Impact of SGLT2 on Glucosuria in HNF1A-MODY

Not Applicable

Completed

• Conditions: Maturity-Onset Diabetes of the Young, Type 3; Type 2 Diabetes
• Interventions: Other: Hyperglycaemic clamp; Drug: Placebo; Drug: Empagliflozin

• Registration Number: NCT05417646
• Lead Sponsor: Steno Diabetes Center Copenhagen

Brief Summary

Maturity onset diabetes of the young (MODY) is a subtype of diabetes which is caused by mutations in specific genes leading to diabetes. The most common cause of MODY is due to mutations in the gene hepatocyte nuclear factor 1 alpha (HNF1A) and is consequently named HNF1A-MODY (or MODY3). HNF1A-MODY is associated with urinary excretion of glucose at lower blood glucose levels compared to other types of diabetes. Normally, glucose is reabsorbed by sodium-glucose cotransporter 2 (SGLT2), but SGLT2 is downregulated due to the mutation in HNF1A. Investigators aim to evaluate the impact of the decreased expression of SGLT2 on glucosuria in patients with HNF1A-MODY compared to patients with type 2 diabetes (T2D) using a single dose of an SGLT2 inhibitor during a glucose clamp experiment.

Detailed Description

Participants: Patients with HNF1A-MODY (n=12) and patients with T2D (n=12)

Study Timeline

• Study First Submitted: 2022-05-24
• Study First Submitted QC: 2022-06-09
• Study First Posted: 2022-06-14
• Study Start: 2022-06-22
• Primary Completion: 2023-06-14
• Study Completion: 2023-06-14
• Status Verified: 2023-07
• Last Update Submitted: 2023-07-25
• Last Update Posted: 2023-07-27

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 21

Inclusion Criteria

• Age ≥18 years
• HNF1A-MODY verified by genetic testing (only patients with HNF1A-MODY)
• Type 2 diabetes diagnosis according to World Health Organization (only patients with type 2 diabetes)
• Treatment with diet and/or a glucose-lowering drug (only patients with HNF1A-MODY)
• Normal haemoglobin (males 8.3-10.5 mmol/l, females 7.3-9.5 mmol/l)
• Informed consent

Exclusion Criteria

• Nephropathy (estimated GFR <60 ml/min/1.73m2 and/or albuminuria)
• Known significant liver disease and/or plasma alanine aminotransferase (ALT) and/or plasma aspartate aminotransferase (AST) above 2 × normal values)
• Pregnancy or breastfeeding
• Treatment with SGLT2 inhibitor
• Fasting plasma glucose > 10 mmol/l
• Family history of HNF1A-MODY (only patients with type 2 diabetes)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Type 2 Diabetes - Placebo	Placebo	3-hour hyperglycemic clamp without inhibition of SGLT2 (placebo comparator to empagliflozin)
Type 2 Diabetes - SGLT2 inhibition	Hyperglycaemic clamp	3-hour hyperglycemic clamp with inhibition of SGLT2 (single-dose empagliflozin 25 mg two hours before clamp)
Type 2 Diabetes - Placebo	Hyperglycaemic clamp	3-hour hyperglycemic clamp without inhibition of SGLT2 (placebo comparator to empagliflozin)
HNF1A-MODY - Placebo	Hyperglycaemic clamp	3-hour hyperglycemic clamp without inhibition of SGLT2 (placebo comparator to empagliflozin)
HNF1A-MODY - Placebo	Placebo	3-hour hyperglycemic clamp without inhibition of SGLT2 (placebo comparator to empagliflozin)
HNF1A-MODY - SGLT2 inhibition	Hyperglycaemic clamp	3-hour hyperglycemic clamp with inhibition of SGLT2 (single-dose empagliflozin 25 mg two hours before clamp)
HNF1A-MODY - SGLT2 inhibition	Empagliflozin	3-hour hyperglycemic clamp with inhibition of SGLT2 (single-dose empagliflozin 25 mg two hours before clamp)
Type 2 Diabetes - SGLT2 inhibition	Empagliflozin	3-hour hyperglycemic clamp with inhibition of SGLT2 (single-dose empagliflozin 25 mg two hours before clamp)

Primary Outcome Measures

Name	Time	Method
Urinary glucose excretion	Assesed during 3 hour hyperglycaemic clamp

Secondary Outcome Measures

Name	Time	Method
Concentration of plasma c-peptide	Assesed during 3 hour hyperglycaemic clamp	Summarized as area under the curve (AUC)
Glucose tissue disposal	Assesed during 3 hour hyperglycaemic clamp	difference between infused and excreted glucose
Concentration of plasma glucagon	Assesed during 3 hour hyperglycaemic clamp	Summarized as AUC
Renal threshold of glucose excretion	Assesed during 3 hour hyperglycaemic clamp	Estimated using plasma glucose concentrations, urinary glucose excretion and GFR
Urinary glucose excretion adjusted for glomerular filtration rate (GFR)	Assesed during 3 hour hyperglycaemic clamp	GFR: 99mTc-diethylenetriaminepentaacetic acid (99mTc-DTPA) plasma clearance
Urine volume	Assesed during 3 hour hyperglycaemic clamp
Urinary creatinine clearance	Assesed during 3 hour hyperglycaemic clamp	Urinary creatinine clearance calculated by plasma creatinine concentration and urinary creatinine excretion
Infused amount of glucose	Assesed during 3 hour hyperglycaemic clamp

Trial Locations

Locations (1)

Steno Diabetes Center Copenhagen; 🇩🇰 Herlev, Denmark