The game gives you three options to pick at the start. A melee weapon, a bow/ranged weapon with ammo, and a shield. Pick two.
I never, ever, ever pick the shield. Because I suck with shields. The game is so fast that trying to get the timing down of a block always ends with me eating the full attack to the face, nevermind trying to do a perfect block and parry. Instead I just dodge roll everything.
Because I dodge roll everything, I almost always use fast weapons. Assassin blade is good because i’m usually rolling behind an enemy already, may as well get a crit out of it. Bows are even better because I don’t have to get close at all. Then if I get some turrets and pick the mutation that reduces the cooldown on abilities? chef kiss
This means, though, that if I get a slow melee weapon or slow crossbow? I’m gonna be crap with it. Rolling behind an enemy doesn’t work because the windup animation is so long they just turn around. I’d have to get good with the timing and synergize it with other abilities, and that doesn’t happen because I either die or I find a fast weapon that I like and can replace it with. I’m not getting practice with the stuff i’m crappy at because the game is hard enough that me being crappy means i’m also soon dead.
I have never once restarted a run. Because of the starting loadout or otherwise. I always give it a try. And the trend has been that since i’ve been unlocking more and more and more equipment i’ve gotten less and less far on average with all of my runs. Near the start once I got the hang of how the game played I would regularly get to the end boss on most runs. Now I often die before even reaching the second one. It’s like i’m getting worse at the game the more I play it, just because i’m not allowed to ever be comfortable with the abilities the game gives me.