Empagliflozin in HNF1A-MODY (MODY3) – a Randomized, Double-blind, Placebo-controlled, Crossover Trial

Objective: Maturity-onset diabetes of the young (MODY) caused by pathogenic variants in HNF1A is a common form of monogenic diabetes. Sulfonylurea is considered first-line treatment of HNF1A-MODY (MODY3), but intensified treatment is often needed. HNF1A encodes a transcription factor involved in the regulation of the sodium-glucose cotransporter 2 (SGLT2). Accordingly, the glucose-lowering efficacy of SGLT2 inhibitors in HNF1A-MODY is questionable. Here, we aim to assess the glucose-lowering effect of the SGLT2 inhibitor empagliflozin as add-on in individuals with HNF1A-MODY. Research Design and Methods: MOD3ST-TRIAL was a randomized, double-blind, placebo-controlled crossover trial. Adults with HNF1A-MODY treated with at least one glucose-lowering drug were randomized to empagliflozin 25 mg for 4 weeks followed by a 2-week washout period and then placebo for 4 weeks or the opposite sequence. The primary outcome was mean glucose assessed by 10 days of continuous glucose monitoring (CGM). Results: Nineteen individuals were randomized and 18 participants (10 women [56%], median HbA1c 7.5 [7.0–8.4] % (58 [53–68] mmol/mol), mean CGM glucose 10.4 [2.5] mmol/l) completed the study. Compared with placebo, empagliflozin lowered mean glucose 2.3 mmol/l (95% CI 1.3 to 3.3, P=0.0001). There were no significant differences in hypoglycemic outcomes. Adverse events were generally mild, transient, and no severe adverse events nor study drug discontinuations were attributable to empagliflozin. Conclusion: Empagliflozin used for four weeks in adjunction with other glucose-lowering treatments markedly improved glycemia compared with placebo in individuals with HNF1A-MODY without significantly increasing risk of hypoglycemia or unexpected adverse effects.