Empagliflozin in HNF1A-MODY (MODY3): a randomised, doubleblind, placebo-controlled, crossover trial

Background and aims: MODY caused by pathogenic variants in HNF1A is a common form of monogenic diabetes. Sulfonylurea (SU) is considered first-line treatment of HNF1A-MODY (MODY3), but SU is associated with hypoglycaemia and body weight gain. HNF1A encodes a transcription factor involved in the regulation of the sodium-glucose cotransporter 2 (SGLT2) in the kidney why the glucose-lowering effect of SGLT2 inhibitors in HNF1A-MODY has been questioned. Here, we assessed the glucose-lowering effect of the SGLT2 inhibitor empagliflozin in individuals with HNF1A-MODY.

Materials and methods: The MOD3ST-TRIAL was a randomised, double-blind, placebo-controlled crossover trial randomising adults with HNF1A-MODY treated with at least one glucose-lowering drug and HbA1c ≥48 mmol/mol 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 continuous glucose monitoring (CGM) during 10 days and was evaluated in participants who tolerated and adhered to both interventions.

Results: Nineteen individuals were randomised (placebo first: n = 10). One participant discontinued the study after two weeks of placebo. Eighteen participants completed the study and were included in the efficacy analyses (baseline: 8 men [44%], median age 48 years [IQR 39-55], median eGFR 110 [95-116] ml/min/1.73 m², median HbA1c 58 [53-68] mmol/mol, mean CGM glucose 10.4 [SD 2.5] mmol/l, mean fasting plasma glucose (FPG) 8.1 [2.2] mmol/l). Compared with placebo, empagliflozin lowered mean glucose (-2.3 mmol/l, 95% CI -3.3 to -1.3, p<0.001, Figure 1A) and FPG (-2.1 mmol/l, 95% CI -3.2 to -1.1, p<0.001) and increased time in range (Figure 1B, p<0.001). There were no significant differences between interventions in hypoglycaemic outcomes. Adverse events were generally mild and transient. No severe adverse events were attributable to empagliflozin.

Conclusion: Four-week empagliflozin treatment added to existing glucose-lowering medicine in individuals with HNF1A-MODY improved glycaemia compared with placebo without significantly increasing risk of hypoglycaemia or severe adverse effects.