Preventing heart events in diabetic patients using specific medications

Inclusion Criteria:

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

Exclusion Criteria:

1. 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.
2. Patients already on maximum dose of RAS-antagonist or beta-blocker.
3. Creatinine \> 2.5mg/dl.
4. Symptomatic hypotension and/or systolic blood pressure (SBP) \< 100 mmHg at Visit 1.
5. Symptomatic bradycardia and/or heart rate (HR) \< 60 bpm at Visit 1
6. Signs of cardiac disease in the ECG such as atrial fibrillation; ST-T abnormalities or any bundle branch block / higher degree atrioventricular (AV) block.
7. 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.
8. 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.
9. A disease other than T2DM lowering the patient's life expectancy to less than two years.
10. Chronic infections or malignancies.
11. Systemic treatment with corticosteroids.
12. Renal replacement therapy.
13. 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.
14. 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).
15. History of noncompliance to medical regimes and patients who are considered potentially unreliable.
16. Current double blind treatment in diabetic trials.
17. Participation in an investigational drug study at the time of enrollment or within the past 90 days.

Eligibility criteria for eye-substudy:

Inclusion criteria:

1. Participation in the PONTIAC 2 Study
2. Written informed consent to participate in the eye-study

Exclusion criteria:

1. Media opacities like cataract or vitreous hemorrhage
2. 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
3. Structural damage to the center of macula in the study eye
4. Atrophy of retinal pigment epithelium, subretinal fibrosis, laser scar within foveal avascular zone (FAZ) or organized hard exudate plaques
5. Ocular disorders in the study eye including retinal vascular occlusion, retinal detachment, macular hole, choroidal neovascularization, macula dystrophies
6. Intraocular surgery (including cataract surgery, Yttrium-Aluminium-Granat (YAG) laser capsulotomy) in the study eye within 3 months preceding Day 0
7. Uncontrolled glaucoma in the study eye (defined as intraocular pressure ≥ 25 mmHg despite treatment with anti-glaucoma medication)
8. History of glaucoma filtration surgery, corneal transplantation in the study eye
9. Inability to obtain fundus photographs or fluorescein angiograms of sufficient quality to be analyzed and graded
10. History of epilepsy