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The Heart Failure Association (HFA) of the European Society of Cardiology (ESC) has recently issued a position paper on the role of sodium-glucose co-transporter 2 (SGLT2) inhibitors in heart failure (HF). The present document provides an update of the position paper, based of new clinical trial evidence. Accordingly, the following recommendations are given: center dot Canagliflozin, dapagliflozin empagliflozin, or ertugliflozin have consistently demonstrated to be effective for the prevention of HF hospitalization in patients with type 2 diabetes mellitus and established cardiovascular disease or at high cardiovascular risk. The specifically listed agents are recommended. center dot Dapagliflozin or empagliflozin are recommended to reduce the combined risk of HF hospitalization and cardiovascular death in symptomatic patients with HF and reduced ejection fraction, already receiving guideline-directed medical therapy, regardless of the presence of type 2 diabetes mellitus.

Background: This is the first randomised controlled trial to assess the impact of unsupervised high-intensity interval training on cardiovascular autonomic function in adults with type 2 diabetes. Methods: A total of 22 individuals with type 2 diabetes (age 60 ± 2 years, 17 males) lay in a supine position for 20 min for evaluation of cardiovascular autonomic function, which included (1) time domain measures of heart rate variability, (2) frequency domain measures of heart rate variability and blood pressure variability and (3) baroreflex receptor sensitivity. Participants were randomised into 12 weeks of high-intensity interval training (3 sessions/week) or standard care control group. Results: After 12 weeks, the between-group change in HbA1c (%) was significant (high-intensity interval training: 7.13 ± 0.31 to 6.87 ± 0.29 vs Control: 7.18 ± 0.17 to 7.36 ± 0.21, p = 0.03). There were no significant changes in measures of heart rate variability; R-R interval (ms) (high-intensity interval training: 954 ± 49 to 973 ± 53 vs Control: 920 ± 6 to 930 ± 32, p = 0.672), low frequency/high frequency (high-intensity interval training: 0.90 ± 0.21 to 0.73 ± 0.07 vs Control: 1.20 ± 0.29 to 1.00 ± 0.17, p = 0.203), or blood pressure variability; systolic blood pressure low frequency/high frequency (high-intensity interval training: 0.86 ± 0.21 to 0.73 ± 0.10 vs Control: 1.06 ± 0.26 to 0.91 ± 0.14, p = 0.169). At baseline, HbA1c was negatively correlated with baroreflex receptor sensitivity (r = –0.592, p

Additional file 1: Table S1. Competing risk regression with prediction of Diabetes Mellitus (n=55) while treating death (n=313) as a competing event.

Type 2 diabetes mellitus (T2DM) is common in patients with heart failure (HF) and associated with considerable morbidity and mortality. Significant advances have recently occurred in the treatment of T2DM, with evidence of several new glucose-lowering medications showing either neutral or beneficial cardiovascular effects. However, some of these agents have safety characteristics with strong practical implications in HF [i.e. dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RA), and sodium-glucose co-transporter type 2 (SGLT-2) inhibitors]. Regarding safety of DPP-4 inhibitors, saxagliptin is not recommended in HF because of a greater risk of HF hospitalisation. There is no compelling evidence of excess HF risk with the other DPP-4 inhibitors. GLP-1 RAs have an overall neutral effect on HF outcomes. However, a signal of harm suggested in two small trials of liraglutide in patients with reduced ejection fraction indicates that their role remains to be defined in established HF. SGLT-2 inhibitors (empagliflozin, canagliflozin and dapagliflozin) have shown a consistent reduction in the risk of HF hospitalisation regardless of baseline cardiovascular risk or history of HF. Accordingly, SGLT-2 inhibitors could be recommended to prevent HF hospitalisation in patients with T2DM and established cardiovascular disease or with multiple risk factors. The recently completed trial with dapagliflozin has shown a significant reduction in cardiovascular mortality and HF events in patients with HF and reduced ejection fraction, with or without T2DM. Several ongoing trials will assess whether the results observed with dapagliflozin could be extended to other SGLT-2 inhibitors in the treatment of HF, with either preserved or reduced ejection fraction, regardless of the presence of T2DM. This position paper aims to summarise relevant clinical trial evidence concerning the role and safety of new glucose-lowering therapies in patients with HF. G.A. reports personal fees from Angelini, Behring, Menarini, outside the submitted work. S.A. reports grants and personal fees from Vifor Int, Abbott Vascular, and personal fees from Bayer, Boehringer Ingelheim, Novartis, Servier, outside the submitted work. J.B. reports personal fees from Novartis, BMS, Pfizer, Servier, Orion, MSD, Boehringer Ingelheim, AstraZeneca, Abiomed, Abbott, and grants and personal fees from Vifor, Bayer, CvRX, Medtronic, outside the submitted work. O.C. reports grants from Servier, Novartis, Vifor, outside the submitted work. A.J.S.C reports personal fees from Actimed, AstraZeneca, Faraday, WL Gore, Menarini, Novartis, Nutricia, Respicardia, Servier, Stealth Peptides, Verona, Vifor, outside the submitted work. F.C. reports personal fees from Novo Nordisk, MSD, Pfizer, Mundipharma, Lilly, AstraZeneca, BMS, outside the submitted work. R.A.D.B reports grants from Abbott, AstraZeneca, Novo Nordisk, Novartis, Roche, and personal fees from Abbott, AstraZeneca, MandalMed, Inc., Novartis, Roche, outside the submitted work. G.F. reports he was Committee member of trials and registries sponsored by Byer, Novartis, Servier, Vifor, Medtronic, Boehringer Ingelheim, outside the submitted work. L.H. reports personal fees from Novartis, during the conduct of the study. M.H. reports grants from Roche Diagnostics, and personal fees from Boerhinger, AstraZeneca during the conduct of the study. P.S.J. reports other from AstraZeneca, personal fees from Novartis, grants from Boehringer Ingelheim, during the conduct of the study; personal fees from Cytokinetics, outside the submitted work. M.K. reports personal fees from Novartis, Servier, BMS, Torrent, Sanofi, AstraZeneca, MSD, Novo Nordisk, outside the submitted work. Y.L. reports personal fees from Servier, Novartis, Boehringer Ingelheim, during the conduct of the study. L.H.L. reports personal fees from Merck, Sanofi, Bayer, Pharmacosmos, Abbott, Medscape; grants from Boehringer Ingelheim, Boston Scientific; grants and personal fees from Vifor-Fresenius, AstraZeneca, Relypsa, Novartis, Mundipharma, outside the submitted work. A.L. reports personal fees from Servier; grants and personal fees from Pfizer; personal fees from Novartis, Roche, Takeda, Boehringer Ingelheim, Amgen, Clinigen Group, Ferring Pharmaceuticals, Eli Lily, BMS, Eisai Ltd, outside the submitted work. M.M. reports grants from European Community during the conduct of the study and personal fees from Bayer, Novartis, and Servier outside the submitted work. W.M. has nothing to disclose. M.C.P. reports personal fees and other from AstraZeneca; personal fees from Novartis, Novo Nordisk, Lilly, Bayer; grants and personal fees from Beohringer Ingelheim, during the conduct of the study.; personal fees from Maquet, Takeda, null, outside the submitted work. M.P. has nothing to disclose. M.M.P. has nothing to disclose. P.P. has nothing to disclose. G.M.C.R. has nothing to disclose. I.S. has nothing to disclose. J.S. has nothing to disclose. P.M.S. received grants/research supports: Ministry of Education, Science and Technological Development of Republic of Serbia; receipt of honoraria or consultation fees from Servier, Boehringher Ingelheim, Hemofarm, Novartis, AstraZeneca; participation in a company sponsored speaker's bureau: Fondazione Internazionale Menarini. T.T. reports personal fees from Cardior Pharmaceuticals GmbH, outside the submitted work. M.V. reports personal fees from Servier during the conduct of the study. Seferovic, PM (reprint author), Univ Belgrade, Fac Med, 8 Koste Todorovica, Belgrade 11000, Serbia, Univ Belgrade, Med Ctr, Heart Failure Ctr, 8 Koste Todorovica, Belgrade 11000, Serbia. seferovic.petar@gmail.com