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Why Do SGLT2 Inhibitors Inhibit Only 30-50% of the Glucose Load Filtered in the Kidneys?

SGLT1 may play a more significant role than previously thought…. 

Anatomical position and the physiologic capacity of the SGLT2 has made us assume that the SGLT1 is only responsible for approximately 20% reabsorption of the filtered glucose load (since the SGLT2 is more proximal to the SGLT1 and has a higher capacity for glucose transport/reabsorption, hence a lower glucose load/concentration passes by the SGLT1). But a new published study demonstrated that SGLT2 in knockout mice still were capable of reabsorbing up to 66% of the filtered glucose load via the SGLT1. This may explain why we do not see the massive glycosuria expected from inhibiting SGLT2. So why do some patients experience up to 50% excretion of glucose load with SGLT2 inhibitors? Well, these numbers are based upon a "normal" blood glucose level. Increased urine glucose excretion (UGE) may be expected in those with higher blood glucose levels/HbA1C due to exceeding transporter capacity and glucose spilling into the urine.

With this physiologic explanation and understanding, we will likely see pharmaceutical companies develop new drug options that also inhibit, or at least partially inhibit the SGLT1 in order to maximize urine glucose excretion. Lexicon Pharmaceuticals is reporting promising results in its phase II study of a SGLT1/SGLT2 inhibitor.

Practice Pearls
  • The sodium glucose cotransporters 2 (SGLT2) are located in the renal proximal tubules and are responsible for reabsorption of >80% of the glucose load.
  • There are 2 different sodium glucose transporters in the proximal renal tubule: SGLT1 which is located in the more distal portion of the proximal renal tubule and has a high affinity but low capacity for glucose and the SGLT2 which is located in the more proximal region of the proximal renal tubule and has a low affinity but high capacity for glucose transport.
  • Inhibiting SGLT2 results in inhibiting reabsorption of <50% of the filtered glucose load which is unexpected due to the SGLT2 high capacity for reabsorption of glucose but new data shows SGLT1 can reabsorb a greater percentage of glucose when faced with higher glucose loads.

Abdul-Ghani, M. et al. Novel Hypothesis to Explain Why SGLT2 Inhibitors Inhibit only 30 – 50% of Filtered Glucose Load in Humans. Diabetes. 62: 3324 – 3328, 2013