Impact of SGLT2 on Glucosuria in HNF1A-MODY (MOD3ST-CLAMP)

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.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes; Maturity-Onset Diabetes of the Young, Type 3
• Intervention / Treatment: Other: Hyperglycaemic clamp; Drug: Empagliflozin; Drug: Placebo

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Herlev, Denmark, 2730
    • Steno Diabetes Center Copenhagen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: HNF1A-MODY - SGLT2 inhibition; 3-hour hyperglycemic clamp with inhibition of SGLT2 (single-dose empagliflozin 25 mg two hours before clamp)	Other: Hyperglycaemic clamp; Three-hour, three-step glucose clamp with plasma glucose targets 10, 14 and 18 mmol/l (each one hour); Drug: Empagliflozin; Single-dose, 25 mg, two hours before clamp
Placebo Comparator: HNF1A-MODY - Placebo; 3-hour hyperglycemic clamp without inhibition of SGLT2 (placebo comparator to empagliflozin)	Other: Hyperglycaemic clamp; Three-hour, three-step glucose clamp with plasma glucose targets 10, 14 and 18 mmol/l (each one hour); Drug: Placebo; Placebo comparator to empagliflozin
Active Comparator: Type 2 Diabetes - SGLT2 inhibition; 3-hour hyperglycemic clamp with inhibition of SGLT2 (single-dose empagliflozin 25 mg two hours before clamp)	Other: Hyperglycaemic clamp; Three-hour, three-step glucose clamp with plasma glucose targets 10, 14 and 18 mmol/l (each one hour); Drug: Empagliflozin; Single-dose, 25 mg, two hours before clamp
Placebo Comparator: Type 2 Diabetes - Placebo; 3-hour hyperglycemic clamp without inhibition of SGLT2 (placebo comparator to empagliflozin)	Other: Hyperglycaemic clamp; Three-hour, three-step glucose clamp with plasma glucose targets 10, 14 and 18 mmol/l (each one hour); Drug: Placebo; Placebo comparator to empagliflozin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Urinary glucose excretion	Assesed during 3 hour hyperglycaemic clamp

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Steno Diabetes Center Copenhagen
• Collaborators: University of Copenhagen
• Investigators: Principal Investigator: Tina Vilsbøll, Steno Diabetes Center Copenhagen

Study record dates

Study Major Dates

• Study Start (Actual): June 22, 2022
• Primary Completion (Actual): June 14, 2023
• Study Completion (Actual): June 14, 2023

Study Registration Dates

• First Submitted: May 24, 2022
• First Submitted That Met QC Criteria: June 9, 2022
• First Posted (Actual): June 14, 2022

Study Record Updates

• Last Update Posted (Actual): July 27, 2023
• Last Update Submitted That Met QC Criteria: July 25, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: Sodium-Glucose Transporter 2 Inhibitors; Sodium-Glucose Transporter 2; Glycosuria
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Empagliflozin
• Other Study ID Numbers: H-21066984

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No