When do you speak out about someone's relationship?

Speak up.

If your friend gets upset, cuts you off, takes you out of the wedding or whatever childish decision like that, he's not much of a friend to begin with.

A true friend would thank you for your advice and let you know you're crazier than a shithouse rat or he values your opinions because he has similar thoughts.

Three years from now when they're going through a divorce or uglier separation, it would be tough for you to honestly say "I could have told you but didn't want to butt in." I'd guess he would appreciate the honesty now instead of after another devastating blowup.

BTW, your friend's girlfriend will continue shitting on him. She's already proven she has diminishing respect for him and is picking nits, like getting upset about him putting a birthday present on her card.