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About
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.
Full 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.
Enrollment
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Inclusion criteria
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:
Unwillingness or other inability to cooperate
Primary purpose
Allocation
Interventional model
Masking
40 participants in 2 patient groups, including a placebo group
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Data sourced from clinicaltrials.gov
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