Why Don't SGLT2 Inhibitors Inhibit as They Should?

May 5, 2015

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.Â 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;2:152â161.

The SGLT2 cotransporter handles about 90% of renal glucose reabsorption. But SGLT2Is only inhibit about 30%-50% of filtered glucose load. Current SGLT2Is induce a maximum of 50-80 g of urinary glucose excretion (UGE) per day. In vitro studies suggest that at drug concentrations used in humans, SGLT2Is should cause 100% inhibition of SGLT2 transporters. Why don’t SGLT2Is function up to capacity?

Max daily UGE with some SGLT2Is occurs at a low dose, then plateaus:Empagliflozin 10 mg: 24-h UGE plateaus at ~77.9 mg; negligible change thereafter(2)Renal secretion may limit full inhibition of SGLT2 receptors if(1): SGLT2Is are preferentially secreted downstream of SGLT2 receptors. Renal secretion of SGLT2Is saturates at high doses. Reabsorption of SGLT2Is in the proximal tubule limits the amount of drug available. SGLT2 receptor concentration is higher in vivo than in vitro. Renal secretion and the slow off rate of SGLT2Is could also explain the prolonged UGE observed after plasma concentrations of these drugs have already decreased.

Differences in UGE by type of SGLT2I could be explained by different rates of renal secretion and different dissociation off-rates(1); differences in SGLT2 and SGLT1 selectivity between specific agents.(3) Study: 54 healthy participants (no T2DM) received CANA 300 mg or DAPA 10 mg for 4 days; underwent mixed-meal tolerance test at baseline and on day 4. Results suggested(3):Postprandial glucose (PPG): Percent excursion from baseline was 10% lower and rise in PPG was slower with CANA 300 mg vs DAPA 10 mg; 4- h UGE: Similar for CANA 300 mg and DAPA 10 mg; 24-h UGE: 25% higher with CANA 300 mg vs DAPA 10 mg (51.4 vs 40.8 g, respectively). Head to head trials are needed that look at effects on A1c by different SGLT2I agents.

The SGLT2I paradox refers to the fact that SGLT2 cotransporters handle about 90% of renal glucose reabsorption, yet SGLT2Is only inhibit about 30%-50% of filtered glucose loadRenal secretion and the slow off rate of SGLT2Is could explain the SGLT2I paradox. Urinary glucose excretion varies by type of SGLT2-I, and could be explained by differences in renal secretion, dissociation off-rates, and SGLT2 vs SGLT1 selectivity between the agents. Head to head trials looking at effects on HbA1c by different SGLT2Is are needed.