Kompany and Fernandinho benched amid Manchester derby ban threat
Jose Mourinho will already be without Paul Pogba for the eagerly anticipated clash after United's influential midfielder was sent off during the second half of Saturday's thrilling 3-1 win over Arsenal.
Guardiola has moved to ensure club captain Kompany and Fernandinho are not similarly sidelined, although winger Leroy Sane starts despite having also picked up four yellow cards this season.
Brazil international Fernandinho had been an ever-present at the base of City's midfield during their storming unbeaten start to the Premier League campaign of 13 wins from 14 matches, scoring twice.
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Kompany has once again suffered from calf problems, meaning his four cautions have been accrued over a mere six league starts.
But with England international John Stones laid low by a hamstring injury, Eliaquim Mangala has been brought in to partner Nicolas Otamendi at the heart of the City defence and keep Kompany's power dry.
Fabian Delph, who has featured predominantly at left-back under Guardiola this season, is set to revert to his favoured midfield role in place of Fernandinho, with the latter's compatriot Danilo coming into the back four.
Victory for City would restore their eight-point advantage over second-placed United at the summit and Guardiola will have further chance to take key players out of the firing line in Wednesday's Champions League dead rubber against Shakhtar Donetsk.
Long-serving former City defender Pablo Zabaleta returns to the Etihad Stadium for the first time as West Ham captain, although on-loan Joe Hart is ineligible to face his parent club.
.@pablo_zabaleta captains the team for the first time! ⓒ#COYI pic.twitter.com/smlUVpSEZc
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Adrian comes in between the posts as David Moyes named a pragmatic line-up, dropping Marko Arnautovic and Andre Ayew to the bench.