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 % (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.