Chronic Kidney Disease, Left Ventricular Diastolic Dysfunction, Type 2 Diabetes Mellitus
Conditions
Keywords
diabetes mellitus, chronic kidney disease, diastolic function, cardiac fibrosis, cardiac strain, cardiac biomarker, renal biomarker
Brief summary
Among adult individuals with type 2 diabetes mellitus and at risk for heart failure with impaired relaxation of the heart mildly reduced kidney filtration function (Type 4 cardiorenal syndrome) this trial will evaluate the quantitative impact of 38 weeks of treatment with exenatide extended-release injections versus placebo. on a cardiac biomarker blood test score, cardiac fibrosis seen on magnetic resonance scanning, cardiac strain identified by ultrasonography and strain rate imaging, and a kidney urine biomarker score.
Detailed description
Primary Aim Among adult individuals with type 2 diabetes mellitus (T2DM) and at risk for diastolic heart failure (DHF) and mildly reduced renal filtration function (Type 4 cardiorenal syndrome), to evaluate the quantitative impact on the MISS (myocardial injury summary score) cardiac biomarker score, cardiac fibrosis by MRI, cardiac strain by ultrasonography and strain rate imaging, and KISS (kidney injury summary score) kidney biomarker score after 38 weeks of treatment with exenatide extended-release or placebo. Secondary Aim To evaluate the inter-relationships between demographic, clinical, and biochemical variables (MISS score, KISS score) and of progressive cardiac fibrosis as assessed by MRI, strain-rate imaging, and in adult individuals with T2DM and at risk for DHF (Type 4 cardiorenal syndrome).
Interventions
DRUGBYDUREON
Exenatide-extended release, Cohorts A and B
DRUGPlacebo
Cohort A only
Sponsors
Baylor Research Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥ 18 * Type 2 diabetes mellitus with hemoglobin A1C 6.6-9.9% with or without the use of insulin * Estimated glomerular filtration rate (eGFR) between 50 and 90 ml/min/1.73 m2
Exclusion criteria
* Allergy or intolerance to gadolinium * Implanted cardiac pacemaker, defibrillator, loop recorder, or other implanted metallic device * Any other metallic implanted device that is a contra-indication to MRI scanning * eGFR \< 50 ml/min/1.73 m2 * eGFR \> 90 ml/min/1.73 m2 * Patient has ever been treated with an approved or investigational GLP-1 receptor agonist e.g. BYETTA™ (exenatide), BYDUREON™ (Exenatide extended-release), VICTOZA™ (liraglutide), or taspoglutide * Patient is enrolled in another experimental protocol which involves the use of an investigational drug or device, or an intervention that would interfere with the conduct of the trial. * Disorders of iron metabolism * Collagen vascular diseases * Myocardial infarction * Use of DDP4 inhibitors, and PPAR gamma agonists * Pregnancy or planned pregnancy during the trial period * Hemoglobin A1C of ≥ 10.0% or \<6.6% * Fasting glucose ≥ 260 mg/dl * Clinically significant abnormal baseline laboratories * Morbid obesity or body girth that prohibits the ability to undergo echocardiography or MRI scanning with high-quality image results * Renal transplantation * Severe gastrointestinal, liver, or neurodegenerative disease * Decompensated liver cirrhosis (Child-Pugh score \>7) * New York Heart Association Class III or IV heart failure * Patients have alanine aminotransaminase (ALT) greater than 5 times the upper limit of the reference range. * Prior pancreatitis * Personal or family history of medullary thyroid adenoma or carcinoma (MTC) * Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). * History of severe hypoglycemia * Prior bariatric surgery
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Galectin-3 | 38 weeks | Mean change in plasma galectin-3 (pg/ml) |
| ST2 | 38 weeks | Mean change in plasma ST2 (pg/ml) |
| NGAL | 38 weeks | Mean change in urine neutrophil gelatinase associated lipocalin (NGAL):creatinine (Cr) ratio |
| KIM-1 | 38 weeks | Mean change in urine kidney injury molecule-1 (KIM-1):Cr ratio |
| L-FABP | 38 weeks | Mean change in urine L-type fatty acid binding protein:Cr ratio |
| IL-18 | 38 weeks | Mean change in urine interleukin-18:Cr ratio |
| Alpha GST | 38 weeks | Mean change in urine alpha glutathione S-transferase (αGST):Cr ratio |
| Troponin I | 38 weeks | Mean change in plasma ultrasensitive troponin I (pg/ml) |
| Pi GST | 38 weeks | Mean change in pi glutathione S-transferase (piGST):Cr ratio |
| NAG | 38 weeks | Mean change in urine N-acetyl-β-D-glucosaminidase (NAG):Cr ratio |
| Cystatin-C | 38 weeks | Mean paired change in urine cystatin-C:Cr ratio (uCysC:Cr) |
| BNP | 38 weeks | Mean change in plasma B-type natriuretic peptide BNP (pg/ml) |
| ACR | 38 weeks | Mean change in urine albumin:Cr ratio (ACR) |
Countries
United States
Contacts
STUDY_CHAIRPeter A McCullough, MD, MPH
Baylor Research Institute
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Exenatide-extended Release Exenatide-extended release (BYDUREON™) 2 mg subcutaneously once per week x 38 weeks | 29 |
| Placebo Matching placebo subcutaneously once per week x 38 weeks | 28 |
| Total | 57 |
Baseline characteristics
| Characteristic | Exenatide-extended Release | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 57.78 Years STANDARD_DEVIATION 12.83 | 55.17 Years STANDARD_DEVIATION 9.64 | 56.50 Years STANDARD_DEVIATION 11.35 |
| Diabetes | 29 Participants | 28 Participants | 57 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 13 Participants | 11 Participants | 24 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) White | 16 Participants | 14 Participants | 30 Participants |
| Sex: Female, Male Female | 16 Participants | 17 Participants | 33 Participants |
| Sex: Female, Male Male | 13 Participants | 11 Participants | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 29 | 0 / 28 |
| other Total, other adverse events | 20 / 29 | 21 / 28 |
| serious Total, serious adverse events | 0 / 29 | 1 / 28 |
Outcome results
Primary
ACR
Mean change in urine albumin:Cr ratio (ACR)
Time frame: 38 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide-extended Release | ACR | End of study (38th week) | 3963.49 ng/mmol Creat | Standard Deviation 3101.13 |
| Exenatide-extended Release | ACR | Baseline | 6678.23 ng/mmol Creat | Standard Deviation 12662.79 |
| Placebo | ACR | Baseline | 9713.65 ng/mmol Creat | Standard Deviation 14380.38 |
| Placebo | ACR | End of study (38th week) | 9825.2 ng/mmol Creat | Standard Deviation 9539.34 |
Primary
Alpha GST
Mean change in urine alpha glutathione S-transferase (αGST):Cr ratio
Time frame: 38 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide-extended Release | Alpha GST | Baseline | 0.06 ng/mmol Creat | Standard Deviation 0.2 |
| Exenatide-extended Release | Alpha GST | End of study (38th week) | 0.05 ng/mmol Creat | Standard Deviation 0.16 |
| Placebo | Alpha GST | Baseline | 0.67 ng/mmol Creat | Standard Deviation 1.83 |
| Placebo | Alpha GST | End of study (38th week) | 0.27 ng/mmol Creat | Standard Deviation 0.56 |
Primary
BNP
Mean change in plasma B-type natriuretic peptide BNP (pg/ml)
Time frame: 38 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide-extended Release | BNP | Baseline | 4.87 pg/ml | Standard Deviation 9.3 |
| Exenatide-extended Release | BNP | End of study (38th week) | 5.59 pg/ml | Standard Deviation 9.59 |
| Placebo | BNP | Baseline | 9.88 pg/ml | Standard Deviation 14.52 |
| Placebo | BNP | End of study (38th week) | 14.02 pg/ml | Standard Deviation 22.53 |
Primary
Cystatin-C
Mean paired change in urine cystatin-C:Cr ratio (uCysC:Cr)
Time frame: 38 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide-extended Release | Cystatin-C | Baseline | 2.07 ng/mmol Creat | Standard Deviation 2.64 |
| Exenatide-extended Release | Cystatin-C | End of study (38th week) | 1.47 ng/mmol Creat | Standard Deviation 1.22 |
| Placebo | Cystatin-C | Baseline | 1.84 ng/mmol Creat | Standard Deviation 1.19 |
| Placebo | Cystatin-C | End of study (38th week) | 1.57 ng/mmol Creat | Standard Deviation 1.17 |
Primary
Galectin-3
Mean change in plasma galectin-3 (pg/ml)
Time frame: 38 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide-extended Release | Galectin-3 | Baseline | 9570.91 pg/ml | Standard Deviation 4990.06 |
| Exenatide-extended Release | Galectin-3 | End of study (38th week) | 9539.21 pg/ml | Standard Deviation 3893.04 |
| Placebo | Galectin-3 | Baseline | 9266.7 pg/ml | Standard Deviation 6032.8 |
| Placebo | Galectin-3 | End of study (38th week) | 8098.78 pg/ml | Standard Deviation 6272.55 |
Primary
IL-18
Mean change in urine interleukin-18:Cr ratio
Time frame: 38 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide-extended Release | IL-18 | Baseline | 1.68 pg/mmol Creat | Standard Deviation 2.4 |
| Exenatide-extended Release | IL-18 | End of study (38th week) | 1.96 pg/mmol Creat | Standard Deviation 3.5 |
| Placebo | IL-18 | Baseline | 3.48 pg/mmol Creat | Standard Deviation 4.69 |
| Placebo | IL-18 | End of study (38th week) | 2.68 pg/mmol Creat | Standard Deviation 2.48 |
Primary
KIM-1
Mean change in urine kidney injury molecule-1 (KIM-1):Cr ratio
Time frame: 38 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide-extended Release | KIM-1 | Baseline | 0.1 ng/mmol Creat | Standard Deviation 0.08 |
| Exenatide-extended Release | KIM-1 | End of study (38th week) | 0.13 ng/mmol Creat | Standard Deviation 0.14 |
| Placebo | KIM-1 | Baseline | 0.13 ng/mmol Creat | Standard Deviation 0.09 |
| Placebo | KIM-1 | End of study (38th week) | 0.1 ng/mmol Creat | Standard Deviation 0.05 |
Primary
L-FABP
Mean change in urine L-type fatty acid binding protein:Cr ratio
Time frame: 38 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide-extended Release | L-FABP | Baseline | 2.61 ng/mmol Creat | Standard Deviation 3.72 |
| Exenatide-extended Release | L-FABP | End of study (38th week) | 2.05 ng/mmol Creat | Standard Deviation 2.18 |
| Placebo | L-FABP | Baseline | 3.24 ng/mmol Creat | Standard Deviation 4.17 |
| Placebo | L-FABP | End of study (38th week) | 3 ng/mmol Creat | Standard Deviation 2.85 |
Primary
NAG
Mean change in urine N-acetyl-β-D-glucosaminidase (NAG):Cr ratio
Time frame: 38 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide-extended Release | NAG | End of study (38th week) | 14.01 ng/mmol Creat | Standard Deviation 14.87 |
| Exenatide-extended Release | NAG | Baseline | 17.35 ng/mmol Creat | Standard Deviation 29.01 |
| Placebo | NAG | Baseline | 18.44 ng/mmol Creat | Standard Deviation 25.01 |
| Placebo | NAG | End of study (38th week) | 24.39 ng/mmol Creat | Standard Deviation 40.37 |
Primary
NGAL
Mean change in urine neutrophil gelatinase associated lipocalin (NGAL):creatinine (Cr) ratio
Time frame: 38 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide-extended Release | NGAL | Baseline | 17.35 ng/mmol Creat | Standard Deviation 29.01 |
| Exenatide-extended Release | NGAL | End of study (38th week) | 14.01 ng/mmol Creat | Standard Deviation 14.87 |
| Placebo | NGAL | Baseline | 18.44 ng/mmol Creat | Standard Deviation 25.01 |
| Placebo | NGAL | End of study (38th week) | 24.39 ng/mmol Creat | Standard Deviation 40.37 |
Primary
Pi GST
Mean change in pi glutathione S-transferase (piGST):Cr ratio
Time frame: 38 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide-extended Release | Pi GST | Baseline | 2.2 ng/mmol Creat | Standard Deviation 3.41 |
| Exenatide-extended Release | Pi GST | End of study (38th week) | 3.03 ng/mmol Creat | Standard Deviation 5.67 |
| Placebo | Pi GST | Baseline | 3.99 ng/mmol Creat | Standard Deviation 3.96 |
| Placebo | Pi GST | End of study (38th week) | 4.27 ng/mmol Creat | Standard Deviation 4.67 |
Primary
ST2
Mean change in plasma ST2 (pg/ml)
Time frame: 38 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide-extended Release | ST2 | Baseline | 635.2 pg/ml | Standard Deviation 449.82 |
| Exenatide-extended Release | ST2 | End of study (38th week) | 524.68 pg/ml | Standard Deviation 423.61 |
| Placebo | ST2 | Baseline | 443.18 pg/ml | Standard Deviation 380.34 |
| Placebo | ST2 | End of study (38th week) | 534.53 pg/ml | Standard Deviation 302.89 |
Primary
Troponin I
Mean change in plasma ultrasensitive troponin I (pg/ml)
Time frame: 38 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide-extended Release | Troponin I | Baseline | 230.85 pg/ml | Standard Deviation 282.73 |
| Exenatide-extended Release | Troponin I | End of study (38th week) | 238.53 pg/ml | Standard Deviation 283.59 |
| Placebo | Troponin I | Baseline | 415.65 pg/ml | Standard Deviation 446.33 |
| Placebo | Troponin I | End of study (38th week) | 504.48 pg/ml | Standard Deviation 599.4 |