[DustyPorViva]

Working with 90 degree angles first will work better towards your design, in my opinion. Once you start messing with diagonals you end up having to fight with pixels because of the way they interact diagonally. That's not to say diagonal < straight, but design-wise 90 degrees is probably better. For example when you work with diagonals, you have to consider how "straight lines" collide at intersections depending on their alignment. Sometimes they collide in a way that makes a 2x2 box, which is most of the time undesirable. Or how you want to portray certain shapes at a diagonal angle can be quite hard(like Crono said, axes can be challenging).

I say make it at 90 degrees, then make the 45 degree version and optimize it there, that way you don't have to worry about optimizing AND design.