Several Preexisting Therapies Associated With Reduced Mortality Risk in Parkinson Disease, Study Shows

In a newly published nationwide observational Norwegian cohort study, researchers identified several preexisting prescription therapies associated with reduced mortality risk over an 8-year period in patients with Parkinson disease (PD). Published in Neurology, findings from this study suggests that these existing medications have promising disease-modifying properties and could be repurposed as candidates for PD in future clinical trials.¹

Among 14,289 individuals with PD (mean age at diagnosis, 72 years; men, 59%), researchers performed a high-throughput screening of medications initiated following PD diagnosis and predicted an 8-year risk of death for 219 drugs using an emulated target trial design. In the study, authors reported 23 drugs that were statistically significantly associated with a lower absolute risk of death. All of the therapies with the exception of 1, mometasone, remained associated with reduced mortality in sensitivity analyses. Investigators also noted that many of the pinpointed drugs regulate and modulate biological pathways relevant to PD.

“In this nationwide screening study emulating [randomized controlled trial] design principles, we identified several drugs that were associated with reduced risk of death among individuals with PD. Among the identified drugs were macrolides, opioids, and melatonin, all of which have been demonstrated to influence mitochondrial quality-control mechanisms, which are central to the suggested pathologic origins of PD, but also to aging in general,” lead author Julia A. Tuominen, MS, researcher in the Department of Global Public Health and Primary Care at the University of Bergen in Norway, and colleagues wrote.¹

Using data from 3 Norwegian health registries,² the analysis included patients who met the study’s prescription-based classification criteria for PD, were older than 25 years at the time of diagnosis, and were not prescribed the target drug in the last 2 years. Researchers emulated a target trial for any drug filled by a minimum of 100 individuals at any pharmacy in Norway and used mortality as an outcome to indicate disease progression. Investigators estimated the effect of drug initiation on the 8-year risk of death, comparing initiators of the target drug with initiators of drugs in the same Anatomical Therapeutic Chemical classification system level 1 group. Additionally, authors used inverse probability of treatment weighting to adjust for potential confounders.

All told, the identified drugs included ranitidine (a histamine-2 blocker); pantoprazole and esomeprazole (proton pump inhibitors); losartan (an angiotensin receptor blocker); atorvastatin (for high cholesterol); and tadalafil (for erectile dysfunction). Other drugs identified were levothyroxine sodium (a thyroid hormone); several antibiotics such as phenoxymethylpenicillin, erythromycin, and azithromycin; 4 nonsteroidal anti-inflammatory drugs (NSAIDs); and opioid analgesics including combined codeine/paracetamol and tramadol. Additional agents included sleep aids like zopiclone and melatonin; mianserin (an antidepressant); mometasone (a nasal corticosteroid); 2 opium-derived cough medicines; and dexamethasone (an ophthalmologic corticosteroid).

The current study had several limitations, including the lack of clinical progression data and cause of death, which led researchers to rely on all-cause mortality as a proxy for disease progression. This approach may reflect general mortality effects rather than PD-specific outcomes. Overlaps between aging and PD-related processes, limitations in registry data, and the absence of diagnostic and treatment adherence details could have introduced confounding results. Additionally, the use of some identified drugs for nonmotor symptoms and variations in symptom profiles across PD subtypes may have contributed to indirect associations with mortality.

“Several of the identified drugs have previously been suggested to modify the course of PD, such as losartan and NSAIDs, or are linked to neuroprotective and immunomodulatory effects in general,” Tuominen et al noted. “We also identified multiple novel candidates with potential for drug repurposing as disease-modifying therapeutic in PD, including tadalafil, mianserin, macrolides, and opioid derivatives. Although these preliminary findings are insufficient to justify immediate clinical use, they warrant further investigation and potential consideration for future clinical trials.”