Treatment of HNF1A-MODY with SGLT2 inhibition

Monogenic diabetes constitutes a heterogenous form of diabetes that is highly inheritable. Monogenic diabetes can be caused by disease-causing variants in several genes. Each affected gene defines a distinct subtype with a distinct phenotype. Disease-causing variants in the gene HNF1A account for a substantial proportion of cases with monogenic diabetes. Individuals with diabetes caused by variants in HNF1A (HNF1A-MODY) typically have early onset of diabetes and impaired beta cell function with impaired insulin secretion. Glycaemia can often be managed with non-insulin glucose-lowering drugs used in the treatment of type 2 diabetes. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are widely used in the treatment of type 2 diabetes, but this drug class has not been investigated in randomised trials for the treatment of HNF1A-MODY. However, the efficacy of SGLT2 inhibitors in individuals with HNF1A-MODY is questionable because the expression of SGLT2, a protein responsible for renal glucose reabsorption, has been shown to be transcriptionally regulated by the transcription factor encoded by HNF1A. Furthermore, individuals with HNF1A-MODY have a lower renal glucose threshold and increased glucosuria.
The aims of this thesis are to 1) explore the involvement of decreased SGLT2 function on urinary glucose excretion in individuals with HNF1A-MODY using an SGLT2 inhibitor, and 2) examine the glucose-lowering effects and safety of the SGLT2 inhibitor empagliflozin in individuals with HNF1A-MODY.
In Study 1, we described the clinical use of an SGLT2 inhibitor in seven individuals with HNF1A-MODY in a case series. Overall, the initiation was associated with improved glycaemia and/or reduced use of insulin and during the 14 person-years of follow-up, the treatments were well-tolerated. In Study 2, we assessed the urinary glucose excretion during a three-hour, three-step hyperglycaemic clamp with and without SGLT2 inhibition in individuals with HNF1A-MODY and individuals with type 2 diabetes. SGLT2 inhibition increased urinary glucose excretion markedly in both groups and there was no significant difference between the groups in the effect of SGLT2 inhibition. This indicates that the glucose transport via SGLT2 in individuals with HNF1A-MODY is not decreased to a large degree. In Study 3, the efficacy and safety of four weeks of treatment with empagliflozin in individuals with HNF1A-MODY were investigated in a randomised, double-blind, placebo-controlled crossover trial. Empagliflozin significantly lowered mean glucose evaluated by continuous glucose monitoring and FPG compared to placebo without raising any concerns of safety issues.
In conclusion, the results of the studies included in this thesis support that SGLT2 inhibitors can be used as a glucose-lowering treatment in HNF1A-MODY.