Synonyms: Zocor®, Lipex®, Lipovas®, Denan®
Therapy Type: Small Molecule (timeline)
Target Type: Cholesterol
Condition(s): Alzheimer's Disease, Mild Cognitive Impairment
U.S. FDA Status: Alzheimer's Disease (Inactive), Mild Cognitive Impairment (Phase 4)
Approved for: Hypercholesterolemia and diabetic cardiomyopathy.
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).
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 Aβ40 or 42 levels, but it did report a correlated reduction of CSF 24S-hydroxycholesterol and Aβ40 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., 2003; Hoglund 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., 2011; news 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 Aβ precursorprotein (sAβPP), 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 Aβ 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.
- Statins Reduce Brain Cholesterol Metabolite
- Scientists See Hope on Horizon Despite Clinical Disappointments
Book page Citations
- Simons M, Schwärzler F, Lütjohann D, von Bergmann K, Beyreuther K, Dichgans J, Wormstall H, Hartmann T, Schulz JB. 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.
- Locatelli S, Lütjohann D, Schmidt HH, Otto C, Beisiegel U, von Bergmann K. 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.
- Sjögren M, Gustafsson K, Syversen S, Olsson A, Edman A, Davidsson P, Wallin A, Blennow K. 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.
- Hoglund K, Thelen KM, Syversen S, Sjogren M, von Bergmann K, Wallin A, Vanmechelen E, Vanderstichele H, Lutjohann D, Blennow K. 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.
- Sano M, Bell KL, Galasko D, Galvin JE, Thomas RG, van Dyck CH, Aisen PS. A randomized, double-blind, placebo-controlled trial of simvastatin to treat Alzheimer disease. Neurology. 2011 Aug 9;77(6):556-63. PubMed.
- Serrano-Pozo A, Vega GL, Lütjohann D, Locascio JJ, Tennis MK, Deng A, Atri A, Hyman BT, Irizarry MC, Growdon JH. Effects of simvastatin on cholesterol metabolism and Alzheimer disease biomarkers. Alzheimer Dis Assoc Disord. 2010 Jul-Sep;24(3):220-6. PubMed.
- Riekse RG, Li G, Petrie EC, Leverenz JB, Vavrek D, Vuletic S, Albers JJ, Montine TJ, Lee VM, Lee M, Seubert P, Galasko D, Schellenberg GD, Hazzard WR, Peskind ER. Effect of statins on Alzheimer's disease biomarkers in cerebrospinal fluid. J Alzheimers Dis. 2006 Dec;10(4):399-406. PubMed.
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- What Role Brain Statins—Sparing Isoprenoids from the Rac?
- Statins—New Data Suggest Benefits for AD/PD
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- A Better GRIP on the Aβ-Lipid Connection
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