You'll have transmission losses no matter what gear or ratio it will be in.
Simply adding more cog's and inertia means higher losses. The more items you try to turn the more loss you generally get as some of the power is sapped away.
But in order usually to get maximum MPG out of your car you need to be in your tallest gear. 5th or 6th or your tallest gear. This lowers the amount of revolutions the engine is doing. Thus lowering the amount of fuel and air the car is using to push/pull the car forward.
To get the best mpg you should really drive at a slow speed with the tallest gear. This then lowers the rpm of the engine and has the least amount of drag. As you cannot change the the aerodynamic co effcient of drag of your car.
If you are deadly serious about MPG and acheiving the best you'd change the camshaft overlap to be very tight increasing low rpm torque. Lowering weight and making the car as aerodynamic as possible.
Breaking the Speed Record: 81 MPH on a Bike
The above link shows a push bike that managed to hit 81mph. This used all the technics to drop drag. Most humans if lucky can put out about 800watts of power in a short period on a push bike. About 1 horse power. Without drag we could simply have an unlimited amount of speed.
If you simply look at Alfa's Engines :-
TS 1.6 = 120 hp Top Speed : 125mph
TS 2.0 = 150 hp Top Speed : 133mph
GTA 3.2 V6 = 250hp Top Speed : 145mph
Power has had to virtually double to get an extra bit of top speed.