Study design, rationale, and baseline characteristics of ATTAIN-HYPERTENSION, a phase 3 trial of the oral GLP-1 receptor agonist orforglipron for hypertension

Up to three-quarters of primary hypertension is epidemiologically attributed to excess adiposity. Incretin-based therapies are consistently associated with reduced blood pressure (BP) in clinical trials; however, no prior trial has investigated incretin-based therapies for hypertension treatment with BP as its primary efficacy outcome. ATTAIN-HYPERTENSION is a phase 3 master protocol directing two identical, randomized, placebo-controlled studies. Participants with BMI≥25kg/m2 and systolic BP (SBP)≥140 mmHg or diastolic BP (DBP)≥90 mmHg, independent of antihypertensive treatment, are randomized 2:1 to orforglipron or placebo. The study includes 5 periods: screening, a 4-week run-in during which treated participants change to standard background medications (olmesartan, amlodipine, hydrochlorothiazide), a 48-week treatment period including dose escalation and return to baseline antihypertensive medication, a 12-week randomized withdrawal period, and a 2-week safety follow-up. Primary end point is the change in office SBP at Week 36. Key secondary end points include change in ambulatory SBP, percent change in hsCRP, percent change in body weight, percent change in triglycerides and non-HDL cholesterol, and change in SBP across the randomized withdrawal period. ATTAIN-HYPERTENSION randomized 538 participants in Trial 1 and 546 in Trial 2 between April 2025 and January 2026 at 100 locations across 10 countries. The randomized population has a mean (SD) age of 53.7 (11.8) years, BMI of 35.6kg/m² (6.9), and office SBP of 144.2 mmHg (10.3). At screening, 55.4% of participants were treated with antihypertensive medication. ATTAIN-HYPERTENSION investigates the efficacy and safety of orforglipron for the treatment of hypertension in adults with overweight or obesity. Described here are the novel trial design, its rationale, and the enrolled population's baseline characteristics. (ClinicalTrials.gov: NCT06948422).