Influence of DPP-4 on Inflammatory Parameters in Diabetics: Gender Aspects
|ClinicalTrials.gov Identifier: NCT01162772|
Recruitment Status : Unknown
Verified July 2010 by Medical University of Vienna.
Recruitment status was: Recruiting
First Posted : July 15, 2010
Last Update Posted : July 16, 2010
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.
|Condition or disease|
|Type 2 Diabetes Mellitus Cardiovascular Risk Endothelial Dysfunction|
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|Study Type :||Observational|
|Estimated Enrollment :||80 participants|
|Official Title:||Influence of a Modern Oral Anti-diabetic Medication on Endothelial Dysfunction and Cardiovascular Risk in Diabetic Women and Men: Gender Aspects|
|Study Start Date :||January 2010|
|Estimated Primary Completion Date :||October 2011|
female, 25-75 years old, no pregnancy, with/out Hormone replacement therapy T2DM, HbA1c > 7% with metformin mono-therapy
25-75 years, T2DM, HbA1c > 7% with metformin mono-therapy
- Endostatin [ Time Frame: Baseline ]ENST, a 20-kDa C-terminal fragment derived from type XVIII collagen, is an endogenous protein that blocks the formation of blood vessels. It inhibits endothelial cell proliferation, migration and angiogenesis. There is evidence for several functions of neovascularisation in plaque growth that maintain perfusion beyond limits of diffusion from the artery lumen and outer adventitial vasa vasorum, deposit pro-atherogenic plasma molecules, recruit immune cells and progenitors, and promote intraplaque hemorrhage . ENST, as an angiostatic factor, might be the weapon of choice to battle these effects
- catecholamine [ Time Frame: baseline ]Catecholamines are released by the adrenal gland in situations of stress such as psychological stress, physical stress or low blood sugar levels . They are water-soluble and 50 % bound to plasma proteins. The three major catecholamines that circulate in the blood are epinephrine, norepinephrine and dopamine. They are mainly produced from the adrenal medulla and the postganglionic fibers of the sympathetic nervous system. The measurement of the catecholamines serves as control parameter for the applied stress situations.
- Endostatin [ Time Frame: after 6 months ]
- catecholamine [ Time Frame: after 6 months ]
- Brain natriuretic peptide [ Time Frame: baseline ]
Brain natriuretic peptide (BNP), a 32-amino acid peptide synthesized predominantly in the left ventricle of the heart as the 108-amino acid prohormone, is a potent vasodilator and a natriuretic factor regulating salt and water homeostasis.. Increased secretion of BNP and Nt-proBNP occurs mainly with increased tension in the ventricular walls, decreased oxygen supply, acute myocardial infarction, chronic cardiac heart failure, and in hypertrophy of the heart.
The Nt-proBNP level was shown to be significantly elevated in the cohort of patients with diabetes.
- Intima media thickness [ Time Frame: baseline ]IMT is a measurement of the thickness of artery walls, usually by external ultrasound, to detect the presence and to track the progression of atherosclerotic lesions. Cross-sectional associations between common carotid artery IMT and cardiovascular risk factors have been demonstrated in several studies
- Sex hormones [ Time Frame: baseline ]Total testosterone concentrations in the low-normal range predict diabetes and the development of the metabolic syndrome as defined by the NCEP in middle-aged men, independently of BMI and other factors related to insulin resistance. Hyperandrogenicity in women is closely associated with insulin resistance and presents a risk factor for CVD and T2DM. Hormone replacement therapy improves glucose homeostasis and lipoprotein profile. T2DM abolishes the female-gender related differences in the risk of CVD, and diabetic women have rates of ischemic heart disease mortality approaching those of men.
- Plasminogen Activator inhibitor-1 [ Time Frame: baseline ]Plasminogen activator inhibitor 1 (PAI-1) is the primary physiological inhibitor of plasminogen activation in vivo. Circulating PAI-1 levels are elevated in patients with coronary heart disease and may play an important role in the development of atherothrombosis by decreasing fibrin degradation. Increased PAI-1 expression can also directly influence vessel wall remodelling. The insulin resistance syndrome, which is characterized partly by obesity with visceral fat accumulation, is considered as a major regulator of PAI-1 expression
- Adrenomedullin [ Time Frame: baseline ]Adrenomedullin (AM) has multi-functional properties, of which the vasodilatory hypotensive effect is the most characteristic. AM secretion, especially in cardiovascular tissues, is regulated mainly by mechanical stressors (shear stress, inflammatory and metabolic factors). Elevation of plasma AM due to overproduction in response to one or more of these stimuli in pathological conditions may explain the raised plasma AM levels present in cardiovascular diseases such as myocardial infarction, hypertension, stroke and diabetes mellitus
- Ultra sensitive C-reactive protein [ Time Frame: baseline ]Endothelial activation and acute-phase reaction correlate with insulin resistance and obesity in T2DM patients. Prospective studies have shown that ultra sensitive C-reactive protein (usCRP) can be used to predict risk of future cardiovascular events
- Asymmetric dimethylarginine [ Time Frame: baseline ]Increased plasma concentration of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is associated with endothelial dysfunction, insulin resistance, and atherosclerosis and might, thus, serve as a marker for cardiovascular morbidity. In T2DM, the release and/or bioavailibility of nitric oxide are diminished. This endogenous nitric oxide synthase inhibitor, ADMA, has recently emerged as a key factor in nitric oxide biosynthesis.
- Adiponectin [ Time Frame: baselie and after 6 months ]Adiponectin is a hormone secreted by visceral adipose tissue beside others like leptin, angiotensin and resistin and exhibits antiinflammatory and insulin-sensitizing properties. Low plasma adiponectin concentrations have been suggested to promote atherosclerosis and have been found to be associated with early CVD onset and multiple atherosclerotic lesions in coronary arteries. Thus, adiponectin concentrations may influence risk of CVD and might serve as one of the screening tests facilitating early intervention
- Apelin [ Time Frame: baseline ]Apelin, a newly discovered adipocytokine and inotropic agent, is produced by white adipose tissue and is also expressed in the kidney and heart. Increasing evidence suggests a role for apelin in the pathology of the cardiovascular system. Plasma apelin is reduced in newly diagnosed and untreated patients with T2DM. Regulation of circulating apelin and adiponectin seems to be in the same manner in patients with T2DM. Dysregulation of apelin might be involved in the mechanism of establishment of overt diabetes mellitus as well as associated atherosclerotic complications.
- Homeostasis model assessment-estimated insulin resistance [ Time Frame: baseline ]
The Homeostasis model assessment of insulin resistance (HOMA-IR) is calculated by multiplying fasting insulin (μU/ml) and fasting blood sugar (mg/dl) divided through 19 (Version 1.2. vom 08.12.2008)
. A HOMA-IR below 1 is regarded as normal whereas a value over 2 is a hint for insulin resistance. The HOMA-IR has been suggested as a method to assess insulin resistance and secretion from the fasting glucose and insulin concentrations. T2DM is characterized by high HOMA IR. The HOMA-IR is an independent predictor of CVD in T2DM.
- Brain natriuretic peptide [ Time Frame: after 6 months ]
- Intima media thickness [ Time Frame: after 6 months ]
- Sex hormones [ Time Frame: after 6 months ]
- Plasminogen Activator inhibitor-1 [ Time Frame: after 6 months ]
- Adrenomedullin [ Time Frame: after 6 months ]
- Ultra sensitive C-reactive protein [ Time Frame: after 6 months ]
- Asymmetric dimethylarginine [ Time Frame: after 6 months ]
- Apelin [ Time Frame: after 6 moths ]
- Homeostasis model assessment-estimated insulin resistance [ Time Frame: after 6 months ]
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01162772
|Contact: Jeanette Strametz-Juranek, MD||0140400 ext firstname.lastname@example.org|
|Contact: Alexandra Kautzky-Willer, MD||0140400 ext email@example.com|
|Medical University of Viemma||Recruiting|
|Vienna, Austria, 1090|
|Contact: Jeanette Strametz-Juranek, MD 0043140400 ext 4618 firstname.lastname@example.org|
|Contact: Alexandra Kautzky-Willer, MD 0140400 ext 4316 email@example.com|
|Principal Investigator: Jeanette Strametz-Juranek, MD|
|Principal Investigator: Alexandra Kautzky-Willer, MD|
|Sub-Investigator: Alia Sabri, MD|
|Sub-Investigator: Lana Kosi, MD|
|Principal Investigator:||Jeanette Strametz-Juranek, MD||MUV, Department of Internal Medicine II, Division of Cardiology|
|Principal Investigator:||Alexandra Kautzky-Willer, MD||MUV, Department of Medicine III, Division of Endocrinology|