Empagliflozin in HNF1A-MODY (MODY3): A Randomized, Double-Blind, Placebo-Controlled, Crossover Trial

Area of Science:

• Endocrinology
• Genetics
• Pharmacology

Background:

• Maturity-onset diabetes of the young (MODY) due to HNF1A variants is common, often requiring intensified treatment beyond first-line sulfonylureas.
• HNF1A influences SGLT2, making the efficacy of SGLT2 inhibitors in HNF1A-MODY uncertain.

Purpose of the Study:

• To assess the glucose-lowering effect of the SGLT2 inhibitor empagliflozin as an add-on therapy in individuals with HNF1A-MODY.

Main Methods:

• A randomized, double-blind, placebo-controlled crossover trial (MOD3ST-TRIAL) involving adults with HNF1A-MODY.
• Participants received empagliflozin (25 mg) for 4 weeks followed by placebo, or vice versa, with a 2-week washout period.
• The primary outcome was mean glucose concentration measured by 10 days of continuous glucose monitoring (CGM).

Main Results:

• Empagliflozin significantly lowered mean glucose levels by 2.3 mmol/L compared to placebo (P = 0.0001).
• No significant differences in hypoglycemia were observed between empagliflozin and placebo.
• Adverse events were mild and transient, with no severe events or discontinuations linked to empagliflozin.

Conclusions:

• Empagliflozin, used for 4 weeks with other glucose-lowering drugs, markedly improved glycemia in HNF1A-MODY patients.
• The treatment did not significantly increase the risk of hypoglycemia or adverse effects.