Summary: In a small randomised, double-blind, crossover clamp study of 11 adults with HNF1A-MODY (MODY3) and 10 with type 2 diabetes, acute SGLT2 inhibition with 25 mg empagliflozin increased urinary glucose excretion to a comparable degree in both groups (24.5 g vs 23.5 g over a 3-hour hyperglycaemic clamp; between-group difference 1.0 g, 95% CI -3.5 to 5.6, P = 0.6). The robust glucosuric response in MODY3 supports SGLT2 inhibition as a mechanistically plausible glucose-lowering option, though clinical efficacy and safety were not assessed here.
PICO Summary
| Element | Detail |
|---|---|
| Population | 21 adults (11 HNF1A-MODY [MODY3], mean age 49 years, GFR 113 mL/min; 10 type 2 diabetes, mean age 63 years, GFR 103 mL/min); single-centre randomised, double-blind, crossover mechanistic study, Denmark. |
| Intervention | Single oral dose of 25 mg empagliflozin given 2 hours before a three-step hyperglycaemic clamp (targets 10, 14, 18 mmol/L), each participant serving as own control (n=21 receiving active phase). |
| Comparison | Matching placebo before an identical hyperglycaemic clamp, in crossover order (n=21 receiving placebo phase). |
| Outcome | Urinary glucose excretion over the 3-hour clamp rose with SGLT2 inhibition by 24.5 g (95% CI 20.6 to 28.3) in HNF1A-MODY and 23.5 g (95% CI 20.4 to 26.5) in type 2 diabetes. The between-group difference in the effect of SGLT2 inhibition was not significant: 1.0 g (95% CI -3.5 to 5.6); P = 0.6. No clinical glycaemic, ARR/NNT, or safety endpoints were reported. |
Expert Commentary
This mechanistic crossover study answers a narrow physiological question and answers it cleanly: acute empagliflozin produces a robust glucosuric response in HNF1A-MODY that is statistically indistinguishable from that seen in type 2 diabetes. The earlier concern that reduced renal SGLT2 expression in HNF1A-MODY might blunt the drug class is not supported by these data. The verdict is that the pharmacodynamic target is engaged, which is a necessary but not sufficient basis for clinical use. The principal limitation is that this is a small, single-dose clamp study of 21 participants with no glycated haemoglobin, hard glycaemic, or safety outcomes; durability, tolerability, and the previously hypothesised dehydration or ketosis risks in lean MODY patients remain untested. The primary comparison was a null between-group difference, which is reassuring rather than a demonstration of superiority, and the work carries notable academic-foundation funding tied to a diabetes industry ecosystem. Can I use this with my patients? Not yet as a labelled strategy, but it strengthens the rationale for cautiously trialling an SGLT2 inhibitor in a euglycaemia-motivated adult with genetically confirmed HNF1A-MODY and preserved renal function who is inadequately controlled on a sulfonylurea, with close monitoring. Adequately powered trials reporting glycaemic efficacy, euglycaemic ketoacidosis risk, and volume status in this lean population are needed before routine adoption.
References
Maagensen H, Jensen JS, Høyerup SO, Thuesen ACB, Krogh J, Holst JJ, et al. Effect of SGLT2 Inhibition on Glucosuria During a Hyperglycemic Clamp in HNF1A-MODY (MODY3) and Type 2 Diabetes. Diabetes Care. 2025;48(9):1536-1544. doi:10.2337/dc25-0737