Circulation

EDITORIAL

Do GLP-1 Receptor Agonists Care if You

Have Heart Failure?

Article, see p 1613 Clare Arnott, BMedSci,

MBBS (Hons), PhD

I
n this edition of the journal, Fudim et al1 conclude that the effects of exenatide Bruce Neal, MB ChB, PhD
on clinical outcomes vary according to whether patients have a history of heart
failure, with benefits in those without a diagnosis of heart failure but no effect
in those with established disease. If there truly is an interaction of treatment ef-
fectiveness with a history of heart failure, then this has important implications for
clinical practice and treatment guidelines. If not, then a high-risk patient group
risks exclusion from treatment with an important class of therapy. The broader
context surrounding these analyses provides insight into where the truth lies.
Intervening in the incretin axis has a checkered history with respect to heart
failure. Five years ago, the SAVOR-TIMI trial (A Multicentre, Randomised, Double-
Blind, Placebo-Controlled Phase IV Trial to Evaluate the Effect of Saxagliptin on
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the Incidence of Cardiovascular Death, Myocardial Infarction or Ischaemic Stroke

in Patients With Type 2 Diabetes)2 of the DPP-4 (dipeptidyl peptidase 4) inhibitor,
saxagliptin, reported an increased risk of heart failure in one of the first large-
scale trials of a DPP-4 inhibitor. However, subsequent results from other large trials
evaluating a series of different drugs in the class failed to confirm an adverse effect
on heart failure, suggesting that the SAVOR-TIMI2 finding may have been a chance
observation for a secondary trial outcome. At the same time, there has at no point
been any evidence of a protective effect of DDP-4 inhibitors for heart failure, either
overall or in any patient subgroup.3
With respect to GLP-1 receptor agonists, there were 2 small studies of liraglu-
tide performed in patients with impaired left ventricular ejection fraction in which
the potential for a heart failure risk mediated via an increase in heart rate was iden-
tified.4,5 This concern has not been borne out as the evidence has accumulated. For
every completed large trial of a GLP-1 receptor agonist, there has been a null find-
ing for heart failure, except the Harmony Outcomes study, where a significant pro-
tective effect was observed.6–12 A recent overview of the 7 completed large-scale
trials suggests that null effects for heart failure were observed because statistical
power in each trial was insufficient to detect a real, but small, benefit. Combining
the data indicates protection against heart failure with a summary hazard ratio of
0.91 and a 95% CI extending from 0.83 to 0.99.13 That analysis provides no evi-
dence of differences in effects between the individual trial results or the different The opinions expressed in this article are
not necessarily those of the editors or
drugs evaluated. While the effects of GLP-1 receptor agonists on heart failure are of the American Heart Association.
modest in size, the benefits seem real and are a welcome additional benefit for
Key Words: Editorials ◼ exenatide
patients with diabetes. ◼ GLP-1 receptor ◼ heart failure
The prespecified secondary analysis from the EXSCEL trial (Exenatide Study of
© 2019 American Heart Association, Inc.
Cardiovascular Event Lowering) reported here sought to determine whether effects
of exenatide on clinical outcomes varied according to the presence or absence of https://www.ahajournals.org/journal/circ

Circulation. 2019;140:1623–1625. DOI: 10.1161/CIRCULATIONAHA.119.043303 November 12, 2019 1623

 Arnott and Neal
heart failure at baseline. Overall, during a median of 3.2
years of follow-up, the EXSCEL trial identified no clear
effect on the composite primary outcome of major ad-
EDITORIAL
verse cardiovascular events, the individual components
of that composite, kidney disease, or hospitalization for
heart failure. The benefits that were observed were for
all-cause death and the combined measure of death
and hospitalized heart failure. Dividing the population
according to the baseline presence or absence of heart
failure identified a reduced risk of death in those with-
out heart failure, but not those with heart failure. The
same was true for the composite outcome of death or
hospitalization for heart failure. P values for an interac-
tion by baseline heart failure were significant in each
case with values of 0.031 and 0.015, respectively. There
was no heterogeneity of treatment effects observed for
any other outcome.
Statistical evidence for differences in the effects of
exenatide between patients with and without heart
failure for 2 outcomes, all-cause death as well as the
composite of death and hospitalized heart failure, en-
hances the perceived validity of the observed hetero-
geneity. However, death is part of both outcomes, and
death events comprise three-fourths of the composite
outcome of death and heart failure. With no separately
significant evidence of heterogeneity for hospitalized
heart failure alone, these analyses reflect a difference in
effect for just 1 outcome, death. As a consequence, the
evidence for heterogeneity of treatment effects by the
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presence or absence of heart failure in the EXSCEL trial
is rather less compelling.
Analyses of the effects of randomized treatment in
participant subgroups are a standard and frequently
prespecified component of clinical trial reporting. Explo-
ration of effects in subsets of the study population seek
to provide a deeper insight into the main trial results
and may inform further about the likely generalizability
of the findings beyond the participants included in the
study. However, whether prespecified or not, subgroup
analyses are usually underpowered and are prone to
both failing to detect true interactions of randomized
treatment with participant characteristics and to pro-
ducing spurious indications of interactions that do not
actually exist. As with all such analyses, the interaction
of exenatide with baseline heart failure reported here
should be treated with caution until confirmed by find-
ings from another trial.
The authors also report new assessments of the ef-
fects of exenatide on heart failure that include both first
and recurrent events. The key advantage of such analy-
ses is that for an outcome occurring multiple times in
some patients, statistical power to detect effects can
be enhanced. In EXSCEL, 450 patients experienced at
least 1 hospitalization for heart failure, but there were
713 heart failure hospitalization events in total. The
effect estimate that included recurrent events (hazard
1624 November 12, 2019
GLP-1 Receptor Agonists and Heart Failure
ratio, 0.82 [95% CI, 0.68–0.99]) was separately statis-
tically significant, while the primary analysis based on
just first events was not (hazard ratio, 0.95 [95% CI,
0.79–1.14]). In light of the summary data for the GLP-
1 receptor class indicating a beneficial effect on heart
failure, this new analysis of EXSCEL that includes recur-
rent events most likely reveals a real effect of exenatide
on heart failure, identifiable because of the additional
statistical power afforded.
There was no evidence that the presence or absence
of heart failure at baseline modified the benefit ob-
served in the analysis that included recurrent events.
This may well be because the primary analysis was sta-
tistically unstable and identified a spurious chance find-
ing. It is also the case that the recurrent event analysis
is biased against the detection of a real interaction of
treatment effects with the presence of heart failure.
Second events in an individual without heart failure at
baseline are events in an individual with heart failure,
but were not counted in this way by the approach to
the analysis of recurrent events that was employed.
A limitation of the reported investigation is the in-
complete data describing ejection fraction, which pre-
cludes a reliable assessment of the effects of exenatide
in patients with heart failure with preserved ejection
fraction compared to those with heart failure associ-
ated with reduced ejection fraction. The differences in
pathogenesis and pathophysiology between heart fail-
ure with preserved ejection fraction and heart failure
with reduced ejection fraction, and the specific mecha-
nism by which GLP-1 receptor agonists produce ben-
efit, which includes large reductions in body weight,
raise an at least theoretical possibility that the benefit
of exenatide in heart failure may differ depending upon
baseline ejection fraction.
The role of exenatide in the management of heart
failure among patients with diabetes also needs to be
considered in the context of other therapies available. In
particular, the sodium glucose cotransporter 2 (SGLT2)
inhibitor class provides a large and clearly proven ben-
efit in reducing heart failure hospitalization. Protection
against vascular events with SGLT2 inhibition is indepen-
dent of baseline heart failure status,14 and as reported
at the 2019 Congress of the European Society of Car-
diology in Paris, also independent of diabetes mellitus
status. The DAPA HF trial (Dapagliflozin and Prevention
of Adverse-Outcomes in Heart Failure) done in patients
with or without a diagnosis of diabetes showed protec-
tion against a broad range of vascular outcomes in pa-
tients with heart failure with reduced ejection fraction
treated with dapagliflozin compared to placebo. In both
DAPA HF and the prior SGLT2 inhibitor trials, the magni-
tude of the protective effect against heart failure is sev-
eral times greater than that achieved with GLP-1 recep-
tor agonists. When feasible, clinicians should prioritize
SGLT2 inhibition among patients with diabetes mellitus
Circulation. 2019;140:1623–1625. DOI: 10.1161/CIRCULATIONAHA.119.043303
 Arnott and Neal
at elevated risk of heart failure, but treatment with a
GLP-1 receptor agonist may provide additional protec-
tion and could be substituted if there is intolerance of
SGLT2 inhibition. A GLP-1 receptor agonist might also
be substituted for other glucose lowering medications
without a clear evidence base of cardiovascular benefit
such as sulfonylureas, biguanides, and even insulin.
In conclusion, preventing heart failure and averting
other cardiovascular outcomes remain priorities in the
management of type 2 diabetes mellitus, and GLP-1
receptor agonists are likely to achieve both. While the
subgroup data presented in this analysis of the EXSCEL
trial provide only weak evidence of a differential effect
on vascular outcomes by baseline heart failure status,
the analyses of recurrent heart failure events provide
important additional support for an effect of exenatide
on heart failure. A formal evaluation of the combined
effects of GLP-1 receptor agonists and SGLT2 inhibi-
tion is warranted given the likely additive benefits for
morbidity and mortality in patients with type 2 diabetes
mellitus and concomitant heart failure.15
ARTICLE INFORMATION
Correspondence
Bruce Neal, MB ChB, PhD, The George Institute for Global Health/UNSW
Sydney, PO Box M201, Missenden Rd, NSW, 2050, Australia. Email bneal@
georgeinstitute.org.au
Downloaded from http://ahajournals.org by on September 8, 2020
Affiliations
Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia
(C.A.). Sydney Medical School, Australia (C.A., B.N.). The George Institute for
Global Health, Sydney, Australia (C.A., B.N.). University of New South Wales
Sydney, Australia (C.A., B.N.). Imperial College London, United Kingdom (B.N.).
Acknowledgments
The authors thank Tamara Young and Brendon Neuen for their review of edito-
rial content.
Disclosures
Dr Neal has worked on the CANVAS and CREDENCE trials of the SGLT2 inhibi-
tor canagliflozin, and his institution has received grant funding, honoraria, and
travel reimbursement from Janssen for this. Dr Arnott has no disclosures.
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