Off taRget Effects of Linagliptin monothErapy on Arterial Stiffness in Early Diabetes

Study Overview
=================
Brief Summary
-----------------
Diabetes is associated with an increased risk for developing premature macrovascular complications. The process of irreversible subclinical damage to the vasculature already starts during its preceding stages. Dipeptidyl peptidase (DPP)-4 inhibitors have been shown to attenuate vascular damage in preclinical studies. Off-target effects on adipose tissue inflammation, liver steatosis and atherosclerotic plaques have been extensively documented in animal studies. Based on these considerations the investigators hypothesize that early therapy with the DPP4 inhibitor linagliptin in subjects with treatment naive type 2 diabetes will lead to beneficial effects on arterial stiffness as measured by pulse wave velocity.

Detailed Description
-----------------
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 the investigators 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 and inflammatory markers independent of its effects on glycemic control.

Official Title
-----------------
Off taRget Effects of Linagliptin monothErapy on Arterial Stiffness in Early Diabetes

Conditions
-----------------
Type 2 Diabetes Mellitus

Intervention / Treatment
-----------------
* Drug: Linagliptin
* Drug: placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Men and women, age 30 to 70 years, AND Treatment naïve type 2 diabetes, as defined as t Fasting plasma glucose ≥ 7.0 mmol/l, OR Random plasma glucose ≥ 11.1 mmol/l, OR HbA1c ≥6,5% Written informed consent Assessable Pulse Wave Velocity measurement at screening 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, e.g., genetic defects in β-cell function, genetic defects in insulin action, diseases of the exocrine pancreas (such as cystic fibrosis), and drug- or chemical-induced (such as in the treatment of HIV/AIDS or after organ transplantation) 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, triglycerides >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

Ages Eligible for Study
-----------------
Minimum Age: 30 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Linagliptin<br>Linagliptin 5 mg/day + lifestyle advise | Drug: Linagliptin<br>* one tablet linagliptin 5 mg/day for 26 weeks<br>* Other names: DPP-4 inhibitor;|
| Placebo Comparator: Placebo<br>Matching placebo + lifestyle advise | Drug: placebo<br>* one tablet matching placebo/day for 26 weeks<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| change from baseline carotid-(right) femoral arterial Pulse Wave Velocity (PWV) at 26 weeks |  | baseline, week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Secondary vascular study parameters | Central Blood Pressure (CBP) and Augmentation Index (AI) obtained from pulse wave analysis, using Sphygmocor Carotid-(left) radial arterial PWV, using Sphygmocor | baseline, week 4, week 26, and 4 weeks after treatment discontinuation (week 30) | 
| Subclinical vascular inflammation (FDG PET-CT) | Target-to-background ratios (TBRs) (18)F-fluorodeoxyglucose positron emission tomography computed tomography coregistration (FDG PET-CT) | 26 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Diabetes, Pulse Wave Velocity, Dipeptidyl peptidase (DPP)-4 inhibitors, Linagliptin, Arterial Stiffness, Subclinical arterial inflammation