Statins: The New Silver Bullet

1
Statins The New Silver Bullet?

• Timothy Huber, MD
• 1st CIVDIV
• Oroville, CA
• EBM Presentation

2
Fool or Magician?
3
Disclaimer

• Off-label use talk commencing here.

4
Learning Objectives

• First, briefly explore physiological basis of
  current research.
• Second and Third
• Explore current areas of research.
• Give the current evidence for future indications
  for statins.

5
What do statins do?

• Beneficial changes to lipid profiles.
• Lower LDL
• Raise HDL
• Some lowering of TG.
• Affect other serum and cell markers.

6
Current Indications

• Primary MI Prevention
• AFCAPS/TexCAPS (not sig gt65 y.o.)
• WOSCOPS
• ASCOT
• Primary MI Prevention in DM
• CARDS

7
Current Indications

• Secondary MI prevention
• 4S, CARE, AVERT, MIRACL, LIPID, HPS, GREACE,
  Reigger et al.
• Risk reduction CV events in perioperative period
  of cardiac revascularization procedures.

8
Current Indications

• Stroke prevention in patients with CAD and/or DM
• Primary and Secondary Cerebrovascular Events
• 4S, LIPID, CARE, CARDS
• Cholesterol Level Reduction in Familial
  Hypercholesterolemia Syndromes

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What About 1st Strokes?

• No current indication for primary stroke
  prevention.
• Unless DM or pre-existing CAD present.
• SPARCL clinical phase wrapped up late 2005.
• High Chol and no clinically evident CAD.
• Using atorvastatin.
• Anticipate preliminary results late 2006.

10
Why look elsewhere?

• Because statins change more serum and cell
  markers than just various types of lipids.
• Do changes in these markers have a physiological
  effect?
• Are these effects clinically relevant?

11
Why look elsewhere?

• Drug companies want to extend their patents.
• Doing the right thing for the patient.

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Selected Non-Lipid Biological Markers Affected by
Statins

• Interleukins 1b, 6, 8, 10
• P-Selectin
• MHC-II Interferon-g
• Leukocyte Function Antigen 1

• C-reactive protein
• Tumor Necrosis Factor-A
• ICAM-1
• VCAM-1
• NO

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Statins Reduce Sytemic Inflammation

• CRP Marker and Player
• Monocyte recruitment
• Monocyte uptake of LDL
• Complement activation
• Increases ICAM/VCAM

• TNF-A
• Increases CRP
• Neutrophil aggregation
• Interleukin stimulation
• PGE2 stimulation
• Induces release of CRH
• Increases insulin resistance.

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Statins Reduce Local Regulators

• ICAM-1 / VCAM-1 Adhesion Molecules
• when expressed, increase the number of monocytes
  able to stick to an area
• Statins reduce ICAM, no effect on VCAM.
• Nitric Oxide Local Vasodilator
• Statins upregulate expression of NO synthetase
• Preservation of proper endothelial function
• Addl reduction in oxidative stresses

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Statins Reduce Other Markers

• Leukocyte Function Antigen (LFA-1)
• Tcell activator
• Interferon-g
• MHC-II regulator

• Inflammatory Interleukins
• 1b,6, 8, 10
• P-selectin
• Chemotaxis
• Endothelial constrictor.

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ENOUGH BASIC SCIENCE!!

• Right?

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Well not really.
18
Statins and DementiaSparks, Sabbagh, et al.,
Arch Neurol 5/05.

• Pilot intent-to-treat, proof of concept RCT
• 40 mg bid atorvastatin vs. placebo
• 98 pts with MMSE 12-28 at intake
• 11 comparison, followed 1 year q3months
• Patients given and followed with neuropsych
  exams.
• 46 completed study

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Statins and DementiaSparks, Sabbagh, et al.,
Arch Neurol May 05.

• Primary Outcomes measured
• D Alzheimer's Disease Assessment
  Scale-cognitive subscale.
• Significant difference only _at_ 6 mo. (p0.003)
• No difference at 3, 9, 12 mo.
• Clinical Global Impression of Change Scale scores
• Trend approaches significance at 9 mo (p0.07)

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Statins and DementiaSparks, Sabbagh, et al.,
Arch Neurol May 05

• Secondary Outcomes
• MMSE outcome NS
• GDS significant difference (p0.04)
• Neuropsychiatric Inventory Scale NS
• Alzheimer's Disease Cooperative Study-Activities
  of Daily Living Inventory NS

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Statins and DementiaSparks, Sabbagh, et al.,
Arch Neurol May 05

• Conclusion As a pilot proof-of concept study,
  significant differences were not expected, but
  benefits identified tend to support the trials
  rationale.
• Small, limited, called for more research.

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Statins and Dementia FPIN Suchecki, et al.,
JFP, JUN 2005

• 3 observational studies suggested protective
  effect.
• Methodological problems
• Selection bias

• 2 RCTs
• PROSPER and the
• 5804 pts
• Pravastatin
• Heart Protection Study,
• gt20,000 patients
• HPS simvastatin
• No delay or prevention.

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Statins and Dementia CLASP

• Cholesterol Lowering Agent to Slow Progression
  (CLASP) of Alzheimer's Disease Study
• 400 pts, RCT using simvastatin
• Following 2 arms for 18 months.
• Ended Dec 2005 no preliminary results.

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Statins and Dementia ACCORD-MIND

• Sub-group of the ACCORD study Action to Control
  Cardiovascular Risk in Diabetes (ACCORD)
• Memory IN Diabetes
• Est. 2800 pts of the ACCORD trial followed for
  FOUR years.

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Statins and Dementia ACCORD-MIND

• Primary Outcomes measured
• Glycemic control
• rate of decline in memory and executive function
• MRI measured cerebral atrophy
• Secondary Outcomes looking at same in the HTN
  and Lipid arms.
• Anticipate end of study April 2009.

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Statins and Glaucoma McGwinn, Arch Ophthal, 2004.

• Asked Are lipid-lowering medications associated
  with Open-Angle Glaucoma
• Matched Case control study
• 50 y/o veterans with new dx of Glaucoma
• 10 age-matched controls per patient.
• Examined VA database records for
• Cholesterol lowering medications
• Co-morbid conditions

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Glaucoma McGwinn, Results

• More protection if
• gt 24 months using statin
• OR 0.60 95 CI 0.39-0.92, p 0.04
• Glaucoma Statin AND a co-morbidity
• Cardiovascular disease present
• OR, 0.63 95 CI, 0.42-0.97
• Lipid metabolism disorder present
• OR, 0.63 95 CI, 0.41-0.99
• NO Cerebrovascular disease present
• OR, 0.76 95 CI, 0.58-0.99

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Glaucoma McGwinn, Results

• BUT
• Protective association also observed with
  nonstatin cholesterol-lowering agents
• OR 0.59 95 CI 0.37-0.97

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Age-Related Macular Degeneration

• Van Leuwen, BMJ, 2003.
• A population based cohort study of 4822 people
  aged 55 years and more.
• Two follow up examinations were performed at
• mean intervals of 2 and 6.5 years.  
• 457 patients used cholesterol lowering drugs for
  one or more days.

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AMD- van Leeuwen

• 419 cases of incident age related maculopathy
  were observed.
• Use of cholesterol lowering drugs at any time was
  not associated with the incidence of age related
  maculopathy (Hazard Ratio 1.0 (95 confidence
  interval 0.7 to 1.5)).

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AMD van Leeuwen

• Cumulative exposure to statins
• lt 1 mo
• 1-12 mo
• gt1y
• No protective effect on the risk of ARMD.

• More adjustments then made for
• BMI - tobacco
• HTN - PVD
• Re-adjustment did not change the association.

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AMD van Leeuwen , Results
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AMD van Leeuwen

• Same results when team performed the same
  analysis with progression of age related
  maculopathy as the outcome variable.
• Final conclusions
• No association between statins and AMD
• No protective effect found

35
AMD

• Smeeth, et al, B J Ophth, 2005
• A case control study of age related macular
  degeneration and use of statins.
• The primary outcome was the odds ratio for the
  association between exposure to statins and AMD.
• United Kingdom General Practice Research
  Database.
• 18 007 people with diagnosed AMD
• 86 169 controls
• Matched for age, sex, and general practice.

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AMD Smeeth, Results

• Crude Odds Ratio for the association between any
  recorded exposure to statins and AMD was 1.32
  (95 CI 1.17 to 1.48)
• Reduced to OR of 0.93 (95 CI 0.81 to 1.07,
  p 0.33) after adjustment.
• No evidence of risk varying by dose, duration, or
  type of individual statins.
• Short and Medium Term no long term (gt3y) looks
  done.

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Statins and Osteoporosis

• Meta-analysis by Bauer, et al. Arch Int Med 2004
• looked at several classic prospective studies
• Study of Osteoporotic Fractures
• Fracture Intervention Trial
• Heart and Estrogen/Progestin Replacement Study
• Rotterdam Study
• AND
• 8 other observational studies
• AND
• 2 clinical trials

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Osteoporosis Bauer, Meta-Analysis

• 4 Prospective Studies
• In statin users, relative hazards (RH) showed
• fewer hip fractures
• 0.19-0.62
• Fewer non-spine fractures
• 0.49-0.95

• 8 Observational Studies.
• In statin users, summary odds ratio (OR) showed
• hip fracture 0.43 (95 CI, 0.25-0.75)
• Non-spine fracture 0.69 (95 CI, 0.55-0.88).

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Bauer, Meta-Analysis of Clinical Trials

• Clinical trial results did not support a
  protective effect from osteoporosis with statin
  use 4S and LIPID trials.
• Hip fracture
• summary OR, 0.87 95 CI, 0.48-1.58
• Non-spine fracture
• summary OR, 1.02 95 CI, 0.83-1.26

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In Autoimmune Diseases, Statins

• In vitro and in vivo (animals and humans)
• Inhibit T cell activation
• Direct inhibition of LFA-1, preventing T cell
  activation.
• Increases Interferon-gamma, preventing
  upregulation of MCH-II genes.
• Reduce ability of WBCs to aggregate
• Reduced expression of ICAM-1 and VCAM-1
• Impair inflammatory response
• Reduce CRP, Interleukins, TNF-alpha, COX, PGE2.

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Systemic Lupus Erythematosus - APPLE

• Atherosclerotic Prevention in Pediatric Lupus
  Erythematosis
• 5 year study comparing atorvastatin vs placebo.
• Looking at 280 pediatric patients (10-19 y/o).
• Primarily looking at atherosclerosis
• Secondary endpoint lupus progression.

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Lupus Erythematosus - LAPS

• Lupus Atherosclerosis Prevention Study
• Primarily looking at atherosclerosis using
  atorvastatin 40 mg vs placebo.
• Secondary looking at lupus progression on statin
• Secondary looking at effect on Bone Mineral
  Density
• Completed, data analysis not completed.

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Rheumatoid Arthritis - TARA

• Trial of Atorvastatin in Rheumatoid Arthritis
• 116 patients, balanced arms with no significant
  differences in age, disease severity, meds,
  comorbidities.
• randomized to 40 mg atorvastatin vs. placebo
• followed 6 months

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Rheumatoid Arthritis TARA results with plt0.05

• Mean DAS28 score - 0.5U in statin group
• ESR 5mm/hr lower from baseline in statin group
• Swollen joint count 2.7 lower w/statin
• Lower IL-6, fibrinogen, LDL, TG in statin group
• No increase is side effects cf. to placebo.

46
Rheumatoid Arthritis TARA conclusions

• Atorvastatin effective in reducing inflammatory
  markers and articular signs in patients with
  active RA despite DMARD therapy.
• Called for larger studies.

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Statins Multiple Sclerosis

• Atorvastatin slowed and reversed autoimmune
  encephalitis in mice.
• Youssef, et al, Nature, 2004.

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Multiple Sclerosis in Humans

• Vollmer, et al., May 2004, Lancet
• 45 patients with remitting-relapsing MS and at
  least 1 MRI-identifiable lesion.
• All given 80mg Simvastatin for 6 months.
• No placebo arm.
• MRIs done at 0, 4, 5, and 6 months 2 blinded
  reviewers.
• 28 patients completed the study.

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Multiple Sclerosis Vollmer, et al.

• Mean number of lesions decreased by 44
• Mean volume of lesions decreased by 41
• No change in relapse rates or disability scores.

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Lung Transplant

• NIH-funded retrospective study, 1995 - 2000
• 200 allograft recipients
• 39 received statins (4 different types)
• 161 used as controls
• Followed for a mean of 3.0 years (/- 1.9)

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Lung Transplant Study Parameters

• Death pre-screened against CAD.
• Acute Graft Rejection
• Obliterative Bronchiolitis Chronic Rejection
• Immunosuppressant use
• long term and boost

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Lung Transplant Study Results over 6 years

• NS Ns15

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Lung Transplants - Results

• Lower doses of immunosuppressants in statin group
• Tacrolimus p0.002
• Cyclosporine p0.02
• Prednisone plt0.001
• Fewer number of steroid pulses plt0.001

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Lung Transplants - Conclusions

• Early use of statins following transplant
• Protects against acute graft rejection.
• Protects against obliterative bronchiolitis and
  chronic rejection.
• Prevents deaths independent of atherosclerotic
  disease.
• Permits lower doses of immunosuppressants.
• Reduces need for boost therapies.

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Renal Tranplants

• Renal Transplant
• Simvastatin worked in rats. Viera, et al, Aug
  2005
• But Fluvastatin didnt work in humans. Holdaas,
  et al, 2001.

56
Statins and Cancer Bandolier

• Pre-1987 epidemiological studies
• an association between low cholesterol levels and
  increased incidence of cancer of the
  gastrointestinal tract.
• Fears of Lipid-lowering agent could increase the
  incidence of gastrointestinal cancers.
• 1987 Statins come on the market.
• Now, multiple studies suggest the opposite.

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Statins and Cancer Bandolier

• 2 case control studies looking at breast and
  prostate ca.
• gt10,000 pt
• Different statins
• Failed to demonstrate a clear association with
  statin use.
• L Blais et al. 3-Hydroxy-3-methylglutaryl
  coenzyme A reductase inhibitors and the risk of
  cancer a nested case-control study. Arch Intern
  Med 2000 160 2363-8.
• PF Coogan et al. Statin use and the risk of
  breast and prostate cancer. Epidemiology 2002 13
  262-7.

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Statins and Cancer Bandolier

• Large meta-analysis showed no link between statin
  use and fatal or non-fatal cancer.
• 5 studies
• gt30,000 pts
• LM Bjerre, J LeLorier. Do statins cause cancer? A
  meta-analysis of large randomized clinical
  trials. Am J Med 2001 110 716-23.

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Bandolier results Non fatal CA

• Include nonmelanoma skin ca
• 2 trials
• CARE, LIPID
• 13173 pts
• Statin events/total
• 374/6593
• Placebo events
• 374/6580
• RR 1.00 (0.87-1.15)

• Exclude nonmelanoma skin ca
• 3 trials
• 4S, WOSCOPS, HPS
• 31575 pts
• Statin events
• 583/15792
• Placebo events
• 576/15781
• RR 1.01 (0.90-1.13)

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Bandolier Fatal Cancers

• Include nonmelanoma skin ca
• 2 trials
• CARE, LIPID
• 13173
• Statin events/total
• 177/6593
• Placebo events/total
• 186/6580
• RR 0.95 (0.78-1.16)

• Exclude nonmelanoma skin ca
• 3 trials
• 4S, WOSCOPS, HPS
• 31575
• Statin events/total
• 436/15792
• Placebo events/total
• 429/15783
• RR 1.02 (0.89-1.16)

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Bandolier All Cancers

• Include nonmelanoma skin ca
• 4 studies
• CARE, LIPID AFCAPS, HPS
• 40314 pts
• Statin events/total
• 2110/20166
• Placebo events/total
• 2067/20148
• RR 1.02 (0.96-1.08)

• Exclude nonmelanoma skin ca
• 4 studies
• 4S, WOSCOPS, HPS AFCAPS
• 38198 pts
• Statin event/total
• 1271/19114
• Placebo event/total
• 1264/19084
• RR1.00 (0.93-1.08)

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Melanoma

• Cochrane Skin Group currently putting together a
  protocol to systematically review the literature.
• 2 large RCTs showed significantly fewer melanomas
  
• Primary outcomes of studies was looking at 2 CAD
  prevention.
• Lovastatin, Gemfibrozil
• Rubins, NEJM 1999341410-8
• Downs, JAMA 19982791615-22

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Colon CA - Dynamed

• Poynter, et al., N Engl J Med. May 2005.
• Case control study, 1953 pts with 2015 controls
• Structured interview and verification of statin
  use with prescription fill/refill reviews
• Statin use for at least five years (vs. the
  nonuse of statins) significantly reduced relative
  risk of colorectal cancer
• Odds Ratio 0.50, 0.40 - 0.63

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Colon Cancer - Dynamed

• Statins do not affect incidence of cancer or
  cancer death (level 1 likely reliable evidence)
  
• Systematic review and meta-analysis of 26
  randomized trials with 86,936 participants, trial
  durations ranged from 1.9 years to 10.4 years
• No significant effect on incidence of colon
  cancer in meta-analysis of 4 trials with 27,972
  patients
• Reference - JAMA 2006 Jan 4295(1)74

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Prostate Cancer

• Shannon et al, Am J Epi, Aug 2005
• Oregon VA system Case control study
• 100 bx proven prostate ca
• 202 matched controlsP
• Examined statin use via pharmacy records
• Reduction in prostate cancer risk
• Odds Ratio 0.38, 0.21 - 0.69)
• Association ONLY with with Gleason scores of 7 or
  higher
• Odds Ratio 0.24, 0.11 - 0.53)

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Summary

• There is a clear physiological and
  pharmacological basis for investigation of
  statins for uses other than lipid control.
• There are multiple studies focusing on a variety
  of diseases that are either just concluded or
  ongoing.
• Statins show early promise in osteoporosis and a
  variety of autoimmune and neoplastic diseases.

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Questions?
68
References

• Pepys MB, Hirschfield GM. C-reactive protein and
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  ClinicalTrials.gov Identifier NCT00065806

69
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