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

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.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes Mellitus
• Intervention / Treatment: Drug: Linagliptin; Drug: placebo

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 Type: Interventional
• Enrollment (Actual): 45
• Phase: Phase 3

Contacts and Locations

Study Locations

• Netherlands
  • Groningen, Netherlands, 9700 RB
    • University Medical Center Groningen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Body Mass Index and Waist-to-Hip ratio	Body Mass Index and Waist-to-Hip ratio	baseline, week 4, week 26, and 4 weeks after treatment discontinuation (week 30)
Blood pressure	24-hours ambulatory blood pressure measurement (24-ABPM)	baseline, week 4, week 26, and 4 weeks after treatment discontinuation (week 30)
Advanced glycation end products	Skin AGE deposition measured and plasma levels of AGEs	baseline, week 4, week 26, and 4 weeks after treatment discontinuation (week 30)
plasma markers of inflammation		baseline, week 26
plasma markers of endothelial dysfunction		baseline, week 26
Glycemic indices	Fasting glucose (FPG) and 2-hour post OGTT glucose (OGTT), HbA1c	baseline, week 4, week 26, and 4 weeks after treatment discontinuation (week 30)
albuminuria	Urinary albumin/creatinine ratio	baseline, week 4, week 26, and 4 weeks after treatment discontinuation (week 30)
Lifestyle	Intake of energy, Eating behaviour, and Physical activity	baseline, week 26

Collaborators and Investigators

• Sponsor: dr. DJ Mulder
• Collaborators: Boehringer Ingelheim
• Investigators: Principal Investigator: Pieter W Kamphuisen, MD PhD, University Medical Center Groningen

Publications and helpful links

General Publications

• Reijrink M, de Boer SA, Spoor DS, Lefrandt JD, Lambers Heerspink HJ, Boellaard R, Greuter MJ, Borra RJH, Hillebrands JL, Slart RHJA, Mulder DJ. Visceral adipose tissue volume is associated with premature atherosclerosis in early type 2 diabetes mellitus independent of traditional risk factors. Atherosclerosis. 2019 Nov;290:87-93. doi: 10.1016/j.atherosclerosis.2019.09.016. Epub 2019 Sep 25.
• de Boer SA, Hovinga-de Boer MC, Heerspink HJ, Lefrandt JD, van Roon AM, Lutgers HL, Glaudemans AW, Kamphuisen PW, Slart RH, Mulder DJ. Arterial Stiffness Is Positively Associated With 18F-fluorodeoxyglucose Positron Emission Tomography-Assessed Subclinical Vascular Inflammation in People With Early Type 2 Diabetes. Diabetes Care. 2016 Aug;39(8):1440-7. doi: 10.2337/dc16-0327. Epub 2016 Jun 8.

Study record dates

Study Major Dates

• Study Start: March 1, 2014
• Primary Completion (Actual): January 1, 2016
• Study Completion (Actual): March 1, 2016

Study Registration Dates

• First Submitted: December 9, 2013
• First Submitted That Met QC Criteria: December 12, 2013
• First Posted (Estimate): December 19, 2013

Study Record Updates

• Last Update Posted (Estimate): May 18, 2016
• Last Update Submitted That Met QC Criteria: May 17, 2016
• Last Verified: May 1, 2016

More Information

Terms related to this study

• Keywords: Diabetes; Arterial Stiffness; Pulse Wave Velocity; Linagliptin; Dipeptidyl peptidase (DPP)-4 inhibitors; Subclinical arterial inflammation
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Linagliptin; Dipeptidyl-Peptidase IV Inhibitors
• Other Study ID Numbers: NL43473.042.13