The Effect of Linagliptin on Mitochondrial and Endothelial Function
Condition: Type II Diabetes Mellitus
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Intervention: Linagliptin; Placebo; Microcirculation testing; Macrocirculation testing; MRI Scans
Intervention description: 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.; Use ultrasound to measure brachial artery flow mediated vasodilation (FMD, endothelium-dependent vasodilation) and nitroglycerin induced dilation (NID, endothelium-independent vasodilation).; 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.
Intervention MeSH terms: Linagliptin
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 45.0
Sex: All
Minimum age: 30 Years
Maximum age: 70 Years
Healthy volunteers: No
Keywords: Type II Diabetes Mellitus; Diabetes; Metabolism; Linagliptin; Tradjenta; Glucose

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.
    

Eligibility 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.