Stop Atherosclerosis in Native Diabetics Study

Diabetes incidence is increasing rapidly in the United States. Diabetes increases the risk for CVD, the major cause of death in diabetic individuals. The conventional cardiovascular risk factors of hyperlipidemia and hypertension add to the progression of diabetic vascular disease. Appropriate treatment targets for LDL-C and blood pressure in diabetic individuals are currently being debated. The Stop Atherosclerosis in Native Diabetics Study is a randomized, open label, 3-year, clinical trial to examine the effects of aggressive LDL-C (goal < 70 mg/dL) and BP (goal < 115/75 mm Hg) reduction versus the standard goals of < 100 mg/dL for LDL-C and < 130/85 mmHg for BP. Five hundred forty-nine American Indian men and women > age 40 with type 2 diabetes were randomized to one of two groups. Lipids and BP are managed using FDA-approved medications in an algorithmic approach. The presence and progression of atherosclerosis are evaluated by carotid ultrasonography; echocardiography assesses cardiac function. The primary endpoint is the composite outcome of change in carotid artery intimal medial thickness and fatal/nonfatal cardiovascular events. These outcomes are combined by using a ranked analysis for carotid thickness and assigning a "worst rank" for a cardiovascular event. Secondary endpoints include carotid plaque score, left ventricular geometry and function, serum CRP, and safety measures. Unique aspects of the study design and analysis plan involve changes during the trial of LDL-C treatment goals for participants with baseline or incident CVD in the conventional group, because of changes in the standard of care, and the use of a composite outcome. Study results will be valuable in understanding the effects of aggressive risk factor reduction on atherosclerosis burden and cardiac function in diabetic individuals in all U.S. populations and will provide evidence for determining optimal LDL-C and BP treatment goals for diabetic patients.

Inclusion criteria

• American Indian men and women 40 years of age or older
• Type 2 DM (according to 1997 ADA criteria and/or previously diagnosed by former ADA or WHO criteria): fasting plasma glucose >= 7.0 mmol/L (126 mg/dL) or 2-hour glucose >= 11.0 mmol/L (>200 mg/dL) after a 75-gram oral glucose tolerance test.
• LDL cholesterol >= 100 mg/dL. within the previous 12 months.
• Systolic BP >= 130 mm Hg. within the previous 12 months.

Exclusion criteria

• New York Heart Association Stage III- IV congestive heart failure.
• SBP >180 mmHg (2% of population) or patients with known causes of hypertension.
• History of angioedema.
• Any medical condition that study physicians believe would interfere with study participation or evaluation of results.
• Mental incapacity and/or cognitive impairment on the part of the patient that would preclude adequate understanding of, or cooperation with, the study protocol.
• Serum hepatic transaminase levels 2X the upper limit of normal.
• Participation in any clinical trial of any investigational medication within 3 months prior to this trial.
• Renal insufficiency as indicated by serum creatinine >2.0 for women and >2.4 for men.
• Diagnosis of primary hyperlipidemia in medical record.
• Secondary hypercholesterolemia due to hypothyroidism or nephrotic syndrome. Patients on stable doses of thyroid replacement therapy will be eligible.
• Presence of malignancy or history of any cancer except skin cancer within the past 5 years.
• Pregnancy or lactation. Premenopausal women will be requested to use birth control methods throughout the study and provided educational materials about the risks of using the study medications during pregnancy.
• Unable to obtain quantifiable carotid measure during screening examination.
• Concomitant long term use of cyclosporins (Sandimmune), macrolide antibiotics (erythromycin -many generic and brand name forms, clarithromycin, Biaxin, and Zithromax), azole antifungals (itraconazole-Sporanox, ritonavir, Norvir, and nelfinavir (Viracept).
• Orthostatic hypotension as defined by the following:

• The individual has a measured fall of >20 mmHg in systolic BP upon standing associated with symptoms lasting more than one minute (or severe symptoms that would not allow further lowering of BP)
• The standing systolic blood pressure is less than 90 mm.
• Triglyceride level >350 mg/dl.
• Severe aortic stenosis with valve area <=1.0 square cm.