The pickup itself, and these pickups specifically, have horrible aerodynamics. And then the engines needed to haul a load don't magically quit drinking heavily when running light. Part of that's because when these trucks were designed and built we had a 55 MPH national speed limit, so overdrive wasn't thought to be needed. Nor was a lock-up torque converter on the typical automatic. And the price of gas wasn't very high.
Take all of those factors and turn the MPH, and therefore the RPM, up 20% as we do today and most of these these trucks are gas guzzlers, with the 460 being the worst. But, as Dave pointed out, if we can get the RPM down there are gains to be made. So get rid of the C6 and go E4OD or ZF5 and enjoy both better MPG and quieter cruising. And reduce the speed to the low 60's and you will see noticeable gains.