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Organ protection by SGLT2 inhibitors: role of metabolic energy and water conservation

Abstract

Therapeutic inhibition of the sodium–glucose co-transporter 2 (SGLT2) leads to substantial loss of energy (in the form of glucose) and additional solutes (in the form of Na+ and its accompanying anions) in urine. However, despite the continuously elevated solute excretion, long-term osmotic diuresis does not occur in humans with SGLT2 inhibition. Rather, patients on SGLT2 inhibitor therapy adjust to the reduction in energy availability and conserve water. The metabolic adaptations that are induced by SGLT2 inhibition are similar to those observed in aestivation — an evolutionarily conserved survival strategy that enables physiological adaptation to energy and water shortage. Aestivators exploit amino acids from muscle to produce glucose and fatty acid fuels. This endogenous energy supply chain is coupled with nitrogen transfer for organic osmolyte production, which allows parallel water conservation. Moreover, this process is often accompanied by a reduction in metabolic rate. By comparing aestivation metabolism with the fuel switches that occur during therapeutic SGLT2 inhibition, we suggest that SGLT2 inhibitors induce aestivation-like metabolic patterns, which may contribute to the improvements in cardiac and renal function observed with this class of therapeutics.

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Fig. 1: Levels of physiological adaptation to arid environments.
Fig. 2: Water and energy conservation metabolism under dehydration stress.
Fig. 3: Reprioritization of fuel utilization pathways during hypometabolism and water conservation.
Fig. 4: Hypothesized key organ-specific metabolic changes in patients on SGLT2 inhibitor therapy.

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A.M., T.K. and J.T. wrote the article. All authors researched data for the article, contributed substantially to discussion of the article’s content and reviewed/edited the manuscript before submission.

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Correspondence to Jens Titze.

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T.K. and A.Y. are employees of Nippon Boehringer Ingelheim Co. Ltd. J.T. and A.N. have received research support from Boehringer Ingelheim International GmbH for a collaborative preclinical study. A.N. has also received speaker honoraria from Taisho Pharmaceutical and Daiichi-Sankyo. J.T. has also received research support from AstraZeneca and received travel support and speaker honoraria from Boehringer Ingelheim International GmbH and AstraZeneca. All other authors declare no competing interests.

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Glossary

Lungfish

Freshwater fish belonging to the subclass Dipnoi, which have lungs and a specialized respiratory system. During periods of draught, lungfish bury themselves into the ground and survive by breathing atmospheric air and encasing themselves in a sheath to avoid dehydration.

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Marton, A., Kaneko, T., Kovalik, JP. et al. Organ protection by SGLT2 inhibitors: role of metabolic energy and water conservation. Nat Rev Nephrol 17, 65–77 (2021). https://doi.org/10.1038/s41581-020-00350-x

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