Design: Randomised, open-label, two-sequence, three-period crossover
Population: Healthy adult volunteers
Primary outcome: Steady-state Cmax and AUC of each drug; 24-hour urinary glucose excretion
Effect: Glimepiride AUC GMR 1.23 (1.14–1.32); enavogliflozin AUC 1.00; urinary glucose GMR 0.78

This randomised, open-label, three-period crossover study in healthy participants gave enavogliflozin 0.3 mg daily, glimepiride 2 mg daily with metformin 1000 mg twice daily, or all three, for six days each, and measured steady-state levels and urinary glucose.

Enavogliflozin exposure was unchanged by the combination (AUC ratio 1.00). Glimepiride AUC rose by about 23% (ratio 1.23, 90% CI 1.14–1.32) and metformin by about 16%. Urinary glucose excretion from enavogliflozin fell by about 22% when given with the other two, yet serum glucose fell most with all three drugs together, showing an additive effect.

The authors judge none of the kinetic changes clinically meaningful. The glimepiride rise is modest, but sulfonylureas are where hypoglycaemia comes from, and these were healthy volunteers with normal glucose. Enavogliflozin is licensed in some Asian markets; its regulatory status in India is not established here.

Adding an SGLT2 inhibitor to a sulfonylurea increases hypoglycaemia risk through additive glucose lowering.
Consider reducing the sulfonylurea dose when an SGLT2 inhibitor is added in a patient near target.
Glimepiride exposure rose about a quarter with enavogliflozin co-administration in this study.
Data from healthy volunteers may not reflect patients with diabetes or kidney impairment.

Why it matters

The kinetic interaction is small; the clinical one with sulfonylureas is the hypoglycaemia that additive lowering brings.

The statistics, in plain English

A geometric mean ratio of 1.23 means glimepiride exposure was on average 23% higher with the combination; the 90% interval of 1.14 to 1.32 sits just outside the usual 0.80–1.25 'no interaction' bounds at its upper end.