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.

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).

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

A total of 57 patients were enrolled from November 2015 to December 2019. Despite original plan of enrolling 104 patients, the recruitment stopped early due to poor accrual

38 weeks from study initiation

Our recruitment stopped early due to low accrual rate. Hence, null findings may be a result of lack of statistical power. Accordingly, our results should be interpreted as hypothesis-generating.