Extended Release Exenatide Versus Placebo In Diabetic Patients With Type 4 Cardiorenal Syndrome
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
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).
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Exenatide-extended release Exenatide-extended release (BYDUREON™) 2 mg subcutaneously once per week x 38 weeks |
Drug: BYDUREON
Exenatide-extended release, Cohorts A and B
|
| Placebo Comparator: Placebo Matching placebo subcutaneously once per week x 38 weeks |
Drug: Placebo
Cohort A only
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Myocardial injury summary score (MISS) [38 weeks]
This is a mathematical integration of the percent change in Ultrasensitive troponin, B-type natriuretic peptide (BNP), Galectin-3, and ST2 by using the following formula (range -1 to +1) MISS(j) = SUM log10 [ Biomarker(i)Peak / Biomarker(i)Baseline ], i = 1, n
- Kidney Injury Summary Score (KISS) [38 weeks]
This is a mathematical integration of the percent change in Tissue Inhibitor of MetalloProteinases-2 (TIMP-2) x Insulin-like Growth Factor Binding Protein-7 (IGFBP-7), also known as the commercially available NephroCheck® Test, Neutrophil gelatinase associated lipocalin (NGAL):creatinine (Cr) ratio, Kidney injury molecule-1 (KIM-1):Cr ratio, L-Fatty acid binding protein:Cr ratio, Interleukin-18:Cr ratio, Alpha glutathione S-transferase (αGST):Cr ratio, Pi glutathione S-transferase (piGST):Cr ratio, N-acetyl-β-D-glucosaminidase (NAG):Cr ratio, Cystatin-C:Cr ratio (uCysC:Cr), Albumin:Cr ratio (ACR) by using the following formula (range -1 to +1) KISS(j) = SUM log10 [ Biomarker(i)Peak / Biomarker(i)Baseline ], i = 1, n
- Cardiac fibrosis [38 weeks]
Mean paired percent change in left ventricular myocardial fibrosis (% of left ventricular mass) by late gadolinium enhancement on cardiac magnetic resonance imaging
- Left ventricular strain [38 weeks]
Mean paired change in left ventricular longitudinal strain (%) by echocardiographic strain-rate imaging (unitless)
Other Outcome Measures
- Galectin-3 [38 weeks]
Mean paired change in plasma galectin-3 (ng/ml)
- ST2 [38 weeks]
Mean paired change in plasma ST2 (ng/ml)
- NephroCheck [38 weeks]
Mean paired change in urine NephroCheck (Tissue Inhibitor of MetalloProteinases-2 x Insulin-like Growth Factor Binding Protein-7) unitless
- NGAL [38 weeks]
Mean paired change in urine neutrophil gelatinase associated lipocalin (NGAL):creatinine (Cr) ratio
- KIM-1 [38 weeks]
Mean paired change in urine kidney injury molecule-1 (KIM-1):Cr ratio
- L-FABP [38 weeks]
Mean paired change in urine L-type fatty acid binding protein:Cr ratio
- IL-18 [38 weeks]
Mean paired change in urine interleukin-18:Cr ratio
- Alpha GST [38 weeks]
Mean paired change in urine alpha glutathione S-transferase (αGST):Cr ratio
- Pi GST [38 weeks]
Mean paired change in pi glutathione S-transferase (piGST):Cr ratio
- NAG [38 weeks]
Mean paired 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)
- ACR [38 weeks]
Mean paired change in urine albumin:Cr ratio (ACR)
- LVMI [38 weeks]
Mean paired change in ventricular mass index (LVMI) (g/m2) by cMRI
- Radial Strain [38 weeks]
Mean paired change in radial strain by strain rate echocardiography (unitless)
- eGFR [38 weeks]
Mean paired change in eGFR (ml/kg/1.72 m2)
- Glycohemoglobin [16 weeks]
Mean paired change in blood glycohemoglobin (hemoglobin A1C) %
- Fasting glucose [16 weeks]
Mean paired change in fasting glucose (mg/dl)
- Troponin I [38 weeks]
Mean paired change in plasma ultrasensitive troponin I (ng/L)
- BNP [38 weeks]
Mean paired change in plasma B-type natriuretic peptide BNP (pg/ml)
Eligibility Criteria
Criteria
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
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eGFR < 50 ml/min/1.73 m2
-
eGFR > 90 ml/min/1.73 m2
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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.
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Disorders of iron metabolism
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Collagen vascular diseases
-
Myocardial infarction
-
Use of DDP4 inhibitors, and PPAR gamma agonists
-
Pregnancy or planned pregnancy during the trial period
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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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Baylor Scott and White Research Institute- Baylor Heart and Vascular Hospital | Dallas | Texas | United States | 75226 |
Sponsors and Collaborators
- Baylor Research Institute
Investigators
- Study Chair: Peter A McCullough, MD, MPH, Baylor Research Institute
Study Documents (Full-Text)
None provided.More Information
Publications
- Best JH, Hoogwerf BJ, Herman WH, Pelletier EM, Smith DB, Wenten M, Hussein MA. Risk of cardiovascular disease events in patients with type 2 diabetes prescribed the glucagon-like peptide 1 (GLP-1) receptor agonist exenatide twice daily or other glucose-lowering therapies: a retrospective analysis of the LifeLink database. Diabetes Care. 2011 Jan;34(1):90-5. doi: 10.2337/dc10-1393. Epub 2010 Oct 7.
- Chinnaiyan KM, Alexander D, Maddens M, McCullough PA. Curriculum in cardiology: integrated diagnosis and management of diastolic heart failure. Am Heart J. 2007 Feb;153(2):189-200. Review.
- Davidson MH. Cardiovascular effects of glucagonlike peptide-1 agonists. Am J Cardiol. 2011 Aug 2;108(3 Suppl):33B-41B. doi: 10.1016/j.amjcard.2011.03.046. Review.
- Jellis C, Martin J, Narula J, Marwick TH. Assessment of nonischemic myocardial fibrosis. J Am Coll Cardiol. 2010 Jul 6;56(2):89-97. doi: 10.1016/j.jacc.2010.02.047. Review.
- Levine GD, Rosai J, Bearman RM, Polliack A. The fine structure of thymoma, with emphasis on its differential diagnosis. A study of ten cases. Am J Pathol. 1975 Oct;81(1):49-86.
- McCullough PA, Olobatoke A, Vanhecke TE. Galectin-3: a novel blood test for the evaluation and management of patients with heart failure. Rev Cardiovasc Med. 2011;12(4):200-10. doi: 10.3909/ricm0624. Review. Erratum in: Rev Cardiovasc Med. 2012;13(1):e52.
- Wang YC, Yu CC, Chiu FC, Tsai CT, Lai LP, Hwang JJ, Lin JL. Soluble ST2 as a biomarker for detecting stable heart failure with a normal ejection fraction in hypertensive patients. J Card Fail. 2013 Mar;19(3):163-8. doi: 10.1016/j.cardfail.2013.01.010.
- 014-149
- D5551L00004/ISSEXEN0013