Will the Blood Pressure-Lowering Effect of Semaglutide Explain the Positive Outcome of the SELECT Trial?

While awaiting the final publication of the SELECT Trial results, it is worth speculating on the mechanisms behind the reported reduction in MACE. Elevated blood pressure is the single most important risk factor for macrovascular atherosclerotic disease. Previous studies with semaglutide have consistently shown a lowering of both systolic and diastolic blood pressure. In SUSTAIN-6, the effect of semaglutide on blood pressure was modest, but non-fatal strokes were the main driver of the positive outcome. Similarly, in the STEP studies, reductions in systolic and/or blood pressure were regularly noted. Although the reported effects of semaglutide on blood pressure may seem modest, this is likely an underestimate, given the generally well-controlled blood pressure in participants and the limited reporting of office blood pressure measurements. Out-of-office and 24-hour ambulatory blood pressure measurements are more reliable measures of blood pressure. Notably, previous weight-loss studies using 24-hour ambulatory blood pressure measurements have reported significant improvements in dipper status. Until proven otherwise, it is likely that a significant proportion of the potential benefits of semaglutide on cardiac function and cardiovascular outcomes is related to its beneficial effects on blood pressure.