Type 2 Diabetes
Conditions
Brief summary
This is a single center, prospective randomized double blind, parallel and placebo controlled study to evaluate oxidative stress and inflammation before and after treatment with linagliptin for 12 weeks. We will also, testing whether Linagliptin is an insulin sensitizer.
Detailed description
This is a single center, prospective randomized double blind, parallel and placebo-controlled study to evaluate oxidative stress and inflammation before and after treatment with linagliptin for 12 weeks. The study enrolls type 2 patients with diabetes.
Interventions
DRUGLinagliptin
5 mg daily oral tablets of linagliptin
DRUGPlacebo
matching placebo giving orally daily
Sponsors
Kaleida Health
University at Buffalo
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
20 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Age 20-80 years inclusive. Type 2 diabetes BMI ≥30 kg/m2 Subjects on statins, ACE inhibitors, thiazolidinediones and antioxidants will be allowed as long as they are on stable doses of these compounds and the dosage in not changed during the course of study. HbA1c ≤ 8.0%
Exclusion criteria
\- Use of GLP-1 agonists or DPP-IV therapy in the last 3 months. History of Pancreatitis. Risk for pancreatitis, i.e., history of gallstones, alcohol abuse, and hypertriglyceridemia. Subjects who are taking antiplatelet or anticoagulant medications will be excluded from the fat biopsy portion of the study. Coronary event or procedure (myocardial infarction, unstable angina, coronary artery bypass, surgery or coronary angioplasty) in the previous four weeks Hepatic disease (liver function tests more than 3 times the upper limit of normal) Renal impairment (serum eGFR \<30 ml/min) Any other life-threatening, non-cardiac disease Uncontrolled hypertension (BP \> 160/100 mm of Hg) Congestive Heart Failure class III or IV. Use of an investigational agent or therapeutic regimen within 30 days of study Participation in any other concurrent clinical trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| JNK-1 Protein in MNC | Week 0, Week 2, Week 4, Week 12 | JNK-1 protein in MNC before and after linagliptin use as compared to placebo. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| IL-1β mRNA Levels | Week 0, Week 2, Week 4, Week 12 | Comparing IL-1B between Linagliptin group and placebo group based on the PCR test, between week 0 and week 12. |
| Oxidative Stress (as ROS Generation Level) | Week 0, Week 2, Week 4, Week 12 | oxidative stress (ROS generation level) following linagliptin. ROS generation measurement by chemiluminescence of PMN cells |
| Insulin Sensitivity by Hyperinsulinemic-euglycemic Clamp | At baseline and week 12 | Insulin sensitivity is measured with HE clamp. Glucose Infusion Rate was titrated to maintain blood glucose concentration at the fasting glucose level. Plasma samples for glucose was obtained at 10-minute intervals starting 30 minutes before the clamp, to quantitate rates of whole-body glucose disposal. Difference from baseline at 12 weeks is calculated and compared to placebo arm |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Patients will be treated for 12 weeks with placebo once daily
Placebo | 20 |
| Linagliptin 5mg Per Day Patients will be treated for 12 weeks with Linagliptin 5mg once daily.
Linagliptin | 20 |
| Total | 40 |
Baseline characteristics
| Characteristic | Total | Placebo | Linagliptin 5mg Per Day |
|---|---|---|---|
| Age, Continuous | 59.85 years STANDARD_DEVIATION 9.15 | 58.9 years STANDARD_DEVIATION 10 | 60.8 years STANDARD_DEVIATION 8.3 |
| BMI | 36.1 kg/m² STANDARD_DEVIATION 5.85 | 37.6 kg/m² STANDARD_DEVIATION 6.9 | 34.6 kg/m² STANDARD_DEVIATION 4.8 |
| Race and Ethnicity Not Collected | 0 Participants | — | — |
| Region of Enrollment United States | 40 participants | 20 participants | 20 participants |
| Sex: Female, Male Female | 19 Participants | 8 Participants | 11 Participants |
| Sex: Female, Male Male | 21 Participants | 12 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 17 | 0 / 17 |
| other Total, other adverse events | 0 / 17 | 0 / 17 |
| serious Total, serious adverse events | 0 / 17 | 0 / 17 |
Outcome results
Primary
JNK-1 Protein in MNC
JNK-1 protein in MNC before and after linagliptin use as compared to placebo.
Time frame: Week 0, Week 2, Week 4, Week 12
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | JNK-1 Protein in MNC | Week 0 | 0.943 Arbitrary Units | Standard Error 0.148 |
| Placebo | JNK-1 Protein in MNC | Week 2 | 1.106 Arbitrary Units | Standard Error 0.214 |
| Placebo | JNK-1 Protein in MNC | Week 4 | 1.933 Arbitrary Units | Standard Error 0.204 |
| Placebo | JNK-1 Protein in MNC | Week 12 | 0.939 Arbitrary Units | Standard Error 0.123 |
| Linagliptin 5mg Per Day | JNK-1 Protein in MNC | Week 12 | 0.550 Arbitrary Units | Standard Error 0.074 |
| Linagliptin 5mg Per Day | JNK-1 Protein in MNC | Week 0 | 0.801 Arbitrary Units | Standard Error 0.129 |
| Linagliptin 5mg Per Day | JNK-1 Protein in MNC | Week 4 | 0.702 Arbitrary Units | Standard Error 0.102 |
| Linagliptin 5mg Per Day | JNK-1 Protein in MNC | Week 2 | 0.789 Arbitrary Units | Standard Error 0.101 |
Secondary
IL-1β mRNA Levels
Comparing IL-1B between Linagliptin group and placebo group based on the PCR test, between week 0 and week 12.
Time frame: Week 0, Week 2, Week 4, Week 12
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | IL-1β mRNA Levels | Week 12 | 0.811 Arbitrary Units | Standard Error 0.196 |
| Placebo | IL-1β mRNA Levels | Week 0 | 0.768 Arbitrary Units | Standard Error 0.161 |
| Placebo | IL-1β mRNA Levels | Week 2 | 0.885 Arbitrary Units | Standard Error 0.21 |
| Placebo | IL-1β mRNA Levels | Week 4 | 0.736 Arbitrary Units | Standard Error 0.144 |
| Linagliptin 5mg Per Day | IL-1β mRNA Levels | Week 4 | 1.063 Arbitrary Units | Standard Error 0.227 |
| Linagliptin 5mg Per Day | IL-1β mRNA Levels | Week 12 | 0.870 Arbitrary Units | Standard Error 0.252 |
| Linagliptin 5mg Per Day | IL-1β mRNA Levels | Week 2 | 1.166 Arbitrary Units | Standard Error 0.24 |
| Linagliptin 5mg Per Day | IL-1β mRNA Levels | Week 0 | 1.276 Arbitrary Units | Standard Error 0.267 |
Secondary
Insulin Sensitivity by Hyperinsulinemic-euglycemic Clamp
Insulin sensitivity is measured with HE clamp. Glucose Infusion Rate was titrated to maintain blood glucose concentration at the fasting glucose level. Plasma samples for glucose was obtained at 10-minute intervals starting 30 minutes before the clamp, to quantitate rates of whole-body glucose disposal. Difference from baseline at 12 weeks is calculated and compared to placebo arm
Time frame: At baseline and week 12
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Insulin Sensitivity by Hyperinsulinemic-euglycemic Clamp | At 12 Weeks | 119 mL/hr | Standard Error 20 |
| Placebo | Insulin Sensitivity by Hyperinsulinemic-euglycemic Clamp | Baseline | 123 mL/hr | Standard Error 21 |
| Linagliptin 5mg Per Day | Insulin Sensitivity by Hyperinsulinemic-euglycemic Clamp | At 12 Weeks | 141 mL/hr | Standard Error 31 |
| Linagliptin 5mg Per Day | Insulin Sensitivity by Hyperinsulinemic-euglycemic Clamp | Baseline | 137 mL/hr | Standard Error 22 |
Secondary
Oxidative Stress (as ROS Generation Level)
oxidative stress (ROS generation level) following linagliptin. ROS generation measurement by chemiluminescence of PMN cells
Time frame: Week 0, Week 2, Week 4, Week 12
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Oxidative Stress (as ROS Generation Level) | Week 0 | 102 mV | Standard Error 13 |
| Placebo | Oxidative Stress (as ROS Generation Level) | Week 2 | 95 mV | Standard Error 13 |
| Placebo | Oxidative Stress (as ROS Generation Level) | Week 4 | 94 mV | Standard Error 11 |
| Placebo | Oxidative Stress (as ROS Generation Level) | Week 12 | 97 mV | Standard Error 10 |
| Linagliptin 5mg Per Day | Oxidative Stress (as ROS Generation Level) | Week 12 | 76 mV | Standard Error 8 |
| Linagliptin 5mg Per Day | Oxidative Stress (as ROS Generation Level) | Week 0 | 91 mV | Standard Error 8 |
| Linagliptin 5mg Per Day | Oxidative Stress (as ROS Generation Level) | Week 4 | 81 mV | Standard Error 8 |
| Linagliptin 5mg Per Day | Oxidative Stress (as ROS Generation Level) | Week 2 | 85 mV | Standard Error 11 |