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 drugs are 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 assess the glucose-lowering effect of the SGLT2 inhibitor empagliflozin as an add-on for treatment of 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 be treated with empagliflozin 25 mg for 4 weeks followed by a 2-week washout period and then received placebo for 4 weeks or the opposite sequence. The primary outcome was mean glucose concentration assessed by 10 days of continuous glucose monitoring (CGM). RESULTS: Nineteen individuals were randomized and 18 participants (n = 10 women [56%]; median [Q1, Q3] HbA1c 7.5% [7.0, 8.4] or 58 [53, 68] mmol/mol, mean [SD] CGM glucose concentration 10.4 [2.5] mmol/L) completed the study. Compared with placebo, empagliflozin lowered the mean glucose level 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 and transient, and no severe adverse events or study drug discontinuations were attributable to empagliflozin. CONCLUSIONS: Empagliflozin used for 4 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.