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. 2024 Mar 1;134(5):e177625.
doi: 10.1172/JCI177625.

SGLT2 inhibitors: cardiorenal metabolic drugs for the ages

Ralph A DeFronzo

SGLT2 inhibitors: cardiorenal metabolic drugs for the ages

Ralph A DeFronzo. J Clin Invest. .
No abstract available

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Conflict of interest statement

Conflict of interest: RAD serves on the advisory boards of AstraZeneca, Novo Nordisk, Boehringer Ingelheim, Intarcia, Aardvark, Renalytix, CORCEPT, and Alnylam. RAD has research grants from Boehringer Ingelheim, AstraZeneca, 89Bio, Amgen, Medality, and CORCEPT. RAD has served on the speakers bureau for AstraZeneca, CORCEPT, and Renalytix.

Figures

Figure 1
Figure 1. SGLT2 inhibitors acutely induce glucosuria, which persists as long as the SGLT2i therapy is continued.
Treatment with SGLT2 inhibitors, such as phlorizin, promotes glucosuria and leads to a decline in fasting plasma glucose concentration, i.e., from 160 to 100 mg/dL. When the fasting plasma glucose declines toward normoglycemic levels, activation of the renal sympathetic nerves stimulates the liver to undergo glucogenesis and glycogenolysis, and quantitatively this increases hepatic glucose production (HGP), matching the glucose amount excreted in the urine, thus preventing hypoglycemia. The decline in plasma glucose concentration creates a state of tissue energy deprivation and leads to a decrease in plasma insulin and an increase in plasma glucagon concentration. These resultant hormonal changes stimulate lipolysis, thus providing substrate for ketogenesis, and reset the liver into the ketogenic mode. Subsequent ketone (β-hydroxybutyrate [β-OH-B]) production provides a fuel-efficient substrate for the heart and the kidney. In muscle, glycogen breakdown is stimulated, providing the carbon skeleton for the synthesis of alanine (Ala), which is released into the circulation and transported to the liver to support gluconeogenesis (known as the alanine cycle). Stimulation of muscle proteolysis also results in the release of alanine as well as other amino acids, in particular the branched-chain amino acids (BCAAs): leucine (Leu); isoleucine (Isoleu); and valine (Val). The liver does not possess BCAA transferase, allowing the BCAAs to be taken up by the heart and kidney where they provide substrate to compensate for the reduction in plasma glucose concentration that occurs secondary to the glucosuric effect of the SGLT2i. PYR, pyruvate.
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