A single dose of dapagliflozin, an SGLT-2 inhibitor, induces higher glycosuria in GCK- and HNF1A-MODY than in type 2 diabetes mellitus

Abstract

AimsSGLT2 inhibitors are a new class of oral hypoglycemic agents used in type 2 diabetes (T2DM). Their effectiveness in maturity onset diabetes of the young (MODY) is unknown. We aimed to assess the response to a single dose of 10 mg dapagliflozin in patients with Hepatocyte Nuclear Factor 1 Alpha (HNF1A)-MODY, Glucokinase (GCK)-MODY, and type 2 diabetes.MethodsWe examined 14 HNF1A-MODY, 19 GCK-MODY, and 12 type 2 diabetes patients. All studied individuals received a single morning dose of 10 mg of dapagliflozin added to their current therapy of diabetes. To assess the response to dapagliflozin we analyzed change in urinary glucose to creatinine ratio and serum 1,5-Anhydroglucitol (1,5-AG) level.ResultsThere were only four patients with positive urine glucose before dapagliflozin administration (one with HNF1A-MODY, two with GCK-MODY, and one with T2DM), whereas after SGLT-2 inhibitor use, glycosuria occurred in all studied participants. Considerable changes in mean glucose to creatinine ratio after dapagliflozin administration were observed in all three groups (20.51 ± 12.08, 23.19 ± 8.10, and 9.84 ± 6.68 mmol/mmol for HNF1A-MODY, GCK-MODY, and T2DM, respectively, p < 0.001 for all comparisons). Post-hoc analysis revealed significant differences in mean glucose to creatinine ratio change between type 2 diabetes and each monogenic diabetes in response to dapagliflozin (p = 0.02, p = 0.003 for HNF1-A and GCK MODY, respectively), but not between the two MODY forms (p = 0.7231). Significant change in serum 1,5-AG was noticed only in T2DM and it was −6.57 ± 7.34 mg/ml (p = 0.04).ConclusionsA single dose of dapagliflozin, an SGLT-2 inhibitor, induces higher glycosuria in GCK- and HNF1A-MODY than in T2DM. Whether flozins are a valid therapeutic option in these forms of MODY requires long-term clinical studies.

SGLT2 inhibition reprograms systemic metabolism via FGF21-dependent and -independent mechanisms

“…Tissue metabolomics analysis revealed a robust reduction in hepatic content of multiple other metabolites, with 163 of 334 measured metabolites significantly altered ( Figure 2I). Carbohydrate-derived metabolites, including glucose/fructose/galactose and 1,5-AG/1-deoxyglucose, were significantly reduced, potentially due to urinary losses of both glucose and 1,5-AG with SGLT2i ( Figure 2, J and K) (12). UDP-GlcNAc, the key endpoint of the hexosamine biosynthesis pathway, and multiple glycolytic metabolites were also significantly lower in CANA-treated mice ( Figure 2J).…”

Monogenic Diabetes in Children and Adolescents: Recognition and Treatment Options

“…The best alternative treatment regimen is not clear, but options include adding basal insulin, GLP-1 agonists, or metformin to SUs. There is a published study of SGLT2 inhibitors in HNF1A-MODY, showing an effect of increased glycosuria [56]. However, this study examined effects after a single dose (dapagliflozin 10 mg).…”

Genetics of Monogenic Diabetes: Present Clinical Challenges

“…Most clinicians use metformin or a dipeptidyl peptidase-4 inhibitor as second-line treatment although there is no particular evidence base. The effect of sodium-glucose transporter-2 inhibitor agents in HNF1A-MODY, who already have decreased expression of SGLT2 and low renal threshold, was shown in a single dose study to induce greater glycosuria than in type 2 diabetes [ 80 ] and it is unknown whether this would lead to greater adverse effects or increased efficacy of the agents.…”