The Effect of Linagliptin on Mitochondrial and Endothelial Function

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01969084

Enrollment

Registered

2013-10-25

Start date

2013-10-31

Completion date

2016-07-31

Last updated

2016-11-18

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Type II Diabetes Mellitus

Keywords

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

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.

Interventions

DRUGLinagliptin

DRUGPlacebo

OTHERMicrocirculation 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.

OTHERMacrocirculation testing

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

OTHERMRI 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.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

30 Years to 70 Years

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
Phosphocreatine (PCR) Recovery Time After Exhaustive or up to 6 Minutes of Leg Exercise.	Baseline and 12 weeks	Change in the time to phosphocreatine recovery between the baseline visit and post-treatment visit following the graded exercise test.

Secondary

Measure	Time frame	Description
Change in Muscle Oxygenation Recovery Time	Baseline and 12 weeks	Change in muscle oxygenation after ischemia inducing occlusion for 4 minutes.
Changes in Vascular Reactivity in the Micro- and Macro-circulation.	Baseline and 12 weeks	Change in markers of macro- and microvascular function from the baseline visit to the post-treatment visit between the two groups.
Changes in SDF1-α and Substance P	Baseline and 12 weeks	—
Changes in Circulating Endothelial Progenitor Cell Phenotypes	Baseline and 12 weeks	The measurements of the various EPC phenotypes were performed at the Beth Israel Deaconess Flow Cytometry Core Facility. Immunofluorescent cell staining was performed on peripheral blood with the use of the fluorescent conjugated antibodies. 1.000.000 events per sample were acquired using a FACS LSR II analyzer (Becton Dickinson, Franklin Lakes, NJ, USA) and the results were analyzed using the Beckman Coulter Kaluza analysis software (Beckman Coulter Inc., Brea, CA, USA).

Countries

United States

Participant flow

Pre-assignment details

45 subjects were enrolled and 41 were randomized to the study

Participants by arm

Arm	Count
Linagliptin Subjects given Linagliptin Linagliptin Microcirculation testing: The endothelial function of the micro-circulation was 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. Macrocirculation testing: Use ultrasound to measure brachial artery flow mediated vasodilation (FMD, endothelium-dependent vasodilation) and nitroglycerin induced dilation (NID, endothelium-independent vasodila	19
Sugar Pill Subjects given sugar pill/placebo Placebo Microcirculation testing: The endothelial function of the micro-circulation was 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. Macrocirculation testing: Use ultrasound to measure brachial artery flow mediated vasodilation (FMD, endothelium-dependent vasodilation) and nitroglycerin induced dilation (NID, endothelium-independent vasod	22
Total	41

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	0	1

Baseline characteristics

Characteristic	Sugar Pill	Linagliptin	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	2 Participants	5 Participants	7 Participants
Age, Categorical Between 18 and 65 years	20 Participants	14 Participants	34 Participants
Age, Continuous	56.76 years STANDARD_DEVIATION 6.79	60.79 years STANDARD_DEVIATION 5.75	58.67 years STANDARD_DEVIATION 6.56
Gender Female	11 Participants	7 Participants	18 Participants
Gender Male	11 Participants	12 Participants	23 Participants
Region of Enrollment United States	22 Participants	19 Participants	41 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	2 / 19	4 / 22
serious Total, serious adverse events	1 / 19	3 / 22

Outcome results

Primary

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.