Effects of Linagliptin on Renal Endothelium Function in Patients With Type 2 Diabetes.

NCT01835678 | Completed Phase 3

• 2 other identifiers: CRC2012LINA2012-002278-30
• Study Type: interventional
• Target: 65
• Locations: 1 country
• Sites: 2

Brief Summary

Diabetes mellitus is a metabolic disease with a growing prevalence worldwide, affecting 171 million people in 2000 and an expected 366 million people in 2030 (1) and therefore diabetic nephropathy is rapidly increasing in the Western hemisphere and represents in up to 50 % the cause of end stage renal disease. Hence, early intervention is desirable to prevent any damage to the kidneys. In the early stage of diabetic nephropathy, endothelium dysfunction is a key pathogenetic process as indicated by increased leakage of albumin through the glomerular barrier (2). Hence, improvement of endothelium function is an attractive therapeutic goal of antidiabetic medication. Endothelial dysfunction, in particular basal nitric oxide activity, has been also identified as pivotal determinant of glomerular filtration rate (3). A new and promising class of antidiabetic drugs are the gliptins. Gliptins act by inhibiting the enzyme dipeptidyl peptidase-4 (DPP-4), which is responsible for the rapid inactivation of glucagon-like peptide-1 (GLP-1) - an incretin hormone of the gut (6 - 8), thereby enhancing and prolonging the effects of GLP-1. GLP-1 - member of the incretin hormones - is released into the blood after meal ingestion and stimulates the insulin secretion in a glucose dependent manner. This accounts for the marked prandial insulin response, which prevents prandial hyperglycemia. Apart from surrogate parameters like reduction of fasting and postprandial blood glucose levels or improvement of HbA1c, the effect of gliptins on micro- and macrovascular function and cardiovascular outcome has not been the primary focus of current studies. However, infusion of GLP-1, the incretin hormone affected by gliptins has been reported to ameliorate endothelial dysfunction in patients suffering from coronary artery disease (9) and it was recently shown that infusion of GLP-1 into healthy human subjects increases both normal and ACh-induced vasodilatation (10). In studies on rats with diabetes, GLP-1 infusion nearly re-established their normal vascular tone (11) and there are further data from experimental animals that indicate a beneficial effect of GLP-1 on endothelial function (12). It is of major interest whether therapy with gliptins improves endothelial function of the micro- and macrovasculature. In face of the burden that diabetic nephropathy causes, the effect of linagliptin on the renal vasculature and endothelium integrity of the renal circulation (as measured by the availability of nitric oxide), is a key stone in order to claim that linagliptin is an effective antidiabetic agents. There is a need to demonstrate that linagliptin is effective beyond its blood glucose lowering actions and improves vascular endothelium function in the kidney.

Conditions

Type 2-diabetes

Outcome Measures

Primary Outcomes (1)

• effect of linagliptin compared to placebo on basal production and release of nitric oxide (NO) from renal vasculature

  The primary objective of the study is the change of renal plasma flow to LNMMA infusion from baseline (given in ml/min) to determine the effect of linagliptin compared to placebo on basal production and release of nitric oxide (NO) from renal vasculature.

  Changes from baseline after 4 weeks of treatment with linagliptin and placebo

Secondary Outcomes (10)

• effects of linagliptin compared to placebo on other renal hemodynamic parameters

  Changes from baseline after 4 weeks of treatment with linagliptin and placebo

• effect of linagliptin compared to placebo on urinary albumin creatinine ratio and tubular markers (e.g. NGAL).

  Changes from baseline after 4 weeks of treatment with linagliptin and placebo

• effect of linagliptin compared to placebo on markers of oxidative stress (e.g. isoprostanes) and inflammation (e.g. hsCRP).

  Changes from baseline after 4 weeks with linagliptin versus placebo

• effect of linagliptin compared to placebo on metabolic parameters (fasting glucose, fasting insulin, triglycerides, total-, LDL- and HDL-cholesterol)

  Changes from baseline after 4 weeks of treatment with linaplitpin and placebo

• effect of linagliptin compared to baseline on the change of renal plasma flow due to L-NMMA-infusion

  Changes from baseline after 4 weeks of treatment with linagliptin and placebo

Study Arms (2)

Linagliptin

ACTIVE COMPARATOR

Linagliptin

Drug: Linagliptin

Placebo

PLACEBO COMPARATOR

Placebo

Drug: Placebo

Interventions

Linagliptin DRUG

orally 5 mg/d for 4 weeks

Linagliptin

Placebo DRUG

orally once a day for 4 weeks

Placebo

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Female and male patients aged between 18 and 70 years

You may not qualify if:

• Any other form of diabetes mellitus than type 2 diabetes mellitus
• Use of insulin, glitazone or gliptins within the past 3 months
• Any other oral antidiabetic drug that can not be discontinued for the study period.
• Urinary albumin excretion (UACR) \> 100 mg/g (early morning spot urine)
• eGFR \<45 ml/min/1.73m² (MDRD Formula)
• Uncontrolled arterial hypertension (RR ≥180/ ≥110mmHg)
• HbA1c ≥ 10%
• Fasting plasma glucose ≥ 240 mg/dl
• Body mass index ≥ 40 kg/m²
• Triglyceride levels ≥ 1000 mg/dl
• HDL-cholesterol levels \<25 mg/dl
• Overt congestive heart failure (CHF) or history of CHF
• Severe disorders of the gastrointestinal tract or other diseases which interfere the pharmacodynamics and pharmacokinetics of study drugs
• Significant laboratory abnormalities such as SGOT or SGPT levels more than 3 x above the upper limit of normal range, serum creatinine \> 2mg/dl
• Drug or alcohol abuses

Sponsors & Collaborators

• University of Erlangen-Nürnberg Medical School: lead

Study Sites (2)

Clinical Research Unit, Department of Nephrology and Hypertension, University of Erlangen-Nürnberg

Erlangen, 91054, Germany

Location

Clinical Research Unit, Department of Nephrology and Hypertension, University of Erlangen-Nürnberg

Nuremberg, 90471, Germany

Location

Related Publications (4)

• Ott C, Schneider MP, Delles C, Schlaich MP, Schmieder RE. Reduction in basal nitric oxide activity causes albuminuria. Diabetes. 2011 Feb;60(2):572-6. doi: 10.2337/db09-1630.

  PMID: 21270268 BACKGROUND

• Schlaich MP, Schmitt D, Ott C, Schmidt BM, Schmieder RE. Basal nitric oxide synthase activity is a major determinant of glomerular haemodynamics in humans. J Hypertens. 2008 Jan;26(1):110-6. doi: 10.1097/HJH.0b013e3282f1a93e.

  PMID: 18090547 BACKGROUND

• Ritt M, Ott C, Raff U, Schneider MP, Schuster I, Hilgers KF, Schlaich MP, Schmieder RE. Renal vascular endothelial function in hypertensive patients with type 2 diabetes mellitus. Am J Kidney Dis. 2009 Feb;53(2):281-9. doi: 10.1053/j.ajkd.2008.10.041. Epub 2008 Dec 19.

  PMID: 19100670 BACKGROUND

• Ott C, Kistner I, Keller M, Friedrich S, Willam C, Bramlage P, Schmieder RE. Effects of linagliptin on renal endothelial function in patients with type 2 diabetes: a randomised clinical trial. Diabetologia. 2016 Dec;59(12):2579-2587. doi: 10.1007/s00125-016-4083-4. Epub 2016 Sep 1.

  PMID: 27586249 RESULT

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

Linagliptin

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Quinazolines

Study Officials

• Roland E Schmieder, MD

  University of Erlangen-Nürnberg

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 18, 2013
• First Posted: April 19, 2013
• Study Start: October 1, 2012
• Primary Completion: March 1, 2014
• Study Completion: April 1, 2014
• Last Updated: January 12, 2018

Record last verified: 2018-01

Locations

DE (2)