Metabolic syndrome identifies a high-risk polypharmacy phenotype in older adults with syncope.

Syncope and polypharmacy are prevalent in older adults and negatively affect quality of life. This study compares the impact of medication regimen complexity, the total number of medications per day as a measure of polypharmacy, and orthostatic hypotension (OH)-inducing drug burden in older adults with syncope. It also sought to determine a polypharmacy threshold warranting medication review and to identify a distinct polypharmacy phenotype among older adults with syncope and metabolic syndrome (MetS). This study included 104 patients presenting with syncope, stratified by age. Therapeutic complexity was measured using the Medication Regimen Complexity Index (MRCI), total number of medications per day, and an OH risk score (OHscore-SGLT2i). Older adults had significantly higher MRCI, total number of medications per day, and OHscore-SGLT2i than younger adults (p < 0.001), with the youngest-old and middle-old subgroups showing the highest therapeutic complexity (p < 0.05). Regression models adjusted for the comorbidity burden confirmed these findings. ROC analysis identified the total number of medications per day as the best discriminator (AUC = 0.841), with an optimal threshold of 3.5 medications. Notably, 85.7% of older adults with syncope and MetS exceeded this threshold (p < 0.001) and were significantly more likely to experience clinically significant polypharmacy with adverse outcomes (OR 18.9). Polypharmacy is the primary driver of therapeutic complexity in older adults with syncope. A threshold of four or more medications per day may prompt polypharmacy review, particularly in older adults with MetS, who may benefit most from targeted deprescribing.