Anders Hostrup Larsen1, Niels Jessen2,3,4, Helene Nørrelund5, Lars Poulsen Tolbod6, Hendrik Johannes Harms6, Søren Feddersen7, Flemming Nielsen7, Kim Brøsen7, Nils Henrik Hansson1, Jørgen Frøkiaer6, Steen Hvitfeldt Poulsen1, Jens Sörensen6,8, Henrik Wiggers1. 1. Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark. 2. Department of Clinical Pharmacology, Aarhus University Hospital, Aarhus, Denmark. 3. Department of Biomedicine, Aarhus University, Aarhus, Denmark. 4. Steno Diabetes Centre Aarhus, Aarhus University Hospital, Aarhus, Denmark. 5. Department of Clinical Epidemiology, Institute of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark. 6. Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Aarhus, Denmark. 7. Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark. 8. Department of Medical Sciences, Uppsala Clinical Research Centre, Uppsala University, Uppsala, Sweden.
Abstract
AIMS: The present study tested the hypothesis that metformin treatment may increase myocardial efficiency (stroke work/myocardial oxygen consumption) in insulin-resistant patients with heart failure and reduced ejection fraction (HFrEF) without diabetes. METHODS AND RESULTS:Thirty-six HFrEF patients (ejection fraction37 ± 8%; median age 66 years) were randomised to metformin (n = 19) or placebo (n = 17) for 3 months in addition to standard heart failure therapy. The primary endpoint was change in myocardial efficiency expressed as the work metabolic index (WMI), assessed by 11 C-acetate positron emission tomography and transthoracic echocardiography. Compared with placebo, metformin treatment (1450 ± 550 mg/day) increased WMI [absolute mean difference, 1.0 mmHg·mL·m-2 ·106 ; 95% confidence interval (CI) 0.1 to 1.8; P = 0.03], equivalent to a 20% relative efficiency increase. Patients with above-median plasma metformin levels displayed greater WMI increase (25% vs. -4%; P = 0.02). Metformin reduced myocardial oxygen consumption (-1.6 mL O2 ·100 g-1 ·min-1 ; P = 0.014). Cardiac stroke work was preserved (-2 J; 95% CI -11 to 7; P = 0.69). Metformin reduced body weight (-2.2 kg; 95% CI -3.6 to -0.8; P = 0.003) and glycated haemoglobin levels (-0.2%; 95% CI -0.3 to 0.0; P = 0.02). Changes in resting and exercise ejection fraction, global longitudinal strain, and exercise capacity did not differ between groups. CONCLUSION:Metformin treatment in non-diabetic HFrEF patients improved myocardial efficiency by reducing myocardial oxygen consumption. Measurement of circulating metformin levels differentiated responders from non-responders. These energy-sparing effects of metformin encourage further large-scale investigations in heart failure patients without diabetes.
RCT Entities:
AIMS: The present study tested the hypothesis that metformin treatment may increase myocardial efficiency (stroke work/myocardial oxygen consumption) in insulin-resistant patients with heart failure and reduced ejection fraction (HFrEF) without diabetes. METHODS AND RESULTS: Thirty-six HFrEFpatients (ejection fraction 37 ± 8%; median age 66 years) were randomised to metformin (n = 19) or placebo (n = 17) for 3 months in addition to standard heart failure therapy. The primary endpoint was change in myocardial efficiency expressed as the work metabolic index (WMI), assessed by 11 C-acetate positron emission tomography and transthoracic echocardiography. Compared with placebo, metformin treatment (1450 ± 550 mg/day) increased WMI [absolute mean difference, 1.0 mmHg·mL·m-2 ·106 ; 95% confidence interval (CI) 0.1 to 1.8; P = 0.03], equivalent to a 20% relative efficiency increase. Patients with above-median plasma metformin levels displayed greater WMI increase (25% vs. -4%; P = 0.02). Metformin reduced myocardial oxygen consumption (-1.6 mL O2 ·100 g-1 ·min-1 ; P = 0.014). Cardiac stroke work was preserved (-2 J; 95% CI -11 to 7; P = 0.69). Metformin reduced body weight (-2.2 kg; 95% CI -3.6 to -0.8; P = 0.003) and glycated haemoglobin levels (-0.2%; 95% CI -0.3 to 0.0; P = 0.02). Changes in resting and exercise ejection fraction, global longitudinal strain, and exercise capacity did not differ between groups. CONCLUSION:Metformin treatment in non-diabetic HFrEFpatients improved myocardial efficiency by reducing myocardial oxygen consumption. Measurement of circulating metformin levels differentiated responders from non-responders. These energy-sparing effects of metformin encourage further large-scale investigations in heart failurepatients without diabetes.
Authors: Henrik Wiggers; Lars Køber; Gunnar Gislason; Morten Schou; Mikael Kjær Poulsen; Søren Vraa; Olav Wendelbo Nielsen; Niels Eske Bruun; Helene Nørrelund; Malene Hollingdal; Anders Barasa; Morten Bøttcher; Karen Dodt; Vibeke Brogaard Hansen; Gitte Nielsen; Anne Sejr Knudsen; Jens Lomholdt; Kirsten Vilain Mikkelsen; Bartlomiej Jonczy; Jens Brønnum-Schou; Monica Petronela Poenaru; Jawdat Abdulla; Ilan Raymond; Kiomars Mahboubi; Karen Sillesen; Kristine Serup-Hansen; Jette Sandberg Madsen; Søren Lund Kristensen; Anders Hostrup Larsen; Hans Erik Bøtker; Christian Torp-Petersen; Hans Eiskjær; Jacob Møller; Christian Hassager; Flemming Hald Steffensen; Bo Martin Bibby; Jens Refsgaard; Dan Eik Høfsten; Søren Mellemkjær; Finn Gustafsson Journal: Am Heart J Date: 2020-10-09 Impact factor: 4.749
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