Hormones and Sexual Function Predict Outcomes in Revascularized Men With Diabetes

Diabetes mellitus (DM) and multi-vessel coronary artery disease (CAD) entail significant
risk for progression of cardiac morbidity and mortality. Compelling recent research points
to biological pathways that link DM and CAD to androgen status and sexual function. We
hypothesize that androgen deficiency (AD) and erectile dysfunction (ED) independently serve
as sentinel indicators, predicting the future development of adverse cardiovascular and
cerebrovascular events in men with diabetes following coronary revascularization.

ED is emerging as a barometer of overall endothelial function. We hypothesize that as a
consequence of this relationship, erectile dysfunction is predictive of cardiovascular
outcomes in men with diabetes and CAD. We also propose that AD affects morbidity and
mortality in men with DM and CAD by influencing presentation and progression of endothelial
dysfunction as well as inflammation and hemostasis.

We propose to investigate four specific aims using 1,143 diabetic men who have
angiographically proven coronary artery disease (CAD) (≥50%) in at least one major
epicardial vessel with or without percutaneous coronary intervention (PCI). Specific aims of
this study are: 1) To determine whether androgen status at baseline independently predicts
primary and secondary endpoints in men (n=1,143) with DM and CAD. 2) To determine whether
erectile dysfunction at baseline independently predicts cardiovascular outcomes in men with
DM and CAD. 3) To determine whether change of androgen status and sexual function over time
independently predict cardiovascular outcomes in men with DM and CAD. 4) To demonstrate
specific mediators and pathways that link sexual function and androgen status to
cardiovascular disease.

The primary endpoint is defined as the combined all-cause mortality, non-fatal myocardial
infarction (MI), and stroke. Secondary endpoints include major adverse cardiovascular and
cerebrovascular events (MACCE), defined as death, nonfatal MI, stroke or revascularization
at one year and angina status as evaluated with the Seattle Angina Questionnaire (SAQ) at 6
months, 12 months, 18 months, 24 months, 30 months and 36 months following catheterization.

Inclusion Criteria:

- Male age [18-75 years];

- Type 2 Diabetes, defined according to the American Diabetes Association as history
of: a) presence of classic symptoms of DM with unequivocal elevation of plasma
glucose (2-hour post-prandial or random of >200 mg/dL (11mmol/L), b) fasting plasma
glucose elevation on more than 1 occasion of at least 126 mg/dL (7mmol/L) or c) HA1C
> 6.5, currently undergoing pharmacological or non-pharmacological treatment;

- Angiographically confirmed Coronary Artery Disease (≥50%) with or without PCI;

- Indication for revascularization based upon symptoms of angina and/or objective
evidence of myocardial ischemia;

- Willingness to comply with all follow-up required study visits; and

- Signed and received copy of informed consent

Exclusion Criteria:

- Severe congestive heart failure (class III or IV according to NYHA, or pulmonary
edema) at the time of enrollment;

- Previous stroke within 6 months;

- Prior history of significant bleeding (within the previous 6 months) that might be
expected to occur during PCI/DES related anticoagulation;

- Acute ST-elevation MI (Q-wave) within 72 hours prior to enrollment requiring
revascularization;

- Abnormal creatine kinase (CK > 2x normal); or abnormal CK-MB levels at time of
randomization;

- Contraindication to either CABG or PCI/DES because of a coexisting clinical
condition];

- Significant leukopenia, neutropenia, thrombocytopenia, anemia, or known bleeding
diathesis;

- Intolerance or contraindication to aspirin or both clopidogrel and ticlopidine;

- Dementia with a Mini Mental Status Examination (MMSE) score of <20;

- Extra-cardiac illness that is expected to limit survival to less than 5 years (e.g.
oxygen-dependent chronic obstructive pulmonary disease, active hepatitis or
significant hepatic failure, severe renal disease);

- Geographically inaccessible for follow-up visits required by protocol.

- Additional Ancillary Study Exclusions. Exclusion criteria that are unique to the
proposed study are prior use of hormonal therapy (HRT) with testosterone in men at
baseline and current use of sex-hormone antagonist medications at baseline.