NT-proBNP Selected Prevention of Cardiac Events in Diabetic Patients

Prior treatment

• History of hypersensitivity to any of the investigated drugs as well as known or suspected contraindications to the study drugs or previous history of intolerance to high dose of RAS-Antagonist or Beta-blocker in the absence of any other blood pressure lowering drugs.
• Systemic treatment with corticosteroids.
• Renal replacement therapy.
• Participation in an investigational drug study at the time of enrollment or within the past 90 days.
  • Eligibility criteria for eye-substudy:
• Intraocular surgery (including cataract surgery, Yttrium-Aluminium-Granat (YAG) laser capsulotomy) in the study eye within 3 months preceding Day 0
• Uncontrolled glaucoma in the study eye (defined as intraocular pressure ≥ 25 mmHg despite treatment with anti-glaucoma medication)

Other illness

• Symptomatic bradycardia and/or heart rate (HR) \< 60 bpm at Visit 1
• Signs of cardiac disease in the ECG such as atrial fibrillation; ST-T abnormalities or any bundle branch block / higher degree atrioventricular (AV) block.
• Coronary artery disease, defined by a history of myocardial infarction, known coronary stenosis \> 70% detected either by angiography or by CT-scan, significant defects in myocardial scintigraphy or positive stress-test echocardiography.
• A disease other than T2DM lowering the patient's life expectancy to less than two years.
• Chronic infections or malignancies.
• History of noncompliance to medical regimes and patients who are considered potentially unreliable.
• Media opacities like cataract or vitreous hemorrhage
• Active intraocular inflammation (grade trace or above) in either eye like infectious conjunctivitis, keratitis, scleritis, endophthalmitis as well as idiopathic or autoimmune-associated uveitis in either eye
• Ocular disorders in the study eye including retinal vascular occlusion, retinal detachment, macular hole, choroidal neovascularization, macula dystrophies
• History of glaucoma filtration surgery, corneal transplantation in the study eye
• History of epilepsy

Lab values

• Creatinine \> 2.5mg/dl.
• Abnormal echocardiography, defined as low ejection fraction \< 50%; wall motion abnormalities suggesting coronary artery disease (CAD), significant valve dysfunction \> grade I or other significant alteration.
• Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means, UNLESS they meet the following definition of post-menopausal: 12 months of natural (spontaneous) amenorrhea or 6 months of spontaneous amenorrhea with serum Follicle Stimulating Hormone (FSH) levels \> 40 mIU/m or 6 weeks post surgical bilateral oophorectomy with or without hysterectomy OR are using one or more of the following acceptable methods of contraception: surgical sterilization (e.g., bilateral tubal ligation), hormonal contraception (implantable, patch, and oral), and double-barrier methods (if accepted by local regulatory authority and ethics committee). Reliable contraception should be maintained throughout the study and for 7 days after study drug discontinuation.
• Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive Human Chorionic Gonadotropin (hCG) laboratory test (\> 5 U/ml).

Other

• Patients already on maximum dose of RAS-antagonist or beta-blocker.
• Symptomatic hypotension and/or systolic blood pressure (SBP) \< 100 mmHg at Visit 1.
• Current double blind treatment in diabetic trials.
• Structural damage to the center of macula in the study eye
• Atrophy of retinal pigment epithelium, subretinal fibrosis, laser scar within foveal avascular zone (FAZ) or organized hard exudate plaques
• Inability to obtain fundus photographs or fluorescein angiograms of sufficient quality to be analyzed and graded

• Type-2 diabetes for at least six months,
• ≥ 18 years of age, men or female,
• Written informed consent to participate in the study and ability to comply with all requirements.
• Participation in the PONTIAC 2 Study
• Written informed consent to participate in the eye-study