Circulation May 31, 2022 Issue

This week, please join author Ronald Goldberg, Editorialist Hertzel Gerstein, and Guest Editor Rury Holman as we discuss the article "Effects of Long-term Metformin and Lifestyle Interventions on Cardiovascular Events in the Diabetes Prevention Program and Its Outcome Study" and the editorial "Shouldn't Preventing Type 2 Diabetes Also Prevent Its Long-Term Consequences?"

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-host. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Centre and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Today. Oh, this feature discussion involves the glance of diabetes. Truly this interview, I felt like I was sitting among gurus and just learning so much about diabetes, the history and the whole topic is about long term metformin and lifestyle interventions on cardiovascular events in the Diabetes Prevention Program and its outcome study. Now, way more than that, we discussed. You have to have to listen. But okay, before that, let's summarize today's issue for our listeners. Shall we, Greg?

Dr. Greg Hundley:

You bet Carolyn. So the first paper that I've got to discuss today really comes to us from the world of interventional cardiology and it's led by Dr. William Fearon from Stanford University Medical Center. Well, Carolyn previous studies have shown quality of life improves after coronary artery revascularization, more so after coronary artery bypass grafting than after PCI. Now this study aimed to evaluate the impact of fractional flow reserve guidance, and current generation zotarolimus drug-eluting stents on quality of life after PCI compared with CABG.

Dr. Greg Hundley:

Now the study emanates from fractional flow reserve versus angiography for multi vessel evaluation or the fame three trial. And Carolyn, that's a multicenter international trial that included 1500 patients with three vessel coronary artery disease who were randomly assigned to either CABG or FFR guided PCI. Now, what did they assess? So quality of life was measured using the European Quality of life Five Dimensions. And we're going to abbreviate that EQ-5D questionnaire baseline, one, and then 12 months following the procedure. Also, Canadian cardiovascular class angina grade and working status were assessed at the same time points, and then also an additional time point in six months. And the primary objective was to compare the EQ-5D summary index at 12 months, and secondary endpoints included angina grade and work status.

Dr. Carolyn Lam:

Ooh, interesting Greg. So quality of life in the theme three trial. All right. So what did they find?

Dr. Greg Hundley:

Right, Carolyn. So the EQ-5D, so that... European Quality of life Five Dimensions summary index at 12 months did not differ between the PCI and CABG groups, but the trajectory over the 12 months at the one month time interval between PCI and CABG did differ. Now, the proportion of patients with the Canadian cardiovascular class or CCS2 or greater angina 12 months was 6.2% versus 3.1% respectively in the PCI group compared with the CABG group. Additionally, a greater percentage of younger patients, so those less than 65 years old were working at 12 months in the PCI group compared with the CABG group. So in summary, Carolyn, in the fame three trial, quality of life after fractional flow reserve guided PCI with current generation DS compared with CABG was similar in one year. And the rate of significant angina was low in both groups and not significantly different. However, the trajectory of improvement in quality of life was significantly better with PCI as was working status in those less than 65 years old.

Dr. Carolyn Lam:

Wow. Thanks Greg. Hey, guess what? It's time for Greg quiz. The next paper is about the Chocolate Touch Study. So, Greg, is this about, A, the benefits of eating chocolate? B, the benefits of chocolate mud baths? Or C, the benefits of a second generation drug coated balloon?

Dr. Greg Hundley:

So, Carolyn, I just have one question. Where in the world do we get the benefits of chocolate mud bath? I don't think that's right. I do love eating chocolate, but I am going to go with the benefits of the second generation drug coated balloon.

Dr. Carolyn Lam:

Yeah, yeah, yeah. I made it easy for you. All right. So first generation drug coated balloons have significantly reduced the rate of restenosis compared to balloon angioplasty alone. However, high rates of bailout stenting and dissections persist. The chocolate touch drug coated balloon is a nitinol constrained balloon designed to reduce acute vessel trauma and inhibit neointima formation and restenosis, so you were right, Greg. In today's study led by Dr. Shishehbor, from University Hospital's Harrington Heart and Vascular Institute at Cleveland, Ohio. They studied 313 patients with claudication or ischemic rest pain, and superficial femoral or popliteal disease. And randomized them one to one to the chocolate touch or Lutonix Drug Coated Balloon at 34 sites in the United States, Europe and New Zealand. The primary efficacy endpoint was drug coated balloon success defined as primary patency at 12 months. The primary safety endpoint was freedom from major adverse events at 12 months. A composite of target limb related death, major amputations, or reintervention. Both primary endpoints was assessed for non-inferiority and have met sequential superiority testing for efficacy was pre-specified.

Dr. Greg Hundley:

Interesting, Carolyn. So this nitinol constrained balloon designed to reduce acute vessel trauma. So, what were the results of this study?

Dr. Carolyn Lam:

So in this trial, the second generation chocolate touch drug coated balloon met both non-inferiority endpoints for efficacy and safety. And was more effective than the Lutonix Drug Coated Balloon at 12 months for the treatment of femoral popliteal disease. Cool, huh?

Dr. Greg Hundley:

Very interesting. Great summary, Carolyn. So Carolyn, my next paper comes to us from the world of preclinical science. And the impact of three dimensional chromatin topology on transcriptional dysregulation and pathogenesis in human dilated cardiomyopathy remains elusive. And so these authors led by Professor Lei Jiang from Guangdong Provincial People's Hospital, and Guangdong Academy of Medical Science, generated a compendium of 3D epigenome and transcriptome maps from 101 biobank human dilated cardiomyopathy, and non-filing heart tissues and mouse models to further interrogate the key transcription factor implicated in 3D chromatin organization, and transcriptional regulation in dilated cardiomyopathy pathogenesis.

Dr. Carolyn Lam:

Oh, wow. Sounds like a lot of work. What did they find, Greg?

Dr. Greg Hundley:

Right, Carolyn. So they found that enhancer promoter connectomes are extensively rewired in human dilated cardiomyopathy, which reside in pre accessible chromatin size and also hand one drives the rewiring of enhancer promoter connectome to induce dilated cardiomyopathy pathogenesis.

Dr. Carolyn Lam:

Okay, Greg. So what are the clinical implications?

Dr. Greg Hundley:

Right, Carolyn. So first, dilated cardiomyopathy enriched enhancer promoter loops identified in this study could be developed as novel 3D genomic biomarkers for dilated cardiomyopathy. And then second Carolyn, targeting hand one might be used as a novel approach for therapeutic intervention in patients with dilated cardiomyopathy.

Dr. Carolyn Lam:

Oh, nice. Greg. Well, also in today's issue, there's an On My Mind paper by Dr. Brook, entitled, “The Doctor is Out, New Tactics and Soldiers For our Losing Battle against Hypertension.” In another paper, we have Molly Klemarczyk bringing us highlights from the Circulation Family of Journals.

Dr. Greg Hundley:

Right, Carolyn. And also from the mailbag, there's a Research Letter from Professor Baggish, entitled, “Cardiovascular Outcomes in Collegiate Athletes, Following SARS-CoV-2 Infection: The 1-Year Follow Up From the Outcomes Registry for Cardiac Condition in Athletes.” Well, Carolyn, how about now we get onto that feature discussion and learn a little bit more about the long term metformin and lifestyle interventions on cardiovascular events in the Diabetes Prevention Program.

Dr. Carolyn Lam:

Hold on to your seats, everyone. Here we go. We know that lifestyle intervention and metformin have been shown to prevent diabetes. However, what is their efficacy in preventing the cardiovascular disease associated with diabetes development? Well, guess what? We're going to have data on that through today's feature paper and what a star crowd I'm talking to today. We have Dr. Ron Goldberg and he's a first end corresponding author from the University of Miami Diabetes Research Institute. We have the editorialist Dr. Hertzel Gerstein from McMaster University Population Health Research Institute. And a guest editor for this paper, Dr. Rury Holman from University of Oxford. I have to admit I'm starstruck. You gentlemen have totally defined the field. I cannot wait to learn more, but shall we start with you, Dr. Goldberg? Could you tell us a little bit more about your paper, what you did, what'd you found?

Dr. Ronald Goldberg:

So the background is that the Diabetes Prevention Program started in 1996 was a Diabetes Prevention Program to test the effects of intensive lifestyle intervention versus metformin, versus placebo on the prevention of diabetes in over 3000 individuals with impaired glucose tolerance, a form of prediabetes. And after demonstrating the efficacy of those interventions over about three years, we went on to do a follow up study in which the metformin group continued to receive it. Everybody got lifestyle because it worked so effectively. And we are now reporting after a further 18 years of follow up on the question of whether these interventions, now 21 years later, had any effect on cardiovascular outcomes. The background to that of course, is that people with prediabetes have a somewhat increased risk for heart disease and that rate increases as diabetes develops, particularly with severity of hyperglycemia and duration of diabetes. So, that was the study and we're now reporting on whether these interventions had a significant effect on the major cardiovascular.

Dr. Carolyn Lam:

Well, first Dr. Goldberg, congratulations on the foresight to get the informed consent and to plan ahead to be able to get these valuable data. But because I know this is going to be a critical point later. Could you tell us a little bit about the completeness of follow up and perhaps surveillance for outcomes before you share the results?

Dr. Ronald Goldberg:

Absolutely. So, 86% of the original randomized group of participants agreed to continue with a follow up study, so there was a loss at that point. And then of course, over 18 years of follow up, there's going to be a further loss. Some due to death and some due to loss to follow up. But despite that, I would say the group that entered the follow up study, we were able to maintain follow up in 85%.

Dr. Carolyn Lam:

Fantastic. And the results?

Dr. Ronald Goldberg:

The findings were that we found no significant effect of either of the two active interventions on our primary cardiovascular outcome, which was nonfatal myocardial infarction, stroke and fatal cardiovascular disease. We also had an extended outcome with more events in it, and similarly found no significant benefit or harm from either of those two intervention.

Dr. Carolyn Lam:

Oh, I love that paper. What a great, great, perhaps surprising conclusion that Dr. Gerstein loved the title of your editorial, you crystallize it. Shouldn't preventing type two diabetes also prevent long term consequences? So please tell us what was your thoughts when you saw this paper and how you frame it?

Dr. Hertzel Gerstein:

Thanks very much, Carolyn. And first of all, I was very impressed by the extensive amount of work and analysis done by Dr. Goldberg and his team. I thought that it's wonderful to see this sort of long term follow up. I've had the privilege in the past of speaking together with the DPP team on their trial and in their long term follow up. And I continue to be impressed by the extensive amounts of work and data collected and a rigor and academic value of the analysis. So, that was my very first impression and obviously it's a pleasure to write on this. I think the findings are clearly important and they both highlight the importance of long-term follow up as well as highlight the difficulties of long-term follow up in a study like this.

Dr. Hertzel Gerstein:

So this was a study done in a trial, originally done in a fairly young cohort of individuals who had very low risk for cardiovascular events. And over their 18 year follow up that Dr. Goldberg Ron described, the actual annual event rate for the primary outcome was 0.6% per year in that ballpark. Now, anybody... I've had the privilege as Ron Avery of doing many cardiovascular trials and we all know that we would never start a trial recruiting people with an event rate of 0.5% per year, 0.6% per year, because we would have to recruit 30,000 people and follow them for seven years in order to accrue enough events to be able to detect a clinically relevant benefit of the therapy. So because of this low event rate, the advantage was the long term follow up, the 26th year, I think it was in the end follow up. No, it was a 21 year median follow up period, because of the long follow up, you get a little bit away from the advantage of the low event rate.

Dr. Hertzel Gerstein:

But even then, over the course of the 21 years, there were only about 310 first cardiovascular events and most cardiovascular outcomes trials, for instance, we need close to at least a 1000, 500 to a 1000 is what we like to see. So that being said, it's perhaps not surprising that we didn't see a benefit of diabetes prevention because even if diabetes reduces the risk of a cardiovascular event by a quarter, by 25%, there would've only been a 50, 50 chance of detecting that with this particular cohort of people.

Dr. Hertzel Gerstein:

So I would say that the most conservative assumption is that diabetes prevention doesn't reduce the event rate by 25% or less or 30, but it's certainly... pardon me, by 25% or more, it could reduce it by 20%, 15% we would not have detected at all, or Ron would not have detected and his team would not have detected it with this thing. So I think that to me is the most important caveat in interpreting this does not mean that diabetes prevention has no effect on cardiovascular outcomes.

Dr. Hertzel Gerstein:

It means that diabetes prevention doesn't have a moderate or smaller effect. So, that's I think the most important message to take and as is even mentioned in the paper by Ron and the team is that there has been at least one diabetes prevention trial conducted in China many, many years ago that showed clearly that people who were randomly assigned to the diabetes prevention arm, 26 years later did have lower cardiovascular events and even death than people who were in the control arm. So, I think this adds to the story but it's clearly like everything, not the final word in this, but it certainly adds a lot of important data.

Dr. Carolyn Lam:

Oh, I would love to hear Dr. Goldberg's response to that. But before that, Dr. Holman, could I ask you to weigh in as well?

Dr. Rury Holman:

Yes. Sure. So, I agree with Hertzel that this is underpowered, but this is a question I've long wanted to see the answer to. And I congratulate Ron and his team for actually doing the work. All major studies should have long term follow up. People should be consented for life so that we can answer these questions. And Hertzel even though the power is perhaps minimal, we still need to do this analysis.

Dr. Rury Holman:

And if there had been a dramatic result, then we'd have all been very excited. I think one of the issues... one, if I could just bring it up, you mentioned the look ahead study in your discussion as being a negative dietary intervention. But I have a slightly different take on that. When you look at that paper in detail, what you see is that the people in the usual care group forgot quite a lot more risk factor reduction medications, and that's because their usual care physicians spotted the fact that their risk factor levels were higher than in the intensive care group, of course it was blinded at that point. But there's a whole point here is, in your paper you show an increase in the statin proportion, which is higher in the placebo group compared with the metformin and your intensive lifestyle, significantly so for the lifestyle one. So I'm just wondering whether even the low power was further blunted by the drop in effects of these other medications.

Dr. Ronald Goldberg:

Thanks very much for those comments guys, I think they're spot on. Let me first respond Hertzel with my thoughts on this, and then go over to your point, Rury. I think it's really interesting to look back over time and realize how much medical management has changed. And that goes right to your point, Rury, that doing a clinical trial like this where the primary care physicians are informed about what we're doing, what... communicated with on a regular basis, particularly when their patients develop diabetes, it just heightens the entire level of medical management. And I think you're absolutely right, but it's interesting to see what's happened to cardiovascular disease over the last 25 years, both in the general population and in the prediabetic population, the risk of cardiovascular disease has gone down. And then on top of that, we've got this very intensive cardio prevention intervention by primary care physicians, with high rates of statin usage, high rates of any hypertensive treatment, even the placebo group to your question, really lost weight.

Dr. Ronald Goldberg:

And they knew full well what was... and this was a very hands on type of study where our participants were really followed now for all these years, really became integrated with the research team. And so everybody knew what everybody else was doing. And so I'm sure the placebo effect was very strong, but I think nevertheless... Oh, and the last point I wanted to make was of course, the severity of the diabetes, even though 60% are developed diabetes, the severity of the diabetes was relatively mild. Even in those who developed diabetes, we know their average A1C was only about 6.7. And so I think that has a lot to do with blunting the acceleration effect of diabetes on cardiovascular disease. So, I think all of these factors contributed together to produce a negative result. But I think an important message, nevertheless.

Dr. Hertzel Gerstein:

I can highlight that point, that Ron was saying is that if diabetes prevention is going to prevent cardiovascular outcomes, it's going to do that because of a difference in glycemic exposure. The diabetes is by definition a disease of an elevated blood sugar. So if diabetes prevention prevents cardio, it means that the blood sugar's going to be lower than it would otherwise be. So if there's very little difference over the long term follow up in blood sugar because of co-intervention and therapy of all the treatment groups, then that would eliminate a lot of the benefits of diabetes prevention, because these are patients who are in this trial, who are being scrutinized even more than they would be if they were out there free range without being involved in any follow up. So, that's a spot on point. Rury, you wanted to comment.

Dr. Rury Holman:

Yeah. So, Hertzel just to expand on that. Obviously the glycemic impact on macrovascular disease is relatively modest compared to the impact on microvascular disease, which of course is what we all saw originally with type 2 diabetes. In fact, in KPDS35, when we looked or calculated what 1% reduction in A1C would do, it would only reduce stroke or MI by about 12 to 14%. So it's quite a shallow slope if you like. And your point is spot on is if that glucose levels are kept low by good treatment and good management role tell us about the great team they have. Then there was no room for a glycemic impact in this particular study. It's another question, whether you think metformin acts by different mechanisms to reduce cardiovascular disease, that's another question I had for Ron that he might like to address, is if there was a magic effect of metformin, why didn't we see that?

Dr. Ronald Goldberg:

And that's a really interesting question, Rury, because you may be aware that we published a paper a few years ago on our assessment of coronary calcification in a subgroup, in about 60% of the population who agreed to do this and who were eligible. And interestingly found that metformin did was accompanied by a reduction in the prevalence of coronary calcium in men, not women.

Dr. Ron Goldberg:

And the effect was actually when we did subgroup analysis, we found it was particularly strong in young men. And actually that gave us some sense of optimism that we might see something when we came to actual events. And of course, as you all know, metformin has beneficial effects on several cardiovascular risk factors. And so the question is whether there is some effect of metformin that might yet be identified, a coronary calcium after all is a surrogate of events and may take time, or it may be that... And we are really interested in the idea that both prediabetes and diabetes are heterogeneous. There's more and more interest in looking at subgroups of individuals who may be more predisposed. And it may be that metformin might have beneficial effects in some of those subgroups.

Dr. Hertzel Gerstein:

But also remember on the other hand, there was a lot of co-intervention with metformin in all groups after the trial was over. So all groups were offered metformin, et cetera. So even if metformin had an effect, it could have easily been washed out by the exposure of all the other groups to metformin during follow up. But Ron, you also touched on both the hope and the frustration too, because if we start thinking about subgroups, we can always think of subgroups. Yeah. But then the problem with subgroups is you have a study, let's say you have a cohort study with 7,000 or 10,000 people and it followed for five years and, oh, well the effect isn't in all 10,000, it's only in 20% of them. So now you have a study of 2000 people, that's not enough to detect an effect in a subgroup.

Dr. Hertzel Gerstein:

So, subgroups just eat away at power in an exponential, not a linear way, so that you just rapidly lose any ability to detect anything. And so, yes, this is going to work in people with these three snips on this gene, in this subpopulation. Good luck, that's the difficulty and the challenge of... We need to find sometimes better or more efficient ways of identifying outcome protective therapies, because we can't keep drilling into some groups because we just don't have the resources to find it really. I don't know what other people feel about that, but.

Dr. Carolyn Lam:

I'm personally so enjoying this conversation as I know the audience is and we covered a lot. I'm sure everyone wants to pick up the paper and the editorial. Now, we talked about being underpowered for the number of studies. We talked about profitable dilution of things like statins, antihypertensive agents, even the crossover of potential treatment in the placebo arm and so on. And then we started talking about, or is it the how you got there and the drug that was used. And here, please don't shoot me, but I just know I have the answers on behalf of everyone else's thinking it. What do you say of people who go, "Well, it's because it's metformin. What if it was an SGLT2 inhibitor? What if it was a GLP-1 receptor agonist?" And as you know, a lot of people say those would in spite of the effect on glucose.

Dr. Hertzel Gerstein:

I can quickly jump in. It's very clear. We've learned this in the last 10 years, is that there are glucose lowering drugs and there are glucose lowering drugs with benefits. And the GLP-1 receptor agonist and the SGLT2 inhibitors are glucose lowering drugs with benefits. They lower glucose, but they seem to have a separate cardioprotective effect. And with the SGLT2 inhibitors that cardioprotective effect does not seem to be related to the glucose lowering. There are a few meta regression analyses that suggest that with the GLP-1 receptor agonist, part of the cardioprotective effect is related to glucose lowering and part is not. And clearly mediation analysis with some of the trials have shown the same thing with the GLP-1 receptor agonist, not really with the SGLT2 inhibitors. So, maybe, that's my spin on this.

Dr. Carolyn Lam:

Dr. Holman.

Dr. Rury Holman:

Yeah. I was going to echo what Hertzel said in that regard, these other agents do have multiple effects. They change weight, they change blood pressure. And so other risk factors are brought into play other than glucose lowerings. We've already agreed, glucose lowering impact on cardiovascular disease is quite modest. I'd rather have it than not, but it wouldn't be my primary way to treat cardiovascular disease. And coming back to Ron's study, which is crucial today, the issue here is whether we could untangle an impact particularly of metformin, which has been foundation drug for type 2 diabetes for so long.

Dr. Rury Holman:

But clearly within the dataset we have here, underpowered it is. There are no clear messages in that respect, which is disappointing, but it doesn't mean that there isn't an effect. With longer follow up, with more data than you might see it. When the study... I'm coming for you Hertzel, was stopped for futility then the hazard ratio has changed, that often the way, not for the right way, but it's often what happens when you stop studies. I wondered if you wanted to comment on that aspect, because I know it's something that you've talked a lot about.

Dr. Carolyn Lam:

Dr. Gerstein. Did you want to?

Dr. Hertzel Gerstein:

I agree with what Rury said. I think the point you're making Rury goes back to power, and the ability to have enough people and enough events to detect and effect and that's clearly true, so...

Dr. Carolyn Lam:

Well, I hate to be the one to break the party up, but we have gone over time and intentionally so, there's just so much learning here. But Dr. Goldberg, could I give you the last say please? What do you think is the important clinical take home message of your paper?

Dr. Ron Goldberg:

Well, I think that the fact that we demonstrated that our study has been able to maintain really low levels of cardiovascular risk factors, low levels of A1C, even though that likely contributed to the negative finding still leaves the physician where the recognition that it is important to identify individuals with prediabetes to Institute Diabetes Prevention Programs, because I think it's entirely possible as I said earlier, and we've begun to identify them, subgroups of individuals who do progress more rapidly and who do warrant a more effective treatment, which would come from an early intervention program.

Dr. Carolyn Lam:

Wow. Thank you so, so much for that. Thank you so much. All three gentlemen for this amazing discussion. Well, audience, you heard it right here on Circulation on the Run from Greg and I thank you for joining us today and don't forget to tune in again next week.

Speaker 6:

This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.