Polypharmacy Intervention Studies in Older Adults: Challenges in Proving Benefits in Hard Clinical Outcomes

Background: Polypharmacy is widespread among older adults and presents significant clinical challenges. Although necessary for managing multimorbidity, inappropriate polypharmacy is linked to adverse drug reactions, drug–drug interactions, cognitive decline, and increased health care utilization. Interventions such as deprescribing and medication reviews aim to mitigate these risks, but their effectiveness in improving clinical outcomes remains uncertain. Areas of Uncertainty: Despite reductions in potentially inappropriate medications, polypharmacy interventions show a limited impact on mortality, hospitalization rates, and quality of life. Variability in intervention intensity, poor implementation strategies, and a lack of integration between pharmacists and prescribers contribute to inconsistent findings. In addition, current deprescribing approaches often fail to account for patient priorities, multimorbidity, and real-world feasibility in primary care settings. Data Sources: This review synthesizes findings from systematic reviews, randomized controlled trials, and meta-analyses evaluating polypharmacy interventions and their clinical impact. Therapeutic Advances: Medication reviews using STOPP/START, Beers Criteria, and Medication Appropriateness Index improve prescribing quality but require a shift toward comprehensive clinical medication reviews. High-intensity interventions involving multidisciplinary teams, including clinical pharmacologists, show promise in reducing hospitalizations and adverse drug reactions. Emerging strategies such as shared decision making, digital deprescribing tools, and artificial intelligence–driven clinical decision support systems may enhance polypharmacy management. Conclusions: To improve clinical outcomes, future polypharmacy interventions must emphasize structured implementation, real-world adaptability, and patient-centered approaches. Integrating clinical pharmacologists, strengthening pharmacist–prescriber collaboration, and leveraging technology will be essential for optimizing medication use in older adults.