There are loads of ways, but they fit a few categories.
(Heck, here's a similar list on Wikipedia)
Most of these stand out only if the writer is consistent enough that the change is unexpected as part of the previous pattern.
Color: when colors contrast, the eye catches a difference. Red is especially good for standing out.
(e.g. Rubrication & Gilding)
You waste your gold and your time if you gild every letter on the page unless that entire page happens to be worth calling out from the rest of the book. (Pictures of some manuscripts)
Weight: I don't know what methods you've attempted, but it's not that tricky to increase line weight if you aren't already pushing the limits of legibility for your letter size.
You can also go down in weight for emphasis, too, if you do find your line weight too high to increase it.
There have multiple nibs for writing for centuries at least, and carving a quill allows one to make these adjustments to taste.
Scale: You want something to pop, it's hard to beat simply making it bigger. Drop caps are one example, but so are using capital letters at all. Again, disruption catches the eye, so dropping size stands out, too.
Different letterforms: (Capitals are actually a combination of this and scale.) If your hand changes enough, it can stand out. That's the principle behind using italics, which has an old pedigree. If your writing in italics, you can switch to a block script for emphasis.
(Discussion of "fonts" in manuscripts)
Symbols and graphics: Underlining is a special case of adding small graphical signifiers around the letters you want to call out. Other examples are diacritics, asterisks, and daggers. Dashes, parentheses, periods, and every other punctuation mark, too. Line or dot leaders for lists helps to distinguish parts. Inline art of other sorts is used, too, such as borders or section divisions using rules or marks.
Flow and layout: the last general case is simply placing the text somewhere other than expected. Sidebars or headings sitting off on their own are examples of this. Drop caps & paragraphs called out by margins and spaces are some more.
Simply adding extra space around things you wish to emphasize (say, the end of a sentence) is a pretty gentle approach to emphasize it.
You might recall that very old manuscripts often lack any punctuation and whitespace. Standards for such were added over time as precisely this sort of graphical embellishment: ways to call out important spots in the text, like where a reader should pause for a period (period) or when they should stop the thought. (comma)
(I'm not sure how we reversed comma and period, but we did)
Rules for punctuation are simply elevation of what worked to a widely accepted standard. It's true that a lot of our formal rules came from typesettters, but many came from their copyist predecessors.
(Most of this is pretty common knowledge, I think, but I intend to come back and insert some references for the less obvious stuff.)