Influence of DPP-4 on Inflammatory Parameters in Diabetics: Gender Aspects

The recruitment status of this study is unknown because the information has not been verified recently.
Verified July 2010 by Medical University of Vienna.
Recruitment status was  Recruiting
Sponsor:
Information provided by:
Medical University of Vienna
ClinicalTrials.gov Identifier:
NCT01162772
First received: July 13, 2010
Last updated: July 15, 2010
Last verified: July 2010
  Purpose

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
Type 2 Diabetes Mellitus
Cardiovascular Risk
Endothelial Dysfunction

Study Type: Observational
Study Design: Time Perspective: Prospective
Official Title: Influence of a Modern Oral Anti-diabetic Medication on Endothelial Dysfunction and Cardiovascular Risk in Diabetic Women and Men: Gender Aspects

Resource links provided by NLM:


Further study details as provided by Medical University of Vienna:

Primary Outcome Measures:
  • Endostatin [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
  • catecholamine [ Time Frame: after 6 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Brain natriuretic peptide [ Time Frame: baseline ] [ Designated as safety issue: No ]

    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]

    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 ] [ Designated as safety issue: No ]
  • Intima media thickness [ Time Frame: after 6 months ] [ Designated as safety issue: No ]
  • Sex hormones [ Time Frame: after 6 months ] [ Designated as safety issue: No ]
  • Plasminogen Activator inhibitor-1 [ Time Frame: after 6 months ] [ Designated as safety issue: No ]
  • Adrenomedullin [ Time Frame: after 6 months ] [ Designated as safety issue: No ]
  • Ultra sensitive C-reactive protein [ Time Frame: after 6 months ] [ Designated as safety issue: No ]
  • Asymmetric dimethylarginine [ Time Frame: after 6 months ] [ Designated as safety issue: No ]
  • Apelin [ Time Frame: after 6 moths ] [ Designated as safety issue: No ]
  • Homeostasis model assessment-estimated insulin resistance [ Time Frame: after 6 months ] [ Designated as safety issue: No ]

Estimated Enrollment: 80
Study Start Date: January 2010
Estimated Primary Completion Date: October 2011 (Final data collection date for primary outcome measure)
Groups/Cohorts
Female Diabetics
female, 25-75 years old, no pregnancy, with/out Hormone replacement therapy T2DM, HbA1c > 7% with metformin mono-therapy
Male diabetics
25-75 years, T2DM, HbA1c > 7% with metformin mono-therapy

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   25 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population

In this study 40 female and 40 male subjects with T2DM, who take metformin as an oral anti-diabetic mono therapy according to the guidelines of the ÖDG.

Criteria

Inclusion Criteria:

  • patients with T2DM
  • metformin therapy
  • HbA1c < 7%
  • 25 - 69 years

Exclusion Criteria:

  • 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01162772

Contacts
Contact: Jeanette Strametz-Juranek, MD 0140400 ext 4816 jeanette.strametz-juranek@meduniwien.ac.at
Contact: Alexandra Kautzky-Willer, MD 0140400 ext 4314 alexandra.kautzky-willer@meduniwien.ac.at

Locations
Austria
Medical University of Viemma Recruiting
Vienna, Austria, 1090
Contact: Jeanette Strametz-Juranek, MD    0043140400 ext 4618    jeanette.strametz-juranek@meduniwien.ac.at   
Contact: Alexandra Kautzky-Willer, MD    0140400 ext 4316    alexandra.kautzky-willer@meduniwien.ac.at   
Principal Investigator: Jeanette Strametz-Juranek, MD         
Principal Investigator: Alexandra Kautzky-Willer, MD         
Sub-Investigator: Alia Sabri, MD         
Sub-Investigator: Lana Kosi, MD         
Sponsors and Collaborators
Medical University of Vienna
Investigators
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
  More Information

No publications provided

Responsible Party: Jeanette Strametz-Juranek, MD, Division of Cardiology
ClinicalTrials.gov Identifier: NCT01162772     History of Changes
Other Study ID Numbers: 575/2008
Study First Received: July 13, 2010
Last Updated: July 15, 2010
Health Authority: Austria: Ethikkommission

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases

ClinicalTrials.gov processed this record on July 28, 2014