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

dr. DJ Mulder

Status and phase

Completed

Phase 3

Conditions

Type 2 Diabetes Mellitus

Treatments

Drug: Linagliptin

Drug: placebo

Study type

Interventional

Funder types

Other

Industry

Identifiers

NCT02015299

NL43473.042.13

Details and patient eligibility

About

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.

Full 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.

Enrollment

45 patients

Sex

All

Ages

30 to 70 years old

Volunteers

No Healthy Volunteers

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