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

Primary Purpose

Type 2 Diabetes Mellitus

Status

Completed

Phase

Phase 3

Locations

Netherlands

Study Type

Interventional

Intervention

Linagliptin

placebo

About this trial

This is an interventional treatment trial for Type 2 Diabetes Mellitus focused on measuring Diabetes, Pulse Wave Velocity, Dipeptidyl peptidase (DPP)-4 inhibitors, Linagliptin, Arterial Stiffness, Subclinical arterial inflammation

Eligibility Criteria

30 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

University Medical Center Groningen

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Linagliptin

Placebo

Arm Description

Linagliptin 5 mg/day + lifestyle advise

Matching placebo + lifestyle advise

Outcomes

Primary Outcome Measures

change from baseline carotid-(right) femoral arterial Pulse Wave Velocity (PWV) at 26 weeks

Secondary Outcome Measures

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

Subclinical vascular inflammation (FDG PET-CT)

Target-to-background ratios (TBRs) (18)F-fluorodeoxyglucose positron emission tomography computed tomography coregistration (FDG PET-CT)

Full Information

NCT ID

NCT02015299

First Posted

December 9, 2013

Last Updated

May 17, 2016

Sponsor

dr. DJ Mulder

Collaborators

Boehringer Ingelheim

1. Study Identification

Unique Protocol Identification Number

NCT02015299

Brief Title

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

Acronym

RELEASE

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

May 2016

Overall Recruitment Status

Completed

Study Start Date

March 2014 (undefined)

Primary Completion Date

January 2016 (Actual)

Study Completion Date

March 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

dr. DJ Mulder

Collaborators

Boehringer Ingelheim

4. Oversight

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Type 2 Diabetes Mellitus

Keywords

Diabetes, Pulse Wave Velocity, Dipeptidyl peptidase (DPP)-4 inhibitors, Linagliptin, Arterial Stiffness, Subclinical arterial inflammation

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

45 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Linagliptin

Arm Type

Experimental

Arm Description

Linagliptin 5 mg/day + lifestyle advise

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Matching placebo + lifestyle advise

Intervention Type

Drug

Intervention Name(s)

Linagliptin

Other Intervention Name(s)

Trajenta, DPP-4 inhibitor

Intervention Description

one tablet linagliptin 5 mg/day for 26 weeks

Intervention Type

Drug

Intervention Name(s)

placebo

Intervention Description

one tablet matching placebo/day for 26 weeks

Primary Outcome Measure Information:

Title

change from baseline carotid-(right) femoral arterial Pulse Wave Velocity (PWV) at 26 weeks

Time Frame

baseline, week 26

Secondary Outcome Measure Information:

Title

Secondary vascular study parameters

Description

Central Blood Pressure (CBP) and Augmentation Index (AI) obtained from pulse wave analysis, using Sphygmocor Carotid-(left) radial arterial PWV, using Sphygmocor

Time Frame

baseline, week 4, week 26, and 4 weeks after treatment discontinuation (week 30)

Title

Subclinical vascular inflammation (FDG PET-CT)

Description

Target-to-background ratios (TBRs) (18)F-fluorodeoxyglucose positron emission tomography computed tomography coregistration (FDG PET-CT)

Time Frame

26 weeks

Other Pre-specified Outcome Measures:

Title

Body Mass Index and Waist-to-Hip ratio

Description

Body Mass Index and Waist-to-Hip ratio

Time Frame

baseline, week 4, week 26, and 4 weeks after treatment discontinuation (week 30)

Title

Blood pressure

Description

24-hours ambulatory blood pressure measurement (24-ABPM)

Time Frame

baseline, week 4, week 26, and 4 weeks after treatment discontinuation (week 30)

Title

Advanced glycation end products

Description

Skin AGE deposition measured and plasma levels of AGEs

Time Frame

baseline, week 4, week 26, and 4 weeks after treatment discontinuation (week 30)

Title

plasma markers of inflammation

Time Frame

baseline, week 26

Title

plasma markers of endothelial dysfunction

Time Frame

baseline, week 26

Title

Glycemic indices

Description

Fasting glucose (FPG) and 2-hour post OGTT glucose (OGTT), HbA1c

Time Frame

baseline, week 4, week 26, and 4 weeks after treatment discontinuation (week 30)

Title

albuminuria

Description

Urinary albumin/creatinine ratio

Time Frame

baseline, week 4, week 26, and 4 weeks after treatment discontinuation (week 30)

Title

Lifestyle

Description

Intake of energy, Eating behaviour, and Physical activity

Time Frame

baseline, week 26

10. Eligibility

Sex

All

Minimum Age & Unit of Time

30 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Pieter W Kamphuisen, MD PhD

Organizational Affiliation

University Medical Center Groningen

Official's Role

Principal Investigator

Facility Information:

Facility Name

University Medical Center Groningen

City

Groningen

ZIP/Postal Code

9700 RB

Country

Netherlands

12. IPD Sharing Statement

Citations:

PubMed Identifier

31604171

Citation

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.

Results Reference

derived

PubMed Identifier

27281773

Citation

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.

Results Reference

derived

Learn more about this trial

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

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