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

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.

Inclusion criteria

• Diagnosis of heart failure NYHA stage I or II - as shown by their medical records
• Stable anti-hypertensive treatment (>4 weeks)
• Male and female patients older than 21 years
• Willingness to participate and ability to provide informed consent
• 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

• Patients with congestive heart failure NYHA stages I (LVEF >40%) without type 2 diabetes mellitus.
• Patients with congestive heart failure NYHA stages III and IV
• Prior serious hypersensitivity reaction to Dapagliflozin (Forxiga®)
• 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
• Pregnant and breast-feeding women
• Diagnosis of type 1 diabetes mellitus
• 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.
• 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
• . Unstable or rapidly progressing renal disease
• Chronic cystitis and recurrent urinary tract infections
• Impaired renal function with eGFR<45 ml/min/1.73m2 or proteinuria > 0.5 g/24h
• Severe hepatic impairment (Child-Pugh class C)
• Any major cardiovascular event/vascular disease within 3 months prior to enrolment, as assessed by the investigator
• Severe edema (as judged by the investigator)
• Active cancer, history of bladder cancer
• HIV infection
• Patients who have received an organ or bone marrow transplant
• Patients who have had major surgery in the past 3 months
• Patients who have severe comorbid conditions likely to compromise survival or study participation
• Patients who exhibit noticeable anxiety and/or claustrophobia or who exhibit severe vertigo when they are moved into the MRI scanner
• Patients with exclusion criteria for the MRI, such as:

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