Frank Ockenfels/Walt Disney Television via Getty Images
Izzie Stevens got cancer, married Alex, survived the cancer, and then sorta just disappeared in season six. She eventually returned for a second and admitted she didn't feel like Seattle was her home anymore. Later, Alex got sent divorce papers, and now we know Izzie secretly had Alex's twins, lives on a ranch in Kansas, and became a surgical oncologist.
Katherine Heigl's exit basically began in 2008 when she withdrew her name from Emmy consideration because she didn't feel like the material deserved it. In 2010, the character disappeared completely. She said in the years since that she would like to return to the character, but Shonda Rhimes did not. "I'm done with that story," she told TVLine in 2015.
Heigl, then a burgeoning romcom star, went on to star in a few more romcoms before returning to TV with State of Affairs, then Doubt, and more recently, she joined Suits and the 2020 series Firefly Lane.