Effects of Glucagon-Like Peptide 1 Receptor Agonist Initiation in Patients With Heart Failure With Reduced Ejection Fraction and Implantable Cardiac Devices

Values are mean ± SD, n (%), or median (Q1-Q3), unless otherwise indicated. ^aP < 0.05. ^bIncludes a history of previous cardioversion or atrial fibrillation/flutter ablation.

ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin II receptor blocker; ARNI = angiotensin II receptor neprilysin inhibitor; BMI = body mass index; CRT-D = cardiac resynchronization therapy with defibrillator; CRT-P = cardiac resynchronization therapy with pacemaker; EP = electrophysiology; eGFR = estimated glomerular filtration rate; GLP1RA = glucagon-like peptide 1 receptor agonist; HbA_1c = glycosylated hemoglobin; HFH = heart failure hospitalization; ICD = implantable cardioverter-defibrillator; LAVI = left atrial volume indexed; LVEDV = left ventricular end-diastolic volume; LVEF = left ventricular ejection fraction; MRA = mineralocorticoid receptor antagonist; NT-proBNP = N-terminal pro–B-type natriuretic peptide; PM = pacemaker; SGLT2 = sodium-glucose cotransporter 2; T2D = type 2 diabetes; TAPSE = tricuspid annular plane systolic excursion; TTE = transthoracic echocardiography; UACR = urinary albumin-to-creatinine ratio; VF = ventricular fibrillation; VT = ventricular tachycardia.

Values in parentheses are 95% CIs. Mixed-effects restricted maximum likelihood regression models were used to test the mean differences between GLP1RA users and GLP1RA nonusers for the different outcomes as dependent variables, with the sequence (0,1,2,3), the baseline value of the outcome, and the baseline between-group differences (body mass index, device type, history of revascularization, and baseline therapy with sodium-glucose cotransporter 2 inhibitors and ivabradine (ie, variables with P < 0.05 from Table 1) as independent variables. AF time and AF burden were categorized as levels with the regression model testing the interlevel trajectories longitudinally, with a positive coefficient indicating transition to a higher level and a negative value indicating a transition to a lower level. Missing values for each variable studied in each individual sequence are displayed in Supplemental Table 6. ^aP < 0.05.

AF = atrial fibrillation; GLP1RA = glucagon-like peptide 1 receptor agonist; RA = right atrial; RV = right ventricular.

Values are n (%), unless otherwise indicated. Proportion of events in GLP1RA users and nonusers compared by chi-square test or Fisher test depending on an expected count ≥5 or <5, respectively. Total counts of events in GLP1RA users and nonusers were compared by negative binomial regression with the event of interest as the in- dependent variable and GLP1RA use as dependent variable, adjusted for the total follow-up time. The distribution of total VT/VF events, total NSVT events, and total shocks/ ATP, by patient are presented in Supplemental Figures 11 to 13, respectively. A sensitivity analysis including patients without a past medical history of VT/VF or VT/VF ablation is presented in Supplemental Table 2 and the distribution of Total VT/VF events, Total NSVT events and Total shocks/ATP in this group of patients are presented in Supplemental Figures 14 to 16, respectively. A sensitivity analysis in those with previous VT/VF events or VT/VF ablation is presented in Supplemental Table 3. ^aP &t; 0.05.

ATP = antitachycardia pacing; GLP1RA = glucagon-like peptide 1 receptor agonist; HF = heart failure; HFH = heart failure hospitalization; NSVT = nonsustained ventricular tachycardia; PVC = premature ventricular complex; VT = ventricular tachycardia; VF = ventricular fibrillation.

Authors and Disclosures

Pedro Marques, MD, MSC^a,b,c; Christoforos K. Travlos, MD^d; Paula Matias, MD^c; João Sérgio Neves, MD, PHD^b,e; Michael A. Tsoukas, MD^f; Thomas A. Mavrakanas, MD^d; Jacqueline Joza, MD^a; João Pedro Ferreira, MD, PHD^b,g; Abhinav Sharma, MD, PHD^a

From the ^aDivision of Cardiology, McGill University Health Centre, Montréal, Québec, Canada; ^bDepartment of Surgery and Physiology, Cardiovascular Research and Development Center, Faculty of Medicine of the University of Porto, Porto, Portugal; ^cInternal Medicine Department, Unidade Local de Saúde de São João, Porto, Portugal; ^dDivision of Nephrology, McGill University Health Centre, Montréal, Québec, Canada; ^eDepartment of Endocrinology, Diabetes, and Metabolism, Unidade Local de Saúde São João, Porto, Portugal; ^fDivision of Endocrinology, McGill University Health Centre, Montréal, Québec, Canada; and the ^gUniversité de Lorraine, Inserm, Centre d’Investigations Cliniques, Plurithématique 14-33, Inserm U1116, CHRU Nancy, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France.

Biykem Bozkurt, MD, PhD, served as acting Editor-in-Chief and main adjudicator for this paper.

FUNDING SUPPORT AND AUTHOR DISCLOSURES Dr Marques has received salary support by an educational grant from Janssen. Dr Neves has received consulting and speaker fees from AstraZeneca, BIAL, Boehringer Ingelheim, Lilly, Merck, and Novo Nordisk. Dr Tsoukas has received personal fees from Boeh- ringer Ingelheim, AstraZeneca, Janssen, Novo Nordisk, and Eli Lilly. Dr Mavrakanas has received speaker honoraria from Daiichi Sankyo, BMS Canada, Janssen, AstraZeneca, and Pfizer, has served on advisory boards for Boehringer Ingelheim, Bayer, GlaxoSmithKline, and Servier, has received an unrestricted research grant from AstraZeneca and operational grants from the Kidney Foundation of Canada, the Heart and Stroke foundation of Canada, and the Canadian Institute of Health Research, is receiving salary support from the Fonds de Recherche Quebec Santé (Junior 1 Clinician Scholar Award number 298742), and is supported by a Krescent New Investigator Award. Dr Joza has received an investigator-initiated external research program grant from Medtronic and honoraria from Boston Scientific and Medtronic. Dr Ferreira has received research support from AstraZeneca, Boehringer Ingelheim, Novartis, Amgen, Salamandra, and Bial. Dr Sharma has received support from the Fonds de Recherche Santé Quebec Junior 1 clinician scholars’ program and the Canadian Institute of Health Research (grant number 175095), and research, grant, or consultation support from Roche Diagnostics, Boehringer Ingelheim, Novartis, Janssen, Novo Nordisk, Servier, AstraZeneca, Bayer, Vifor, and Takeda. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

ADDRESS FOR CORRESPONDENCE: Dr Pedro Marques, Faculdade de Medicina, Hospital Sao Joao, Medicina Interna, Alameda Hernani Monteiro, Porto, Portugal. E-mail: pedromsmarq@gmail.com. OR Dr Abhinav Sharma, Division of Cardiology, McGill University Health Centre, 1650 Cedar Avenue, Montreal, Québec H3G 1A4, Canada. E-mail: abhinav.sharma@mcgill.ca.

Sidebar

Perspectives

COMPETENCY IN MEDICAL KNOWLEDGE: This study is the first to evaluate the impact of GLP1RA use on heart rate and arrhythmic burden with the use of data from implanted cardiac devices in patients with HFrEF. The findings demonstrate that GLP1RA initiation is associated with significant increases in heart rate and a higher burden of ventricular arrhythmias, raising concerns about their safety in this population. Although these therapies are gaining traction for cardiometabolic risk reduction, their use in HFrEF, particularly among patients with elevated arrhythmic risk, may carry unintended harm. The study highlights the value of device-derived data to assess drug effects on cardiac rhythm and their utility in assessing the safety of incretin-based therapies in HFrEF.

TRANSLATIONAL OUTLOOK: GLP1RAs are increasingly used for cardiometabolic risk modification in patients with obesity and diabetes, including those with heart failure. However, this study suggests that in patients with HFrEF, GLP1RAs may have unintended proarrhythmic effects. Mechanistic studies and prospective randomized trials are needed to better characterize the impact of incretin-based therapies in HFrEF and to identify which subgroups may safely be prescribed these therapies.