Sodium glucose co-transporter-2 (SGLT-2) inhibitors are being increasingly used in the management of diabetes mellitus for better cardiovascular and kidney outcomes. The common adverse effects mentioned in the literature include polyuria, genitourinary infections, hypotension, volume depletion and increased risk of euglycemic ketoacidosis.[[1]] It is advised to stop these drugs in the periprocedural period and to restart post-operatively only once the patient is eating and drinking normally or close to discharge from hospital.[[2]] We herein report an unusual clinical scenario where restarting SGLT-2 inhibitors was detrimental to the overall glucose control.

Case report

A 71-year-old male, with a background of type 2 diabetes mellitus, developed uncontrolled hyperglycaemia after radical cysto-prostatectomy and ileal conduit formation for high-risk (T1 high grade and CIS) bladder cancer. His antidiabetic home medications, metformin 500mg twice daily and empagliflozin 10mg daily, were kept on hold during the peri-operative period. Periprocedural glucose control was done with short acting insulin. As per protocol, home doses of antidiabetic medications were reinitiated on post-operative day 2. Laboratory results reveal that despite increasing the dose of empagliflozin to 25mg daily, blood glucose remained uncontrolled (see Figure 1). Stopping empagliflozin and up-titration of metformin to 1000mg twice daily resulted in sustained normo-glycaemia. Moreover, ketonaemia started to develop (ß-hydroxybutyrate of 2.3) after increasing the dose of empagliflozin, thus providing further motivation to stop the empagliflozin. Renal profile, blood counts and lipid levels in both the pre-operative and post-operative periods remained largely unchanged (except for transient, anticipated post-operative changes) and have been included in Table 1 below.

View Figure 1 & Table 1.

Discussion

Empagliflozin, a SGLT-2 inhibitor, blocks the reabsorption of up to 90% of filtered glucose in the proximal convoluted tubule (PCT), thereby increasing total urinary excretion of glucose.[[3]] This urinary glucose is then stored in the bladder until micturition occurs. In the setting of an ileal conduit, urine is stored in a section of ileum, which acts as an artificial bladder. Ileum has SGLT-1 transmembrane proteins which re-absorb the excreted urinary glucose, thereby minimising the effects of the SGLT-2 inhibitor. The enterocytes can upregulate Na-dependent glucose transport after exposure to glucose in a timeframe of a few minutes.[[4]] These intracellular transporters are recruited resulting in SGLT-1 appearance at the apical membrane. Moreover, intestinal glucose transporter (GLUT-2) also translocates to the apical surface in response to high intra-luminal glucose levels. This would enable SGLT-1-independent glucose uptake at high luminal glucose concentrations as postulated in our case. Furthermore, selectivity for SGLT-2 relative to SGLT-1 inhibition is 2,700-fold for highly selective empagliflozin.[[5]] Thus, empagliflozin induced glucosuria resulted in a positive feedback loop of more glucose resorption via the ileal conduit worsening hyperglycaemia in our case. An extensive literature survey did not yield any previous case reports on this topic.

Conclusion

In the setting of a new ileal conduit formation, prescribers should avoid highly selective SGLT-2 inhibitors like empagliflozin. This scenario could be an indication to use novel dual SGLT1/2 inhibitors like sotagliflozin and licogliflozin. More data would be required to further validate these results in this select group of individuals.