I can touch 20 MPG even with 70-75MPH cruising speeds with a 4WD Xterra. That is tank after tank repeatable numbers. Drops a couple digits if towing. And been over 20 many times, sometimes even back to back.
So a 2WD is good for a couple more MPG over a 4WD. For a stock truck that isn't being driving like a race car those published numbers are likely very accurate. I bet I could get a repeatable 22 MPG out of a 2WD V6 Frontier. And get that consitently and with normal driving patterns (none of that hypermiling crap).