Influence of a Modern Oral Anti-diabetic Medication on Endothelial Dysfunction and Cardiovascular Risk in Diabetic Women and Men: Gender Aspects
试验速览
- 阶段
- 不适用
- 入组人数
- 80
- 试验地点
- 1
- 主要终点
- Endostatin
研究概览
简要总结
Cardiovascular events are the most common cause for death in type 2 diabetes mellitus (T2DM) patients. Male diabetics have a 2 to 3 fold risk for cardiovascular disease (CVD) whereas female diabetes patients have a 3 to 7 fold risk for suffering from a CVD.
Endothelial dysfunction (ED) plays a central role in the development of atherosclerotic lesions. Moreover, ED represents an important diagnostic and prognostic parameter to estimate the cardiovascular risk in an early state. Experimental and clinical studies indicate that T2DM is closely associated with ED, which may be the consequence of a reduced bioactivity of nitric oxide (NO).
The success of diabetes therapy is monitored by the long-term parameter HbA1c. However, only two thirds of all patients with T2DM in the USA and Europe find themselves in the recommended HbA1c span (6.5-7.0 %). Consequently, oral anti-diabetic medication needs permanent adjustment and intensification in order to delaying the progress of T2DM.
Recently, two peptide hormones with insulinotropic effects were identified. These hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are secreted by the gastrointestinal tract after exposure to glucose in nutrition. Physiological effects are increased insulin secretion, inhibition of glucagon secretion and reduction of body weight. Furthermore, these incretins are reduced in patients with impaired glucose tolerance. Thus, the therapeutic approach lies within the elevation of GLP-1 and GIP by preventing their degradation through the enzyme DPP-4 (dipeptidylpeptidase 4).
Thereby, the so-called gliptins inhibit the DPP-4 enzymes. Best results in HbA1c reduction were achieved when gliptins were combined with metformin, glimepiride or pioglitazone.
In this study, patients with T2DM, who are taking metformin as first line medication but do not achieve a HbA1c below 7.0 %, will routinely get an add-on therapy with gliptins (Vildagliptin or Sitagliptin) as second line therapy according to the guidelines of the Österreichische Diabetes Gesellschaft (ÖDG) prescribed by a medical doctor not involved in this study. This medication is a ÖDG standard therapy in T2DM, which patients receive anyway despite this study. Therefore, the therapy with gliptins is not a study medication and is not influenced by the study either. Only patients, who will meet the inclusion criteria of the study and voluntarily participate in the study, will be investigated.
详细描述
The World Health Organization (WHO) estimates that more than 180 million people worldwide have diabetes. This number is likely to more than double by 2030. Further, the WHO proclaims that diabetes causes about 5 % of all deaths globally each year. Cardiovascular events are the most common cause for death in T2DM patients . According to the VERONA study, which observed 6000 T2DM patients over 10 years, 44 % of all deaths were caused by CVD, primarily heart attack and stroke . Interesting is the fact that male diabetics have a 2 to 3 fold risk for CVD whereas female T2DM patients have a 3 to 7 fold risk for suffering a cardiovascular event although there is no satisfying explanation for this phenomenon.
CVD is caused by atherosclerosis, a condition arising from ED. Hence, ED represents an important diagnostic and prognostic parameter to estimate the cardiovascular risk in a very early state. Such ED is frequently caused by a reduced bioactivity of NO. This molecule is synthesized in endothelial cells by oxidation of L-arginine in a reaction catalyzed by the endothelial nitric oxide synthase . NO is able to protect the vessel wall due to its vasodilatating, anti-adhesive and anti-proliferative activities. Experimental and clinical studies demonstrate that T2DM is closely associated with ED, which may be the consequence of a reduced bioactivity of NO. Central mechanisms explaining this defect in T2DM are the inactivation of NO by reactive oxygen species, the reduction in the amounts of co-factors necessary for NO-synthesis, such as biopterin and NADPH, as well as the inhibition of endothelial NO-synthase by phosphorylation (protein kinase C) and O-glycosylation (hexosamine pathway) .
Endostatin (ENST), an anti-angiogenetic factor, blocks endothelial cell proliferation and migration, induces endothelial cell apoptosis and inhibits thereby angiogenesis . Basal plasma levels of ENST are higher in T2DM patients and thus may be the missing link to explain the inactivation of NO as pro-angiogenetic factor in the process of atherosclerosis.
In T2DM, the high glucose load in the blood leads to swelling of the basement membrane and thus to microangiopathy. This favors the genesis of hypertension due to glomerulosclerosis. Eventually, three factors promote the increased risk for heart attack and stroke:
- Hypertension
- Increase of VLDL (due to low insulin levels)
- and elevated clotting disposition (due to hyperglycemia induced production of fibrinogen, coagulation factor V and VIII) .
研究设计
- 研究类型
- Observational
- 时间视角
- Prospective
入排标准
- 年龄范围
- 25 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •patients with T2DM
- •metformin therapy
- •HbA1c < 7%
- •25 - 69 years
排除标准
- •pregnant women
- •untreated thyroid dysfunction
- •renal insufficiency (creatinine clearance < 60 ml/min)
- •unstable coronary heart disease
- •NYHA III or IV
- •severe hepatic dysfunction except steatosis (GOT and GPT three times higher than ULN)
- •patients undergoing cortisone therapy
- •condition post stroke within the last 6 months
结局指标
主要结局
Endostatin
时间窗: after 6 months
catecholamine
时间窗: after 6 months
次要结局
- Brain natriuretic peptide(after 6 months)
- Intima media thickness(after 6 months)
- Sex hormones(after 6 months)
- Plasminogen Activator inhibitor-1(after 6 months)
- Adrenomedullin(after 6 months)
- Ultra sensitive C-reactive protein(after 6 months)
- Asymmetric dimethylarginine(after 6 months)
- Adiponectin(baselie and after 6 months)
- Apelin(after 6 moths)
- Homeostasis model assessment-estimated insulin resistance(after 6 months)