Single dose of empagliflozin increases in vivo cardiac energy status in diabetic db/db mice

Desiree Abdurrachim, Emmy Manders, Klaas Nicolay, Eric Mayoux, Jeanine J. Prompers

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Scopus)

Abstract

In the EMPA-REG OUTCOME trial, empagliflozin, a potent and specific inhibitor of the sodium glucose co-transporter 2, showed impressive benefits on cardiovascular outcome in patients with Type 2 diabetes.1 Empagliflozin reduced three-point primary composite outcome (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) by 14%, which was mainly attributed to a 38% relative risk reduction in cardiovascular death.1 A 35% relative risk reduction in hospitalization for heart failure and a 32% relative risk reduction in all-cause mortality was also reported.1 However, the underlying mechanisms explaining these beneficial outcomes are yet to be elucidated. Deprivation of cardiac energy, characterized by a decreased cardiac phosphocreatine-to-ATP ratio (PCr/ATP), has been proposed to play a major role in the development of heart failure.2 Empagliflozin increases plasma ketone body levels and it has therefore been hypothesized that a shift in energy substrate metabolism towards ketones or an increased availability of ketones as add-on fuel could explain the positive cardiovascular outcomes in the EMPA-REG study.3

To test the ‘fuel hypothesis’, we investigated whether an increase in plasma ketones by empagliflozin was accompanied by an increase in cardiac PCr/ATP. We administered a single dose of empagliflozin in fasting db/db mice, to simulate a situation in which plasma ketone levels are immediately increased. This acute experimental design allows investigating the effect of alterations in fuel availability on changes in cardiac PCr/ATP ratio without interference from other factors, such as cardiac remodelling after long-term treatment. Using 31P magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI), we measured in vivo cardiac PCr/ATP and function, respectively.
Original languageEnglish
Pages (from-to)1843-1844
Number of pages2
JournalCardiovascular Research
Volume114
Issue number14
DOIs
Publication statusPublished - 1 Dec 2018

Fingerprint

Phosphocreatine
Ketones
Risk Reduction Behavior
Adenosine Triphosphate
Sodium-Glucose Transporter 2
Symporters
Ketone Bodies
Energy Metabolism
Fasting
Hospitalization
Research Design
Magnetic Resonance Spectroscopy
Heart Failure
Stroke
Myocardial Infarction
Magnetic Resonance Imaging
empagliflozin
Mortality
Therapeutics

Cite this

Abdurrachim, Desiree ; Manders, Emmy ; Nicolay, Klaas ; Mayoux, Eric ; Prompers, Jeanine J. / Single dose of empagliflozin increases in vivo cardiac energy status in diabetic db/db mice. In: Cardiovascular Research. 2018 ; Vol. 114, No. 14. pp. 1843-1844.
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abstract = "In the EMPA-REG OUTCOME trial, empagliflozin, a potent and specific inhibitor of the sodium glucose co-transporter 2, showed impressive benefits on cardiovascular outcome in patients with Type 2 diabetes.1 Empagliflozin reduced three-point primary composite outcome (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) by 14{\%}, which was mainly attributed to a 38{\%} relative risk reduction in cardiovascular death.1 A 35{\%} relative risk reduction in hospitalization for heart failure and a 32{\%} relative risk reduction in all-cause mortality was also reported.1 However, the underlying mechanisms explaining these beneficial outcomes are yet to be elucidated. Deprivation of cardiac energy, characterized by a decreased cardiac phosphocreatine-to-ATP ratio (PCr/ATP), has been proposed to play a major role in the development of heart failure.2 Empagliflozin increases plasma ketone body levels and it has therefore been hypothesized that a shift in energy substrate metabolism towards ketones or an increased availability of ketones as add-on fuel could explain the positive cardiovascular outcomes in the EMPA-REG study.3To test the ‘fuel hypothesis’, we investigated whether an increase in plasma ketones by empagliflozin was accompanied by an increase in cardiac PCr/ATP. We administered a single dose of empagliflozin in fasting db/db mice, to simulate a situation in which plasma ketone levels are immediately increased. This acute experimental design allows investigating the effect of alterations in fuel availability on changes in cardiac PCr/ATP ratio without interference from other factors, such as cardiac remodelling after long-term treatment. Using 31P magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI), we measured in vivo cardiac PCr/ATP and function, respectively.",
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Single dose of empagliflozin increases in vivo cardiac energy status in diabetic db/db mice. / Abdurrachim, Desiree; Manders, Emmy; Nicolay, Klaas; Mayoux, Eric; Prompers, Jeanine J.

In: Cardiovascular Research, Vol. 114, No. 14, 01.12.2018, p. 1843-1844.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Single dose of empagliflozin increases in vivo cardiac energy status in diabetic db/db mice

AU - Abdurrachim, Desiree

AU - Manders, Emmy

AU - Nicolay, Klaas

AU - Mayoux, Eric

AU - Prompers, Jeanine J.

PY - 2018/12/1

Y1 - 2018/12/1

N2 - In the EMPA-REG OUTCOME trial, empagliflozin, a potent and specific inhibitor of the sodium glucose co-transporter 2, showed impressive benefits on cardiovascular outcome in patients with Type 2 diabetes.1 Empagliflozin reduced three-point primary composite outcome (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) by 14%, which was mainly attributed to a 38% relative risk reduction in cardiovascular death.1 A 35% relative risk reduction in hospitalization for heart failure and a 32% relative risk reduction in all-cause mortality was also reported.1 However, the underlying mechanisms explaining these beneficial outcomes are yet to be elucidated. Deprivation of cardiac energy, characterized by a decreased cardiac phosphocreatine-to-ATP ratio (PCr/ATP), has been proposed to play a major role in the development of heart failure.2 Empagliflozin increases plasma ketone body levels and it has therefore been hypothesized that a shift in energy substrate metabolism towards ketones or an increased availability of ketones as add-on fuel could explain the positive cardiovascular outcomes in the EMPA-REG study.3To test the ‘fuel hypothesis’, we investigated whether an increase in plasma ketones by empagliflozin was accompanied by an increase in cardiac PCr/ATP. We administered a single dose of empagliflozin in fasting db/db mice, to simulate a situation in which plasma ketone levels are immediately increased. This acute experimental design allows investigating the effect of alterations in fuel availability on changes in cardiac PCr/ATP ratio without interference from other factors, such as cardiac remodelling after long-term treatment. Using 31P magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI), we measured in vivo cardiac PCr/ATP and function, respectively.

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