Sex differences by design and outcome in the Safety of Urate Elevation in PD (SURE-PD) trial

Abstract

Objective: To investigate whether women and men with Parkinson disease (PD) differ in their biochemical and clinical responses to long-term treatment with inosine.

Methods: The Safety of Urate Elevation in Parkinson's Disease (SURE-PD) trial enrolled 75 people with early PD and baseline serum urate below 6 mg/dL and randomized them to 3 double-blinded treatment arms: oral placebo or inosine titrated to produce mild (6.1-7.0 mg/dL) or moderate (7.1-8.0 mg/dL) serum urate elevation for up to 2 years. Parkinsonism, serum urate, and plasma antioxidant capacity were measured at baseline and repeatedly on treatment; CSF urate was assessed once, at 3 months. Here in secondary analyses results are stratified by sex.

Results: Inosine produced an absolute increase in average serum urate from baseline that was 50% greater in women (3.0 mg/dL) than in men (2.0 mg/dL), consistent with expected lower baseline levels in women. Similarly, only among women was CSF urate significantly greater on mild or moderate inosine (+87% [p < 0.001] and +98% [p < 0.001], respectively) than on placebo (in contrast to men: +10% [p = 0.6] and +14% [p = 0.4], respectively). Women in the higher inosine dosing group showed a 7.0 Unified Parkinson's Disease Rating Scale (UPDRS) points/year lower rate of decline vs placebo (p = 0.01). In women, slower rates of UPDRS change were associated with greater increases in serum urate (r = -0.52; p = 0.001), and with greater increases in plasma antioxidant capacity (r = -0.44; p = 0.006). No significant associations were observed in men.

Conclusions: Inosine produced greater increases in serum and CSF urate in women compared to men in the SURE-PD trial, consistent with the study's design and with preliminary evidence for slower clinical decline in early PD among women treated with urate-elevating doses of inosine.

Clinicaltrialsgov identifier: NCT00833690.

Classification of evidence: This study provides Class II evidence that inosine produced greater urate elevation in women than men and may slow PD progression in women.

Figure 1. Greater effects of inosine on serum and CSF urate in women than men

(A) Serum urate was measured prior to treatment randomization (baseline), after steady-state dosing of inosine was achieved (2 months visit), and on the last visit on study drug (∼18 months), and values are presented for each of the 3 treatment arms (placebo, and inosine [Ino] dosed to produce a mild or moderate [mod] elevation in serum urate in women and men) (upper panel). Values plotted are point estimates and standard errors from the shared-baseline, repeated-measures, mixed model analysis of variance (ANOVA). (B) CSF urate was measured only once, at the 3-month visit, and is shown for each treatment group, stratified for women and men (upper panel). Values plotted are point estimates and standard errors from the two-way ANOVA.

Figure 2. Rates of long-term change in total Unified Parkinson’s Disease Rating Scale (UPDRS) (parts I–III) scores by treatment group

(A) Women. (B) Men. Values plotted are from the shared-baseline, random-slopes mixed model (**p = 0.01; ns = nonsignificant compared to placebo). Ino = inosine.

Figure 3. Individual profiles of total Unified Parkinson’s Disease Rating Scale (UPDRS) (parts I–III) scores

Individual profiles of total UPDRS (parts I–III) scores over months to years, and before (filled symbols) and after (unfilled symbols) need for dopaminergic therapy was determined for each participant randomized to (A) placebo, or to Inosine titrated to a (B) mildly (mild) or (C) moderately (mod) elevated serum urate range, and stratified by sex. Estimated rate (indicated by a dashed line in each profile) of UPDRS total score change prior to initiation of dopaminergic treatment were based on the shared-baseline, random-slopes mixed model. Total UPDRS scores following determination of need for levodopa or other antiparkinsonian medication (indicated by unfilled Post-Rx symbols) often were lower (better) than what was projected (dashed line) rate of change based on total UPDRS scores prior to the determination, consistent with symptomatic benefit in some patients.

Figure 4. Kaplan-Meier plot of time to need for dopaminergic therapy

(A) Women. (B) Men.

Figure 5. Relationships between change in serum urate and estimated rate of clinical decline

(A) Women. (B) Men. For each participant, the increase in serum urate from baseline to the average of on-treatment values was plotted against the individual's annualized change in total UPDRS score estimated from the random-slopes model shown in figure 2. The placebo group data (circles) appear on the left of each plot given the expected lack of any urate change. Although a clustering of men in the placebo group showed no decline during the trial (filled circles in lower left), contributing to an overall trend toward worsening with increasing urate among men, the trend was not significant. UPDRS = Unified Parkinson’s Disease Rating Scale.

Figure 6. Relationships between change in plasma total antioxidant capacity and rate of clinical decline

(A) Women. (B) Men. For each participant, the increase in plasma ferric reducing antioxidant power (FRAP) from baseline to the average of on-treatment (6 months and ∼18 months visit) values was plotted against the individual's annualized change in total UPDRS score using the conservative mixed model slope estimate shown in figure 2. The placebo group data (circles) appear on the left of each plot given the lack of FRAP change as expected in this group. Although a clustering of men in the placebo group showed no clinical decline during the trial (filled circles in lower left), contributing to an overall trend toward worsening with increasing FRAP (like urate) among men, the trend was not significant. UPDRS = Unified Parkinson’s Disease Rating Scale.