1. To assess whether linagliptin compared with placebo improves arterial stiffness in treatment naïve subjects with type 2 diabetes.2. To assess whether linagliptin compared with placebo improves blood pressure parameters, inflammatory and…
ID
Source
Brief title
Condition
- Glucose metabolism disorders (incl diabetes mellitus)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Difference in mean Pulse Wave Velocity (PWV) after 26 weeks between the
Linagliptin and placebo treated group.
Secondary outcome
- Central Blood Pressure (CBP) and Augmentation Index (AI) obtained from pulse
wave analysis, using Sphygmocor
- Carotid-(left) radial arterial PWV, using Sphygmocor
- Body Mass Index (BMI) and Waist-to-Hip ratio
- 24-hours ambulatory blood pressure measurement (24-ABPM)
- Urinary albumin/creatinine ratio (mean of 2 separate morning portions (ACR)
- plasma markers of inflammation ( i.e. high-sensitivity C-reactive protein
(hs-CRP); Interleukin-6; TNF-α, serum amyloid-A (SAA), myeloperoxidase (MPO))
- plasma markers of endothelial dysfunction (i.e. vascular cell adhesion
molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1),
soluble E-selectin, von Willebrand factor, tissue-type plasminogen activator),
in vitro stimulated cytokine production by peripheral blood mononuclear cells
(PBMC)
- Glycemic indices: fasting glucose (FPG) and 2-hour post OGTT glucose (OGTT),
HbA1c, fasting insulin, and derived indices (HOMA-β (as a surrogate marker for
β -cell function) and HOMA-IR (insulin resistance), Matsuda index (insulin
sensitivity)
- Skin AGE deposition measured as skin autofluorescence using AGE reader and
plasma levels of AGEs (N(*)-(carboxymethyl) lysine (CML), N(*)-(Carboxyethyl)
lysine (CEL)
- Intake of energy, Eating behaviour, and Physical activity
- Target-to-background ratios (TBRs) (18)F-fluorodeoxyglucose positron
emission tomography computed tomography coregistration (FDG PET-CT)
Background summary
Patients with type 2 diabetes mellitus (T2DM) are at increased risk for
developing premature macrovascular complications. The process of irreversible
subclinical damage to the vasculature already starts during its preceding
stages. At diagnosis, patients with T2DM already have evidence of subclinical
vascular damage. Recent trials have shown no benefit of glucose lowering
therapy when started later in the course of the disease, implicating that early
interventions could be more effective in preventing macrovascular
complications. Dipeptidyl peptidase (DPP)-4 inhibitors are oral antidiabetic
drugs that increase the action of the naturally gut hormone glucagon-like
peptide-1 (GLP-1), leading to improvement of postprandial insulin secretion,
without hypoglycaemia or weight gain. DPP4 inhibitors improve beta-cell
function and insulin resistance. More importantly, off-target effects on
adipose tissue inflammation, liver steatosis and atherosclerotic plaques have
been extensively documented in animal studies. Furthermore, DDP4 inhibitors
improve the cardiovascular risk profile in small clinical studies. Based on
these considerations we hypothesize that early therapy with the DPP4 inhibitor
linagliptin in subjects with type 2 diabetes will lead to beneficial effects on
arterial stiffness, blood pressure, inflammatory markers and vascular
inflammation, independent of its effects on glycemic control.
Study objective
1. To assess whether linagliptin compared with placebo improves arterial
stiffness in treatment naïve subjects with type 2 diabetes.
2. To assess whether linagliptin compared with placebo improves blood pressure
parameters, inflammatory and endothelial function markers, albuminuria, and
vascular inflammation in treatment naïve subjects with type 2 diabetes.
3. To determine whether the off-target effects on arterial stiffness blood
pressure parameters, inflammatory endothelial function markers and vascular
inflammation are concordant with changes in glucose parameters, including HbA1c
fasting plasma glucose, and beta-cell and insulin sensitivity indices.
Study design
Single center, prospective, randomized, placebo controlled double-blind
intervention trial
Intervention
Participants will be treated with:
- Linagliptin 5 mg/day + lifestyle advise, OR
- Matching placebo + lifestyle advise
Study burden and risks
Burden and risks: The efficacy and safety of linagliptin in patients with T2DM
have been shown in different studies. The risks for hypoglycaemia are less with
DPP4-inhibitors compared to metformin or sulfonylurea derivatives. DPP4
inhibitors do not cause weight gain, unlike sulfonylurea derivatives. Only
subjects with an HbA1c that would be treated with lifestyle advice and would
not directly need drug treatment in clinical practice will be included, so that
the guidelines for the management of type 2 diabetes are followed. Patients
visit the outpatient clinic 6 times and during each visit blood pressure is
measured and 30 mL of peripheral blood is drawn by venapuncture. Additionally,
an FDG PET-CT scan wil be performed. For this test, 18F-FDG wil be
administrated intravenously and a scan will be performed with a radiation
burden of 4.2 mSv . This is considered a moderate risk (category III, ICRP 62).
Benefits: We expect that linagliptin improves PWV and may hence have a
beneficial effect on the vessel wall in patients with treatment naïve
diabetes. Also, the FDG PET-CT scan may yield abnormalities (such as
malignancies in early stages) that would not have been discovered otherwise and
may allow earier intervention.
Hanzeplein 1
Groningen 9713GZ
NL
Hanzeplein 1
Groningen 9713GZ
NL
Listed location countries
Age
Inclusion criteria
- Men and women, age 30 to 70 years, AND
- Treatment naïve type 2 diabetes, as defined as the presence of one of the following (American Diabetes Association definition:
- Fasting plasma glucose >= 7.0 mmol/l, OR
- Random plasma glucose >= 11.1 mmol/l, OR
- HbA1c >=6,5%
- written informed consent
Exclusion criteria
- Current or previous use of glycemic control medications
- Type 1 diabetes
- Gestational diabetes mellitus
- Other specific types of diabetes due to other causes
- Uncontrolled hypertension, defined as systolic blood pressure >160 or a diastolic blood pressure >100 mmHg at screening visit
- Severe dyslipidemia indicating primary dyslipidemia, defined as total cholesterol >8 mmol/l, tryglicerides >10 mmol/l of high density lipoprotein cholesterol <0.6 mmol/l
- Current use of weight loss medication or previous weight loss surgery
- History of severe gastrointestinal disease
- Clinical contraindications to DPP4-inhibitors
- Previous cardiovascular disease, defined as stable coronary artery disease or acute coronary syndrome, stroke or transient ischemic attack, peripheral artery disease
- Symptomatic heart failure, New York Heart Association (NYHA) class II-IV
- Women who are currently pregnant,planning to become pregnant,breastfeeding women, or women with child bearing potential not using appropriate contraceptive measures
- Clinically significant liver disease or hepatic function greater than 3 times upper limit of normal
- Known impaired renal function or eGFR <30 ml/min/1.73m2
- Patients who are mentally incompetent and cannot sign a Patient Informed Consent
- Current active malignancy or in the previous 6 months
- Documented HIV infection
- Use of rifampicin
- Known or suspected allergy to 18F-FDG or its components
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2012-005220-15-NL |
| CCMO | NL43473.042.13 |