Effect of SGLT2 Inhibition on Glucosuria During a Hyperglycemic Clamp in HNF1A-MODY (MODY3) and Type 2 Diabetes
Henrik Maagensen, Johanne S. Jensen, Stine O. Høyerup, Anne C.B. Thuesen, Jesper Krogh, Jens J. Holst, Henrik Vestergaard, Peter Rossing, Torben Hansen, Filip K. Knop, Sofie Hædersdal, Tina VilsbøllOBJECTIVE
Pathogenic variants of HNF1A cause maturity-onset diabetes of the young type 3 (HNF1A-MODY; also known as MODY3). Individuals with HNF1A-MODY are primarily treated with sulfonylureas; however, little is known about the effect of sodium–glucose cotransporter 2 (SGLT2) inhibitors in HNF1A-MODY. Interestingly, HNF1A-MODY is associated with increased glucosuria, which has been attributed to lower expression of SGLT2 as observed in HNF1A-knockout mice. We investigated the impact of acute SGLT2 inhibition on glucosuria in individuals with HNF1A-MODY or type 2 diabetes.
RESEARCH DESIGN AND METHODS
In a randomized, double-blind, crossover study, individuals with HNF1A-MODY or type 2 diabetes underwent two three-step hyperglycemic clamps targeted at 1-h periods of 10, 14, and 18 mmol/L glucose with and without acute SGLT2 inhibition (25 mg empagliflozin or placebo administrated 2 h before clamp procedures).
RESULTS
Eleven individuals with HNF1A-MODY (age [mean ± SD] 49 ± 15 years; glomerular filtration rate [GFR; mean ± SD] 113 ± 18 mL/min) and 10 individuals with type 2 diabetes (age 63 ± 7 years; GFR 103 ± 27 mL/min) were included. During the 3-h hyperglycemic clamp, SGLT2 inhibition increased urinary glucose excretion in both groups (HNF1A-MODY: 24.5 g [95% CI 20.6, 28.3]; type 2 diabetes: 23.5 g [95% CI 20.4, 26.5]). The effect of SGLT2 inhibition was not significantly different between the groups (1.0 g [95% CI −3.5, 5.6]; P = 0.6).
CONCLUSIONS
The robust effect of SGLT2 inhibition on urinary glucose excretion in participants with HNF1A-MODY points to SGLT2 inhibition as a relevant glucose-lowering treatment strategy in individuals with HNF1A-MODY.