It's disheartening to me to always read the same jump in logic whenever this topic comes up. I'm quoting you, but this is more of a general misconception that pops up very regularly nowadays, lately with Indivisible as well, which has gotten me fairly annoyed, being a 2D artist having to solve optimization issues on a daily basis.
More often that not, the issue stems from a lack of available RAM, not a lack of skill. The fact that the aesthetic is "simple" has no bearing on the amount of memory required to have the game running at all. In the case of Isaac, I presume the game must have some form of keeping an entire run in memory since you can forward/backtrack levels using specific items, which would make memory consumption immediately very high, and that's without considering all other potential RAM-consuming issues (sprite size, animations, etc)
Do note in this case, that's just guesswork based on my own experiences, but you'll also notice the platforms having issues with 2D games are most commonly Vita, 3DS and WiiU. From what I understand, 3DS has 128Mb, Vita has 512Mb and WiiU has 1Gb of available RAM for all purposes, which is fairly limiting as far as 2D games are concerned nowadays, due in no small part to increasing sprite resolutions.
(And just to preemptively adress that question: no, 3D games don't necessarily take up more RAM - or less, for that matter. It all depends on the modelization and texturing techniques. It's quite possible to have 3D games using a lot less RAM than 2D, just as the other way around is possible. The bottom line is, everything in a game needs to be stored in memory, and what matters is the amount you can/want to load/unload at any given time. Some games need to have more stuff available readily than others, depending on the loading methods available, aesthetics and rendering considerations nonwithstanding.
I am also not saying programmer/artist skill is never a factor to consider, just that it shouldn't be the first one you jump to when you try to understand and argue about why something doesn't work the way you expect it to)