The Effect of Linagliptin on Mitochondrial and Endothelial Function

NCT01969084 | Completed Phase 4 Results

• 2 other identifiers: 2013P-000057IIS trial 1218.137
• Study Type: interventional
• Target: 45
• Locations: 1 country
• Sites: 1

Brief Summary

Investigators propose to examine the effect of 12 weeks of Linagliptin, a diabetes drug, treatment on inflammation as well as vascular and mitochondrial function in diabetic patients. Investigators hypothesize that Linagliptin will reduce the proinflammatory state, improve endothelial function, increase the blood flow at the muscle microcirculation level and improve mitochondrial function. In this study, investigators will perform tests that evaluate the function of small and large blood vessels by employing ultrasound and laser doppler techniques. In addition MRI scans that evaluate the mitochondrial function of the lower extremity muscles at rest and during exercise will also be employed. Forty subjects with Type 2 diabetes will be studied for twelve weeks and half of them will be randomly assigned to receive linagliptin while the other half will receive placebo. All tests will be performed at the beginning and the end of the study.

Conditions

Type II Diabetes Mellitus

Keywords

Type II Diabetes Mellitus; Diabetes; Metabolism; Linagliptin; Tradjenta; Glucose

Outcome Measures

Primary Outcomes (1)

• Phosphocreatine (PCR) Recovery Time After Exhaustive or up to 6 Minutes of Leg Exercise.

  Change in the time to phosphocreatine recovery between the baseline visit and post-treatment visit following the graded exercise test.

  Baseline and 12 weeks

Secondary Outcomes (4)

• Change in Muscle Oxygenation Recovery Time

  Baseline and 12 weeks

• Changes in Vascular Reactivity in the Micro- and Macro-circulation.

  Baseline and 12 weeks

• Changes in SDF1-α and Substance P

  Baseline and 12 weeks

• Changes in Circulating Endothelial Progenitor Cell Phenotypes

  Baseline and 12 weeks

Study Arms (2)

Linagliptin

EXPERIMENTAL

Subjects given Linagliptin

Drug: Linagliptin; Other: Microcirculation testing; Other: Macrocirculation testing; Other: MRI Scans

Sugar pill

PLACEBO COMPARATOR

Subjects given sugar pill/placebo

Drug: Placebo; Other: Microcirculation testing; Other: Macrocirculation testing; Other: MRI Scans

Interventions

Linagliptin DRUG

Also known as: Tradjenta

Linagliptin

Placebo DRUG

Sugar pill

Microcirculation testing OTHER

The endothelial function of the micro-circulation will be assessed by measuring the hyperemic response of the vessels in the superficial skin of the forearm after the iontophoresis of acetylcholine. The endothelium independent vasodilation will be assessed by the iontophoresis of sodium nitroprusside. Laser Doppler perfusion imaging will be used to measure relative changes in flow velocity.Visible and NIR Medical Hyperspectral Imaging (MHSI) data will be collected with a HyperMed OxyView MHSI System (HyperMed, Inc., Watertown, MA). MHSI images will be obtained from same forearm area where the iontophoresis of acetylcholine and sodium nitroprusside will be performed, before and after the iontophoresis test.

Linagliptin; Sugar pill

Macrocirculation testing OTHER

Use ultrasound to measure brachial artery flow mediated vasodilation (FMD, endothelium-dependent vasodilation) and nitroglycerin induced dilation (NID, endothelium-independent vasodilation).

Linagliptin; Sugar pill

MRI Scans OTHER

Phosphorus-31 MRI data will be obtained during an exercise protocol. Muscle oxygenation will be measured using the blood oxygenation level-dependent magnetic resonance imaging (BOLD MRI) technique after induced hyperemia.

Linagliptin; Sugar pill

Eligibility Criteria

• Age: 30 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with T2DM whose medical or lifestyle treatment regimen is stable and not expected to be changed during the study period. Patients will be considered stable on their treatment regimen if there have not been any changes in the type of their antidiabetic medications over the past 3 months and/or there have not been any changes in their blood glucose levels that have caused them to see their health care provider more often than usual over the preceding three months. The diagnosis of T2DM will be according to the American Diabetes Association criteria. Subjects previously diagnosed with T2DM will not require confirmatory testing.
• Age 30-70 years
• Patients on insulin should be on a stable insulin regimen for at least 4 months prior to enrollment.
• Patients on antidiabetic treatment will be eligible if they are stable and no change in their treatment is planned for the next three months while they are in the study.
• HBA1c ≤ 10.0

You may not qualify if:

• Patient with unstable diabetes that has resulted in hyperosmolar coma, DKA, and/or documented increase or decrease in HbA1c of more than 2.0% within the previous 6 months
• Treatment with DPP4 Inhibitors or GLP-1 agonists. Patients who discontinued such treatment should be at least free for a 3-month period.
• Severe proliferative retinopathy that renders the subject legally blinded
• Previously intermittent claudication or diagnosed severe peripheral arterial disease requiring intervention.
• History of Deep Vein Thrombosis (DVT) within the past 3 months.
• Significant limb swelling due to lymphedema
• Previous diagnosis of severe gastroparesis diabeticorum due to autonomic neuropathy that has necessitated hospital admission
• Presence of non-healing foot ulceration due to severe peripheral diabetic neuropathy
• History of pancreatitis
• Documented diabetic nephropathy manifested as macro-albuminuria before enrollment in the study, (2 of 3 urine specimens collected within a 3-6 month period with urine albumin\> 300 ug/mg creatinine - according to the ADA position statement)
• Smokers. Smokers will be defined as any subject who reports tobacco use during the three months before to study enrollment.
• Active or uncontrolled cardiovascular disease as follows:
• Myocardial infarction, or angina within 12 months of study participation
• Arrhythmia (uncontrolled, highly symptomatic, requires treatment or life-threatening).
• Patients with congestive heart failure requiring pharmacologic management, particularly when accompanied by hypoperfusion and hypoxemia due to unstable or acute failure, are at increased risk of lactic acidosis.

Sponsors & Collaborators

• Beth Israel Deaconess Medical Center: lead

Study Sites (1)

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

Related Publications (1)

• Baltzis D, Dushay JR, Loader J, Wu J, Greenman RL, Roustit M, Veves A. Effect of Linagliptin on Vascular Function: A Randomized, Placebo-controlled Study. J Clin Endocrinol Metab. 2016 Nov;101(11):4205-4213. doi: 10.1210/jc.2016-2655. Epub 2016 Sep 1.

  PMID: 27583476 RESULT

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Diabetes Mellitus

Interventions

Linagliptin; Magnetic Resonance Spectroscopy

Condition Hierarchy (Ancestors)

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; Spectrum Analysis; Chemistry Techniques, Analytical; Investigative Techniques

Results Point of Contact

• Title: Aristidis Veves
• Organization: Beth Israel deaconess Medical Center

617 632 7075

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Research Director, Microcirculation Lab and Joslin-Beth Israel Deaconess Foot Center

Study Record Dates

• First Submitted: August 29, 2013
• First Posted: October 25, 2013
• Study Start: October 1, 2013
• Primary Completion: July 1, 2016
• Study Completion: July 1, 2016
• Last Updated: November 18, 2016
• Results First Posted: November 18, 2016

Record last verified: 2016-11

Locations

US (1)