Blood Pressure Lowering Only or More? Has the Jury Reached Its Verdict?

There is a great need for antihypertensive agents that go beyond blood pressure lowering to treat the underlying pathophysiologic conditions that contribute to cardiovascular disease. However, the results of published outcome studies have been variable because they have investigated patients with complicated, high-risk hypertension. Although this ensures a sufficient number of cardiovascular events to demonstrate drug–drug differences, the potent effects of blood pressure lowering in high-risk patients obscures differential non–blood pressure effects. Despite these limitations, reductions in the risk of stroke, atrial fibrillation, and diabetes mellitus have been demonstrated with renin-angiotensin-aldosterone system blockade. Guidelines currently recommend thiazide diuretics in stage 1 hypertension, but this is based on data from high-risk patients, and extrapolation to stage 1 disease may not be appropriate. Both blood pressure and cardiovascular risk increase exponentially from early in a patient’s life, leading to clinically relevant differences in the pathophysiology of stage 1 versus complicated hypertension. Importantly, patients with stage 1 hypertension typically require 30–40 years of treatment. Thus, secondary effects of antihypertensive drugs on various blood pressure–independent cardiovascular risk factors are likely to become manifest. Clinical trials in mild forms of hypertension are essential to investigate the non–blood pressure effects of antihypertensive agents.