Cholesterol Med Fails to Slow Disease Progression
Results of Phase 2 trial of simvastatin likely dash hopes for Phase 3 study
Treatment with simvastatin, a medication used to lower cholesterol levels, did not slow the progression of Parkinson’s disease  over a two-year period, according to published data from a Phase 2 trial.
Overall, the data provide “no evidence to support proceeding to a phase 3 trial,” the researchers wrote, noting that several questions about the potential relationship between this type of treatment and Parkinson’s remain unanswered.
The study, “Evaluation of Simvastatin as a Disease-Modifying Treatment for Patients With Parkinson’s Disease: A Randomized Clinical Trial,” was published in JAMA Neurology.Â
Statins are a class of medications widely used to treat people with high cholesterol. Epidemiological studies have suggested that the use of these medications reduces the incidence of Parkinson’s disease.
Moreover, preclinical studies have demonstrated that statins can modify signaling pathways implicated in the neurodegenerative disease, together suggesting these medications may be able to slow Parkinson’s progression.
One medication in particular — simvastatin — was thought to offer particular potential for Parkinson’s. Simvastatin is one of the most brain-penetrant statin medications, meaning that it more easily passes through the selective blood-brain barrier and into the brain where it can take effect.
The PD STAT Phase 2 trial (NCT02787590) aimed to investigate simvastatin’s ability to slow disease progression among Parkinson’s patients, ages 40–90, who were recruited at study sites in the United Kingdom.
A total of 235 patients were enrolled in the trial and assigned randomly to receive either a placebo or simvastatin — given at a dose of 40 mg for one month followed by 80 mg thereafter — once daily for 24 months (about two years). A final follow-up visit also was conducted at month 26.
Overall, 216 patients completed the first month of treatment and entered the high-dose phase, 178 of whom completed all 24 months of treatment.
Patients had not used statin medications previously for any reason, but were using standard dopaminergic Parkinson’s medications.
Most patients were white (99%) and male (59%), with a mean age of about 65. Patients, on average, were living with moderate disease severity, reflected by the Hoehn and Yahr (assessment tool) stage of 3 or less when using medication.
Clinical assessments were performed at months one, six, 12, 24, and 26. At the 12, 24, and 26 month visits, patients were asked not to take their standard dopaminergic medications in order to best ascertain the effects of simvastatin in an “off-medication” state.
The main study goal
The study’s main goal was to assess changes in motor function from the study’s start (baseline) after two years of treatment. This was measured with the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS) part III.
As previously reported, simvastatin was deemed “futile” at easing motor symptoms in the off-medication state, which essentially means the treatment did not significantly differ from the placebo at slowing motor progression.
While simvastatin-treated patients demonstrated a non-significant worsening of MDS-UPDRS part III scores compared with the placebo group, the team noted a “lower-than-expected progression rate in the placebo-allocated group.”
Alternatively, it has been suggested that lower cholesterol levels may be linked to Parkinson’s progression, which could have affected the study’s findings. As expected, a reduction in cholesterol levels was observed with simvastatin treatment.
Other measures, including motor and non-motor symptoms, cognition, and quality of life also were not different between the two groups.
Overall, the frequency and severity of adverse events did not differ between the two groups.
Side effect: Muscle pain
A total of 321 adverse events among 72 participants occurred that were considered related to simvastatin treatment. Most were known side effects of the medication and increased as the dose increased, with the most common being muscle pain.
“In this study, we have robustly demonstrated futility of simvastatin for slowing motor progression in patients with moderate severity [Parkinson’s disease],” the researchers wrote.
They noted, however, that the potential influences of ongoing use of dopaminergic medications, or the fact that patients were at a moderate and not an early stage of disease, cannot be ruled out.
A better understanding of these and other influential factors will be needed to “inform whether, when, and in whom statins merit further investigation as disease-modifying therapy in [Parkinson’s],” the team concluded.
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