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

NCT ID: NCT02015299

Last Updated: 2016-05-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 45 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-03-31
• Study Completion Date: 2016-03-31

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.

Conditions

Type 2 Diabetes Mellitus

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Linagliptin

Linagliptin 5 mg/day + lifestyle advise

Group Type: EXPERIMENTAL

Linagliptin

Intervention Type: DRUG

one tablet linagliptin 5 mg/day for 26 weeks

Placebo

Matching placebo + lifestyle advise

Group Type: PLACEBO_COMPARATOR

placebo

Intervention Type: DRUG

one tablet matching placebo/day for 26 weeks

Interventions

Linagliptin

one tablet linagliptin 5 mg/day for 26 weeks

Intervention Type: DRUG

placebo

one tablet matching placebo/day for 26 weeks

Intervention Type: DRUG

Other Intervention Names

Trajenta; DPP-4 inhibitor

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

• Minimum Eligible Age: 30 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Boehringer Ingelheim

INDUSTRY

Sponsor Role: collaborator

dr. DJ Mulder

OTHER

Sponsor Role: lead

Responsible Party

dr. DJ Mulder

MD, PhD

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Pieter W Kamphuisen, MD PhD

Role: PRINCIPAL_INVESTIGATOR

University Medical Center Groningen

Locations

University Medical Center Groningen

Groningen, Provincie Groningen, Netherlands

Countries

Netherlands

References

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.

Reference Type: DERIVED

PMID: 31604171 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 27281773 (View on PubMed)

Other Identifiers

NL43473.042.13

Identifier Type: -

Identifier Source: org_study_id