Four hundred and ninety-nine men and women ≥ age 40 with type 2 diabetes and no history of a CVD event were randomly assigned to an aggressive (n=252) or standard intervention group (n=247). All participants were American Indian, as defined by Indian Health Service (IHS) criteria, had type 2 diabetes as defined by 1997 ADA criteria, LDL-C ≥100 mg/dL, and systolic blood pressure >130 mmHg within the previous 12 months. All participants provided written informed consent and the study was approved by the Institutional Review Boards of the participating institutions and IHS as well as by the sponsor, the National Institutes of Health, an independent Data and Safety Monitoring Board, and all participating American Indian communities. Details of the SANDS study design and methods have been published.8
Study personnel performed lipid and blood pressure management for both groups. All other medical care, including diabetes management, was performed by the participants’ IHS providers. For lipid management (), if lifestyle modification was unsuccessful, statin monotherapy was initiated. If the LDL-C goal was not reached with the maximal tolerable statin dosage, combination therapy with ezetimibe, bile acid resin, or a fiber supplement was used. The non-HDL-C goal was then addressed using fish oil, fenofibrate, or niacin ().8
Statins did not exceed mid-maximal dosages when used in combination with a fibrate. Lipid management was performed by trained mid-level practitioners, including nurse practitioners and physician assistants, with input from field physicians and an expert lipidologist. Systolic blood pressure was treated to goals of 115 mmHg and 130 mmHg in the aggressive and standard groups, respectively.9
Baseline and follow-up visits
All procedures followed standardized methods and were performed by trained, certified personnel. The baseline visit included a physical exam, collection of demographic data, health history, and medication use. Height, weight, waist circumference, and seated blood pressure were measured. Food frequency, physical activity, and quality of life questionnaires were administered, and fasting blood and urine samples collected for measures of lipid profile, complete metabolic profile, apolipoproteins B and A1, glucose, insulin, hemoglobin A1c, and C-reactive protein.
Based on the intent-to-treat criteria, the participants were followed from the date of randomization until trial completion, death, loss to follow up, or request for no further contact regardless of their adherence to the medication intervention. All participants were scheduled for a visit at 1 month, with follow-up visits scheduled every 3 months until 36 months. At each follow-up visit, a lipid profile was measured using a Cholestech LDX device (Cholestech Corporation, Hayward, CA) standardized against the laboratory assay. Medications were adjusted to meet treatment goals, side effects were assessed, and information on health outcomes was obtained. Liver function studies were conducted at baseline, 1, 3, and 6 months, and every 6 months thereafter, according to the IHS protocol for initiating or changing statin therapy dosage. In addition to the regular visits, interim visits were added as necessary for medication adjustment and/or side effect management. At each visit, participants were encouraged to take an active role in their treatment. Participants and field staff worked closely to achieve the treatment goal with minimal effect on quality of life. Participants suffering from myalgias caused by statins were switched to a different statin. Creatine kinase (CK) levels were obtained on any participant with a myalgia significant enough to warrant a change in medication.
Fasting blood and urine samples were obtained at 18 and 36 months and forwarded to the core laboratory for repeat of all measures obtained at baseline. In addition, at 6, 12, 24, and 30 months, a fasting blood sample was obtained for a complete laboratory lipoprotein profile.
Adverse Event Data Assessment
At each visit after randomization, information was collected on AEs. These were defined as being possibly, probably, or definitely related to pharmacotherapy. Serious adverse events (SAEs) were defined as those requiring medical attention. All AEs and SAEs were reviewed by the Morbidity and Mortality Committee and the Data Safety and Monitoring Board. The AEs were presented blinded to treatment arm for the Morbidity and Mortality Committee and unblinded for the Data Safety and Monitoring Board.
Field staff at each study site were certified in performance of the Cholestech LDX device. A field service technical representative retrained the field staff every 8 months to ensure proper technique and accurate results. Cholestech LDX measurements were obtained quarterly, and serum was collected biannually for repeat lipid analysis at the core laboratory. Measures between the Cholestech LDX and the central laboratory for LDL-C were well correlated ().
Comparison of Point-of–Care LDL Cholesterol with Central Laboratory Measures
Baseline characteristics of the SANDS participants were compared between the standard and aggressive treatment groups using the t-test for continuous variables and the chi-square test for categorical variables. The continuous variables that did not follow the normal distribution were log-transformed or described using geometric means and corresponding 95% confidence intervals. All two-sided significance tests were based on a significance level of .05.
Mean changes in LDL-C, HDL-C, triglycerides, and non-HDL-C, along with other CVD risk factors between baseline and 36 months, were compared between the treatment groups, and significant changes were determined using two-sided t-tests. Unpaired t-tests were used to compare groups. The mean or median of the 24-, 30-, and 36-month values was used as the end-of-study measurement for all lipids.
The proportion of participants who used each type of hypolipidemic drug (statins, ezetimibe, niacin, fibrate, and fish oil) was compared between the treatment groups using the chi-square test. The mean number of hypolipidemic drugs used by the participants was computed for the aggressive and standard groups and compared using a nonparametric test. Agreement between the point-of-care (Cholestech) LDL-C and the LDL-C measured in a central laboratory was evaluated using an ordinary least squares regression.
The proportion of participants with at least one AE and the number of AEs per group were compared using the chi-square test and t-tests, respectively. The most frequently occurring AEs were also compared between treatment groups.