Diabetes Clinical Trial
— LEDAOfficial 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.
Status | Not yet recruiting |
Enrollment | 418 |
Est. completion date | September 2018 |
Est. primary completion date | January 2018 |
Accepts healthy volunteers | No |
Gender | Both |
Age group | 18 Years to 100 Years |
Eligibility |
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. |
Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Caregiver, Investigator), Primary Purpose: Treatment
Country | Name | City | State |
---|---|---|---|
Italy | Internal and Medical Specialities Department - Policlinico Umberto I | Rome |
Lead Sponsor | Collaborator |
---|---|
University of Roma La Sapienza |
Italy,
Davì G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med. 2007 Dec 13;357(24):2482-94. Review. — View Citation
Larivière R, Moreau C, Rodrigue ME, Lebel M. Thromboxane blockade reduces blood pressure and progression of renal failure independent of endothelin-1 in uremic rats. Prostaglandins Leukot Essent Fatty Acids. 2004 Aug;71(2):103-9. — View Citation
Lomnicka M, Karouni K, Sue M, Wessel LA, Bing RJ. Effects of nonsteroidal anti-inflammatory drugs on prostacyclin and thromboxane in the kidney. Pharmacology. 2003 Jul;68(3):147-53. — View Citation
Pastori D, Pignatelli P, Perticone F, Sciacqua A, Carnevale R, Farcomeni A, Basili S, Corazza GR, Davì G, Lip GY, Violi F; ARAPACIS (Atrial Fibrillation Registry for Ankle-Brachial Index Prevalence Assessment-Collaborative Italian Study) study group. Aspirin and renal insufficiency progression in patients with atrial fibrillation and chronic kidney disease. Int J Cardiol. 2016 Aug 14;223:619-624. doi: 10.1016/j.ijcard.2016.08.224. [Epub ahead of print] — View Citation
Patrono C, Ciabattoni G, Pinca E, Pugliese F, Castrucci G, De Salvo A, Satta MA, Peskar BA. Low dose aspirin and inhibition of thromboxane B2 production in healthy subjects. Thromb Res. 1980 Feb 1-15;17(3-4):317-27. — View Citation
Stevens PE, Levin A; Kidney Disease: Improving Global Outcomes Chronic Kidney Disease Guideline Development Work Group Members. Evaluation and management of chronic kidney disease: synopsis of the kidney disease: improving global outcomes 2012 clinical practice guideline. Ann Intern Med. 2013 Jun 4;158(11):825-30. doi: 10.7326/0003-4819-158-11-201306040-00007. — View Citation
Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004 May;27(5):1047-53. — View Citation
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Changes in renal function in diabetic patients treated with aspirin | 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. |
1 year | No |
Secondary | Relationship between changes of Thromboxane B2 excretion and renal function in diabetic patients treated with aspirin | 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. | 1 year | No |
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