Hepato-renal Regulation of Water Conservation in Heart Failure Patients With SGLT-2 Inhibitor Treatment (DAPA-Shuttle1)

The purpose of this study is to investigate the effects of Dapagliflozin (FORXIGA) 10mg (n=20) and placebo (n=20) on the renal concentration mechanism, mobilization of Na+ from tissue stores, and mobilization of muscle glycogen and fat, in patients heart failure NYHA classes I and II,with or w/o T2DM in a 4-week double-blind, placebo-controlled, randomized study with 2 treatment arms.

Study Overview

• Status: Completed
• Conditions: Heart Failure; Diabetes Mellitus
• Intervention / Treatment: Drug: Dapagliflozin 10 MG [Forxiga]

Detailed Description

Sodium-glucose co-transporter-2 (SGLT-2) inhibitors are a new class of oral medications used for T2DM, which lower blood glucose levels by increasing renal sodium (Na+) and glucose excretion. However, their applications seem to go beyond glycemic control. Recent studies have shown that treatment with SGLT-2 inhibitors significantly improves cardiovascular outcome, with unprecedented reductions in cardiovascular mortality and heart failure hospitalizations. The underlying mechanism of this surprising effect is unclear.

Our hypothesis is that increased Na+ and glucose excretion induced by SGLT-2 inhibitors predisposes to water loss, to which the body responds by increasing urea production in an effort to prevent dehydration. Urea is accumulated in the renal medulla, where it provides the alternative osmotic driving force for water reabsorption. However, hepatic urea production is an energy-intense process, for which amino acids from skeletal muscle are the ideal fuel because they provide both the nitrogen and the energy needed for urea generation. Alanine is transported from muscle to the liver, where it serves as a substrate for new pyruvate generation, which can then be used for the urea cycle, glucose production or ketone body generation. In the same time, as increasing amounts of alanine are shuttled to the liver, muscle will deplete its glucose reservoirs and reprioritize fuel utilization in favour of fatty acids.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 4

Contacts and Locations

Study Locations

• Singapore
  • Singapore, Singapore, 169609
    • National Heart Centre Singapore

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Diagnosis of heart failure NYHA stage I or II - as shown by their medical records
2. Stable anti-hypertensive treatment (>4 weeks)
3. Male and female patients older than 21 years
4. Willingness to participate and ability to provide informed consent
5. Willingness to use effective birth control if of childbearing potential. Any kind of contraception method will be allowed for the period of the study

Exclusion Criteria:

1. Patients with congestive heart failure NYHA stages I (LVEF >40%) without type 2 diabetes mellitus.
2. Patients with congestive heart failure NYHA stages III and IV
3. Prior serious hypersensitivity reaction to Dapagliflozin (Forxiga®)
4. Treatment with any SGLT-2 inhibitor or combined SGLT-1 and 2 inhibitors within 1 week prior to Visit 1 or during screening period until Visit 1
5. Pregnant and breast-feeding women
6. Diagnosis of type 1 diabetes mellitus
7. Patients with type 2 diabetes mellitus with HbA1C > 10.5% from most recent medical records or antidiabetic therapies other than metformin, sulfonylureas or gliptins at screening.
8. Patients with type 2 diabetes mellitus whose antidiabetic treatment (metformin and/or sulfonylureas and/or gliptins) has been changed or unstable within 6 weeks prior to Visit 1
9. . Unstable or rapidly progressing renal disease
10. Chronic cystitis and recurrent urinary tract infections
11. Impaired renal function with eGFR<45 ml/min/1.73m2 or proteinuria > 0.5 g/24h
12. Severe hepatic impairment (Child-Pugh class C)
13. Any major cardiovascular event/vascular disease within 3 months prior to enrolment, as assessed by the investigator
14. Severe edema (as judged by the investigator)
15. Active cancer, history of bladder cancer
16. HIV infection
17. Patients who have received an organ or bone marrow transplant
18. Patients who have had major surgery in the past 3 months
19. Patients who have severe comorbid conditions likely to compromise survival or study participation
20. Patients who exhibit noticeable anxiety and/or claustrophobia or who exhibit severe vertigo when they are moved into the MRI scanner

21. Patients with exclusion criteria for the MRI, such as:

    1. implanted devices (surgical clips, heart pacemakers or defibrillators, cochlear implants)
    2. iron-based tattoos
    3. any other pieces of metal or devices that are not MR-Safe anywhere in the body
22. Unwillingness or other inability to cooperate

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Experimental; Dapagliflozin, 10mg, oral dose, once every day	Drug: Dapagliflozin 10 MG [Forxiga]; 24 Hour Urine Collection, Sodium (23Na) MRI and Magnetic Resonance (MR) spectroscopy scan, Blood collection for metabolomic and osmolyte analysis; Other Names: Placebo
Placebo Comparator: Control; Matching placebo for dapagliflozin, oral dose, once every day	Drug: Dapagliflozin 10 MG [Forxiga]; 24 Hour Urine Collection, Sodium (23Na) MRI and Magnetic Resonance (MR) spectroscopy scan, Blood collection for metabolomic and osmolyte analysis; Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To demonstrate that SGLT-2 inhibition induces urea-dominated renal water conservation within the renal concentration mechanism. ( Change from baseline in urinary osmolyte concentration	Change from baseline in urinary osmolyte concentration; Change from baseline in Na+; Change from baseline in urea concentration	Baseline, Day 3, and Day 28.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To demonstrate that SGLT-2 inhibition increases plasma co-peptin levels in an effort to prevent dehydration	The investigators will study the changes in plasma co-peptin levels shortly after SGLT-2 inhibitor treatment initiation.	Baseline, Day 3 and Day 28
Analysis of skin and muscle Na+ content	The investigators will compare the changes in skin and muscle Na+ content shortly after SGLT-2 inhibitor treatment initiation. Tissue Na+ content will be measured non-invasively with 23NaMRI, using a Siemens 3T MRI scanner system.	Baseline, Day 3, and Day 28.
Analysis of glycogen and fat content in skeletal muscle and liver	The investigators will compare changes from baseline in muscle and liver lipid content (measured with 1HMRS) and assess glycogen content by metabolomic analysis in patients treated with dapagliflozin versus those receiving placebo	Baseline, Day 3 and Day 28

Collaborators and Investigators

• Sponsor: National Heart Centre Singapore
• Collaborators: Duke-NUS Medical School (Singapore)

Study record dates

Study Major Dates

• Study Start (Actual): November 11, 2019
• Primary Completion (Actual): November 10, 2021
• Study Completion (Actual): November 10, 2021

Study Registration Dates

• First Submitted: August 26, 2019
• First Submitted That Met QC Criteria: September 4, 2019
• First Posted (Actual): September 6, 2019

Study Record Updates

• Last Update Posted (Actual): April 13, 2023
• Last Update Submitted That Met QC Criteria: April 11, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin
• Other Study ID Numbers: 2018/2414

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