Therapeutics

Atorvastatin

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Overview

Name: Atorvastatin
Synonyms: Lipitor™ , Zarator®, Sortis®, Tahor®
Chemical Name: (3R,5R)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid
Therapy Type: Small Molecule
Target Type: Cholesterol
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Inactive)
Company: Pfizer
Approved for: Hypercholesterolaemia

Background

Atorvastatin is an oral statin drug that was developed by Pfizer’s predecessor, Parke-Davis. It is marketed under different names for hypercholesterolemia worldwide, including the United States, European Union, and Japan. The original tablets and a chewable formulation are approved for children with familial hypercholesterolemia in the European Union. Generic equvalents have been available in a growing number of countries since 2010.

Statin drugs such as atorvastatin and simvastatin lower peripheral cholesterol production to prevent heart attacks and other expressions of cardiovascular disease. Atorvastatin inhibits hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, a liver enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis. Statins are pleiotropic drugs. Besides lowing cholesterol synthesis, they can also alter the production of isoprenoids (Ostrowski et al., 2007), and the expression of genes related to cell growth, signaling, trafficking, and apoptosis (Johnson-Anuna et al., 2005), for example.

Atorvastatin became of interest for Alzheimer's disease when epidemiological studies began noting that chronic statin use appeared to protect against incident AD (reviewed in Shepardson et al., 2011), and subsequent cell- and animal-based studies detailed various biological pathways by which statins might benefit not only cardiovascular but also Alzheimer's disease pathogenesis.

Findings

Three clinical studies have assessed atorvastatin in Alzheimer's disease, and development of this drug for this indication has ended.

From 2000 to 2004, a Phase 2 pilot study compared a one-year course of atorvastatin to placebo in 67 patients with mild to moderate Alzheimer's disease who were also taking a cholinesterase inhibitor drug and Vitamin E. This study reported trends in favor of a benefit on cognition and function but fell short of achieving statistical significance (Sparks et al., 2005Sparks et al., 2005).

Between 2002 and 2007, Pfizer ran a 641-patient Phase 3 trial at 99 sites in the United States, Canada, European Union, Australia, and South Africa to evaluate 80 mg/day of atorvastatin as an add-on to donepezil therapy in mild to moderate AD. Called Lipitor's Effect on Alzheimer's Dementia (LEADe), this trial assessed changes in the ADAS-Cog and ADCS-CGIC batteries as co-primary cognitive and functional endpoints, respectively, and measured rate of change in whole brain and hippocampal volume in patients who enrolled in an MRI substudy. When it read out, this large trial found no clinical benefit over 18 months of treatment (Jones et al., 2008Feldman et al. 2010Fillit 2010). This is considered the definitive trial on atorvastatin in symptomatic Alzheimer's disease.

In 2006, a pilot study at the University of Wisconsin, Madison, tested whether atorvastatin therapy improved brain function as measurable by MRI and ultrasound in 16 middle-aged, cognitively normal adults who had a parent with Alzheimer's disease and enrolled to take atorvastatin for four months. This study reported a benefit on the neurovascular response and cerebral blood flow for atorvastatin (Xu et al., 2008Carlsson et al., 2012). For all clinical trials of atorvastatin in AD, see clinicaltrials.gov.

In addition to Alzheimer's disease, atorvastatin has been investigated in a Phase 2 study for clinically isolated syndrome (CIS), a term denoting the first neurological episode of inflammatory demyelnation that sometimes precedes multiple sclerosis. This trial missed its primary endpoint.

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References

Therapeutics Citations

  1. Simvastatin

Paper Citations

  1. . Atorvastatin for the treatment of mild to moderate Alzheimer disease: preliminary results. Arch Neurol. 2005 May;62(5):753-7. PubMed.
  2. . Atorvastatin therapy lowers circulating cholesterol but not free radical activity in advance of identifiable clinical benefit in the treatment of mild-to-moderate AD. Curr Alzheimer Res. 2005 Jul;2(3):343-53. PubMed.
  3. . The Atorvastatin/Donepezil in Alzheimer's Disease Study (LEADe): design and baseline characteristics. Alzheimers Dement. 2008 Mar;4(2):145-53. PubMed.
  4. . Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease: LEADe. Neurology. 2010 Mar 23;74(12):956-64. PubMed.
  5. . Atorvastatin does not slow cognitive decline in patients with mild to moderate probable Alzheimer's disease who are taking donepezil. Evid Based Ment Health. 2010 Nov;13(4):117. PubMed.
  6. . Atorvastatin therapy is associated with greater and faster cerebral hemodynamic response. Brain Imaging Behav. 2008 Jun 1;2(2):94. PubMed.
  7. . Effects of Atorvastatin on Cerebral Blood Flow in Middle-Aged Adults at Risk for Alzheimer's Disease: A Pilot Study. Curr Alzheimer Res. 2011 Nov 28; PubMed.
  8. . Chronic administration of statins alters multiple gene expression patterns in mouse cerebral cortex. J Pharmacol Exp Ther. 2005 Feb;312(2):786-93. PubMed.
  9. . Cholesterol level and statin use in Alzheimer disease: I. Review of epidemiological and preclinical studies. Arch Neurol. 2011 Oct;68(10):1239-44. PubMed.

External Citations

  1. clinicaltrials.gov
  2. Ostrowski et al., 2007

Further Reading

Papers

  1. . Long-term use of statins reduces the risk of hospitalization for dementia. Atherosclerosis. 2013 Oct;230(2):171-6. PubMed.
  2. . Statins have therapeutic potential for the treatment of Alzheimer's disease, likely via protection of the neurovascular unit in the AD brain. J Neurol Sci. 2012 Jul 13; PubMed.
  3. . Statins to treat Alzheimer's disease: an incomplete story. Expert Rev Neurother. 2012 Jan;12(1):27-30. PubMed.
  4. . Biliverdin reductase-A: a novel drug target for atorvastatin in a dog pre-clinical model of Alzheimer disease. J Neurochem. 2012 Jan;120(1):135-146. PubMed.
  5. . Statins for the treatment of dementia. Cochrane Database Syst Rev. 2010;(8):CD007514. PubMed.
  6. . Statins and cognitive functioning in the elderly: a population-based study. J Alzheimers Dis. 2010;21(1):95-102. PubMed.
  7. . Circulating cholesterol levels, apolipoprotein E genotype and dementia severity influence the benefit of atorvastatin treatment in Alzheimer's disease: results of the Alzheimer's Disease Cholesterol-Lowering Treatment (ADCLT) trial. Acta Neurol Scand Suppl. 2006;185:3-7. PubMed.