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

Type 2 Diabetes Mellitus Clinical Trial

— RELEASE  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02015299
• Other study ID #: NL43473.042.13
• Status: Completed
• Phase: Phase 3
• First received: December 9, 2013
• Last updated: May 17, 2016
• Start date: March 2014
• Est. completion date: March 2016

Study information

• Verified date: May 2016
• Source: University Medical Center Groningen
• Contact: n/a
• Is FDA regulated: No
• Health authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 45
• Est. completion date: March 2016
• Est. primary completion date: January 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 30 Years to 70 Years

Eligibility

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 ß-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

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 2
• Type 2 Diabetes Mellitus

Intervention

Drug:
• Linagliptin
one tablet linagliptin 5 mg/day for 26 weeks
• placebo
one tablet matching placebo/day for 26 weeks

Locations

Country	Name	City	State
Netherlands	University Medical Center Groningen	Groningen

Sponsors (2)

Lead Sponsor	Collaborator
dr. DJ Mulder	Boehringer Ingelheim

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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)	No
Other	Blood pressure	24-hours ambulatory blood pressure measurement (24-ABPM)	baseline, week 4, week 26, and 4 weeks after treatment discontinuation (week 30)	No
Other	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)	No
Other	plasma markers of inflammation		baseline, week 26	No
Other	plasma markers of endothelial dysfunction		baseline, week 26	No
Other	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)	No
Other	albuminuria	Urinary albumin/creatinine ratio	baseline, week 4, week 26, and 4 weeks after treatment discontinuation (week 30)	No
Other	Lifestyle	Intake of energy, Eating behaviour, and Physical activity	baseline, week 26	No
Primary	change from baseline carotid-(right) femoral arterial Pulse Wave Velocity (PWV) at 26 weeks		baseline, week 26	No
Secondary	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)	No
Secondary	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	No