T'is unfortunate that almost every function that does anything useful needs to call at least one perl API

Indeed ... though it's also often the case that many functions that call the Perl API don't really need to.
Here's a simplistic example:

use strict;
use warnings;

use Inline C => Config =>
  PRE_HEAD => '#define PERL_NO_GET_CONTEXT 1',
;

use Inline C => <<'EOC';
/*
SV * foo(int x) {
   return newSViv(x);
}
*/

int foo(int x) {
   return x;
}

EOC

my $x = foo(-1234);https://perlconference.us/tpc-2018-slc/
print $x;
[download]

Both renditions of foo() do essentially the same thing.
But the rendition that has been commented out won't work when PERL_NO_GET_CONTEXT is defined, whereas the other rendition will.

So there are possibilities even with the current Inline::C, depending upon how much time and energy you're prepared to devote in order to avoid the Perl API.
But mostly, it's not worth the effort.
(Of course, ideally you wouldn't even have to concern yourself with such matters when using Inline::C - and Ingy has indicated (in the link I provided earlier) that this might all be fixed in Inline::C following the Perl Conference that begins in the next day or so.
In the meantime, if you want to define PERL_NO_GET_CONTEXT, then I think you're generally going to have to create an XS module.

Cheers,
Rob