• Change from Baseline in mean trough, sitting, clinic Systolic Blood Pressure. [ Time Frame: Week 8 ] [ Designated as safety issue: No ]
  

• Change from Baseline in mean trough, sitting, clinic Systolic Blood Pressure. [ Time Frame: Week 4 ] [ Designated as safety issue: No ]
  
• Change from Baseline in trough, sitting, clinic Diastolic Blood Pressure [ Time Frame: Weeks 4 and 8 ] [ Designated as safety issue: No ]
  
• Change from Baseline in mean trough Systolic Blood Pressure and Diastolic Blood Pressure through ambulatory blood pressure monitoring (22 to 24 hours after dosing). [ Time Frame: Weeks 4 and 8 ] [ Designated as safety issue: No ]
  
• Change from Baseline in 24-hour mean Systolic Blood Pressure and Diastolic Blood Pressure through ambulatory blood pressure monitoring. [ Time Frame: Weeks 4 and 8 ] [ Designated as safety issue: No ]
  
• Change from Baseline in mean daytime (6 AM to 10 PM) Systolic Blood Pressure and Diastolic Blood Pressure through ambulatory blood pressure monitoring. [ Time Frame: Weeks 4 and 8 ] [ Designated as safety issue: No ]
  
• Change from Baseline in mean nighttime (12 AM to 6 AM) Systolic Blood Pressure and Diastolic Blood Pressure through ambulatory blood pressure monitoring. [ Time Frame: Weeks 4 and 8 ] [ Designated as safety issue: No ]
  
• Change from Baseline in mean Systolic Blood Pressure and Diastolic Blood Pressure at 0 to 12 hours after dosing through ambulatory blood pressure monitoring. [ Time Frame: Weeks 4 and 8 ] [ Designated as safety issue: No ]
  
• Proportion of subjects who reached their Systolic and Diastolic blood pressure targets, defined as defined as <140/90 mm Hg for subjects without type 2 diabetes or CKD or <130/80 mm Hg for subjects with type 2 diabetes or CKD [ Time Frame: Weeks 2, 4, 6 and Week 8 ] [ Designated as safety issue: No ]
  
• Proportion of subjects who reached their Systolic blood pressure targets, defined as defined as <140 mm Hg for subjects without type 2 diabetes or CKD or <130 mm Hg for subjects with type 2 diabetes or CKD [ Time Frame: Weeks 2, 4, 6 and Week 8 ] [ Designated as safety issue: No ]
  
• Proportion of subjects who reached their Diastolic blood pressure targets, defined as defined as <90 mm Hg for subjects without type 2 diabetes or CKD or <80 mm Hg for subjects with type 2 diabetes or CKD [ Time Frame: Weeks 2, 4, 6 and Week 8 ] [ Designated as safety issue: No ]
  

According to the World Health Organization, hypertension is the most common attributable cause of preventable death in developed nations, as uncontrolled hypertension greatly increases the risk of cardiovascular disease, cerebrovascular disease and renal failure. As the population ages, the prevalence of hypertension will continue to increase if broad and effective preventive measures are not implemented. Despite the availability of antihypertensive agents, hypertension remains inadequately controlled; only about one-third of patients continue to maintain control successfully.

Although most antihypertensive agents are effective at the appropriate dose, the majority have side effects that limit their use. As a class, angiotensin II receptor blockers generally are considered more tolerable than other classes of antihypertensive agents. TAK-491 is an angiotensin II receptor blocker being evaluated by Takeda to treat essential hypertension. Treatments for essential hypertension commonly include use of a thiazide-type diuretic, either alone or as part of combination treatment. Although chlorthalidone was commonly prescribed in the past, its use has widely been replaced with hydrochlorothiazide, presumably due to a lack of available combination products containing chlorthalidone, the assumption that hydrochlorothiazide and chlorthalidone have similar antihypertensive effects and cardiovascular benefits, and the perception that chlorthalidone use is associated with a greater frequency of hypokalemia. However, the frequency of hypokalemia with chlorthalidone use is relatively low in the dose range of 12.5 to 25 mg and these doses have been shown to be associated with potent blood pressure reduction. Several long-term outcomes trials have shown that blood pressure reductions associated with chlorthalidone treatment reduce risk of cardiovascular morbidity and mortality.

Most hypertensive patients require two or more agents to achieve target blood pressure and diuretics are commonly used in combination with other antihypertensive agents.

Subjects participating in this study will be randomized to receive one of 3 possible dosing combinations of TAK-491 with either chlorthalidone or olmesartan medoxomil-hydrochlorothiazide over 8 weeks. The total duration of the study is approximately 13 weeks. Participants will make a total of 11 visits to the clinic, and will be required to participate in a follow-up telephone call 14 days after last dose of the study drug for adverse event assessment.