simvastatin mechanism is independent from cholesterol

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simvastatin mechanism is independent from cholesterol

Post by frodo » Mon Jun 18, 2018 4:33 am

Whatever simvastatin does in MS is independent from its cholesterol function


The analysis of clinical trials is limited to pre-specified outcomes, thereby precluding a mechanistic understanding of the treatment response.

Multivariate mechanistic models can elucidate the causal chain of events by simultaneous analysis of multi-modal data that link intermediate variables to outcomes of interest. A double-blind, randomised, controlled, phase 2 clinical trial in secondary progressive multiple sclerosis (MS-STAT, NCT00647348) demonstrated that simvastatin (80mg/day) over two years reduced the brain atrophy rate and was associated with beneficial effects on cognitive and disability outcomes.

Therefore, this trial offers an opportunity to apply mechanistic models to investigate the hypothesised pathways that link simvastatin to clinical outcome measures, either directly or indirectly via changes in serum total cholesterol levels and to determine which is the more likely. We re-analysed the MS-STAT trial in which 140 patients with secondary progressive multiple sclerosis were randomised (1:1) to receive placebo or simvastatin (80 mg/day). At baseline and after one and two years patients underwent brain magnetic resonance imaging; their cognitive and physical disability were assessed on the block design test and Expanded Disability Status Scale (EDSS). Serum total cholesterol levels were measured at each visit.

We calculated the annual percentage change of brain volume loss using mixed-effects models. With multivariate mechanistic models and Bayesian mediation analyses, a cholesterol-dependent model was compared to a cholesterol-independent model. As described previously, the simvastatin group showed a slower rate of brain atrophy and clinical deterioration (as reflected by both the EDSS and the block design test) and a faster decline in serum cholesterol levels (all p <0.05), when compared with placebo. The cholesterol-independent model, in which simvastatin has a direct effect on the clinical outcome measures and brain atrophy, independent of its impact on lowering the serum cholesterol levels, was the more likely model.

When we deconstructed the total treatment effect on EDSS and block design, into indirect effects, which were mediated by brain atrophy, and direct effects, brain atrophy was responsible for 31% of the total treatment effect on EDSS (beta=-0.037, 95% credible interval [CI]=-0.075, -0.010), and 35% of the total treatment effect on block design (beta=0.33, 95% CI=0.06, 0.72). The effect of simvastatin on both outcomes was independent of serum cholesterol levels (EDSS: beta=-0.139, 95% credible interval=-0.255,-0.025; brain atrophy: beta=0.32, 95% credible interval=0.09,0.54).

The effect of simvastatin on disability and cognitive worsening is partially mediated by brain atrophy but is independent of cholesterol reduction. Our mechanistic approach can be applied to other medications to elucidate the pathways underlying treatment effects in progressive MS.

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