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Aspirin and Renal Disease Progression in Patients With Type 2 Diabetes (LEDA)

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ClinicalTrials.gov Identifier: NCT02895113
Recruitment Status : Unknown
Verified September 2016 by Francesco Violi, University of Roma La Sapienza.
Recruitment status was:  Not yet recruiting
First Posted : September 9, 2016
Last Update Posted : September 9, 2016
Sponsor:
Information provided by (Responsible Party):
Francesco Violi, University of Roma La Sapienza

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Diabetes Drug: Aspirin Other: Placebo Phase 3

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Detailed Description:

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 418 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Care Provider, Investigator)
Primary Purpose: Treatment
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.
Study Start Date : January 2017
Estimated Primary Completion Date : January 2018
Estimated Study Completion Date : September 2018

Resource links provided by the National Library of Medicine

Drug Information available for: Aspirin

Arm Intervention/treatment
Experimental: Aspirin
Patients will be treated with aspirin 100 mg/day for one year
Drug: Aspirin
Patients suffering from type 2 diabetes will be randomized to receive 100 mg/day or placebo for one year
Other Names:
  • Cardioaspirin
  • Acetylsalicylic acid

Placebo Comparator: Placebo
Patients will be treated with placebo for one year
Other: Placebo
Patients in this arm will be treated with placebo




Primary Outcome Measures :
  1. Changes in renal function in diabetic patients treated with aspirin [ Time Frame: 1 year ]

    The aim of our study is to evaluate the decline in renal function in diabetic patients treated with low-dose aspirin (100 mg/day) vs. untreated diabetic patients. In particular, we will evaluate:

    • The absolute change in eGFR, calculated as the difference between eGFR at 12 months - baseline eGFR;
    • The rapid decline in renal function, defined as a reduction of eGFR ≥5 ml/min at 1 years.
    • The change of renal function class (from G1 to G2, from G2 to G3a and so on) at 6 and 12 months.


Secondary Outcome Measures :
  1. Relationship between changes of Thromboxane B2 excretion and renal function in diabetic patients treated with aspirin [ Time Frame: 1 year ]
    As secondary endpoint, we will evaluate changes in the urinary excretion TxB2 both baseline and at one year. Changing levels of urinary TxB2 will then be related to renal function.



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Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of type 2 diabetes: random blood glucose ≥ 200 mg / dl, fasting blood glucose ≥ 126 mg/dl, blood glucose 2 hours after oral glucose tolerance test (75 g) ≥200 mg/dl, treatment with glucose-lowering agents.

Exclusion Criteria:

  1. History of cardiovascular or cerebrovascular events;
  2. Presence of inadequate glycaemic control (glycosylated haemoglobin ≥8%);
  3. Clinical diagnosis of type 1 diabetes (diagnosis of diabetes and insulin use before 35 years of age);
  4. Patients with renal impairment in G4 stage (eGFR <30 ml/min) at baseline;
  5. Chronic active infection or evidence of malignancy in the last 5 years;
  6. Autoimmune systemic disease;
  7. Cardiac arrhythmia;
  8. Use of non-steroidal anti-inflammatory drugs, vitamin supplements, or other antiplatelet agents in the previous 30 days;
  9. Liver Failure (eg cirrhosis);
  10. Use of anticoagulants;
  11. Life expectancy <1 year;
  12. Known allergy to aspirin.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02895113


Contacts
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Contact: Francesco Violi, MD +390649970893 francesco.violi@uniroma1.it
Contact: Daniele Pastori, MD +390649970893 daniele.pastori@uniroma1.it

Locations
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Italy
Internal and Medical Specialities Department - Policlinico Umberto I
Rome, Italy, 00161
Sponsors and Collaborators
University of Roma La Sapienza
Investigators
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Principal Investigator: Francesco Violi, MD Sapienza University of Rome

Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Francesco Violi, Full professor, University of Roma La Sapienza
ClinicalTrials.gov Identifier: NCT02895113     History of Changes
Other Study ID Numbers: LEDA study
First Posted: September 9, 2016    Key Record Dates
Last Update Posted: September 9, 2016
Last Verified: September 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Francesco Violi, University of Roma La Sapienza:
Aspirin
Diabetes
Renal function
Thromboxane
Additional relevant MeSH terms:
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Aspirin
Kidney Diseases
Diabetes Mellitus
Disease Progression
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Disease Attributes
Pathologic Processes
Urologic Diseases
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Platelet Aggregation Inhibitors
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Antipyretics