The Effect of Linagliptin on Mitochondrial and Endothelial Function

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by Beth Israel Deaconess Medical Center
Sponsor:
Information provided by (Responsible Party):
Aristidis Veves, Beth Israel Deaconess Medical Center
ClinicalTrials.gov Identifier:
NCT01969084
First received: August 29, 2013
Last updated: July 15, 2014
Last verified: July 2014
  Purpose

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.


Condition Intervention Phase
Type II Diabetes Mellitus
Drug: Linagliptin
Drug: Placebo
Other: Microcirculation testing
Other: Macrocirculation testing
Other: MRI Scans
Phase 4

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

Resource links provided by NLM:


Further study details as provided by Beth Israel Deaconess Medical Center:

Primary Outcome Measures:
  • Phosphocreatine (PCR) recovery time after exhaustive or up to 6 minutes of leg exercise. [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Changes in the endothelium dependent vasodilation in the micro- and macro-circulation. [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
  • Changes in SDF1-α, SP and circulating EPCs. [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
  • Changes in the muscle energy reserves [expressed as PCR and inorganic phosphorous (Pi)] during resting and graded exercise. [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]

Estimated Enrollment: 40
Study Start Date: October 2013
Estimated Study Completion Date: March 2015
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Linagliptin
Subjects given Linagliptin
Drug: Linagliptin
Other Name: Tradjenta
Other: Microcirculation testing
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.
Other: Macrocirculation testing
Use ultrasound to measure brachial artery flow mediated vasodilation (FMD, endothelium-dependent vasodilation) and nitroglycerin induced dilation (NID, endothelium-independent vasodilation).
Other: MRI Scans
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.
Placebo Comparator: Sugar pill
Subjects given sugar pill/placebo
Drug: Placebo Other: Microcirculation testing
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.
Other: Macrocirculation testing
Use ultrasound to measure brachial artery flow mediated vasodilation (FMD, endothelium-dependent vasodilation) and nitroglycerin induced dilation (NID, endothelium-independent vasodilation).
Other: MRI Scans
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.

  Eligibility

Ages Eligible for Study:   30 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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:

    1. Myocardial infarction, or angina within 12 months of study participation
    2. Arrhythmia (uncontrolled, highly symptomatic, requires treatment or life-threatening).
    3. 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.
    4. Stroke or transient ischemic attack within 12 months of study participation
    5. Uncontrolled hypertension: SBP> 180 mmHg or DBP> 105 mmHg (2 abnormal readings during visit)
  • Liver disease (AST, ALT Alk Phos levels >2x upper normal limit) at the time of enrollment
  • Renal disease (creatinine > 2 mg/dL and/or estimated GFR <30 mL/min, history of dialysis, nephrotic syndrome) at the time of enrollment.
  • Severe dyslipidemia (triglycerides>600 mg/dL or cholesterol >350 mg/dL) Subjects with hypertriglyceridemia may be retested in 2-3 weeks as the values can fluctuate tremendously within a few days. In the event that the retested value allows the patient to be enrolled, a planned deviation will be submitted to the CCI.
  • Any other serious chronic disease requiring active treatment.
  • Pregnancy or Lactation
  • Females of childbearing potential not using an effective form of birth control as determined by the investigators.
  • Subjects on any of the following medications:

    1. Systemic (not inhaled) Glucocorticoids
    2. Antineoplastic agents
    3. Rifampin
  • Patient is known to have a history of immunodeficiency diseases, including a positive HIV (ELISA and Western blot) and/or positive Hepatitis B surface antigen (HBsAg) or Hepatitis C test result in the past.
  • History of drug or alcohol abuse within the 12 months prior to dosing or evidence of such abuse as indicated by the laboratory assays conducted during the screening or baseline evaluations.
  • Acute or chronic metabolic acidosis, including diabetic ketoacidosis.
  • History of hypersensitivity reaction to linagliptin (such as urticaria, angioedema, or bronchial hyperreactivity) or metformin.
  • Contraindications to MRI: Medically unstable or hematologic, renal, or hepatic dysfunction, cardiac pacemaker, Intracranial clips, metal implants, or external clips within 10 mm of the head,
  • Metal in eyes.
  • Pregnant or nursing women -
  • Claustrophobia.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01969084

Contacts
Contact: Rhianna M Hibbler, BS 6176328420 rhibbler@bidmc.harvard.edu
Contact: Camille Borland, BS 6176328429 cborland@bidmc.harvard.edu

Locations
United States, Massachusetts
Beth Israel Deaconess Medical Center Recruiting
Boston, Massachusetts, United States, 02215
Contact: Camille Borland, BS    617-632-8429    cborland@bidmc.harvard.edu   
Sponsors and Collaborators
Beth Israel Deaconess Medical Center
  More Information

No publications provided

Responsible Party: Aristidis Veves, Research Director, Microcirculation Lab and Joslin-Beth Israel Deaconess Foot Center, Beth Israel Deaconess Medical Center
ClinicalTrials.gov Identifier: NCT01969084     History of Changes
Other Study ID Numbers: 2013P-000057, IIS trial 1218.137
Study First Received: August 29, 2013
Last Updated: July 15, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Beth Israel Deaconess Medical Center:
Type II Diabetes Mellitus
Diabetes
Metabolism
Linagliptin
Tradjenta
Glucose

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Linagliptin
Hypoglycemic Agents
Physiological Effects of Drugs
Pharmacologic Actions
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Dipeptidyl-Peptidase IV Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 18, 2014