I'm not sure if there's a clear cut answer to this question. Of course, it depends on a lot of variables: which park you're playing in, how you and your opponent's teams stack up against each other, whether the games will likely be high scoring or low scoring contests.
It would be easier if the games were handled on an individual basis. If your up by a couple of runs and your all-star closer is coming in to shut it down, you'd bring in a defensive sub. On the other hand, if your closer is too tired to pitch and your playing a team that brings the lumber, you'd probably keep the better hitter in the lineup, just in case your team needs to generate some runs late in the game. The problem is that these games aren't played on an individual basis and you sort of have to guess whether it'll be a good idea to bring in a defensive sub.
On more that one occasion, I've had defensive subs come into games where my lead has slipped away and the sub is hitting in a pressure situation, e.g, two outs with runners on second and third. In those situations, I'll kick myself for not keeping the better hitter in the lineup, even if he's a defensive liability.
The more I play this game, the more I'm starting to form the opinion that defensive subs usually aren't that good of an idea. Why take a power bat out of the lineup and replace it with a light hitter.
Anyway, those are my thoughts and I'd like to hear what you guys think about this issue.