Limited effect of SGLT2 inhibitors on the heart’s fuel consumption
SGLT2 inhibitors protect against heart disease in people with diabetes. It is suggested that the beneficial effects are due to increased production of ketones, partly because we have previously shown that ketones are an efficient cardiac substrate that can potentially reduce oxygen deficiency in the heart.
To investigate whether this is the case, we studied the effect of the SGLT2 inhibitor empagliflozin on energy expenditure in the heart. Our hypothesis was that SGLT2 inhibitor treatment increases the heart’s ketone metabolism, thereby reducing the metabolism of other substrates and resulting in reduced oxygen consumption in the heart. We included 13 individuals with type 2 diabetes; they were examined after 4 weeks’ treatment with SGLT2 inhibitor and placebo in a randomized crossover trial, and the heart’s energy expenditure was studied using PET/CT scans.
“We are therefore currently investigating whether alternating fasts and a ketogenic diet, where a greater increase in the ketone level is observed, have the beneficial effects previously observed with infusion of ketones.”
We found that treatment with an SGLT2 inhibitor led to a raised level of circulating ketones, but that it affected neither the heart’s metabolism of free fatty acids nor its oxygen consumption. On the other hand, SGLT2 inhibitor treatment did reduce cardiac sugar metabolism and reduced blood flow to the heart. However, these effects were relatively modest and are not thought to contribute significantly to the heart-protecting effects of treatment.
A possible explanation for the modest effects is that there is a very small increase in ketones during SGLT2 inhibitor treatment. We are therefore currently investigating whether alternating fasts and a ketogenic diet, where a greater increase in the ketone level is observed, have the beneficial effects previously observed with infusion of ketones. For this, we have developed a new PET/CT ketone tracer that enables us to measure the heart’s ketone consumption directly.
Katrine Meyer Lauritsen
Department of Clinical Medicine - Medical Research Laboratory[P1]
Staff specialist, clinical associate professor, member of the DDA's Committee For Education
Steno Diabetes Center Aarhus
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Published in Diabetes: 17 December 2020.
Katrine M Lauritsen 1 2 3 , Bent R R Nielsen 4 , Lars P Tolbod 5 , Mogens Johannsen 6 , Jakob Hansen 6 , Troels K Hansen 1 , Henrik Wiggers 4 , Niels Møller 1 2 , Lars C Gormsen 5 , Esben Søndergaard 7 2 3
SGLT2 Inhibition Does Not Affect Myocardial Fatty Acid Oxidation or Uptake, But Reduces Myocardial Glucose Uptake and Blood Flow in Individuals With Type 2 Diabetes – a Randomized Double-Blind, Placebo-Controlled Crossover Trial