one thing that is commonly missed, is how efficient the engine is at xxxx rpm at ?? mph.
if the engine spins too fast, it will lose mpg.
if it spins too SLOW, it may be lugging, thus also loosing mpg.
also, it may be possible to loose mpg regardless of rpm, because the engine may be too small vs weight of vehicle.
in this instance, a larger engine may give better mpg because it isn't working as hard as the smaller engine.
all in all, it amounts to the total combination of engine, transmission, rear gear, tire diameter [and width], and vehicle weight, that needs to be "tuned" for maximum miles per gallon.
and we are not even talking, thinking about, or incorporating, aerodynamics. that can also increase or decrease the mpg of any combination. sometimes by a lot, or sometimes by an almost minuscule, undetectable amount.