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.
试验速览
- 阶段
- 3 期
- 发起方
- 入组人数
- 418
- 试验地点
- 1
- 主要终点
- Changes in renal function in diabetic patients treated with aspirin
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Care Provider, Investigator)
入排标准
- 年龄范围
- 18 Years 至 100 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •History of cardiovascular or cerebrovascular events;
- •Presence of inadequate glycaemic control (glycosylated haemoglobin ≥8%);
- •Clinical diagnosis of type 1 diabetes (diagnosis of diabetes and insulin use before 35 years of age);
- •Patients with renal impairment in G4 stage (eGFR <30 ml/min) at baseline;
- •Chronic active infection or evidence of malignancy in the last 5 years;
- •Autoimmune systemic disease;
- •Cardiac arrhythmia;
- •Use of non-steroidal anti-inflammatory drugs, vitamin supplements, or other antiplatelet agents in the previous 30 days;
- •Liver Failure (eg cirrhosis);
- •Use of anticoagulants;
- •Life expectancy <1 year;
- •Known allergy to aspirin.
研究组 & 干预措施
Placebo
Patients will be treated with placebo for one year
干预措施: Placebo (Other)
Aspirin
Patients will be treated with aspirin 100 mg/day for one year
干预措施: Aspirin (Drug)
结局指标
主要结局
Changes in renal function in diabetic patients treated with aspirin
时间窗: 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.
次要结局
- Relationship between changes of Thromboxane B2 excretion and renal function in diabetic patients treated with aspirin(1 year)
研究者
Francesco Violi
Full professor
University of Roma La Sapienza