I really like the smaller buttons. They don't get in the way or get accidentally pushed. I think the big buttons like the K2 has would dominate the bezel and make it more difficult to handle with one hand.
I usually hold mine with my thumb resting between the screen and keypad. But everyone is correct that any one position after a few minutes is uncomfortable and that goes with all readers. I too have to change the position of my grip ever few minutes. But I have mild carpel tunnel and arthritis.