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Why Don't SGLT2 Inhibitors Inhibit as They Should?

The Paradox: SGLT2 inhibitors should cause 100% inhibition of SGLT2 in humans. They only inhibit by 30%-50%. Why?

The 3 approved sodium glucose cotransporter 2 inhibitors (SGLT2Is [cangliflozin, dapagliflozin, empagliflozin]) all produce dose-dependent glucosuria. The maximal amount of glucose actually excreted, however, has been found to be much lower than that taken up by SGLT2 in individuals with normal glucose tolerance, and does not exceed 30%-50% of the filtered glucose load.The slides above take a condensed look at the paradox and at some evidence-based theories on what might actually be taking place. References1. Liu J, Lee TW, DeFronzo RA. Why do SGLT2Is inhibit only 30-50% of renal glucose reabsorption in humans? Diabetes. 2012;61:2199-2204.2. Heise T, Seman L, Macha S, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple rising doses of empagliflozin in patients with type 2 diabetes mellitus. Diabetes Ther. 2013;4:331-345. doi:10.1007/s13300-013-0030-2. Epub 2013 Jul 10.3. Sha S, Polidori D, Farrell K, et al. Pharmacodynamic differences between canagliflozin and dapagliflozin: results of a randomized, double-blind, crossover study. Diabetes Obes Metab. 2015;17:188-197. doi:10.1111/dom.12418. Epub 2015 Jan 5.4. Inzucchi SE, Zinman B, Wanner C, et al. SGLT-2 Inhibitors and cardiovascular risk: Proposed pathways and review of ongoing trials. Diab Vasc Dis Res. 2015;12:90-100. doi:10.1177/1479164114559852. Epub 2015 Jan 14.5. Seman L, Sreeraj M, Nehmiz G, et al. Empagliflozin (BI 10773), a potent and selective SGLT2I, induces dose-dependent glucosuria in healthy subjects. Clin Pharmacol Drug Devel. 2013;2:152–161.