I am struggling with the same issue. I am a bass player, I have created myself some presets where I use the HX Effects in front of my amp, which sound good, but I wanted to play around with guitar sounds as well, and whatever I did with any kind of overdrive it sounded like crap. I tried my guitar straight into the sound card into an amp simulation plugin in my DAW and it sounds like the amp it claims to represent, say a Fender Twin or a Marshall, clean but on the verge of breakup. Then I plugged the guitar into the HX FX, blank preset, and into the sound card to simulate what would happen if I ran the same setup into a Marshall, and it sounded nasty and brittle.If I hit the analog bypass, it sounds normal. Then I plugged the HX straight into a mixer, and I realized that the "blank slate" sounds radically different from analog bypass. It's significantly louder and brighter, like there is a treble booster that I can't turn off. So it's not so much "tone suck", rather it's built-in boost.
The closest I got to getting "DSP transparency" between empty preset and analog bypass is to set global input to Line and leave output at Instrument level. But it still sounds tinny, so I have to "burn" one effect slot with a parametric EQ to shelve off a lot of highs from 4K up...
I don't have an actual guitar amp to try it in, I don't know if it's got something to do with impedance, but if the idea is to ditch your "physical" pedalboard and replace it with this unit, then it's definitely not a 1 to 1 replacement.
I haven't tried comparing the effect loop send with the main out yet, I don't know if the treble boost is at the beginning or the end of the processing chain, but if you are hitting the front end of an amp with something this bright, it's definitely going to change the characteristics of how the preamp "breaks up" with more gain.