A Randomized, Double Blind, Cross-Over, Placebo-Controlled Clinical Trial to Assess the Effects of Candesartan on the Carbohydrate Metabolism, of Non Diabetic, Non Hypertensive Subjects With Dysglycemia and Abdominal Obesity."ARAMIA"
试验速览
- 阶段
- 4 期
- 状态
- 终止
- 发起方
- 入组人数
- 56
- 试验地点
- 1
- 主要终点
- Changes in HOMA index value
研究概览
简要总结
Hypothesis:
The use of candesartan 16-32 mg/d for 6 months improves the carbohydrate metabolism, and decreases the plasmatic levels of adipocytokines and oxidative stress markers, in non diabetic, non hypertensive subjects with dysglycemia and abdominal obesity, and these effects are independent of the changes in arterial blood pressure.
General Objectives:
The objective is to study the impact of the treatment with candesartan in the carbohydrate metabolism and the plasmatic levels of adipocytokines and oxidative stress markers, in non diabetic, non hypertensive subjects with dysglycemia and abdominal obesity.
Study Design:
This is a randomized, double blind, cross-over, placebo-controlled, clinical trial to assess the effects of candesartan (up to 32 mg/d for 6 months), over the carbohydrate metabolism, plasma levels of adipocytokines and concentrations of oxidative stress markers in non diabetic, non hypertensive, dysglycemic and obese subjects from Colombia. The total duration of the study is 36 months.
Population:
One hundred non diabetic, dysglycemic and obese, subjects of both genders, over 18 years old, will be included. To be included subjects should have blood pressure values under 140/90 mmHg and should be receiving no antihypertensive medical treatment.
Procedures:
Subjects whom fulfill all selection criteria will be included in a run-in period of 15 days with placebo and hygiene-dietary measures (MHD) including educational, nutritional and exercise support. The patients that during this "Run in" phase have a compliance equal to or greater than 80% will be randomized to one of the two treatment groups ("Group A" receiving candesartan 16/32 mg/d for 6 months and then placebo for 6 months, or "Group B" receiving placebo during the first 6 months and then candesartan 16/32 mg/d during the last 6 months) in a 1:1 proportion by blocks of 4 subjects. Randomization will be performed by the AstraZeneca clinical department. Both groups will concurrently receive the standard treatment with MHD. Control visits will be programmed every month. Metabolic parameters, including C-reactive protein (CRP), interleukin-6 (IL-6), adiponectin, leptin, insulin, malonaldehyde and 8-isoprostanes, will be evaluated every 6 months (at the beginning and end of each treatment).
Statistical Analysis:
The analysis strategy will be performed by intention-to-treat. In a descriptive analysis, the averages and proportions will be obtained with their corresponding 95% confidence intervals for the clinically relevant variables during the baseline evaluation. In order to evaluate the differences between the groups, the Student's t test, Mann-Whitney and Fischer's exact tests will be used according to the nature of the study variables. Multiple lineal regression will be used with the purpose of comparing the treatment groups from baseline and its changes up to the 6th month of treatment.
Ethical Aspects:
The study will be conducted according to the Helsinki declaration, the good clinical practices guidelines and the Colombian legislation. Prior to entering the study, patients must sign a written informed consent that has been approved by the Institutional Ethics Committee of Fundación Cardiovascular de Colombia.
详细描述
Background:
During the last years, the worldwide prevalence of diabetes mellitus type II (DM2) has increased dramatically, impacting the cardiovascular morbidity and mortality. It has been estimated that more than 171 million people suffer this disease (2.8% of the worldwide population) and it's predicted that it will increase to 366 million (6.5 %) in 2030, from which 298 million will be from developing countries. Currently, in Latin America, the DM2 prevalence ranges are between 1.2% and 8%, and it is expected to increase 38% during the next 10 years, with higher levels in the urban zones.
Recently, we have demonstrated that the Colombian population with a lower abdominal circumference than those reported in Caucasian populations presented an increased risk of developed metabolic syndrome and coronary artery disease. Moreover, abdominal obesity in our population is associated with higher levels of inflammatory markers, as C-reactive protein (CRP) and proinflammatory cytokines. Nowadays, the relationship between abdominal obesity, inflammation, insulin resistance, diabetes mellitus type 2, metabolic syndrome and cardiovascular disease is a crucial aim of research, especially in populations as the Colombian, that is in high risk of being affected by the epidemic of diabetes mellitus and cardiovascular disease. The occurrence of DM2 is associated with a 2 to 4 fold increase in the risk of developing coronary disease. The diabetic patients that present unstable angina have a greater risk of developing acute myocardial infarct (AMI) and the diabetic patients with AMI have more risk of death than the non-diabetic patients. Additionally, the subjects with DM2 have an increased risk of experiencing cardiovascular events (1.5 to 3 times), and greater recurrence and mortality for these causes. The incidence and severity of the peripheral arterial disease are also increased from 2 to 4 times in diabetic patients.
The current criteria for DM2 diagnosis established by the American Association of Diabetes is a glucose level in fasting >126 mg/dl, which has been established based on the risk of suffering ophthalmic and renal micro-vascular complications with values superior to this limit. Nevertheless, several works have shown that patients with altered fasting glucose levels (≥100 mg/dl - <126 mg/dl) have an increased risk of cardiovascular morbidity and mortality.
We recently reported in Colombia, the existence of a strong association between the presence of cardiovascular risk factors and altered fasting plasma glucose, this association being greater with the presence of abnormal glucose blood levels after the glucose overload test. This association has been explained since the hyperglycemia per-se may be implicated in the development of atherosclerosis due to metabolic and structural changes at the endothelial level. At long term it may result in irreversible alterations; a "non-returning" point leading to cardiovascular complications typical of diabetes. According to these observations, our group has recently shown that patients with altered glycemia in fasting, regardless of other classic factors of cardiovascular risk, present a greater risk of coronary disease, supporting the hypothesis that the hyperglycemia leads to structural changes in the endothelial wall.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •The subjects that fulfill the following inclusion criteria will be eligible to participate in the study:
- •Men and women older than 18 years of age.
- •Waist perimeter > 90 cm in males or > 80 cm in females
- •Have plasma glucose levels in fasting between 100 and 125 mg/dL and/or on glucose tolerance test at 2 hours > 140 mg/dL and < 200 mg/dL.
- •Having a treatment compliance of over 80% at the end of the run-in phase.
- •All women with childbearing potential must have a secure contraceptive method. A secure method will be considered as sterilization by surgical methods, postmenopausal condition with an age greater than 45 years and a menopausal period equal to or greater than two years. In premenopausal women, the use of two barrier contraceptive methods including 1 month after the conclusion of the active phase of study treatment.
排除标准
- •Individuals with any of the following characteristics will be excluded:
- •Prior diagnosis of type 1 or 2 diabetes mellitus, chronic or acute renal insufficiency, coronary disease clinically evident (acute myocardial infarction, chest angina, myocardial revascularization) or cardiac insufficiency, or history of prior cardiovascular events (AMI, CVD, or CABG).
- •Significant chronic disease (terminal stage cirrhosis or hepatic disease or cancer) that affects the survival of patients at 12 months.
- •Chronic inflammatory diseases of obesity (lupus erythematosus, rheumatoid arthritis, etc.)
- •Infectious acute or chronic processes of any etiology with an occurrence within the 4 weeks prior to the beginning of the study.
- •Use of steroid hormones or NSAIDs 1 month prior to the beginning of the study.
- •The patient is participating in a program or under treatment to lose weight during the 8 weeks prior to the study entry.
- •The patient requires (for any circumstance) treatment with immunosuppressive agents.
- •Has participated in a clinical trial in the 8 weeks prior to the study entry.
- •At the study entry, the patient is considering the possibility of a surgical procedure during the next 12 months.
- •History of severe chronic gastritis or any condition of the gastrointestinal tract that may affect the absorption and/or distribution of any drug administered orally.
- •Alteration of the hepatic function tests. The maximum value for ALT or AST will be considered as > 2 times the upper normal limit.
- •Triglycerides > 600 mg/dl.
- •History of the use of psychoactive drugs or abuse of alcohol.
- •Positive pregnancy test in the screening visit.
- •Concomitant treatment with any other antihypertensive drug.
- •Contraindication to receive treatment with candesartan.
- •Pathological alterations of aortic or mitral cardiac valves (stenosis or insufficiency) or hypertrophic cardiomyopathy.
- •Denial to sign informed consent, or any mental condition that makes the patient part of a susceptible population
研究组 & 干预措施
1
干预措施: Candesartan (Drug)
2
干预措施: Placebo (Drug)
结局指标
主要结局
Changes in HOMA index value
时间窗: 6 months after beginning the treatment
次要结局
- Changes in serum insulin, leptin and adiponectin, inflammatory markers and oxidative stress markers(6 months after beginning the treatment)
- Changes in baseline glucose, and post-charge glucose plasma levels(6 months after beginning the treatment)