Disclaimer: Iakus and I fundamentally disagree on the nature of a continuation canon (he opposes, I support one), and that is perfectly OK.
IsaacShep wrote...
iakus wrote...
I can just imagine trying to come up with a stroy:
"Okay then this quarian captain tells the player..."
"Wait, what if the quarians were wiped out?"
"Okay, this krogan merc has some info-"
"What if the genophage wasn't cured?"
::sigh:: Okay this drell..."
"Kaje got hit?"
FRAK!!!! 
Which is not different to "And then Mordin says... And then Wrex says..." in ME3. There would obviously have to be replacement content. And yes, it backfired in ME3 but there was allllllllllllot more variables with ME2 squadmates than Krogan, Quarian, Geth, Rachni. And they can totally not make the most important characters be Krogan/Geth/Rachni/Quarian at all. There are tons of other races. The choice can be honored in many other ways. Having an exclusive mission to Rachni homeworld if they survived. Exclusive mission to Dyson Sphere if Geth are alive. Or have an exclusive squadmate from one of these races.
Besides that ME3 seemed to move the Geth away from the Dyson sphere with the individuality nonsense, you hit the good point that there's no reason that the major subplots of the first three game will have to be significant in the next three. Even just looking at the nominal (and typically bad) demographics of ME1-3, species like the Quarians and Krogan got far more attention than they warranted based on their population size: the Quarians in particular were a few million total in a galaxy of hundreds of billions, if not trillions, but they were treated as some major population group. Meanwhile, Terminus empires that certainly existed and likely far outnumbered them were never never formally introduced even though their existence is known.
The point isn't that this was wrong of Bioware to do, but simply to recognize that the amount of attention focused on these groups is (by the nature of fiction) arbitrary. These races got as much attention as they did because they were considered major subplots: with their subplots resolved there's no reason they must be major in this new setting. Their role in the narrative, if not in the galaxy, can be relatively minor, leaving them at the margins (and thus easily representable) parts of the game.
Naturally setting will have a lot to do with it... and this is one reason I actually think the Destroy ending would make a best carryover-consequence setting for a 'continuation canon*', because of the isolation imposed by a lack of relays. Even with relays being slowly rebuilt, whether there's a Krogan Empire or The Last Of The Krogan faction they can both remain largely off-screen with only a few, if any, Krogan appearing (due to distances involved). In a galaxy in which Relay-style FTL is still extremely limited or even non-existent, say such as at a time when the galaxy is starting to build new relays, you can easily justify the relatively marginal presence of large factions by distances involved. (Hence why the Krogan Empire or Rachni Hiveworlds are a distant threat, if a threat at all.)
Likewise, a Destroy setting in which non-Relay, 'conventional' FTL is dominant could shape the role or presence of other factions. The Quarians, if they survived, could become (by virtue of their many ships) a major trading power: with trade caravans rather than as refugees, even as a majority of the Quarians live on Rannoch you could still have traders trawling the stars, and these traders (if they exist) would be your primary interaction with the Quarians.
Really, the biggest drawback of Destroy after the 'there can be no canon' dispute is the lack of Geth: that's something that could be handwaved/retconned/changed (oh, hey, the Geth suspected it might happen and made a fail-safe/someone came by and turned the Geth back on afterwards: tensions exist), but showing the Geth consequences might be the most controversial of the ME trilogy arcs.
*A continuation canon is my informal shorthand for an assumed galaxy state used for the purpose of future development: it differs from the idea of a single, solitary canon by virtue of acknowledging that it only carries forward one particular path of multiple valid outcome, which would naturally progress differently in their own continuations. This is the sort of setting which might be introduced as 'Not all Shepards chose Destroy, but for those who did the story continues like so...' It does not claim that all Shepards chose Destroy, it simply acknowledges that some variances in the desired story are too much to ignore and so accepts a foundational backstory for progress. It's not an unknown concept: two largely successful models of continuation canons include The Witcher 2 (which did effectively canonize a romance from TW1, among other things), and Dragon Age Origins: Awakening (which allowed players to retcon their Warden's Sacrifice by importing a dead warden for the Expansion). Even ME2 has a continuation canon in the suicide mission: whatever happens in a Base Kept/Shepard Dead ending, we'll never know.