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

While we eagerly await the final publication of the results of the SELECT Trial of semaglutide in participants with overweight or obesity with established cardiovascular disease (but without diabetes), it may be of interest to speculate on the mechanisms by which treatment may have resulted in the reported 20% reduction in major adverse cardiovascular events (MACE).

After smoking, elevated blood pressure is the single most important risk factor for macrovascular atherosclerotic disease (even in people with type 2 diabetes!). Previous studies with semaglutide have shown a consistent lowering of both systolic and diastolic blood pressure. 

In SUSTAIN-6, which showed significant reduction in MACE with semaglutide in participants with type 2 diabetes, the effect of semaglutide on blood pressure was only modest, however, the main driver of positive outcome was non-fatal strokes, an outcome which is particularly sensitive to changes in blood pressure. 

Likewise, in the family of STEP studies with semaglutide in participants with overweight or obesity, reductions in systolic and/or blood pressure reduction were regularly noted.

Although the reported effects of semaglutide on blood pressure (ranging between 3 to 7 mmHg) may seem modest, this is likely to be an underestimate, given that blood pressure in participants was generally well-controlled to begin with and the studies only report office blood pressure, which is highly susceptible to white-coat effects. In fact, out-of-office and 24-hour ambulatory blood pressure measurements have been consistently shown to be more reliable measures of blood pressure than office measurements.  

Furthermore, the nocturnal drop in blood pressure, the lack of which (in non-dippers) is well recognised as a major CV risk factor, can only be assessed with 24-hour ambulatory measurements and would be completely missed by office measurements. 

This is of particular interest, as previous weight-loss studies (both surgical and non-surgical) using 24-hour ambulatory blood pressure measurements have notably reported significant improvements in dipper status.

Until proven otherwise, I would maintain that a significant proportion of the potential benefits of semaglutide (and other weight-loss medications) on cardiac function and cardiovascular outcomes is likely related to their beneficial effects on blood pressure, the magnitude of which may well be underestimated with office measurements alone. 

Berlin, D

Disclaimer: I have received honoraria as an independent medical, research and/or educational consultant from various companies including Aidhere, Allurion, Boehringer Ingelheim, Currax, Eli-Lilly, Johnson & Johnson, Medscape, MDBriefcase, Novo Nordisk, Oviva and Xenobiosciences.