Lower risk of dementia with Lewy bodies among users of glycolysis enhancing drugs in a new user, active comparator design

Background Terazosin, doxazosin, and alfuzosin (Tz/Dz/Az) are α-1 adrenergic receptor antagonists that also bind to and activate a key ATP-producing enzyme in glycolysis. Recent work has suggested a potentially neuroprotective effect of use of Tz/Dz/Az in Parkinson’s disease in both animal and human studies. We investigated neuroprotective effects of Tz/Dz/Az in a closely related disease, dementia with Lewy bodies (DLB ) . Methods We used a new user active comparator design in the merative Marketscan database to identify men with no history of DLB who were newly started on Tz/Dz/Az or two comparator medications. Our comparator medications were other drugs commonly used to treat benign prostatic hyperplasia that do not increase ATP: the α-1 adrenergic receptor antagonist tamsulosin or 5α-reductase inhibitors (5ARI). We matched the cohorts on propensity scores and duration of follow-up. We followed the matched cohorts forward to estimate the hazard of developing DLB. Results Men who were newly started on Tz/Dz/Az had lower hazard of developing DLB then matched men taking tamsulosin (HR=0.60, p<0.001) or 5ARI (HR=0.73, p=0.012) while the hazard in men taking tamsulosin was similar to that of men taking 5ARI (HR=1.17, p=0.12). These results were robust to several sensitivity analyses. Conclusions These data demonstrate that Tz/Dz/Az in decreases the risk of DLB. When combined with the literature of Tz/Dz/Az on PD, our findings suggest that glycolysis-enhancing drugs may be broadly protective in neurodegenerative synucleinopathies. These observational associations must be further evaluated for causality in future randomized trials.