Very few give this any consideration, but .... the E450's gearing can easily be made taller after you buy a used one or by insisting on it from the dealer on a new one so as to approach the E350's slightly better all-around mileage.
Put taller tires on the E450. This makes all gears taller - including overdrive - for better mileage.
We use 215/85R16 on our E450 instead of what came on it - 225/75R16. Believe it or not, the 215 tire has a larger diameter than the 225 tire. One poster here in the forums even has 235/75R16 tires on their E450 Class C - for great ground clearance and overall taller gearing. Larger diameter tires have other advantages, as well.