Victor, is there any reason PyType_GetFlags() can't be converted to a macro or an inlined function?  That seems like a simple and robust fix that won't get in the way of anything else you're doing.

We shouldn't disregard macOS timings. It is an important platform —dominant in data science, dominant among most of my clients, and dominant among the core developers at the last sprint.

None of the inlining should depend on LTO and PGO.  That is fragile and will create hard-to-explain variations between builds (even consecutive builds on the same platform).  Third-party extensions, SO and DLL files won't benefit from that.  Also, it makes it difficult to individually optimize and analyze a function without a costly rebuild at every step.