CV Protection in the EMPA-REG OUTCOME Trial: A "Thrifty Substrate" Hypothesis.
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It is hypothesized that under conditions of mild, persistent hyperketonemia, such as those that prevail during treatment with SGLT2 inhibitors, β-hydroxybutyrate is freely taken up by the heart and oxidized in preference to fatty acids, which improves the transduction of oxygen consumption into work efficiency at the mitochondrial level.Abstract:
The striking and unexpected relative risk reductions in cardiovascular (CV) mortality (38%), hospitalization for heart failure (35%), and death from any cause (32%) observed in the EMPA-REG OUTCOME trial using an inhibitor of sodium-glucose cotransporter 2 (SGLT2) in patients with type 2 diabetes and high CV risk have raised the possibility that mechanisms other than those observed in the trial-modest improvement in glycemic control, small decrease in body weight, and persistent reductions in blood pressure and uric acid level-may be at play. We hypothesize that under conditions of mild, persistent hyperketonemia, such as those that prevail during treatment with SGLT2 inhibitors, β-hydroxybutyrate is freely taken up by the heart (among other organs) and oxidized in preference to fatty acids. This fuel selection improves the transduction of oxygen consumption into work efficiency at the mitochondrial level. In addition, the hemoconcentration that typically follows SGLT2 inhibition enhances oxygen release to the tissues, thereby establishing a powerful synergy with the metabolic substrate shift. These mechanisms would cooperate with other SGLT2 inhibition-induced changes (chiefly, enhanced diuresis and reduced blood pressure) to achieve the degree of cardioprotection revealed in the EMPA-REG OUTCOME trial. This hypothesis opens up new lines of investigation into the pathogenesis and treatment of diabetic and nondiabetic heart disease.read more
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References
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2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
Piotr Ponikowski,Adriaan A. Voors,Stefan D. Anker,Héctor Bueno,John G.F. Cleland,Andrew J.S. Coats,Volkmar Falk,José Ramón González-Juanatey,Veli-Pekka Harjola,Ewa A. Jankowska,Mariell Jessup,Cecilia Linde,Petros Nihoyannopoulos,John Parissis,Burkert Pieske,Jillian P. Riley,Giuseppe M.C. Rosano,Luis M. Ruilope,Frank Ruschitzka,Frans H. Rutten,Peter van der Meer,Gerasimos Filippatos,John J.V. McMurray,Victor Aboyans,Stephan Achenbach,Stefan Agewall,Nawwar Al-Attar,John Atherton,Johann Bauersachs,A. John Camm,Scipione Carerj,Claudio Ceconi,Antonio Coca,Perry M. Elliott,Çetin Erol,Justin A. Ezekowitz,Covadonga Fernández-Golfín,Donna Fitzsimons,Marco Guazzi,Maxime Guenoun,Gerd Hasenfuss,Gerhard Hindricks,Arno W. Hoes,Bernard Iung,Tiny Jaarsma,Paulus Kirchhof,Juhani Knuuti,Philippe Kolh,Stavros Konstantinides,Mitja Lainscak,Patrizio Lancellotti,Gregory Y.H. Lip,Francesco Maisano,Christian Mueller,Mark C. Petrie,Massimo F Piepoli,Silvia G. Priori,Adam Torbicki,Hiroyuki Tsutsui,Dirk J. van Veldhuisen,Stephan Windecker,Clyde W. Yancy,José Luis Zamorano +62 more
TL;DR: Authors/Task Force Members: Piotr Ponikowski* (Chairperson) (Poland), Adriaan A. Voors* (Co-Chair person) (The Netherlands), Stefan D. Anker (Germany), Héctor Bueno (Spain), John G. F. Cleland (UK), Andrew J. S. Coats (UK)
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TL;DR: Patients with type 2 diabetes at high risk for cardiovascular events who received empagliflozin, as compared with placebo, had a lower rate of the primary composite cardiovascular outcome and of death from any cause when the study drug was added to standard care.
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Kenneth Dickstein,Alain Cohen-Solal,Gerasimos Filippatos,John J.V. McMurray,Piotr Ponikowski,Philip A. Poole-Wilson,Anna Strömberg,Dirk J. van Veldhuisen,Dan Atar,Arno W. Hoes,Andre Keren,Alexandre Mebazaa,Markku S. Nieminen,Silvia G. Priori,Karl Swedberg +14 more
TL;DR: Authors/Task Force Members: John J. McMurray (Chairperson) (UK), Stamatis Adamopoulos (Greece), Stefan D. Anker (Germany), Angelo Auricchio (Switzerland), Michael Böhm ( Germany), Kenneth Dickstein (Norway), Volkmar Falk (Sw Switzerland), Gerasimos Filippatos (G Greece), Cândida Fonseca (Portugal), Miguel Angel Gomez-Sanchez (Spain).
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ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC.
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TL;DR: ESC guidelines for the diagnosis and treatment of acute and chronic heart failure have been developed in collaboration with the Heart Failure Association (HFA) of the ESC 2012 Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 as mentioned in this paper.