Effects of Linagliptin on Endothelial- , Renal-, and Retinal Function in Patients With Hypertension and Albuminuria

Arterial Hypertension Clinical Trial

Official title:

Effects of Linagliptin on Endothelial- , Renal-, and Retinal Function in Comparison to Placebo in Patients With Hypertension and Albuminuria

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02376075
• Other study ID #: ikfe-Lina-003
• Secondary ID: 2012-004300-35
• Status: Completed
• Phase: Phase 3
• First received: February 11, 2015
• Last updated: February 25, 2015
• Start date: January 2013
• Est. completion date: September 2014

Study information

• Verified date: February 2015
• Source: ikfe-CRO GmbH
• Contact: n/a
• Is FDA regulated: No
• Health authority: Germany: Federal Institute for Drugs and Medical DevicesGermany: Ethics Commission
• Study type: Interventional

Clinical Trial Summary

A recent study with the DPP-IV inhibitor Linagliptin showed an improvement in the urinary albumin creatinine ratio in patients with diabetic nephropathy. Gutzwiller et. Al. have shown that GLP-1 increases renal Na secretion and inhibits renal H secretion, further indicating some direct renal effects of GLP-1.

Therefore, it seems likely that treatment with the DPP-IV inhibitor Linagliptin evolves several beneficial effects on microvascular and endothelial function beyond glucose control which most probably have an impact on the progression of renal and retinal microvascular disease.

The objective of this trial is to investigate the effect of Linagliptin in comparison to placebo on the UACR in patients with high blood pressure and an increased albumin excretion. Numerous, equivalent endothelial, renal, and retinal parameters serve as objectives of the study. All study parameters will be handled in an exploratory sense for the generation of models to further discuss the role of DPP-IV inhibition on renal and retinal physiology.

Description:

Renal tissue damage and an increase in the albumin excretion rate is a strong predictor for the development and progression of endothelial dysfunction and the development of microvascular and/or macrovascular complications. Increased blood pressure as well as increased glucose levels were found to impair renal- and retinal function, and a close association in the incidence and progression rate of retinopathy and nephropathy could be observed. Endothelial dysfunction and alterations in microvascular blood flow are early pathogenetic features in the development of renal and retinal tissue damage as found in patients with arterial hypertension and / or diabetes mellitus. A couple of studies have shown that urinary albumin excretion is associated with morphological and functional alterations in retinal microvascular blood flow. In patients with arterial hypertension blood pressure lowering treatment were shown to decrease the albumin excretion rate and to improve endothelial function of the retinal vasculature.

Recently DPP-IV Inhibitors have been introduced in the treatment of type 2 diabetes mellitus. Beside the metabolic effects of this drug class, several pleiotropic effects beyond metabolic control were documented in numerous studies, and are the topic of ongoing clinical research. Treatment with DPP-IV inhibitors was found to improve myocardial and endothelial function, to improve blood lipids, to lower blood pressure and to improve markers of renal function. GLP-1 receptors in vessels, kidney and the heart might account for those glucose independent effects of GLP-1. However, it is also conceivable that DPP-IV inhibition might exert vascular effects independent from GLP-1. In vitro studies demonstrated that DPP-IV is expressed in endothelial cells, and the inhibition of DPP-IV reduced the microvascular tone through direct mediation of the nitric oxide system. Therefore, it seems conceivable that the glucose independent effects of DPP-IV inhibition might be mediated through GLP-1 receptor signaling and /or direct inhibition of the enzyme DPP-IV in vascular, renal, or retinal cells.

A recent study with the DPP-IV inhibitor Linagliptin showed an improvement in the urinary albumin creatinine ratio in patients with diabetic nephropathy. Gutzwiller et. Al. have shown that GLP-1 increases renal Na secretion and inhibits renal H secretion, further indicating some direct renal effects of GLP-1.

Therefore, it seems likely that treatment with the DPP-IV inhibitor Linagliptin evolves several beneficial effects on microvascular and endothelial function beyond glucose control which most probably have an impact on the progression of renal and retinal microvascular disease.

The objective of this trial is to investigate the effect of Linagliptin in comparison to placebo on the UACR in patients with high blood pressure and an increased albumin excretion. Numerous, equivalent endothelial, renal, and retinal parameters serve as objectives of the study. All study parameters will be handled in an exploratory sense for the generation of models to further discuss the role of DPP-IV inhibition on renal and retinal physiology.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 43
• Est. completion date: September 2014
• Est. primary completion date: September 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 45 Years to 80 Years

Eligibility

Inclusion Criteria:

• Patient has signed and dated written informed consent to participate in the trial

• Arterial hypertension

• Stable antihypertensive treatment within the last 3 months

• Age = 45 - = 80 years

• Micro- or macroalbuminuria defined as UACR in morning urine > 20 mg/g in female and > 30 mg/g in male and/or arterial hypertension for more than 5 years currently treated with two or more antihypertensive drugs to control blood pressure and a history of cardiovascular disease or stroke.

• Patient consents that his/her family physician will be informed of trial participation

Exclusion Criteria:

• History of type 1 diabetes

• History of type 2 diabetes

• Uncontrolled hypertension (systolic blood pressure >180 mmHg and/or diastolic blood pressure >100 mmHg)

• Acute infections

• Any history of glomerulonephritis

• Any kidney disease not caused by hypertension as judged by the Investigator

• Glomerular filtration rate (GFR) < 30 ml/min (estimated by use of the Modification of Diet in Renal Disease (MDRD) formula)

• Medical history of hypersensitivity to the study drugs or to drugs with similar chemical structures

• History of severe or multiple allergies

• Treatment with any other investigational drug within 3 months before trial entry

• Progressive fatal disease

• History of drug or alcohol abuse in the past 2 years

• Condition after kidney transplantation

• Serum potassium > 5.5 mmol/L

• Pregnancy or breast feeding

• Sexually active woman of childbearing age not practicing a highly effective method of birth control as defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, hormonal IUDs, sexual abstinence or vasectomised partner.

• Acute myocardial infarction, open heart surgery or cerebral event (stroke/TIA) within the previous 3 months

• Any elective surgery during study participation

• Uncontrolled unstable angina pectoris

• Intake of Coumarin or coumarin derived compounds such as phenprocoumon (Marcumar) or warfarin (Coumadin, Warfant)

• Intake of rifampicin or carbamazepine

• HbA1c = 6,5%

• A Body Mass Index of > 35 kg/m²

• CHF NYHA stage III - IV

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Outcomes Assessor)

Related Conditions & MeSH terms

• Albuminuria
• Arterial Hypertension
• Hypertension

Intervention

Drug:
• Linagliptin
Intake of tablets containing 5 mg Linagliptin, administered once daily as add on to pre-existing antihypertensive treatment for 6 weeks
• Placebo
Intake of Placebo, administered once daily as add on to pre-existing antihypertensive treatment for 6 weeks

Locations

Country	Name	City	State
Germany	Profil Mainz GmbH & Co. KG	Mainz	Rhineland-Palatinate

Sponsors (3)

Lead Sponsor	Collaborator
ikfe-CRO GmbH	Ikfe GmbH, MLM Medical Labs Mönchengladbach

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Albumin/Creatinine Ratio (UACR) in 24h urine change between Baseline and Visit 4		up to 14 weeks of study drug intake	No
Secondary	24 hour urinary sodium excretion change between Baseline and Visit 4		after 14 weeks of study drug intake	No
Secondary	Fasting cystatin C change between Baseline and V4		up to 14 weeks of study drug intake	No
Secondary	Fasting cGMP change between Baseline and Visit 4		after 14 weeks of study drug intake	No
Secondary	Fasting serum ADMA change between Baseline and V4		up to 14 weeks of study drug intake	No
Secondary	Fasting hsCRP change between Baseline and Visit 4		up to 14 weeks of study drug intake	No
Secondary	Fasting TGF-ß1 change between Baseline and Visit 4		after 14 weeks of study drug intake	No
Secondary	Retinal endothelial function change between Baseline and Visit 4		up to 14 weeks of study drug intake	No
Secondary	Retinal microvascular blood flow change between Baseline and Visit 4		up to 14 weeks of study drug intake	No
Secondary	24h blood pressure measurements change between Baseline and Visit 4		up to 14 weeks of study drug intake	No
Secondary	HbA1c change between Baseline and Visit 4		up to 14 weeks of study drug intake	No
Secondary	Body weight change during study participation		up to 14 weeks of study drug intake	No
Secondary	Adverse events during study participation		up to 14 weeks of study drug intake	No