Circulation May 10, 2022 Issue

This week, please join Guest Host Mercedes Carnethon and
Author Brendon Neuen as they discuss the article "Sodium-Glucose
Cotransporter 2 Inhibitors and Risk of Hyperkalemia in People
With Type 2 Diabetes: A Meta-Analysis of Individual Participant
Data from Randomized, Controlled Trials."


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-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National
Heart Center 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:


Greg, this week's feature paper is on one of my favorite topics,
SGLT2 inhibitors. And this time, looking at their association
with the risk of hyperkalemia in people with type-two diabetes.
Now this is something we've all been waiting to look at. It's a
meta-analysis of individual participant data from randomized
controlled trials, so a very important, clinically applicable
discussion coming right up. But first, I'm actually going to talk
to you about text messages.


Dr. Greg Hundley:


Wow, Carolyn. I can't wait to hear about this article.


Dr. Carolyn Lam:


Well, specifically the TEXTMEDS randomized clinical trial, which
is our first paper today. It is a trial that examined the
effectiveness of text-message delivered cardiac education and
support on medication adherence following an acute coronary
syndrome.


Dr. Carolyn Lam:


This is from Dr. Clara Chow from University of Sydney and her
colleagues, who performed a single blind multi-center randomized
controlled trial of post-ACS patients across 18 rural and urban
centers and three time zones in Australia. The control group
received usual care, and the intervention group additionally
received multiple motivational and supportive weekly text
messages on medications, and healthy lifestyle, with the
opportunity for two-way communication.


Dr. Greg Hundley:


Wow, Carolyn. So text messaging to facilitate medication
adherence. I can't wait to hear. So what did they find?


Dr. Carolyn Lam:


I think the design, it's such a neat study. However, the study
found no significant impact on the primary outcome of medication
adherence at six and 12 months, nor on LDL cholesterol or blood
pressure.


Dr. Carolyn Lam:


However, intervention participants were more likely to achieve a
normal body mass index and to eat guideline-recommended servings
of fruit and vegetables. Qualitative analysis demonstrated a high
level of acceptability, utility in being a unified source of
information, high program engagement, and emotional support,
especially during times of uncertainty.


Dr. Greg Hundley:


Interesting, Carolyn. Sounds like an impact on diet, so what did
we learn from this study?


Dr. Carolyn Lam:


Well, customized and personalized text message-based prevention
programs are indeed a scalable and low-cost means of delivering
consistent education and support to patients following
hospitalization for ACS. So this study shows it's feasible. The
lack of impact, however, on medical adherence, though with better
adherence to healthy lifestyle practices, suggests that maybe
external factors, such as cost, may strongly influence medical
adherence. These need to be addressed, in addition to education
programs, to improve medical adherence. But all of this is
discussed in a beautiful editorial entitled, "Opportunities and
Challenges of Mobile Health Tools to Promote Health Behaviors" by
Drs. Sharma and Avram.


Dr. Greg Hundley:


Very nice. Carolyn, what a great summary. Well, my paper comes to
us from Professor Mario Delmar from New York University School of
Medicine, and Carolyn, exercise training as well as
catecholaminergic stimulation increases the incidence of
arrhythmic events in patients affected with arrhythmogenic right
ventricular cardiomyopathy or ARVC, and this correlates with
plakophilin-2 mutations. Now, Carolyn, separate data show that
reduced abundance of plakophilin-2 leads to dysregulation of
intracellular calcium homeostasis, and Carolyn, these authors
studied the relation between exercise and or catecholaminergic
stimulation, intracellular calcium homeostasis, and
arrhythmogenesis in plakophilin-2 deficient murine hearts.


Dr. Carolyn Lam:


Ooh. So what were the effects?


Dr. Greg Hundley:


Right, Carolyn. For training, the mice underwent 75 minutes of
treadmill running once per day, five days each week, for six
weeks. And the authors observed that exercise disproportionately
affected calcium intracellular homeostasis in plakifilin-2
deficient hearts, in a manner facilitated by stimulation of
intracellular, beta-adrenergic receptors or hyper-phosphorylation
of phospholamban.


Dr. Greg Hundley:


Now these cellular changes created a pro-arrhythmogenic state
that can be mitigated by plakophilin receptor blockade.
Additionally, Carolyn, these authors' data unveiled an
arrhythmogenic mechanism for exercise-induced or
catecholaminergic life-threatening arrhythmias in the setting of
a deficit in plakophilin-2. They suggest that membrane-permeable
beta blockers are potentially more efficient for ARVC patients.


Dr. Greg Hundley:


And also they highlight the potential for ryanodine-receptor
channel blockers as treatment for the control of heart rhythm in
this population at risk, and propose that plakophilin dependent
and phospholamban-dependent, ARVC-related arrhythmias have a
common mechanism.


Dr. Carolyn Lam:


Wow, thanks again, Greg. That was really, really a nice
explanation. Well, for this next original paper, it looks at the
question of the association between major bleeding and non-major
clinically relevant bleeding, with subsequent mortality in
hospitalized patients, and authors did this by exploring this
relationship in the MAGELLAN and MARINER trials of extended
thrombo-prophylaxis in hospitalized medical patients.


Dr. Greg Hundley:


Wow. Carolyn. I can't quite remember, and maybe for our
listeners, remind us of the design of the MAGELLAN and the
MARINER trials.


Dr. Carolyn Lam:


These trials evaluated, whether rivaroxaban compared with
enoxaparin or placebo, could prevent venous thromboembolism
without increased bleeding. The authors, led by Dr. Spyropoulos
from the Feinstein Institute of Medical Research in New York,
hypothesized that patients with major bleeding, but not those
with non-major clinically relevant bleeding, would be at an
increased risk of all-cause mortality. So Greg, would you like to
guess what they found?


Dr. Greg Hundley:


Oh, Carolyn, you've put me on the spot here. I'm not sure.


Dr. Carolyn Lam:


Maybe just, did the authors get it right or wrong? Just....


Dr. Greg Hundley:


I'm saying, they got it right.


Dr. Carolyn Lam:


Oh, always clever. They found that compared to patients with no
bleeding, the risk of all-cause mortality for patient with
non-major clinically relevant bleeding was not increased in
MARINER, but was increased in MAGELLAN. Major bleeding, however,
was associated with a higher incidence of all-cause mortality in
both studies, while trivial bleeding was not associated with
mortality in either study. These results really inform the risk
benefit calculus of extended thromboprophylaxis in medically ill
patients.


Dr. Greg Hundley:


Wow. Carolyn, great presentation. We've got some other articles
in this issue. And let me tell you about two that I have. First
is a Research Letter from Professor Frankel entitled "Trends in
Opioid Use after Cardiac-Implantable Electronic Device Procedures
in the United States, between the years of 2004 and 2020." And
Tracy Hampton, from the National Association of Science Writers,
presents some very recent news in the world of cardiology.


Dr. Carolyn Lam:


Nice. Well, there's an exchange of letters as well between Drs.
Yang and Nagareddy regarding the article "Retention of NLP3
Inflammasome-Primed Neutrophils in the Bone Marrow is Essential
for Myocardial Infarction-Induced Granulopoiesis." And finally,
in the Editor’s Page, a nice piece from Drs. Joe Hill, Darren
McGuire, and James de Lemos on “Circulation: Best Papers, 2021.”
Gosh, really, really nice issue. Now let's go on, though, to the
feature discussion, yeah?


Dr. Greg Hundley:


You bet.


Dr. Mercedes Carnethon:


Welcome to this episode of Circulation on the Run podcast. My
name is Mercedes Carnethon, one of the associate editors, and I'm
a professor of preventive medicine at the Northwestern University
Feinberg school of Medicine. I'm really excited today to have a
guest with us. Dr. Brendon Neuen, who has shared with us his
really outstanding research on SGLT2 inhibitors and the risk of
hyperkalemia in people with type-two diabetes, a meta-analysis.
So welcome to our podcast today, Brendon.


Dr. Brendon Neuen:


Thanks very much for having me Mercedes. It's a real pleasure to
be here.


Dr. Mercedes Carnethon:


Well, thank you for joining us. We're really pleased that you
chose Circulation to share with us your really important
findings. Can you tell us a little bit about the rationale for
your study and how you carried out your work?


Dr. Brendon Neuen:


Yeah, absolutely. So we know that in people with diabetes and
people with CKD, hyperkalemia is a common occurrence, and it's a
problem for two reasons as you'd be aware. Firstly, it is
associated with cardiac dysrhythmias and secondly, perhaps at
least as importantly, it limits the optimal use of treatments
that reduce kidney disease progression and heart failure events.
So that is, agents that block the renin angiotensin aldosterone
system.


Dr. Brendon Neuen:


We now know, and we've got robust evidence from large outcome
trials, that SGLT2 inhibitors reduce the risk of heart failure
and kidney disease progression in people with and without
diabetes, but we haven't really, up and until now, systematically
evaluated their effect on potassium outcomes, particularly
hyperkalemia. And so we set out to assess whether these agents
affect serum potassium levels and alter the risk of hyperkalemia
as well as hypokalemia.


Dr. Mercedes Carnethon:


Thank you. That sounds like a really excellent and well needed
study, given how much we've heard within the field about the
benefits of SGLT2 inhibitors. It's nice to see a careful
evaluation of what some of the considerations are in their use.
So tell us a little bit about how you carried out this study and
what you ultimately found.


Dr. Brendon Neuen:


What we did was, we identified clinical trials that enrolled
people with type two diabetes at high cardiovascular risk or with
chronic kidney disease. And what we did is, we approached the
investigators of each of these trials and asked them to
collaborate on a large meta-analysis using individual participant
data.


Dr. Brendon Neuen:


What that allowed us to do was, then, standardize across all of
the trials of different outcome definitions, and allowed us to
assess the effective SGLT2 inhibitors on a primary outcome of
time to first serum potassium greater than or equal to six,
defined as serious hyperkalemia, as well as hypokalemia,
investigator-reported hyperkalemia events, and a range of other
potassium-related outcomes in a broad population, including
people with chronic kidney disease, people with heart failure,
and people using different concomitant medications, such as
diuretics and MRAs in the background.


Dr. Mercedes Carnethon:


So thank you, Brendon, for the explanation of the use of the
meta-analytic design and the entry criteria of type-two diabetes
and chronic kidney disease. Can you tell us, what were the
outcomes across these studies?


Dr. Brendon Neuen:


The primary outcome we evaluated was time to first serious
hyperkalemia, defined as a serum potassium greater than or equal
to six, as well as a range of other potassium-related outcomes,
including investigator reported hyperkalemia, change in potassium
over time, as well as hypokalemia, defined as a serum potassium
less than 3.5.


Dr. Brendon Neuen:


What we found was that overall SGLT2 inhibitors reduce the risk
of serious hyperkalemia by about 16%. And that effect was
consistent across the agents within the class, and across
different subpopulations and trials. This effect was supported by
a 20% risk reduction in investigator-reported hyperemia events
and importantly, there was no difference in risk of hypokalemia,
that is a serum potassium less than 3.5, between SGLT2-treated
and placebo-treated participants.


Dr. Mercedes Carnethon:


Thank you for that summary. You know, one of the very impressive
aspects of this clinical trial is certainly the size and the
number of participants. Brendon, I was really struck by your
description of the consistency of findings across the subgroups.
And in particular, when I reviewed the findings in the paper, I
noticed that serious hyperkalemia was higher in those with poorer
kidney function. Did you find that surprising?


Dr. Brendon Neuen:


From clinical practice, we know that one of the major
determinants of hyperkalemia risk is kidney function. It's a
major problem that we run into in people with more advanced CKD.
And what that means is that for people with more advanced chronic
kidney disease, who are at high risk of hyperkalemia, the
absolute benefits of SGLT2 inhibition on hyperkalemia risk are
likely greater in these individuals, because they're at high risk
of this outcome.


Dr. Brendon Neuen:


Other patients who might be at increased risk of hyperkalemia
include those with heart failure or those taking
mineralocorticoid receptor antagonists at baseline. And so you'd
expect that if the relative effects are consistent across many
subgroups, then the absolute risk reductions are likely to be
larger in people taking MRAs or people with more advanced CKD.


Dr. Mercedes Carnethon:


Thank you so much for summarizing the importance of these
findings and what they mean for our clinical audience. It's
wonderful to have this sort of information from a meta-analysis
because it allows us large sample sizes, where we can do things
like you describe, such as describing subgroup effects.


Dr. Mercedes Carnethon:


It also presents us with very robust evidence that can be taken
into clinical practice for our clinical audience to use. Based on
what you found, how do you anticipate that these findings can be
used by our clinicians?


Dr. Brendon Neuen:


Well, thanks, Mercedes. I think the reduction in risk of
hyperkalemia that is observed in these data suggests that SGLT2
inhibitors might enable better use of other proven therapies that
reduce cardio-renal risk in people with chronic kidney disease
and people with heart failure. We all know that in treating these
high risk patients, hyperkalemia is a problem. And by reducing
the risk of hyperkalemia with SGLT2 inhibitors, it might enable
better use of renin angiotensin system blockade and
mineralocorticoid receptor antagonists in people with chronic
kidney disease and heart failure.


Dr. Mercedes Carnethon:


So you've provided a really excellent overall summary of the
impact of these finding for clinical practice and the possible
next steps. I wanted to end on a note of asking you what
surprised you about these findings that might lead to further
future investigations.


Dr. Brendon Neuen:


Thanks, Mercedes. I think that's a really interesting question.
What was somewhat surprising, but also reassuring, was the
consistency of the treatment effect on hyperkalemia, regardless
of how we defined it, whether that was defined based on
investigator-reported hyperkalemia events or central
laboratory-measured serum, potassium levels, the treatment effect
was very consistent. And I think that gives us some confidence
about the robustness of these findings and their application to
clinical practice.


Dr. Mercedes Carnethon:


Well, thank you so much, Brendon. I have really enjoyed this
discussion with you today and this really important paper that is
describing an important safety outcome for SGLT2 inhibitors in
patients with type two diabetes. And again, I really want to
thank you for sharing your excellent work with us here at
Circulation. I anticipate that our readership, when they leave
this podcast and pick up their journals, will be thrilled to read
about all of the details about the excellent work that you and
your team have carried out. So thank you very much for joining us
today.


Dr. Brendon Neuen:


Thanks very much for having me, Mercedes. It was a real pleasure.


Dr. Mercedes Carnethon:


Thank you, and thank you again to our audience for joining us for
this episode of Circulation on the Run.


Speaker 5:


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.