PHARMAPULSE

European Heart Journal - Cardiovascular Pharmacotherapy (2023) 0, 1–2

https://doi.org/10.1093/ehjcvp/pvad072

GLP-1 receptor agonists: new game changing

drugs in patients with heart failure with

Downloaded from https://academic.oup.com/ehjcvp/advance-article/doi/10.1093/ehjcvp/pvad072/7287363 by guest on 26 October 2023

preserved ejection fraction and obesity
1,∗ 2
Eri Toda Kato , Basil S. Lewis and Koh Ono3
1
Department of Cardiovascular Medicine and Department of Clinical Laboratory Department, Kyoto University Hospital, 6068507 Kyoto, Japan; 2 Ruth and Bruce Rappaport School
of Medicine of the Technion-Israel Institute of Technology, 3525433 Haifa, Israel; and 3 Department of Cardiovascular Medicine, Kyoto University Hospital, 6068507 Kyoto, Japan

Received 27 September 2023; accepted 29 September 2023; online publish-ahead-of-print 30 September 2023

Over the past decade, glucagon-like peptide-1 receptor agonists

(GLP-1 RAs) have emerged as potent glucose lowering drugs for
individuals with type 2 diabetes (T2DM). GLP-1 RAs have exhibited
a significant reduction in major adverse cardiac events (MACE), po-
sitioning them alongside sodium-glucose co-transporter 2 inhibitors
(SGLT2is) as key drugs for the management of T2DM.1–4
People living with obesity have an increased risk of cardiovascular
disease and an increased incidence of heart failure (HF), notably
HF with preserved ejection fraction (HFpEF). GLP-1 RAs modu-
late energy intake and facilitate weight loss by attenuating appetite
and hunger, as well as promoting satiety. The research study to
investigate how well semaglutide works in people living with heart
failure and obesity (STEP-HFpEF) trial, an international, double-blind,
placebo-controlled study, assessed the impact of once-weekly subcu-
taneous semaglutide (2.4 mg) in individuals with HFpEF (EF ≥45%)
and obesity (BMI >30), specifically excluding those with diabetes or
A1c levels ≥6.5.5 At 52 weeks, semaglutide demonstrated significant
improvements over placebo in KCCQ-CSS (16.6 vs. 8.7), weight re-
duction (−13.3 vs.−2.6%), and 6-min walk test (21.5 vs. 1.2 m). In
addition, patients randomized to semaglutide had lower HF events
(1 vs. 12). Despite limited number of events and the study’s non-
cardiovascular (CV) outcome nature, the result aligns with previous
meta-analyses, suggesting the potential efficacy of GLP-1 RAs’ in
reducing the risk of HF. Importantly, semaglutide had fewer serious
adverse events, a pivotal finding given the historical safety concerns
with developments in weight loss drugs.
The upcoming semaglutide effects on heart disease and stroke
in patients with overweight or obesity SELECT trial evaluated the
effect of semaglutide on harder clinical outcome endpoints, the triple
endpoint of CV death, non-fatal myocardial infarction (MI) or non-fatal
stroke, in people with established CV disease who were overweighted
or obese with no prior history of diabetes. With 1270 MACE events,
the SELECT trial demonstrated a statistically significant reduction in
MACE of 20% for people treated with semaglutide. All three compo-
nents of the primary endpoint contributed to the reduction in MACE.
While the SELECT trial was not a dedicated HF trial, it should provide
further confirmation and additional insights into the existing body of
knowledge.
A critical question remains: Are the observed benefits primarily
a result of weight reduction, or are other pathophysiologic mecha-
Figure 1 Proposed mechanism of GLP-1 RA on HFpEF with
obesity.
nisms at play? Obesity is a metabolic disorder that contribute to the
pathophysiology of HFpEF via both direct and indirect molecular and
physiological mechanisms. These include modulation of cardiac load,
plasma volume, filling pressures, energy expenditure, sympathetic
nervous system activity, cardio-renal interactions, and accumulation
of fat and lipid. Importantly, the inflammatory cascade serves as
a pivotal pathway, triggering endothelial dysfunction, microvascular
dysfunction, atrial fibrosis, and insulin resistance, all of which inter-
act synergistically to contribute to the development of coronary
artery disease, atrial fibrillation, hypertension, diabetes, chronic kid-
ney disease, and ultimately, HFpEF. Notably, in the STEP-HFpEF
trial, the semaglutide group exhibited a significant reduction in C-
reactive protein levels when compared to the placebo group (43.5 vs.
7.3%), hinting at semaglutide’s potential role in mitigating inflammation
(Figure 1).
In summary, GLP-1 RAs, effective glucose-lowering drugs, have now
emerged as key agents in managing obesity, and efforts are underway
to explore their efficacy in treating HF and cardiometabolic benefits
in adolescents. Continued research confirming the broad cardio-
protective impact of GLP-1 RAs beyond A1c reduction could enable
early, evidence-based interventions for CV risks, thereby addressing
public health concerns of obesity and HF while clarifying underlying
mechanisms.

∗
Corresponding author: Corresponding author: Tel: +81-75-751-3111; Fax: +81-75-751-3299; Email: erikato@kuhp.kyoto-u.ac.jp
© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.
All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
2 E.T. Kato et al.
Data availability
No new data were generated or analysed in support of this research.
Conflict of interest: ETK reports receiving lecture fees from Novo
Nordisk, Eli Lilly, and AstraZeneca unrelated to the current work.
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