Therapeutics

Simvastatin

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Overview

Name: Simvastatin
Synonyms: Zocor®, Lipex®, Lipovas®, Denan®
Therapy Type: Small Molecule
Target Type: Cholesterol
Condition(s): Alzheimer's Disease, Mild Cognitive Impairment
U.S. FDA Status: Alzheimer's Disease (Inactive), Mild Cognitive Impairment (Phase 4)
Company: Merck
Approved for: Hypercholesterolemia and diabetic cardiomyopathy.

Background

Simvastatin is an oral HMG-CoA reductase inhibitor prescribed extensively throughout the world for the treatment of hypercholesterolemia and diabetic cardiomyopathy. Simvastatin was developed by Merck, Sharp & Dohme. Since its FDA approval in 1991, it has come to be marketed by a variety of companies under different brand names in different  countries. The drug's indication calls for it to be used along with dietary changes to reduce elevated levels of total or LDL cholesterol and triglycerides.

Elevated LDL cholesterol and low HDL cholesterol both are risk factors for heart disease. Simvastatin is a methylated form of lovastatin. In vivo, it is hydrolyzed to generate a metabolite that competes with the substrate HMG-CoA for the liver enzyme HMG-CoA reductase; this interference with the enzyme's activity reduces the level of the cholesterol precursor mevalonic acid.

Simvastatin reduces mortality and the risk of nonfatal heart attacks in people with hypercholesterolemia. Its side effects include a risk for muscle injury, and its label and dosing regimen has been updated accordingly. In the United Kingdom, simvastatin is available over the counter; in some countries generic forms are sold. Simvastatin is widely used in a secondary prevention mode in routine medical care, where  screening for elevated risk of cardiovascular disease with a cholesterol blood test in midlife can trigger prescription of statin therapy. Along with other statins, the clinical success and development path of simvastatin has served as a conceptual model for developing anti-amyloid drugs as a secondary prevention tool to treat preclinical Alzheimer's disease (see eFAD essay).

Simvastatin, which crosses the blood-brain barrier, has been tested for the treatment of symptomatic and preclinical Alzheimer's disease. The rationale grew out of epidemiological research that suggested significant overlap between cardiovascular and Alzheimer's diseases. For example, long-term statin treatment to lower cholesterol was shown to confer some protection against incident Alzheimer's and AD neuropathology at death. A large body of literature on cell biology and animal studies suggests that statin treatment affects APP processing, lowers levels of the Aβ peptide, and might have neuroprotective effects. Small clinical trials generated signals of a possible benefit that did not hold up in larger treatment trials; trials targeting earlier stages of the disease are still ongoing (see below).

Findings

Widespread clinical interest in statins for the treatment of Alzheimer's began around 2002, when a clinical trial in Germany reported a signal that simvastatin treatment was able to lower both cholesterol and Aβ levels in the CSF of Alzheimer's disease patients. This six-month study was negative on the overall outcome of CSF 40 or 42 levels, but it did report a correlated reduction of CSF 24S-hydroxycholesterol and 40 as seen in post-hoc analysis of the more mildly affected subgroup. The same year, an open-label study of six months of simvastatin treatment in 18 AD patients at a memory clinic in Germany reported reductions detected in the blood of brain-derived 24S-hydroxycholesterol as being an indicator that simvastatin affected cholesterol production in the brain of AD patients. (See Simons et al., 2002; Locatelli et al., 2002; news story.)

In 2003, an open-label biochemical study of 19 people with Alzheimer's disease conducted in Sweden reported changes in CSF metabolites of APP processing and a signal for cognitive improvement in response to three months of simvastatin treatment. However, subsequent results based on 12 months of treatment in the same patients showed that while brain cholesterol metabolism indeed changed, there was no clear change in CSF or plasma levels of Aβ42. Analysis of APP isoforms suggested that simvastatin treatment may favor the nonamyloidogenic pathway of APP processing, but the clinical relevance of this finding was unclear. (See Sjogren et al., 2003Hoglund et al., 2005.)

These early signals did not translate into a clinical benefit in the multicenter CLASP trial of 406 patients with mild to moderate AD conducted in North America by the Alzheimer's Diseases Cooperative Study between 2003 and 2007. CLASP evaluated the safety and efficacy of an 18-month course of simvastatin to slow the progression of AD as measured by the ADAS-Cog and global clinical change as measured by the ADCS-CGIC. In this trial, simvastatin safely lowered lipid levels but did not stem progressive decline in cognition or function (see Sano et al., 2011news story). CLASP came to be seen as definitive evidence that simvastatin does not benefit symptomatic Alzheimer's disease.

Other studies continue to investigate simvastatin for its effects at earlier stages of the disease, i.e., amnestic mild cognitive impairment/prodromal Alzheimer's disease, and in cognitively normal people at elevated risk of developing AD.

An open-label study of three months of simvastatin treatment in 12 patients with AD or amnestic mild cognitive impairment and hypercholesterolemia reduced cholesterol synthesis in the brain but had no effect on CSF biomarkers of AD (Serrano-Pozo et al., 2010).

Between 2002 and 2005, a 14-week Phase 4 trial in 35 cognitively normal people with elevated blood cholesterol compared simvastatin and pravastatin—a different statin that does not enter the brain—for their ability to alter CSF levels of AD and inflammatory markers. This study reported that simvastatin, but not pravastatin, reduced CSF levels of phospho-tau-181 but had no effect on total tau, Aβ42, Aβ40, soluble  precursorprotein  (sPP), or F2-isoprostanes (Riekse et al., 2006). This study was conducted at the University of Washington in Seattle, which is currently recruiting for a follow-up study that started in 2010 and is set to run until 2015. This second trial is evaluating how one year of simvastatin treatment in 120 cognitively normal, middle-aged adults affects CSF levels of Aβ42, t-tau, p-tau181, inflammatory markers, and neuroprotection as measured via CSF levels of the growth factor BDNF.

The University of Wisconsin, Madison, is evaluating simvastatin in cognitively normal people who are at elevated risk because they have a parent with AD.  Between 2005 and 2009, the ESPRIT study compared simvastatin to placebo for changes in CSF levels of Aβ, as well as markers of cholesterol metabolism and inflammation. This study included an MRI substudy to assess cerebral perfusion, as well as cognitive testing. These investigators found no specific effect of simvastatin on CSF  or tau levels, but did report a benefit on aspects of cognitive function (Carlsson et al., 2008). In 2009, this site began SHARP, a follow-up study attempting to evaluate a longer course of simvastatin on similar outcome measures, but this trial, NCT00939822, appears to have been halted.

A larger study began in 2009 and is set to run through 2019. At 17 centers throughout Germany, the SIMaMCI study will randomize 445 people with both self-reported and measurable memory impairment but preserved function to a two-year course of either 60 mg of simvastatin or placebo once daily . This study measures the time until participants "convert" to dementia, with conversion being defined as an increase of the Clinical Dementia Rating (CDR) score past 0.5. The trial also measures change in the ADAS-Cog battery and in the Free and Cued Selective Reminding Test (FCSRT), a memory test frequently used at the prodromal stage of AD.

For all clinical trials of simvastatin in AD, see clinicaltrials.gov.

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References

News Citations

  1. Statins Reduce Brain Cholesterol Metabolite
  2. Scientists See Hope on Horizon Despite Clinical Disappointments

Book page Citations

  1. Prevention With Statins: Can the Brain Learn From the Heart?

Paper Citations

  1. . Treatment with simvastatin in normocholesterolemic patients with Alzheimer's disease: A 26-week randomized, placebo-controlled, double-blind trial. Ann Neurol. 2002 Sep;52(3):346-50. PubMed.
  2. . Reduction of plasma 24S-hydroxycholesterol (cerebrosterol) levels using high-dosage simvastatin in patients with hypercholesterolemia: evidence that simvastatin affects cholesterol metabolism in the human brain. Arch Neurol. 2002 Feb;59(2):213-6. PubMed.
  3. . Treatment with simvastatin in patients with Alzheimer's disease lowers both alpha- and beta-cleaved amyloid precursor protein. Dement Geriatr Cogn Disord. 2003;16(1):25-30. PubMed.
  4. . The effect of simvastatin treatment on the amyloid precursor protein and brain cholesterol metabolism in patients with Alzheimer's disease. Dement Geriatr Cogn Disord. 2005;19(5-6):256-65. PubMed.
  5. . A randomized, double-blind, placebo-controlled trial of simvastatin to treat Alzheimer disease. Neurology. 2011 Aug 9;77(6):556-63. PubMed.
  6. . Effects of simvastatin on cholesterol metabolism and Alzheimer disease biomarkers. Alzheimer Dis Assoc Disord. 2010 Jul-Sep;24(3):220-6. PubMed.
  7. . Effect of statins on Alzheimer's disease biomarkers in cerebrospinal fluid. J Alzheimers Dis. 2006 Dec;10(4):399-406. PubMed.
  8. . Effects of simvastatin on cerebrospinal fluid biomarkers and cognition in middle-aged adults at risk for Alzheimer's disease. J Alzheimers Dis. 2008 Mar;13(2):187-97. PubMed.

External Citations

  1. NCT00939822
  2. clinicaltrials.gov

Further Reading

News

  1. Philadelphia: All Is Not Well with the Statin Story
  2. Trial Troika—Immunotherapy Interrupted, Lipitor Lags, Dimebon Delivers
  3. What Role Brain Statins—Sparing Isoprenoids from the Rac?
  4. Statins—New Data Suggest Benefits for AD/PD
  5. Some Ministrokes Increase Risk of Dementia; Statins Leave Amyloid Untouched
  6. A Better GRIP on the Aβ-Lipid Connection

Papers

  1. . Long-term use of statins reduces the risk of hospitalization for dementia. Atherosclerosis. 2013 Oct;230(2):171-6. PubMed.
  2. . Statins to treat Alzheimer's disease: an incomplete story. Expert Rev Neurother. 2012 Jan;12(1):27-30. PubMed.
  3. . Efficient four-drug cocktail therapy targeting amyloid-β peptide for Alzheimer's disease. J Neurosci Res. 2010 Dec;88(16):3588-97. PubMed.
  4. . Statin therapy is associated with reduced neuropathologic changes of Alzheimer disease. Neurology. 2007 Aug 28;69(9) PubMed.
  5. . Statins, incident Alzheimer disease, change in cognitive function, and neuropathology. Neurology. 2008 May 6;70(19 Pt 2):1795-802. PubMed.