Clinical Trial Details
— Status: Not yet recruiting
Administrative data
NCT number |
NCT06240403 |
Other study ID # |
339442 |
Secondary ID |
|
Status |
Not yet recruiting |
Phase |
Phase 2
|
First received |
|
Last updated |
|
Start date |
September 1, 2024 |
Est. completion date |
August 28, 2028 |
Study information
Verified date |
January 2024 |
Source |
University of Leeds |
Contact |
Klaus Witte |
Phone |
00447768254073 |
Email |
k.k.witte[@]leeds.ac.uk |
Is FDA regulated |
No |
Health authority |
|
Study type |
Interventional
|
Clinical Trial Summary
In pilot studies the investigators have shown that subcutaneous adipose tissue (SAT) from
patients with reduced ejection fraction heart failure (HFrEF) and type 2 diabetes mellitus
(T2DM) is dysfunctional. Endothelial cells from the adipose tissue from these patients are
senescent and have deleterious effects on healthy human subcutaneous adipocytes, including
increasing expression of IL-6 (gene and protein) and reducing glucose uptake. Digoxin, a
well-established treatment for HFrEF, selectively clears these senescent endothelial cells
and prevents adipocyte dysfunction. This study will examine the effect of digoxin on adipose
tissue on the burden of senescent cells.
Description:
Type 2 diabetes mellitus and advanced heart failure: a lethal combination. T2DM is a
progressive disorder affecting over 400 million people worldwide, a figure which will reach
600 million by 2035. Globally, T2DM causes one cardiovascular death every 12 seconds and
accounts for 8.4% of all deaths in people between the age of 20-79. A common cardiovascular
sequela of T2DM is chronic heart failure (CHF) due to reduced left ventricular ejection
fraction (HFrEF). Despite 'state of the art' therapies, 1 in 7 patients with the combination
of T2DM and HFrEF will be dead or admitted to hospital within 2 years. More than 30% of
patients with HFrEF suffer from T2DM, with incidence of T2DM rising to half in those
hospitalised for heart failure.
Multiple mechanisms have been proposed to explain the increased incidence of HFrEF in
patients with T2DM, including the hypertrophic influence of insulin, the adverse effects of
hyperglycaemia, increased oxidative stress, and neurohumoral activation. More recently,
increasing attention has been paid to insulin resistance as a driver of HFrEF. Resistance to
insulin-mediated glucose uptake in its canonical target tissues (liver, muscle and fat) is
well-established as a critical perturbation contributing to the progression of T2DM, and as a
result, reversing or overcoming this has become a well-accepted therapeutic paradigm.
A study of Swedish individuals found that insulin resistance predicted the development of
HFrEF independently of established risk factors. In another study, plasma levels of
proinsulin (a marker of insulin resistance) were higher in people who developed HFrEF 20
years before diagnosis. There is also accumulating evidence that HFrEF augments the risk of
developing T2DM and drives its progression, with a stronger relationship between the two in
those with more severe HFrEF. The investigators have shown that the deleterious effect of
T2DM on HFrEF outcomes is similar in patients with and without ischaemic aetiology,
supporting the hypothesis that metabolic dysfunction may at least in part drive the
progression of HFrEF in patients with the additional burden of T2DM. These studies raise the
possibility of a vicious cycle, whereby HFrEF induces metabolic dysfunction which in turn
accelerates cardiac dysfunction.
Subcutaneous adipose tissue microvascular endothelial cell senescence in patients with type 2
diabetes mellitus and HFrEF. Subcutaneous adipose tissue (SAT) is the largest AT depot in
humans and the most important in terms of its contribution to glucose and lipid homeostasis.
Evidence from large scale human genetic, clinical, and preclinical studies, supports the
hypothesis that in obese insulin resistant humans dysfunctional SAT is less efficient at
glucose uptake and lipid storage, which as a result leads to impaired glucose tolerance and
deposition of lipids in tissues ill-equipped to deal with this challenge. While Shimizu et.
al. showed that AT dysfunction in murine models is mechanistically linked to the development
and progression of HFrEF, very little is known about SAT function in humans with HFrEF. The
investigators have performed a detailed examination of SAT from humans with HFrEF with and
without T2DM. SAT from patients with HFrEF and T2DM (despite similar body mass index to those
without T2DM) had larger adipocytes, increased fibrosis and reduced vascular sprouting in
vitro. They took this work further showing that SAT MVEC had increased production of the free
radical superoxide and reduced population doubling rate. Stimulated by these findings, which
raised the intriguing possibility that SAT MVEC may be adopting a senescent phenotype, the
investigators quantified hallmarks of cellular senescence. SAT MVEC from patients with HFrEF
and T2DM had: 1) Reduced proliferation in an EdU assay a sensitive method to detect
proliferation in live mammalian cells; 2) Increased expression of senescence associated
β-Galactosidase; 3) Reduced mitochondrial ATP generation. A sine qua non of senescent cells
is secretion of a complex combination of factors collectively referred to as the senescence
associated secretory phenotype (SASP). To assess this, the investigators took conditioned
media from MVEC and using a cytokine multiplex assay, demonstrated higher concentrations of
IL-6 relative to total cell protein (3.4 [0.8] vs. 1.6 [0.4]; P<0.05) in MVEC conditioned
media from patients with HFrEF and T2DM versus HFrEF without T2DM.
Senescent MVEC communicate via SASP with healthy adipocytes to induce a pro-inflammatory
phenotype. Through SASP, senescent cells are thought to induce an inflammatory state that can
provoke local tissue damage leading to a persistent, self-reinforcing, inflammatory
microenvironment. The bulk of evidence demonstrating deleterious cell-cell communication
facilitated by SASP has been generated using animal models. For example genetically induced
EC specific senescence in mice leads to adipocyte and whole-body insulin resistance. The
investigators developed a co-culture system to allow them to examine human SAT MVEC to
adipocyte communication. When MVEC from patients with HFrEF and T2DM were co-cultured with
healthy human subcutaneous adipocytes, IL-6 mRNA and protein were increased, and glucose
uptake decreased, compared to adipocytes cultured with MVEC from HFrEF patients without T2DM.
IL-6 is a complex pleiotropic cytokine with multiple effects that may influence glucose
homeostasis. Consistent with this IL-6 has a negative effect on adipocyte glucose uptake. It
is thought that up to 35% of circulating IL-6 derives from AT. With this in mind the
investigators measured serum IL-6 concentration in patients with HFrEF and T2DM and found it
to be significantly higher compared to patients with HFrEF alone (HF 3.9pg/ml [0.5] c.f. HFDM
8.1pg/ml [1.2]; P<0.01). These data demonstrate the possibility of a deleterious signalling
circuit between senescent MVEC and SAT adipocytes, which in turn may contribute to systemic
metabolic dysregulation.
Senolytics. Drugs targeting the deleterious impact of senescent cells can be broadly
described as: i) senomorphic agents that target pathological SASP signalling and ii)
senolytic agents that specifically eliminate senescent cells. The first published study in
humans of senolytic agents examined the effect of Dasatinib plus Quercetin in patients with
idiopathic pulmonary fibrosis, and demonstrated that Dasatinib plus Quercetin improved a
number of markers of physical performance in patients with this disorder. Recently Hickson
et. al. showed that 11 days after a short course of Dasatinib plus Quercetin in individuals
with advanced T2DM, senescent cell burden in SAT was reduced with a commensurate favourable
effect on SASP.
Digoxin induced senolysis: a new role for an old drug. Recent reports raise the intriguing
possibility that the cardiac glycoside digoxin may have senolytic actions. Consistent with
this, digoxin reduced β-galactosidase, enhanced proliferation and reduced IL-6 secretion by
>15%. In SAT MVEC from patients with HFrEF and T2DM. When SAT MVEC from patients with HFrEF
and T2DM pre-treated with digoxin were co-cultured with healthy subcutaneous adipocytes,
normal levels of glucose uptake were achieved.
Clinical trials of digoxin in patients with HFrEF. It is well established that digoxin safely
improves haemodynamics, symptoms and the deleterious neurohumoral profile of patients with
advanced HFrEF. In the DIG trial, digoxin safely reduced the risk of HF death and
hospitalisation at serum concentrations between 0.5-0.9ng/mL which is usually achieved by a
daily dose of 125mcg. The RADIANCE study which compared continuing digoxin therapy with its
withdrawal from background ACEI and loop diuretic therapy showed an increased risk of HF
within 14 days in those in whom digoxin was withdrawn. The DIG trial had limited biochemical
investigations and did not include HbA1c or fasting/non-fasting glucose, but a recent
subgroup analysis showed data supporting the safety of digoxin in patients with HFrEF and a
clinical diagnosis of diabetes per se. Despite these data, digoxin use has fallen
substantially over the last 2 decades; once prescribed to 80% of patients with HFrEF, it is
now taken by less than 40% of patients. The investigators' data raise the intriguing
possibility that digoxin may be used as a senolytic agent to normalise SAT dysfunction in
patients with advanced HFrEF and T2DM.
Hypothesis: Digoxin administered to patients with HFrEF and T2DM reduces microvascular
endothelial cell senescence and improves subcutaneous adipose tissue function.
Fundamental aims:
1. To examine the effect of digoxin on SAT senescent MVEC burden in patients with HFrEF and
T2DM.
2. To examine the effect of systemic digoxin on phenotypic hallmarks of SAT MVEC senescence
and SAT dysfunction.