So, I have a 6D and a D600 in hand right now...

that's the only forced change in hand position. count how many things you can change with your left hand still on the bottom of the camera or lens, and still holding the camera the same between the two ergonomic systems.

Nikon has always had this "it's more ergonomic" pet theory .. but if you really use both, while canon atypically looks more simplistic - it allows for alot of things to be done quickly and without changing hand positioning.  they only force the mode of two handed changes for core overall changes - or pro bodies - who don't want settings to change.

I could do the same thing on canon and i believe sony where the button is along the top right hand forefinger placement. far easier and far more ergonomic. AF modes on all canon cameras are settable in custom banks.

not to mention if I want to tweak MLU and self timer on nikon, I have to set the dial to MLU, then go into the settings to set the exposure delay.

proper support of a camera shouldn't matter if it's a large lens or not, and these are FF cameras we're talking about - the majority of lenses will front weigh the camera. and if you do have a 24-70 2.8 lens or a 70-200 2.8 lens, moving your left hand off of supporting the lens to make changes over time will add more stress to your right hand as it more times than naught has to support the full weight of the camera and lens as you make changes.  the more i'm supporting the camera with both hands, the less strain overall.