It depends on what you are optimizing.
Performance then it is probably best to go for large.
AI then I would want you to optimize medium. I mostly play medium because I find large has too many cities for me to micro manage. I like to top out at around 10-12 cities at most with roughly the same number of outposts. Any more and it is too hard to track what is going on. Your 'fire shrine in the south east' getting destroyed can take 2 or 3 minutes to find. When you go to a city for production you have to try and remember your goal for the city.
I would also imagine (as someone else stated) that the new players you want to buy this game will probably start on medium, therefore make it the most consistent fun.