I was having lots of issues with my DT25 connected to Pod HD500. The volume would swing widely and I would would get a loud pop when changing presets from dirty to clean (topography II to I).
I tried lots of things but what finally worked was to unplug the USB connection to the Pod HDEdit software before using the rig to play songs. It must have been that the Pod HD was trying to communicate with the DT25 (via the L6 link) as well as sync with the POD HDedit software at the same time which was a lot to do while changing a preset.
I would still use the PodHD edit to set up presets and effects, etc, but then remove it and do the final tweaking (like channel volume settings) on the unit itself. I'd also recommend keeping each preset as simple as you can (remove or turn off effects you don't really use) to keep processing time as short as possible.
Just thought I'd share this if anyone has the same issue.