I like to think of the 25th as the nightmare amendment for our modern days when there is like a 15 minute window to respond to nuclear attack. What if, when Ike was recovering from a heart attack the Russians decided to attack? What if Kennedy were left alive, but a vegetable after Dallas? The 25th provides for these scenarios as well as replacing a VP. It really isn’t a mechanism for removing a President unless he just isn’t ‘there’ anymore.
I remember that one president temporarily handed power to his VP while undergoing anesthesia. So the 25th has been invoked.
Reagan once, in 1985, making George H.W. Bush the Acting President for about 8 hours. Twice by Bush 43, once in 2002 and once in 2007, making Dick Cheney the Acting President for over 2 hours each time.