Deprescribing to Reduce Harm From Polypharmacy in Chronic Disease: What Works, for Whom, and at What Cost

Background: Polypharmacy is common in chronic disease and can increase adverse drug events, prescribing cascades, and regimen complexity. Deprescribing is the planned, supervised reduction or discontinuation of medicines where harms outweigh benefits in a patient’s current context. This review compares deprescribing strategies, focusing on what works, for whom, and at what cost. Methods: A focused evidence synthesis was conducted using PubMed and targeted cross-checking (January 1, 2000 to January 31, 2026). Priority was given to systematic reviews/meta-analyses and pragmatic randomised or cluster randomised trials evaluating deprescribing or structured medication review with deprescribing intent in chronic disease and polypharmacy contexts. Results: Deprescribing interventions consistently improve prescribing outcomes and reduce exposure to high-risk medicines. Patient-activated education can produce substantial discontinuation for targeted drug classes, exemplified by EMPOWER (27% discontinuation versus 5% at 6 months). Pharmacist-led interventions reduce inappropriate medication exposure and can support simplification. Disease-specific medication reduction can maintain short-term disease control in carefully selected patients, exemplified by OPTIMISE where systolic blood pressure control remained noninferior at 12 weeks after antihypertensive reduction. Effects on admissions and mortality vary and appear more likely when interventions target high-risk patients and high-harm medicines. Conclusions: Deprescribing reliably improves prescribing quality and can meaningfully reduce exposure to high-risk medicines, particularly through patient activation and pharmacist-integrated workflows. Clinical endpoint benefits depend on targeting, implementation fidelity, and monitoring capacity.