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.