Thiazides

Eligible participants were assigned to a systolic blood-pressure target of either less than 140 mm Hg (the standard-treatment group) or less than 120 mm Hg (the intensive-treatment group). Randomization was stratified according to clinical site. Participants and study personnel were aware of the study-group assignments, but outcome adjudicators were not.
After the participants underwent randomization, their baseline antihypertensive regimens were adjusted on the basis of the study-group assignment. The treatment algorithms were similar to those used in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.^{22 (link)} These algorithms and our formulary are listed in Figures S1 and S2 and Table S1 in the Supplementary Appendix. All major classes of antihypertensive agents were included in the formulary and were provided at no cost to the participants. SPRINT investigators could also prescribe other antihypertensive medications (not provided by the study). The protocol encouraged, but did not mandate, the use of drug classes with the strongest evidence for reduction in cardiovascular outcomes, including thiazide-type diuretics (encouraged as the first-line agent), loop diuretics (for participants with advanced chronic kidney disease), and beta-adrenergic blockers (for those with coronary artery disease).^{5 (link),27 (link)} Chlorthalidone was encouraged as the primary thiazide-type diuretic, and amlodipine as the preferred calcium-channel blocker.^{28 (link),29 (link)} Azilsartan and azilsartan combined with chlorthalidone were donated by Takeda Pharmaceuticals International and Arbor Pharmaceuticals; neither company had any other role in the study.
Participants were seen monthly for the first 3 months and every 3 months thereafter. Medications for participants in the intensive-treatment group were adjusted on a monthly basis to target a systolic blood pressure of less than 120 mm Hg. For participants in the standard-treatment group, medications were adjusted to target a systolic blood pressure of 135 to 139 mm Hg, and the dose was reduced if systolic blood pressure was less than 130 mm Hg on a single visit or less than 135 mm Hg on two consecutive visits. Dose adjustment was based on a mean of three blood-pressure measurements at an office visit while the patient was seated and after 5 minutes of quiet rest; the measurements were made with the use of an automated measurement system (Model 907, Omron Healthcare). Lifestyle modification was encouraged as part of the management strategy. Retention in the study and adherence to treatment were monitored prospectively and routinely throughout the trial.^{26 (link)}

Eligible participants were African American or Caucasian men and women who were biological offspring of parents with type 2 diabetes. Ethnicity was assessed by self-report of non-Hispanic White or non-Hispanic Black heritage. The parental history of type 2 diabetes is verified using a diabetes-focused medical history questionnaire. The inclusion and exclusion criteria are summarized in Table 1. Pre-existing diabetes was excluded using the 1997 ADA criterion for fasting plasma glucose (FPG) (≥126 mg/dL)^{13 (link)} and the 1985 WHO criterion for 75-gram oral glucose tolerance test (OGTT) (2-hour plasma glucose [PG]} >200 mg/dL).¹⁴ The goal was to enroll offspring of diabetic parents who had normal fasting glucose (NFG) and/or NGT at baseline, so as to permit detection of progression to prediabetes during follow-up. Normal fasting glucose (<100 mg/dL) and IFG (100–125 mg/dL) was defined according to the 2003 revised ADA criteria^{12 (link)} and IGT was defined by the 1985 WHO criterion (2-hour PG 140–199 mg/dL) during OGTT.¹⁴ Most exclusion criteria were chosen to reduce the risk of their confounding effects on planned assessments, body composition, insulin sensitivity and insulin secretion, among others. Because thiazide diuretics and beta-blockers can induce insulin resistance,^{15 (link)} persons using thiazides (>25 mg/day) or beta-blockers were excluded. The study protocol was approved by the University of Tennessee Health Science Center Institutional Review Board and all participants gave written informed consent.