Impact of SGLT2 Inhibition on Glucosuria in HNF1A-MODY

Pathogenic variants in HNF1A leads to maturity-onset diabetes of the young type 3 (HNF1A-MODY, MODY3) which is correlated with comparable hyper-glucosuria that has been assigned to decreased expression of sodium-glucose cotransporter 2 (SGLT2) in HNF1A knockout mice; questioning SGLT2 as a significant therapy target in these individuals. Henrik Maagensen & team aimed to evaluate effect of SGT2i treatment in patients with MODY3 compared with patients with T2DM. The findings were presented at the 84^th Scientific Sessions of the ADA Congress 2024, held in Orlando from 21^st – 24^th June 2024.

The team performed a randomized, double-blind, crossover study in which persons with MODY3 and type 2 diabetes (T2D) underwent two three-step hyperglycemic clamps targeted at 10, 14, and 18 mmol/L (1h each) with and without acute SGLT2 inhibition (25 mg empagliflozin or placebo 2h before clamp).

Participants characteristics were: MODY3 (N = 11, 5 men; age (mean, SD) 49 ± 15 years; BMI 24.5 ± 3.9 kg/m²; HbA1c 6.7 ± 0.7%; eGFR 109 ± 14 mL/min/1.73 m²); T2D (n = 10, 8 men; age 63 ± 7 years; BMI 26.4 ± 3.5 kg/m²; HbA1c 6.7 ± 0.6%; eGFR 93 ± 12 mL/min/1.73 m²). In both groups, SGLT2 inhibition showed strong effects on urinary glucose excretion, urine volume, infused glucose, and plasma glucose AUC (table). No relevant differences were observed among groups in the effects of SGLT2 inhibition.

The authors concluded that the similar impacts of SGLT2 inhibition was observed in persons with MODY3 and T2D, indicating SGLT2 inhibition act as a significant glucose-lowering management strategy in persons with MODY3 in spite of the probably lower SGLT2 expression.