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Well, here's one example as someone who played Mass Effect 2 without playing one first ( I eventually played Genesis as I said).
The Rachni are extinct, Wrex died and the Krogan are so far from uniting that they'll be warring up until the Reaper invasion, most aliens hate humans for allowing the council to die and Anderson is a little bitch for an all-human council.
I went through and made sure to save the Rachni, Wrex and the council and things seemed a lot better this last go. I made all my decisions with amassing a giant galactic army against the Reapers in mind. Trying to cure the Genophage, remaining a spectre, saving my entire crew, and saving the collector base.
I think the Protheans lost against the Reapers because they went it alone. With all their technology (remember they disable a Reaper with some sort of super weapon) they still couldn't mount a successful war with the Reapers. If the humans don't have cooperation with everyone I think it's possible that you could end up losing the game.
Think of it like this, if you didn't get people's loyalty throughout the game and/or didn't make the right decisions you could "win" the game but end up dying. You can actually play the third game without Shepard.
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