Diabetes Clinical Trial
Official title:
Effect of Aspirin on Renal Disease Progression in Patients With Type 2 Diabetes: a Multicentre Double-blind, Placebo-controlled, Randomised Trial. The LEDA (renaL disEase Progression by Aspirin in Diabetic pAtients) Study.
The pathophysiology of diabetes is multifactorial. Beyond genetic susceptibility loci, a lot
of acquired risk factors are involved in the development and progression of the disease.
Chronic complications of diabetes can be divided into vascular and nonvascular. The risk of
developing complications increases with the duration of hyperglycemia, and usually become
apparent in the second decade of hyperglycemia. Vascular complications are further
subdivided into microvascular (retinopathy, nephropathy and neuropathy) and macrovascular
(coronary artery disease, peripheral arterial disease, cerebrovascular disease). It is
estimated that the annual decline of estimated glomerular filtration rate (eGFR) in diabetic
adults is about 2.1-2.7 ml/min.
While there is consolidated evidence about the use of aspirin (ASA) for secondary prevention
in diabetic patients, there is no consensus on the use in primary prevention; the use of ASA
in these patients is at physician discretion.
ASA is an effective antithrombotic agent that inhibits the production of thromboxane (Tx) A2
and other prostaglandins by blocking cyclooxygenase (COX). In patients treated with aspirin,
serum TxB₂ level is the most reliable in vivo indicator of COX-1 inhibition than TxA2, due
to its short half-life and artifacts associated with platelet activation ex vivo.
COX are present in the kidney in the macula densa, in the medulla and in the interstitium.
Experimental animals models have demonstrated that COX are involved in regulation of renal
blood flow. In particular, in a murine animal model, after the administration of COX
inhibitors such as aspirin and celecoxib, it was observed an improvement in renal plasma
flow and eGFR, suggesting a role for Tx in the progression of renal damage However, data on
the relationship between aspirin and renal function in humans are scarce. In a recent work
lead on a large cohort of 800 patients with non-valvular atrial fibrillation, ASA use was
associated with a reduced progression of eGFR <45 ml/min during 2 years of follow-up.
Furthermore, basal levels of urinary excretion of TxB2, correlated inversely with the use of
aspirin and with the decrease of eGFR at follow-up.
The aim of the study is to evaluate the decline in renal function in diabetic patients
treated with low-dose aspirin (100 mg/day) vs. untreated diabetic patients.
Epidemiological data show that type 2 diabetes has an epidemic trend worldwide. The increase
in food intake, the greater availability of refined grains and the reduction of physical
activity had, in fact, negative effects in most areas. It is expected that the number of
people suffering from diabetes will double in the period 2000-2030.The most important
increase is expected in developing countries, where the prevalence of obesity has rapidly
increased. Unlike developing countries, in Europe and in US the higher incidence of diabetes
is primarily related to the increased life expectancy of the general population and of
diabetic people in particular, and secondary to the higher incidence of the disease. The
Casale Monferrato Study indicate an increase of 44% (2.6% vs. 3.8%) in the period 1988-2000.
The prevalence of obesity in diabetic patients (Body Mass Index, BMI> 30 kg / m2) increased
from 23% to 34%. Whereas in subjects aged <65 years the increase in the prevalence of type 2
diabetes was non-significant (1.1% vs. 1.7%), in the age group > 65 years, the increase was
significant (6.5% vs. 9.1%). In particular, a doubling of the prevalence in the age ≥80
years was recorded (3.5% vs. 7.2%). The most recent data from the Turin Study show that in
2003 the prevalence of overt diabetes was 4.9% in 2003. Thus, there was a doubling of cases
over a period of 15 years (1988-2003); in the age group 65-74 years, the prevalence rose to
13% and in the age> 74 years to 14%. It is also estimated that 1.5-2% of the population is
affected by misdiagnosed diabetes.
The pathophysiology of diabetes is multifactorial. Beyond genetic susceptibility loci, a lot
of acquired risk factors are involved in the development and progression of the disease. The
most important are Impaired Fasting Glucose (IFG) (odds ratio, OR = 11), Impaired Glucose
Tolerance (IGT) (OR = 3.9), the weight (overweight: OR = 3.4 and obesity: OR = 9.9),
dyslipidemia (OR = 1.6), hypertension (OR = 2.3).
Chronic complications of diabetes can be divided into vascular and nonvascular. The risk of
developing complications increases with the duration of hyperglycemia, and usually become
apparent in the second decade of hyperglycemia. Vascular complications are further
subdivided into microvascular (retinopathy, nephropathy and neuropathy) and macrovascular
(coronary artery disease, peripheral arterial disease, cerebrovascular disease). In
particular, the worsening of renal function seems to be a peculiar characteristic of the
patients suffering from diabetes. It is estimated that the annual decline of estimated
glomerular filtration rate (eGFR) in diabetic adults is about 2.1-2.7 ml/min.
Aspirin and Diabetes The efficacy and the safety of acetylsalicylic acid (aspirin, ASA) as
an antithrombotic agent has been assessed in different subsets, both in apparently healthy
people at low risk of vascular complications (primary prevention), and in high-risk
patients, such as those with a previous myocardial infarction or acute ischemic stroke
(secondary prevention). Diabetic patients represent an important group in whom treatment
with ASA should be carefully considered. The evidence that type 2 diabetic patients taking
glucose-lowering agents have similar cardiovascular risk compared to non-diabetic with a
previous myocardial infarction, could make reasonable the use of an antiplatelet drug as
primary prevention strategy for cardiovascular diseases. However, while there is
consolidated evidence about the use of ASA for secondary prevention in diabetic patients,
there is no consensus on the use in primary prevention; ASA use in these patients is at
physician discretion.
Mechanism of action of aspirin. Aspirin is an effective antithrombotic agent that inhibits,
the production of thromboxane (Tx) A2 and other prostaglandins by blocking cyclooxygenase
(COX) enzyme. There have been described two isoforms of COX, the COX-1, which is widely
expressed and which plays a function of gastric cyto-protection, and COX-2 expressed upon
external stimuli and mainly in inflammatory and immune cells. Low-dosage ASA can inhibit
COX-1, while at high dosage, ASA can inhibit both COX-1 and COX-2 enzymes.
The antiplatelet action of ASA is via specific inhibition of COX in platelets, through the
acetylation of serine-529 of COX-1. This enzyme possesses both cyclooxygenase activity
[converting arachidonate into prostaglandin G2 (PGG2)] and peroxidase [converting PGG2 into
PGH2, the biochemical precursor of many other prostaglandins and Tx]. In platelets, this
inhibitory effect has as a result, the reduced production of prostaglandins and TxA2, which
is a strong platelet agonist. This inhibitory effect is irreversible so that TxA2-mediated
platelet aggregation can be restored only through the synthesis of new platelets. Thus,
after ASA administration, platelet aggregation is inhibited up to 7 days.
In patients treated with low doses of aspirin, serum TxB₂ level is a most reliable in vivo
indicator of COX-1 inhibition than TxA2, due to its short half-life and artifacts associated
with platelet activation ex vivo.
Both urinary levels of 11-dehydro-TxB₂ and 2.3-dinor-TxB₂, the most abundant metabolite of
TxB₂, have been proven to be platelet activation surrogates. As 11-dehydro-TxB₂ is excreted
in higher amounts and has a longer half-life, is the marker of choice.
Thromboxane binds to TP receptor, commonly found on platelets, smooth muscle cells,
endothelium and vessels. They exert vasoconstriction function on blood vessels, platelet
aggregation and induce the initial stages of coagulation. In particular, Tx is entailed in
the reduction of renal blood flow and glomerular filtration rate.
Optimal dosage of aspirin. Randomized placebo-controlled studies have shown that aspirin is
effective as an antithrombotic agent at a dosage ranging from 50 to 1500 mg/day; however,
long-term clinical efficacy requires daily dosage of 50 up to 100 mg/day.
Patrono et al. assessed a relationship between aspirin dose and TxB2 levels. This study
showed that a single dose of 100 mg of drug was able to reduce by 98% the concentration of
serum levels of Tx during the first hour. Single doses of 100-400 mg were able to reduce of
94-98% after 24 and 48 hours, with an inhibition rate up to 90-92% at 72 hrs. Serum Tx
decreased to normal levels after a period compatible with the platelet half-life. More than
90% of platelet inhibition could be maintained over one month by giving 200 mg of aspirin
every 72 hours.
Aspirin, eicosanoids and renal function As previously reported, ASA is able to inhibit Tx
production by inhibiting COX; COX are present in the kidney in the macula densa, in the
medulla and in the interstitium. In the macula densa this enzyme seems to favour renin
production (eg. salt restriction, use of ACE inhibitors, renovascular hypertension).
Experimental animals models have demonstrated that COX are involved in regulation of renal
blood flow. In particular, in a murine animal model, after the administration of COX
inhibitors such as aspirin and celecoxib, it was observed an improvement in renal plasma
flow and eGFR, suggesting a role for Tx in the progression of renal damage.
However, data on the relationship between aspirin and renal function in humans are not
available. In a recent work that included a large cohort of 800 patients with non-valvular
atrial fibrillation, the use of aspirin was associated with a reduced progression of eGFR
<45 ml/min during 2 years of follow-up. In particular, patients not receiving aspirin had an
incidence of GFR <45 ml/min of 15% vs. 5% of those treated with aspirin 100 mg/day.
Furthermore, basal levels of urinary excretion of TxB2, correlated inversely with the use of
aspirin and with the decrease of eGFR at follow-up.
;
Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Caregiver, Investigator), Primary Purpose: Treatment
Status | Clinical Trial | Phase | |
---|---|---|---|
Completed |
NCT05594446 -
Morphometric Study of the Legs and Feet of Diabetic Patients in Order to Collect Data Intended to be Used to Measure by Dynamometry the Pressures Exerted by Several Medical Compression Socks at the Level of the Forefoot
|
||
Completed |
NCT03975309 -
DHS MIND Metabolomics
|
||
Completed |
NCT01855399 -
Technologically Enhanced Coaching: A Program to Improve Diabetes Outcomes
|
N/A | |
Completed |
NCT01819129 -
Efficacy and Safety of FIAsp Compared to Insulin Aspart in Combination With Insulin Glargine and Metformin in Adults With Type 2 Diabetes
|
Phase 3 | |
Recruiting |
NCT04984226 -
Sodium Bicarbonate and Mitochondrial Energetics in Persons With CKD
|
Phase 2 | |
Recruiting |
NCT05007990 -
Caregiving Networks Across Disease Context and the Life Course
|
||
Active, not recruiting |
NCT04420936 -
Pragmatic Research in Healthcare Settings to Improve Diabetes and Obesity Prevention and Care for Our Program
|
N/A | |
Recruiting |
NCT03549559 -
Imaging Histone Deacetylase in the Heart
|
N/A | |
Completed |
NCT04903496 -
Clinical Characteristics and Disease Burden of Diabetic Patients Based on Tianjin Regional Database
|
||
Completed |
NCT01437592 -
Investigating the Pharmacokinetic Properties of NN1250 in Healthy Chinese Subjects
|
Phase 1 | |
Completed |
NCT01696266 -
An International Survey on Hypoglycaemia Among Insulin-treated Patients With Diabetes
|
||
Completed |
NCT04082585 -
Total Health Improvement Program Research Project
|
||
Completed |
NCT03390179 -
Hyperglycemic Response and Steroid Administration After Surgery (DexGlySurgery)
|
||
Not yet recruiting |
NCT05029804 -
Effect of Walking Exercise Training on Adherence to Disease Management and Metabolic Control in Diabetes
|
N/A | |
Recruiting |
NCT05294822 -
Autologous Regenerative Islet Transplantation for Insulin-dependent Diabetes
|
N/A | |
Completed |
NCT04427982 -
Dance and Diabetes/Prediabetes Self-Management
|
N/A | |
Completed |
NCT02356848 -
STEP UP to Avert Amputation in Diabetes
|
N/A | |
Completed |
NCT03292185 -
A Trial to Investigate the Single Dose Pharmacokinetics of Insulin Degludec/Liraglutide Compared With Insulin Degludec and Liraglutide in Healthy Chinese Subjects
|
Phase 1 | |
Active, not recruiting |
NCT05477368 -
Examining the Feasibility of Prolonged Ketone Supplement Drink Consumption in Adults With Type 2 Diabetes
|
N/A | |
Completed |
NCT04496401 -
PK Study in Diabetic Transplant récipients : From Twice-daily Tacrolimus to Once-daily Extended-release Tacrolimus
|
Phase 4 |