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

Phase 3

Completed

• Conditions: Type 2 Diabetes Mellitus
• Interventions: Drug: Linagliptin; Drug: placebo

• Registration Number: NCT02015299
• Lead Sponsor: dr. DJ Mulder

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.

Study Timeline

• Study First Submitted: 2013-12-09
• Study First Submitted QC: 2013-12-12
• Study First Posted: 2013-12-19
• Study Start: 2014-03
• Primary Completion: 2016-01
• Study Completion: 2016-03
• Status Verified: 2016-05
• Last Update Submitted: 2016-05-17
• Last Update Posted: 2016-05-18

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 45

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Linagliptin	Linagliptin	Linagliptin 5 mg/day + lifestyle advise
Placebo	placebo	Matching placebo + lifestyle advise

Primary Outcome Measures

Name	Time	Method
change from baseline carotid-(right) femoral arterial Pulse Wave Velocity (PWV) at 26 weeks	baseline, week 26

Secondary Outcome Measures

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

Trial Locations

Locations (1)

University Medical Center Groningen; 🇳🇱 Groningen, Netherlands