The program itself isn’t really bigger, what makes the difference is that it won’t use the dependencies installed by your native package manager, it will download them, it also will download various runtimes if needed for the program, these runtimes are not really supposed to be ran if you compile the package yourself for your distribution, but if you use Flatpak, it is going to run all these runtimes for the program to work, these runtimes will use more RAM than the native build, if the runtime is not optimised, then it will also contribute to higher use of CPU and everything else in general.
It will differ from program to program, but I’ll let you know that I have natively compiled EasyEffects (real-time audio manipulation) and also have tried the Flatpak build. The native version hardly uses more than 5% CPU, and is also lightweight in terms of RAM. But the Flatpak build took significantly more RAM usage and my CPU went 80% whenever I played music with the same preset that I tested on the native build. Flatpak also had to download 700-900 MB worth of internet (no idea how much space it took after installation) for the program to run.