have no heart failure signal whatsoever. So, so we're making baby steps forward. But, but to the point of the criticism of the field, we weren't making things better. And then In September of 2015, September 15th, by the way, it's a day that is marked in history, we had the very first positive outcomes trial in the field of diabetes with the EMPA REG outcome trial showing that empagliflozin, each of two different doses randomized in that trial, had the same cardiovascular efficacy, a 16% reduction, cardiovascular death in mind, stroke. And what we never anticipated and has led to an entire field of study is a 30% reduction in heart failure. And so that was revolutionary. That was the very first positive outcomes trial. And as you know, we've had a series of validating trials with other SGLT2 inhibitors. And then we'll talk ultimately about the GLP1 receptor agonist and how we're skating to where the puck is going to, to expand. Dual agonist, tri agonist. And the field is, it's, it's amazing, this progress.
- [08:18]
A
You know, I love that quote that you're alluding to. It's a Wayne Gretzky quote.
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B
Wayne Gretzky, right.
- [08:25]
A
When he was asked, I believe, why are you the best hockey player? Because he was not the fastest or the strongest. He said, because I don't care where the puck is. I've spent my whole life obsessed with where the puck is going. Right. That announcement in September really changed the whole direction of the field because we had, prior to that, I mean, the UK pds, dcct. It had shown effect on microvascular disease but it wasn't until the 10 year follow ups that we saw an effect on macrovascular disease. And really for the first time we said, wow, we could accomplish what we thought we could. And if I remember correctly, the number needed to treat was something, something like 1 in 33. It was an incredibly powerful number needed to treat. So this was not a small effect and it just increased anticipation for all of the trials to come. Can you briefly talk about what you think are some of the most important of those additional trials?
- [09:35]
B
Yeah. And to your point, from the emperoreg trial, the number needed to treat is around 30 and, and remember, so people getting into these trials, not just inpa reg outcome, but all of the trials we've done since these people are really well treated from a cardiovascular perspective. They're entering these trials with LDLs in the 70 range, systolic blood pressure in the 130 range. They're on antiplatelet therapy. So we are now incrementally adding to the risk reduction with these novel therapies. First, the SGLT2 inhibitors and pretty much at the same level of risk reduction, the GLP1 receptor agonist. When we're looking at cardiovascular death, MI and stroke, and we know that each of these two classes of medicines that have completely revolutionized the care of people with diabetes in heart disease or heart disease risk is the SGLT2 inhibitors have potent effects on heart failure, risk reduction, chronic kidney disease progression. We see the GLP1 receptor agonist favorably affecting weight and all of the ancillary benefits of weight control, blood pressure lipid profiles. And we're beginning, and we'll talk a little bit about the surpass. We're beginning to see kidney disease risk reduction as well in each of these classes which seem to be complementary one to the other. And so we're now establishing pillars of therapy. We used to call it a poll of therapy. We had one single therapy, the SGLT2 inhibitors. Now we have the GLP1 receptor agonist. So just like treating reduced ejection fraction heart failure, we have parallel pillars of evidence based medicines that are working in very different mechanisms. And we may get to talk about this. It's no longer either or for people at sufficient risk with diabetes, it's both of these therapies. I had the privilege of being on the writing committee for the European Society of Cardiology diabetes guidelines and we unequivocally took out the either or between GLP1 receptor agonist and SGLT2 inhibitors for people with sufficient risk as defined by the eligibility for the trials and now the product labeling from the regulatory agencies. It's not either or these. And we're in. And back to your point about UK pds, that was mostly about glucose control. And I don't want to leave this conversation saying that glucose control is not important. But we haven't been studying glucose control in these cardiovascular outcomes trials. We actually have designed the trials oppositely for what we call glucose, glucose equipoise. We want both of the arms to be treated as close as possible to the same hemoglobin A1C. And we're testing is the drug doing anything pernicious or favorable for the cardiovascular outcomes. And so I want to divide. We're not talking about treating glucose. And this is the message I give as a cardiologist to my cardiology colleagues. I'm not asking you to manage glucose, but these drugs improve cardiovascular outcomes in patients at sufficient risk.
- [12:34]
A
Yeah, it really has been amazing. As all of that information continued to accumulate over the five years after, you know, from 2015 to 2020, the LEADER trial, the Dapagliflozin trial, et cetera, the GLP1, the other GLP1 trials and SGLT2 trials, it allowed the standards of Care to move away from what we now call a glucocentric model of diabetes care to a broader, more personalized model that takes into account someone's cardiovascular risk, someone's obesity level, and recommends that we pick the right medicine to address the person's individual risk. Glucose is still important, particularly for microvascular disease prevention, but it's no longer the, the only focus.
- [13:36]
B
Right? And, and to push that point, what's really remarkable, and people who don't read these standards of care and guidelines, which they're boring as all, I get it, but for the last two years, the ADA has taken out. So if, if you have cardiovascular disease, high estimated risk for cardiovascular disease, prevalent heart failure and or CKD, there's an algorithm that includes the SGLT2 inhibitors and the GLP1 receptor agonist and even pyoglitazone. And what's nowhere in that algorithm is metformin. And so the ADA has now acknowledged with these comorbidities that metformin is no longer a first line drug and it is at, at a minimum, a fourth line drug. And so that's really important. Now I'll turn that around. For people without these comorbidities, metformin still a super first option. But realize where we've gone with the evidence from the trials that we've conducted, metformin is nowhere in the equation.
- [14:44]
A
It is pretty amazing. And I think you're right that not everyone reads the guidelines. I'm really glad that you mentioned that. And it is such a mark shift so quickly that it's taking a while for people to really understand it. And that shift is based on all the things that you just talked about. The very, very clear and rigorous evidence in repeatedly repeated different trials with different medicines of, in the both the SGLT2 and the GLP1 classes of benefit across a range of outcomes. Cardiovascular disease, heart failure, kidney disease. Let's move on now to 2020 and the FDA revisited the cardiovascular guidance. Can you update us on what that discussion was like and what they concluded moving forward?
- [15:46]
B
Yeah, you know, they, they, the FDA backed off the requirement across the board for cardiovascular outcomes assessment and I will say unequivocally and as often as I can publicly, they got this wrong. So we have to do these large scale outcomes trials and I will tell you three examples so we don't have to even call them cardiovascular outcomes trials. But unless you have 15,000 patient years of observation, you're going to miss important uncommon but serious adverse effects. I was on the executive committee of three trials that we stopped for. Nothing to do with glucose control or cardiovascular outcomes. So the very first once weekly GLP1 receptor agonist, tasboglutide, we had to stop. 50% of patients in our outcomes trial, 50% had antibodies and had we had anaphylaxis, anaphylactoid reactions, this drug would have come to the market. With the previous guidance and with the present guidance, we did a trial of Aliglitazar a dual PPAR alpha gamma agonists in people with diabetes after an acute coronary syndrome. A 40% increased risk for GI bleeding. Stop the trial. We don't expect a PPAR alpha gamma agonist to cause GI bleeding. We did the Fasticle, found the grand 360 trial of a GPR gluc, a G protein coupled receptor 40 agonist which is a glucose appropriate insulin secretag. Tenfold elevated liver enzyme risk killed the trial, killed the compound, killed the entire class. We would have never seen these had we not been doing large outcomes trials. So the FDA gets this wrong, we have to do big trials.
- [17:29]
A
That makes a lot of sense. What was the FDA's rationale in no longer requiring that?
- [17:35]
B
I have no idea. I think what they saw was everybody complaining that we're, we're not in, in 10 years we've not seen a Bad outcome from a cardiovascular perspective. But they're comply. They're completely ignoring the fact that in three, these three trial programs that would have brought a drug to market before, killed the compounds before. You know, the FDA has the experience with Fin formin, it was on the market for 17 years. A lot of people died because they never required the outcomes. They pulled it from the market. Then we have the trial. The UGDP University group diabetes program that studied Tolbutamide proves statistically Tolbutamide killed people, increased cardiovascular and all cause mortality. And instead of taking it off the market, the FDA puts in the product label and it's still in every sulfonylurea product label today that oral hypoglycemics may increase cardiovascular mortality. We're prescribing a medication class to persons that in the product label effectively says that this drug may increase your mortality.
- [18:43]
A
Just to clarify on that point, so that our listeners understand that in the product label. But if I remember correctly, there was a trial of a sulfonylurea. Can you remind me about that?
- [19:00]
B
So I was on the executive committee of the Carolina trial where we, we studied linagliptin head to head, randomized against glimepiride. And when the drug company designed the trial, I told them they couldn't do that, do a non inferiority trial against a unproven comparator. They fired me from the committee.
- [19:19]
A
Oh God.
- [19:20]
B
And started the trial. And then they called me about a year and a half later and said the FDA changed their mind, they agree with you that we can't do this trial. So we have to do a placebo controlled trial. And they invited me to be the chair of the Carmelina trial which studied linagliptin versus placebo. And then they put me back on the executive committee of the Carolina trial. And so now we have parallel trials, one testing against an unproven active comparator and one testing against a placebo. And so at the end of the day, what we were able to show is that linagliptin versus glimepiride completely neutral from a cardiovascular perspective. And in the Carmelina trial, linagliptin versus placebo, completely neutral. So no benefit, but no harm. And so by the transitive property, we can at least vindicate glimepiride. And glimepiride seems to be no different from a placebo from a cardiovascular perspective. So at least we have one sulfonylurea that in a large scale randomized comparison shows probably no cardiovascular harm.
- [20:26]
A
Yeah, you know, it's interesting Darren, when I'm listening to you, it just is in this era where there's so much skepticism about science, it is wonderful to hear the way that you think things through and the carefulness and also the courage where you stood up for what you saw to be correct. And that's what helps us advance the science. It's honest thinking and the courage to follow through on that.
- [20:54]
B
Well, thank you, Neil. And. And in retrospect, I'm proud not just of that I stood up. I'm proud of Behringer Ingelheim, who also stepped up and said, you know, you're right. Let's do the placebo controlled trial. We're going to do both trials. They could have completely canceled the Carolina trial because the FDA said this, this will not lead to a product label. But instead they completed both of the trials honoring the people who had volunteered to be in the trials and all the persons working on the trials. So. And it gives us a robust data set that we with some confidence can say, at least this one sulfonylurea looks to be okay.
- [21:34]
A
Yeah. And you know, your point about future cardiovascular trials is such an important one because now we're on the cusp of having new classes of agents both for diabetes and obesity, and it will be up to the companies to decide whether or not it is worthwhile to run this cardiovascular vascular outcome trials. But I agree with you both for all the reasons you stated, but also just as a practicing clinician making decisions about what medicines to use. Part of it is this data set we have about, has the medicine been shown to achieve the outcomes that we hope that it will? Let's go on now and talk about the surpass cvot, which is a large, important trial and also has a number of new features that weren't there in other trials to that date. Can you tell us about the surpass cvot, both the results that are available at this point? At this point, we have a lot of results that were announced. The publication, I believe, is not out yet. And also along with what those results were, what you felt were the important methodologic advances.
- [22:49]
B
Yeah. So the surpassed cvot. So I will take you back in history. So about 10 years ago, I was invited by the ADA to give a plenary session lecture about how we might, now that we have some positive outcomes trials, how we might change what we're doing to the next level. And one of the propositions I made during that lecture was we need to pivot to active comparative controlled trials testing against a proven anti hyperglycemic Therapy. And at the very end of that lecture, the leadership of Eli Lilly approached me at the podium.
- [23:26]
A
Wow.
- [23:27]
B
And says, we need to talk to you and we need to design this trial. And we began that day 10 years ago designing the Surpass trial. And the Surpass trial is the very first anti hyperglycemic trial to test against an active proven comparator.
- [23:43]
A
Can I ask you to pause there for a second? Because just so our listeners understand the rationale for that, why did you think that we needed to do that?
- [23:52]
B
Yeah. So when we embarked on these cardiovascular outcomes trials, since there was no proven safe anti hyperglycemic, we had to do the trials against a placebo. And how many trials do we have to do against a placebo before we start testing against a proven therapy? And so in the GLP1 receptor agonist space, we did eight mega trials against a placebo, all effectively showing the same thing. So can we do a ninth? When does it become unethical? And then for trial operation perspective, when you have drugs that are proven and effective and available, you risk drop in and drop out. And so it compromises the conduct of the trial. And it's also ethically challenging to leave people on a placebo for three or four or five years when they can have an effective therapy. And, you know, I'll put this in the context of the direct oral anticoagulant therapies, the tablets that we've developed for atrial fibrillation, we tested every one of them against warfarin, against a proven active comparator. In cardiology, we've been doing proven active comparator non fiordi trials for decades, and now we have the privilege in the diabetes space to do the same. Where we have proven active comparators, we can show that the present experimental therapy is not inferior to a proven one. And then to your point, what's really creative about Surpass is the FDA has at least signed off on and we'll see how the public accepts it. And the advisory committee accepts it it, but they signed off on letting us to do an imputed placebo analysis. So we can pretend mathematically, if we had a placebo control group, what would the drug. And we haven't talked about surpass. So we're testing tirzepatide, or once weekly injectable incretin modulator against dulaglutide. If we can prove that tirzepatide is not inferior to dulaglutide, we can also impute what we might have seen with the placebo. And when we do that, we see a 26% reduction in cardiovascular death, MI and stroke, which is the, the highest level of reduction in the field. Now that's, that's all smoke and mirrors. And we will be the first to admit that this is all imputation and it's not an actual trial. But I think as we've done with the doacs, with the direct oral anticoagulants, all of us in cardiology who use these drugs are fully confident they're better than a placebo. And we never had to do the formal imputed placebo analysis. But we all accept that if it's not inferior and even superior to warfarin, it has to be better than a placebo. And we'll see how the public and the FDA accepts it. But I, we are, I am very proud of the sponsor, Eli Lilly, and, and, and the FDA of at least acknowledging that this is a possible path forward. So we can not be doing placebo controlled trials.
- [26:48]
A
It seems like an important one because to do otherwise ongoing puts people at risk who could have that three to five years of benefit of drugs that are proving to have good outcomes. So it sounds like that was prescient of you back 10 years ago to recognize that and of Eli Lilly to, to then act on it.
- [27:12]
B
And, and it's a serious ethical consideration. So persons who have eligibility for GLP1 receptor agonist, for example, but for whatever reason they can't get them, they are expensive and many people do not have access. So they're willing to get into a trial to have a 50, 50 chance of getting the drug. Well, that becomes an ethical dilemma when you're putting people in trials because they're vulnerable. That's an ethical consideration and that's not the way to conduct international clinical trials.
- [27:45]
A
It's important. With Surpass cvot, it was a active comparator of dulaglutide to tirzepatide. And then what did they find?
- [27:57]
B
Yeah, so then I'll remind the audience. So dulaglutide previously had been proven superior to placebo in the Rewind trial and led to a product label indication for cardiovascular risk reduction. It's a once weekly injectable GLP1 receptor agonist. We designed surpass with tirzepatide, which is a dual agonist, GLP1 and GIP agonist, also a once weekly injectable. And so we're testing a different therapeutic slightly against a proven therapeutic head to head. We had over 13,000 patients in the Surpass trial. We began enrollment. Let me remind You. We began enrollment May of 2020. There was this thing called Covid.
- [28:41]
A
Oh God.
- [28:42]
B
We did this entire trial during COVID during a war in the Ukraine, during unrest in the Middle east. And at the end of surpass we had 99.2% complete vital status follow up. We only lost 0.8% of the participants. So the trial conduct was impeccable, despite all of the global challenges we had of international clinical trials. And so what we showed in surpass was Tirzepatide was non inferior to dulaglutide. The point estimate was 0.92, so favorable point estimate, 8% relative risk reduction directionally. And the upper confidence limit was 1.01. So we barely missed superiority. But we can say unequivocally it's not inferior. And so once we prove that non inferiority, that gives us the statistical privilege we pre specified to compare against an imputed placebo. And that's when we show the 26% reduction. We've also done an analysis. This was presented at the EASD primary presentation. We took the Rewind trial of dulaglutide and we took people from the rewind trial who would have had all of the eligibility for the surpass trial.
- [29:59]
A
Let me pause there for a second so our audience understands. Rewind trial had a broad inclusion criteria of people with established ascvd, but a large number in that trial did not have ascvd.
- [30:13]
B
Exactly.
- [30:14]
A
And in the comparison you're talking about, you took. I want to make sure I'm understanding it correctly. You took the people in Rewind who had ASCVD similar to what was in the surpass trial, is that correct?
- [30:28]
B
That's exactly right. And to your point, the Rewind trial, the majority of people had high risk but not prevalent cbd. And so we took the subset who had CBD and Rewind and we tested the effect of dilaglutide versus placebo. And then we put superimposed the Tirzepatide versus dilaglutide onto that subset. Again in a lot of smoke and mirrors analytically. And we found almost exactly the same thing if we took the entire class of the GLP1 receptor agonist at 28% reduction in cardiovascular death, MI and stroke. And so however we slice and dice in sensitivity analysis, we come up with almost exactly the same result for an imputed placebo control.
- [31:14]
A
I love that concept. I understand there's a lot of statistics involved, but for someone like me, it makes it directly understandable. And that's a 28% decrease in mace. Over what period of time was it?
- [31:30]
B
Median follow up of about four years.
- [31:32]
A
Four years. So that's a, that's a big deal. You know, from a patient outcome point of view that's an important decrease and.
- [31:40]
B
It is a is, it is important. And as you and I have done on a previous podcast, we talked about the sole trial with oral semaglutide. And as we've meta analyzed all the GLP1 receptor agonist trials, including now the flow trial of injection injectable semaglutide and the sole trial results from oral semaglutide, we get exactly the same estimate from the class of a of a 14% relative risk reduction. So when we do an imputed placebo in surpass, it's a 26%. So it's almost twice what we see of the GLP1 receptor agonist class. And again with the caveat that these are all mathematical models, we didn't directly test against placebo, but it gives us confidence that tirzepatide would have been better than a placebo and it may be the best in class.
- [32:35]
A
Pretty amazing results and thanks for explaining it so clearly. I know that our listeners will appreciate that we're about out of time. Are there any final thoughts that you have for our listeners?
- [32:47]
B
Well, stay tuned. The field is going crazy and as we pivot now from focusing on treating people with diabetes and risk for cardiovascular disease to treating people with overweight and obesity from everything we've learned about these nutrient stimulated hormonal modulators, which is a mouthful, obesity medications, so we've pivoted now we're taking the entire incretin modulation and modulating other pathways like glucagon. And now we're doing and to your point, you know, the FDA is no longer the European medicine, they're no longer requiring the outcomes trials. But what is wonderfully reassuring is that companies are racing towards doing cardiovascular outcomes assessment even though they don't have to do it. So these new medicines, we're now focusing on people with overweight and obesity and not just diabetes. And we're doing cardiovascular outcomes trials left and right and the field is, is we're going to be talking for 15 years about these.
- [33:48]
A
Well, that's exciting and we're definitely going to have you back to do some talking for our listeners here. Dr. Darren McGuire, thank you so much for joining us.
- [33:57]
B
All right, thanks so much, Neil. This is always fun and most of.
- [34:01]
A
All, as always, thanks to our listeners. Thank you for joining us on this second of a two part series on the CVOTs. This special series of Diabetes Core Update is sponsored by Lilly. We thank you for listening. For the American diabetes association, I'm Dr. Neal Skolnick. Till next time, stay safe and keep learning.
- [34:35]
B
Sam.