Dementia & Statins: Forget About It?

Cassandra Sanchez, Pharm.D. PGY2 Geriatric Pharmacy Resident

South Texas Veterans Health Care System, San Antonio, Texas Division of Pharmacotherapy, The University of Texas at Austin College of Pharmacy

Pharmacotherapy Education and Research Center The University of Texas Health Science Center at San Antonio

November 14, 2014

Learning Objectives

1. Describe the differences in pathophysiology and presentation of specific dementia subtypes2. Discuss the rationale for the use of HMG-CoA reductase inhibitors (statins) in dementia3. Review the literature regarding the use of HMG-CoA reductase inhibitors in the treatment of Alzheimer’s disease

and prevention of vascular dementia4. Formulate a recommendation regarding the use of HMG-CoA reductase inhibitors in dementia

Sanchez 2

I. Dementia A. General term used to describe the decline in cognitive function affecting a person’s ability to independently perform

activities of daily living (ADLs)1,2

B. Dementia is now subsumed under new entity of major and mild neurocognitive disorders (NCD) based on the

Diagnostic and Statistical Manual of Mental Disorders (DSM-V) further specified into subtypes due to Alzheimer’s disease, Parkinson’s disease, frontotemporal, Lewy bodies, or other conditions

2,3

C. Significant cognitive decline from previous level in ≥1 cognitive domains: complex attention, executive function, learning and memory, language, perceptual-motor, or social cognition

2,3

II. Cognitive Domains

3

A. Complex attention i. Sustained attention, divided attention, selective attention, processing speed

Major—increased difficulty with multiple stimuli; easily distracted; difficulty with multistep tasks; difficulty holding new information in mind

Mild—normal tasks take longer; needs more double checking than before; find errors in routine tasks B. Executive function

i. Planning, decision making, working memory, responding to feedback/error correction, overriding habits/inhibiton, mental flexibility

Major—abandons complex projects; needs to focus on one task at a time; rely upon others for planning instrumental daily activities (iADLs) or make decisions

Minor—increased difficulty multitasking or resuming a task when interrupted; extra effort required to plan, organize, and make decisions

C. Learning and memory i. Immediate memory, recent memory, very-long-term memory

Major—repeats self often in conversation; requires frequent reorientation and reminders; cannot keep track of short list of items when shopping or of plans for the day

Mild—difficutly recalling recent events; relies more on written lists and reminders; loses track of bills paid

D. Language i. Expressive language (naming, grammar and receptive language)

Major—significant impairment in understanding or expressing language; difficulty naming things or people; reduced output of spoken communication

Mild—word-finding difficulty; subtle grammatical errors E. Perceptual-motor

i. Visual perception

Major—significant difficulty with previous familiar tasks (driving, using tools) or navigating in familiar environments

Mild—more reliance on others for directions or maps; greater effort needed for spatial tasks such as sewing or knitting

F. Social cognition i. Recognition of emotions, theory of mind

Major—clear unacceptable social behavior in terms of dress, grooming, or topics of conversation; no regard or awareness of the reactions of others; no insight to changes; makes decisions without regard to safety

Mild—subtle changes in personality; less able to recognize social cues or facial expressions; decreased empathy, decreased inhibition, or episodic apathy or restlessness

III. Epidemiology

A. Dementia affects about 1-2% of the population over 65 years of age and 30% of people over 85 yearsof age3

B. Alzheimer’s disease (AD) is the most common type of dementia accounting for 60-80% of dementia cases1-5

i. AD is not a normal part of aging

5

C. Vascular dementia (VaD) is the second most common type of dementia accounting for 20-30% of dementia cases1-3

D. Dementia with lewy bodies (DLB) is the third most common cause of dementia accounting for 10-25% of cases

1,3

E. Frontotemporal dementia (FTD) believed to be less common than AD, VaD, and DLB1

i. FTD accounts for 10-15% of dementia cases1

Dementia

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F. Others2,3

i. Mixed dementia

ii. Parkinson’s disease dementia iii. Creutzfeldt Jakob disease iv. HIV infection

IV. Pathophysiology & Presentation of Dementias

Table 1. Pathophyisology & Presentation of Specific Neurocognitive Disorders1,3-7

Specific Neurocognitive Disorders

Pathophysiology Presentation

Alzheimer’s Disease (AD)

Amyloid plaques from β-amyloid (Aβ) peptide accumulation [extracellular]

Neurofibrillary tangles from abnormally hyperphosphorylated tau proteins [intracellular]

Insidious onset and gradual worsening progression of cognitive and behavioral symptoms

Manifests with memory and learning impairment

Vascular Dementia (VaD)

History of stroke or TIA

Large and small artery infarctions, recurrent infarctions, or hypoperfusion

Mood and personality changes

Memory loss occurs later in disease

Vascular changes on MRI or CT

Dementia with Lewy Bodies (DLB)

Lewy bodies are round, eosinophilic, intracytoplasmic inclusions found in neurons

α-synuclein protein aggregates in neurons in brain stem, cortex, substantia nigra and limbic system

Fluctuating cognition in attention and alertness (major cognitive deficits observed at least 1 year before the motor symptoms)

Recurrent visual hallucinations

Spontaneous parkinsonism

Rapid eye movement (REM) sleep disorder

Autonomic dysfunction (orthostatic hypotension, incontinence)

Frontotemporal Dementia (FTD)

Atrophy of brain’s frontal and/or temporal lobes

o Behavioral variant FTD (bvFTD) o Primary progressive aphasia (PPA) o FTD movement disorders

Onset around 50-60s

Early behavioral disinhibition

Personality changes

Decline in language ability “aphasia”

Parkinson’s Disease

Dementia (PDD)

Lewy bodies (α-synuclein protein) aggregate in substantia nigra

Parkinson’s disease history

Cognitive deficits occurs ~ 1 year after onset of motor symptoms [one year rule]

Mixed Dementia

Presence of one or more types of dementia at the same time (ex. Alzheimer’s disease + vascular dementia)

V. “Reversible” Causes of Cognitive Impairment

2,5

A. Conditions i. Vitamin B12 deficiency

ii. Thyroid dysfunction iii. Electrolyte abnormalities iv. Uremia v. Neurosyphilli

vi. Liver dysfunction B. Medications

i. Anticholinergic agents ii. Opioids

iii. Benzodiazepines iv. Corticosteroids v. Antiparkinsonian medications

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VI. Diagnostic Criteria

Table 2. Diagnostic Criteria for Dementia/Neurocognitive Disorder3,8,9

DSM-IV DSM-V NINCDS-ADRDA

A. Memory impairment

B. One of more of the following cognitive disturbances:

Aphasia

Apraxia

Agnosia

Executive functioning

C. Cognitive deficits cause considerable impairment in social or occupational functioning and represent a decline from previous functioning

D. Onset is gradual, with continuing cognitive decline

E. Cognitive deficits cannot be attributable to other causes

F. Deficits are not caused by delirium

Major NCD A. Evidence of significant

cognitive decline from a previous level of performance in ≥1 cognitive domains based on:

1. Concern of the individual, knowledgeable informant, or the clinician

2. Impairment in cognitive performance by standardized neuropsychological testing, or another quantified clinical assessment

B. Cognitive deficits interfere with independence in everyday activities

C. Cognitive deficits do not occur exclusively in the context of a delirium

D. Cognitive deficits are not better explained by another mental disorder (depression, schizophrenia)

Mild NCD A. Evidence of modest

cognitive decline from a previous level of performance in ≥1 cognitive domains based on:

1. Concern of the individual, knowledgeable informant, or the clinician

2. Impairment in cognitive performance by standardized neuropsychological testing, or another quantified clinical assessment

B. Cognitive deficits do not interfere with independence in everyday activities

C. Cognitive deficits do not occur exclusively in the context of a delirium

D. Cognitive deficits are not better explained by another mental disorder (depression, schizophrenia)

I. Interfere with the ability to function at work or at usual activities; and

II. Represent a decline from previous level of functioning and performance; and

III. Are not explained by delirium or major psychiatric disorder; and

IV. Cognitive impairment is detected and diagnosed through a combination of 1.

history & 2.

cognitive assessment

V. Cognitive or behavioral impairment involving a minimum of 2 of the following domains: a. Impaired ability to acquire

and remember new information

b. Impaired reasoning and handling of complex tasks, poor judgment

c. Impaired visuospatial abilities

d. Impaired language functions (speaking, reading, writing)

e. Changes in personality, behavior, or comportment

Specify whether due to: Alzheimer’s disease, frontotemporal lobar degeneration, Lewy body disease, vascular disease, or

Parkinson’s disease DSM-IV & V-Diagnostic and Statistical Manual of Mental Disorders, 4th & 5th edition; NINCDS-ADRDA-National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s Disease and Related Disorders Association

Table 3. DSM-V Specific Diagnostic Criteria for Alzheimer’s Disease & Vascular dementia3

[see Appendix 1 for other types of dementia]

Specific Neurocognitive

Disorders

Diagnostic Criteria

Alzheimer’s Disease (AD)

A. Meet criteria for major or mild neurocognitive disorder B. Insidious onset and gradual progression of impairment in one or more cognitive domains (for major NCD, at

least two domains must be impaired) C. Meet criteria for probable or possible AD as follows:

For major neurocognitive disorder: Probable AD is diagnosed if either of the following is present; otherwise, possible AD should be diagnosed.

1. Evidence of a causative AD genetic mutation from family history or genetic testing 2. All three of the following are present:

a. Clear evidence of decline in memory and learning and at least one other cognitive domain (based on history or neuropsychological testing)

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b. Steadily progressive, gradual decline in cognition, without extended plateaus c. No evidence of mixed etiology

For mild neurocognitive disorder: Probable AD is diagnosed if there is evidence of a causative AD genetic mutation from either genetic testing or family history. Possible AD is diagnosed if there is no evidence of a causative AD genetic mutation from either genetic testing or family history, and all three of the following are present:

1. Clear evidence of decline in memory and learning 2. Steadily progressive, gradual decline in cognition, without extended plateaus 3. No evidence of mixed etiology

D. The disturbance is not better explained by cerebrovascular disease, another neurodegenerative disease, the effects of a substance, or another mental, neurological, or systemic disorder

Vascular Dementia (VaD)

A. Meet criteria for major or mild neurocognitive disorder B. The clinical features are consistent with a vascular etiology, as suggested by either of the following:

1. Onset of the cognitive deficits is temporally related to one or more cerebrovascular events 2. Evidence for decline is prominent in complex attention (including processing speed) and frontal-

executive function C. There is evidence of the presence of cerebrovascular disease from history, physical examination, and/or

neuroimaging considered sufficient to account for the neurocognitive deficits D. The symptoms are not better explained by another brain disease or systemic disorder

Probable vascular NCD is diagnosed if one of the following is present; otherwise possible vascular NCD should be diagnosed: 1. Clinical criteria are supported by neuroimaging evidence of significant parenchymal injury attributed to

cerebrovascular disease 2. The neurocognitive syndrome is temporally related to one or more documented cerebrovascular events 3. Both clinical and genetic evidence of cerebrovascular disease is present

Possible vascular NCD is diagnosed if the clinical criteria are met but neuroimaging is not available and the temporal relationship of the neurocognitive syndrome with one or more cerebrovascular events is not established

VII. Screening Tools

Table 4. Dementia Screening Tests10-15

Exam Name Description Scoring

Mini Mental Status Exam (MMSE)

0-30 point scale (0=worst)

Average decline in score is 3-4 points per year without treatment

Normal: ≥27 Mild: 20-26

Moderate: 10-20 Severe: < 10

Alzheimer’s Disease Assessment Scale-Cognitive Section

(ADAS-cog)

Used for clinical trials; extensive comprehensive test

Measures language & memory skills

0-70 point scale

Higher score=more impairment

Alzheimer’s Disease Cooperative Study Clinical Global Impression

of Change (ADCS-CGIC)

Clincian’s impression of change

1-7 point Likert-type scale assessing change from baseline in 15 areas

Representative of improvement or worsening in a patient

Not “scored” per se o 1= marked improvement o 2= moderate improvement o 3=minimal improvement o 4= no change o 5= minimal worsening o 6=moderate worsening o 7= marked worsening

Neuropsychiatric Inventory (NPI)

12 symptoms rated on frequency of 1-4 and severity of 1-3; product=total score

Measures psychiatric and behavioral symptoms

0-144 point scale

Higher score=more impairment

Saint Louis University Mental Status Examination (SLUMS)

30 point scale

Higher score=less impairment

Accounts for education status & detects mild cognitive impairment

High School Less High School

27-30 Normal 25-30

21-26 Mild Cognitive Disorder

20-24

1-20 Dementia 1-19

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VIII. Treatment

I. Cholesterol & AD Relationship

A. β-Amyloid (Aβ) formation & lipid rafts i. AD pathophysiology is proposed to be due to the accumulation of Aβ

5-8,25,26

ii. Amyloidogenic processing, Aβ formation, of amyloid precursor protein (APP) takes place in the small membrane-bound domains known as lipid rafts within the cell membrane

6,25,26 [see Figure 2]

a. Lipid rafts are tightly packaged membrane micro-environments enriched in cholesterol and sphingolipids

6,25,26

Figure 2. Processing of Amyloid Precursor Protein (APP)6

Table 5. Pharmacological Treatment for Dementia16-24

Class Cholinesterase Inhibitors NMDA Inhibitor

Medication Donepezil (Aricept) Rivastigmine (Exelon) Galantamine (Razadyne) Memantine (Namenda)

Indication

FDA: Mild-severe AD Non-FDA: Mild-

moderate PDD & DLB

FDA: Mild-moderate AD & PDD

Non-FDA: DLB

FDA: Mild-moderate AD Non-FDA: Severe dementia AD,

mild-moderate PDD & DLB

FDA: Moderate-severe AD Non-FDA: Moderate-

severe vascular dementia

Dose & Titration

Tablet Tablet Patch IR Tablet ER Capsule IR Tablet ER Capsule

Starting: 5 mg/day Titration: 10 mg/day after 4-6 wks 23 mg/day after ≥ 12 wks

Starting: 1.5 mg BID Titration: ↑3 mg daily q 2 wks Max: 6 mg BID

Starting: 4.6 mg/day Titration: 9.5 mg/day after 4 wks 13.3 mg/day after 4 wks

Starting: 4 mg BID Titration: 8 mg BID after 4wks 12 mg BID after 4 wks

Starting: 8 mg QD Titration: 16 mg QD after 4 wks 24 mg QD after 4 wks

Starting: 5 mg QD Titration: ↑5 mg after ≥1 wk Max: 20 mg/day (divided doses)

Starting: 7 mg QD Titration: ↑ 7 mg weekly Max: 28 mg/day

MOA

Reversible, selective acetylcholinesterase inhibitor

Pseudo-irreversible, nonselective actetyl-and butylcholinesterase inhibitor

Reversible, selective acetylcholinesterase inhibitor & nicotine receptor modulator

N-methyl-D-aspartate (NMDA) receptor antagonist

Side Effects SLUDGE (salivation, lacrimation, urination, defecation, gastrointestinal upset, emesis), bradycardia, syncope, anorexia

Constipation, dizziness, confusion, headache

Administration

Take with or without food Available in ODT

Take with food Therapy is stopped ≤3 days, restart at same or lower dose Therapy is stopped >3 days, restart at lowest dose & titrate

Take with or without food

Cholesterol & Dementia: What's the relationship?

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iii. Enzymes β-secretase (BACE-1) and γ-secretase are responsible for the production of Aβ and are located and active in these lipid rafts

25-27

iv. In vivo and in vitro studies have shown that an increase in cholesterol levels lead to enhanced β- and γ-secretase activity APP metabolism via the amylodigenic pathwayAβ production

6,25, 26

v. A decrease in intracellular cholesterol leads to rupture of the lipid rafts thus favoring α-secretase non-amyloidogenic pathway decrease in Aβ levels

6,26

B. Cholesterol levels

i. Cholesterol is a vital component of cell membranes and plays a role in the maintenance of neuronal plasticity and function with all cholesterol used in the brain synthesized within the CNS

27

ii. Blood and brain cholesterol pools are separated by the blood brain barrier (BBB) with homeostasis of brain cholesterol being critical

a. Two oxidized cholesterol metabolites: 24S-hydroxychloesterol and 27-hydroxycholesterol can pass across the BBB into the plasma

25-28

b. Higher levels of 24S-hydroxycholesterol in the cerebral spinal fluid (CSF) and peripheral blood could be indicative of increased cholesterol load and metabolism in the brain

26,27

c. Reports of increased 24S-hydroxycholesterol levels in AD patients when compared to control subjects

25-27,32

iii. Elevated serum cholesterol levels have also been proposed to be a risk factor for the development of Alzheimer’s disease and other dementias

2,25,28-32

a. Studies have shown high cholesterol levels during midlife increases the risk for developing AD later in life

2,25,28,32

iv. Studies in in vitro cell cultures and animal models have shown the strongest evidence correlating increased cholesterol levels as a factor in the development of AD

23,28,30,32

a. Increased cholesterol levels leads to an increase in Aβ production and accumulation in the brain, while a decrease in cholesterol levels has shown a reduction in Aβ levels

25, 29-31

b. However, in vivo studies don’t translate with the same results v. Prospective studies have shown an association between elevated serum cholesterol levels and an

increased susceptibility to AD25,32-34

II. Cholesterol and VaD Relationship

A. Risk factor for VaD25,26

i. Elevated cholesterol levels play a role in the development of atherosclerosis or atherosclerotic plaques

which reduce the patency of intracranial blood vessels causing hypoperfusion and ischemic brain damage

26

a. Within 3 months following a stroke, 20-30% of individuals are diagnosed with dementia3

ii. High levels of LDL and low levels of HDL are established risk factors for coronary artery disease and carotid artery atherosclerosis which can lead to cognitive impairment through cerebral hypoperfusion or embolism

25

iii. Treatment with statins have shown clinical significance in reducing cardiovascular and cerebrovascular disease amongst a wide patient population

iv. Stroke is a major risk factor for VaD and clinical trials indicate statins significantly decrease stroke risk in vascular patients including patients with stroke. By reducing risk of stroke, statins may also reduce the incidence of post-stroke dementia

25

I. Pharmacokinetic Properties of Statins25,35

i. Classification based on lipophilicity or hydrophilicity

Kivipelto

Notkola

Prospective, population-based study

Found ApoE4 allele, high total cholesterol levels and elevated systolic blood pressure at midlife to be risk factors for AD

o Midlife blood pressure obtained once for most participants

o Questionable midlife cholesterol levels obtained

Prospective study

Found high serum cholesterol levels increased the risk of developing AD after adjusting for the presence of ApoE4 allele and age

o Small sample size

HMG-CoA Reductase Inhibitors

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ii. Lipophilic statins are able to cross the BBB and penetrate cell membranes more effectively and may be more efficient in the treatment of dementia than the hydrophilic statins

II. Side Effects of Statins

Table 7. Side Effects of Statins36-41

Lovastatin

Simvastatin

Atorvastatin

Fluvastatin

Pravastatin

Rouvastatin

Gastrointestinal 2.5-3.5% 5.4-7.3% 6-14.1% 1.4-7.9% 4-10.5% 1.9-6.3%

Myalgia 3% 3.7% 8.4% 3.8-5% 1-2.9% 1.9-12.7%

Arthralgia 5-6% - 11.7% - - 3.8-10.1%

Increased liver enzymes 1.9% 1% 0.2-2.3% 0.2-4.9% 1.2% 2.2%

Rhabdomyolysis - 0-0.4% - - - -

III. 2013 ACC/AHA Lipid Guidelines

IV. Current Guideline Recommendations on Statins & Dementia

V. 2012 Food and Drug Administration (FDA) Safety Warning

46

i. FDA warned against non-serious and reversible cognitive impairment (memory loss, forgetfulness and confusion) experienced by some statin users with cardiovascular benefits outweighing the small increased side effect risk

ii. Warning was based on post-marketing adverse event reports and not associated with fixed or progressive dementia iii. FDA review did not reveal an association between the adverse event and a specific statin, age of the individual, statin

dose, or concomitant medication use iv. Data from observational and clinical studies did not suggest that cognitive changes associated with statin use are v. common or lead to clinically significant cognitive decline

Table 6. Properties of Statins

Drug Name Lipophillic

Lovastatin (Mevacor) Yes

Simvastatin (Zocor) Yes

Atorvastatin (Lipitor) Yes

Fluvastatin (Lesol) Yes

Pravastatin (Pravachol) No

Rouvastatin (Crestor) No

Table 8. 2013 ACC/AHA Guidelines Recommendations42

Four Statin Benefit Groups

1. Individuals with clinical atherosclerotic cardiovascular disease (ASCVD)/“secondary prevention” 2. Individuals with primary elevations of LDL ≥190 mg/dL 3. Individuals 40-75 years of age with diabetes mellitus (DM) with LDL 70-189 mg/dL without clinical ASCVD 4. Individuals without clinical ASCVD or DM, 40-75 years old with LDL 70-189 mg/dL and an estimated 10-yr ASCVD risk ≥7.5%

High-Intensity Statin Therapy Moderate-Intensity statin

Clinical ASCVD/secondary prevention*

LDL ≥ 190 mg/dL

Individuals 40-75 years of age with DM and an estimated 10-year ASCVD risk ≥ 7.5%

Individuals 40-75 years of age with diabetes with LDL 70-189 mg/dL without clinical ASCVD

Individuals without clinical ASCVD or DM, 40-75 years old with LDL 70-189 mg/dL and an estimated 10-year ASCVD risk ≥7.5%**

*If >75 years old or intolerant, use moderate intensity statin **Reasonable to treat with moderate-to-high intensity statin

Table 9. Guideline Recommendations on Statin Therapy for Dementia Management43-45

2008 American College of Physicians Guidelines

2001 American Academy of

Neurology Guidelines 2006 National Institute for Health and Care Excellence (NICE)

Guidelines

No recommendation stated

Statins should not be prescribed as a specific treatment for the primary prevention of dementia

For secondary prevention of dementia, vascular and modifiable risk factors (including raised cholesterol) should be reviewed in people with dementia and if appropriate, treat

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I. Statins in Prevention of Vascular Dementia

Heart Protection Study Collaborative Group. Lancet 2002;360:7-22.47

[HSP Study]

Objective To assess the long term effects of cholesterol-lowering therapy on vascular and non-vascular mortality and major morbidity in a wide range of circumstances

Trial Design Randomized, placebo-controlled study

Population

Inclusion Criteria

Men or women aged 40-80 years

Non-fasting blood total cholesterol concentration of at least 135 mg/dL

High risk of death from coronary heart disease over the next 5 years from past medical history defined as: (i). coronary disease (MI, unstable or stable angina, coronary artery bypass graft, or angioplasty); or (ii). occlusive disease of non-coronary arteries (non-disabling stroke not thought to be hemorrhagic, transient cerebral ischemia, leg artery stenosis, carotid endarterectomy, other arterial surgery or angioplasty); or (iii). diabetes mellitus (type 1 or 2); or (iv). treated hypertension

Exclusion Criteria

Chronic liver disease (cirrhosis or hepatitis) or evidence of abnormal liver function (ALT >1.5 X ULN)

Severe renal disease or evidence of impaired renal function

Inflammatory muscle disease (dermatomyositis or polymyositis) or evidence of muscle problems (creatinine kinase >3 x ULN)

Concurrent treatment with cyclosporine, fibrates, high dose niacin

Child-bearing potential

Severe heart failure

Some life-threatening condition other than vascular disease or diabetes

Conditions that might limit long-term compliance (severely disabling stroke, dementia, or psychiatric disorder)

Intervention Simvastatin 40 mg daily (n=10,269) vs. placebo (n=10,267)

Outcomes

Primary Outcome: Effects on death from all causes, from coronary heart disease, and from all other causes

Secondary Outcome: Effects on (i). specific non-coronary causes of death; (ii). major coronary events (non-fatal MI or death from coronary disease), and major vascular events (major coronary events, strokes of any type, and coronary or non-coronary revascularizations) during the first 2 years and during last year of scheduled treatment; and (iii). non-fatal or fatal strokes of any type

Tertiary Outcomes: Site specific cancer, cerebral hemorrhage, vascular procedures, hospitalizations from angina and for fractures, cognitive impairment and loss of respiratory function

o Cognitive function assessed by modified Telephone Interview for Cognitive Status (TICS-m) questionnaire either face-to face or over the telephone (score of 22/39 was prespecified as indicative of some cognitive impairment)

Results

Baseline Characteristics

28% of individuals were ≥ 70 years of age

25% of individuals were women

41% of individuals had previous MI

9% of individuals had cerebrovascular disease

Mean total cholesterol: 106 mg/dL

Mean LDL: 61 mg/dL

Tertiary Outcomes

Mean TICS-m score at end of trial o Simvastatin vs. placebo: 24.08 vs. 26.06; difference 0.02 [standard error 0.07]

No significant differences were observed overall in participants classified as cognitively impaired o Simvastatin: 23.7%; Placebo: 24.2%

No significant differences were observed over in subgroup defined with respect to their age at study entry o Simvastatin vs. placebo: <65 years-17.1% vs. 17.8%; 65-69 years: 25.8% vs. 25.4%; 70-80 years: 34.6% vs. 36.2%

No significant differences were observed in subgroup defined with respect to history of cerebrovascular disease o No prior stroke—simvastatin vs. placebo: 22.8% vs. 23.3% o Prior stoke—simvastatin vs. placebo: 31.9% vs. 33.3%

Development of dementia o Simvastatin vs. placebo: 31 (0.3%) vs. 31 (0.3%)

Lipids/Cholesterol

Mean difference in concentrations (simvastatin minus placebo)

Follow-up (years) Total Cholesterol (mg/dL) LDL Cholesterol (mg/dL)

1 -30.6 ±1.44 -23.4 ±1.08

3 -21.6 ± 1.62 -16.2 ± 1.44

5 -14.4 ± 0.54 -12.6 ± 0.54

Study Average -21.6 ±3.6 -18 ± 3.6

Safety Data

Clinical Evidence

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Results

Symptom Simvastatin (n=10,269) Placebo (n=10,267)

Elevated ALT 2-4 X ULN 139(1.35%) 131 (1.28%)

Elevated ALT >4 X ULN 43 (0.42%) 32 (0.31%)

Elevated CK 4-10 X ULN 19 (0.19%) 13 (0.13%)

Elevated CK >10 X ULN 11 (0.11%) 6 (0.06%)

Myopathy no rhabdomyolysis 5 (0.5%) 1 (0.1%)

Myopathy with rhabdomyolysis 5 (0.5%) 3 (0.03%)

Author’s Conclusions

No significant change in cognitive function was observed over 5 years between simvastatin vs. placebo in high risk vascular and non-vascular patients

Critique

Strengths

Randomized, placebo-controlled clinical trial with large patient population

Lager numberof high CV risk patients (DM, stroke, HTN, history of CV disease)

Mean follow-up was 5 years

Excluded patients diagnosed with dementia

Limitations

Cognitive function measured based on modified Telephone Interview for Cognitive Status (TICS-m)

No baseline cognitive function assessed

Study was not powered to assess the tertirary outcome

Cognitive function was only assessed at the end of the study

Take Home Points

No significant differences noted in overall cognition and in respect to age or previous stroke history between patients treated with simvastatin versus placebo over a 5 year period

Shepherd J, et al. Lancet 2002;360:1623-30.48

[PROSPER Study]

Objective To ascertain if treatment with pravastatin reduces the risk of cardiac events, stroke, cognitive decline, and disability in those with existing (secondary prevention) and in those at high risk of developing (primary prevention) vascular disease

Trial Design Randomized, multicenter, double-blind, placebo-controlled study

Population

Inclusion Criteria

Men and women from Scotland, Ireland, and Netherlands

Men and women 70-82 years if they have pre-existing vascular disease (coronary, cerebral, or peripheral) or raised risk of such disease because of smoking, hypertension, or diabetes

Total cholesterol 72-162 mg/dL & triglycerides <108 mg/dL

Exclusion Criteria

Those using < 75% or > 120% of the placebo medication in lead-in period

Poor cognitive function (MMSE <24)

Intervention Pravastatin 40 mg daily (n=2,891) vs. placebo (n=2,913)

Outcomes

Primary Outcome: Combined endpoint of definite or suspect death from coronary heart disease, non-fatal myocardial infarction, and fatal or non-fatal stroke

Secondary Outcome: Examination of coronary and cerebrovascular components separately

Tertiary Outcome: Assessment of transient ischemic attack, disability, and cognitive function

Results

Baseline Characteristics

Mean age in both groups: 75 years

Mean total cholesterol in both groups: 102.7 mg/dL

Mean MMSE baseline score in both groups: 28

Mean Barthel index score in both groups: 13.6

Mean instrumental assessment of activities of daily living score (iADLs) in both groups: 13.6

11% of patients enrolled history of stroke or TIA ; 44% of patients with a history of vascular disease

Tertiary Outcome

Cognitive function declined at the same rate in both treatment groups

No difference between the 2nd

baseline & last on-treatment value for the number of correct letter digit codes o Pravastatin-placebo -0.01 (95%CI -0.24—0.23, p=0.95)

No difference between the 2nd

baseline & last on-treatment value in the number of words remembered in the picture word learning test

o Pravastatin-placebo 0.02 (95%CI -0.12—0.16, p=0.80)

No difference between the 2nd

baseline & last on-treatment value for the time needed to complete the Stroop test o Pravastatin-placebo 0.8s (95%CI -0.4—2, p=0.19)

No difference between the 2nd

baseline & last on-treatment value for the MMSE score o Pravastatin-placebo 0.06 (95%CI -0.04—0.16, p=0.26)

No difference between the 2nd

baseline & last on-treatment value in activity levels over time as measured by the Barthel index

o Pravastatin-placebo 0.06 (95%CI -0.03—0.15, p=0.18)

No difference between the 2nd

baseline & last on-treatment value in instrumental activities of daily living (iADL) questionnaire

o Pravastatin-placebo 0.03 (95% CI -0.08—0.14, p=0.59)

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II. Statin in Treatment of Alzheimer’s Disease

Results

Lipids/Cholesterol

After 3 months of therapy mean LDL:

Pravastatin: 45.05 mg/dL o Pravastatin group: 34% lower than the placebo group for compliant individuals; 32% lower for entire cohort

At second annual visit:

Pravastatin group: LDL decreased 33% in compliant individuals; 27% lower for the entire cohort

Safety Data

After 3 months of therapy:

No cases in either group with a creatine kinase concentration > 10 X ULN

One case in each group with increased plasma concentration of alanine and aspartate transaminases >3 X ULN

Symptom Pravastatin (n=2891) Placebo (n=2913)

One or more adverse events 1608 (56%) 1604 (55%)

Myalgia 36 32

Rhabdomyolysis 0 0

Author’s Conclusions

Pravastatin therapy didn’t show benefit in slowing the decline in cognitive function over the 3 years in patients with or at high risk of developing cardiovascular disease and stroke

Critique

Strengths

Randomized, double-blind, placebo-controlled study design

Large population

Mean follow up of 3.2 years

Accounted for baseline assessment exams

Included those with existing and high risk of developing cardiovascular and cerebrovascular disease including vascular disease, stroke & TIA history

Limitations

Study was not powered to assess the tertiary outcome

No mention on patient’s enrolled with a diagnosis of dementia

Statin used in the study was hydrophillic

Take Home Points Pravastatin had no significant effects on cognitive decline among patients with existing vascular disease and those at high risk of developing vascular disease

Feldman HH, et al. Neurology 2010;74(12):956-964.20,42

[LEADe Study]

Objective To evaluate the efficacy and safety of atorvastatin in patients with mild to moderate AD receiving therapy with acetylcholinesterase inhibitor (AchEI), donepezil

Trial Design Randomized, international, multicenter, double-blind, placebo-controlled, parallel-group study

Population

Inclusion Criteria

Male or female aged 50-90 years

Diagnosis of probable AD according to the DMS-IV criteria and NINCDS-ADRDA

Mild to moderate AD defined by MMSE score of 13-25 at screening

MRI or cranial CT within 12 months of entry consistent with diagnosis of AD

Receiving donepezil 10 mg for at least 3 months before screening

DM enrolled patient: stable blood sugars with diet or treatment were permitted with a HgbA1c <10% and fasting glucose levels <170 mg/dL and LDL between 95-135 mg/dL

LDL 95-195 mg/dL

Not requiring another lipid-lowering agent at the opinion of the investigator

Caregiver who was in contact at least 5 days/week for a minimum of 10 waking hour/week

Modified Hachinski Ischemic Score ≤4

Exclusion Criteria

Taking medications that affect lipid metabolism or cholinesterase activity other than donepezil within 3 months of screening

Hypersensitivity to HMG-CoA reductase inhibitors

Clinically significant or unstable medical condition including dermatologic, hematologic, pulmonary, cardiovascular, renal, hepatic, gastrointestinal, genitourinary, endocrine or neurologic disease

Medical conditions that could impact the bioavailability or metabolism or the study medication or affect results of the study

Intervention

18 months (treatment period) of placebo + donepezil 10 mg daily (n=317) or atorvastatin 80 mg + donepezil 10 mg daily (n=297); followed by 2-month atorvastatin withdrawal period which participants either continued atorvastatin 80 mg + donepezil 10 mg daily or switched to placebo + donepezil 10 mg daily ; participants receiving placebo + donepezil 10 mg contued to receive same therapy

Outcomes

Primary outcome: Change in ADAS-cog & ADCS-CGIC score at month 18 from baseline Secondary outcome: Change in NPI, modified ADAS-cog, MMSE, Clinical Dementia Rating Sum of Boxes (CDR-SB), and Alzheimer’s Disease Functional Assessment and Change Scale (ASDFACS) score at month 18 from baseline

Sanchez 12

Results

Baseline Characteristics

Mean age in both groups: 74 years

Mean donepezil use in both groups: 409 days

Mean total cholesterol in both groups: 224 mg/dL

Mean ApoE4 frequency in both groups: 60%

Mean ADAS-cog in both groups: 23

Mean MMSE in both groups: 22

Primary Outcome

No significant difference in (A). ADAS-cog & (B). ADCS-CGIC score change between treatment groups

Visit Treatment difference between atorvastatin 80 mg + donepezil 10 mg vs. placebo + donepezil 10 mg

ADAS-cog Score

LS Means Difference (SE)

95% CI of LS Means Difference

P-value between Treatment

Overall (month 0-18) -0.532 (0.467) [-1.450-0.386] 0.2556

LOCF -1.112 (0.640) [-2.268-0.144] 0.0827

ASCD-CGIC Score

Overall (month 0-18) 0.021 (0.061) [-0.099-0.141] 0.7292

LOCF 0.160 (0.086) [-0.009-0.328] 0.0628 LS-least squares; SE-standard error; LOCF-last observations carried forward

Secondary Outcome

No significant difference in NPI, ADFACS, CDR-SB, MMSE, and modified ADAS-cog between treatment groups

Lipids/Cholesterol

Lipids: Mean LDL decrease (after 3 months of therapy):

Atorvastatin: -72.4 mg/dL (-50.2%)

Placebo: -1.0 mg/dL (-0.2%) o Changes remained constant through month 18

Safety Data

Treatment-Related Atorvastatin (n=324) Placebo (n=325)

Number of adverse events 192 102

Subjects with adverse events 103 (32.8%) 61 (18.8%)

Subjects with severe adverse events* 6 (1.9%) 3 (0.9%)

Incidence of persistent elevations in AST/ALT levels**

24 (11.9%) 25 (10.3%)

Myalgia 10 (4.9%) 11 (5.4%)

*hepatitis, acute renal failure/rhabdomyolysis/pancreatitis, abdominal pain/nausea/chest discomfort, transaminase elevation, liver disorder, and gastrointestinal hemorrhage **3 X upper limit of normal on 2 consecutive measures 4 to 10 days apart

Author’s Conclusions

Therapy with atorvastatin as a treatment for mild to moderate AD was not associated with significant clinical benefit over 18 months compared with placebo

Sanchez 13

Sano M, et al. Neurology. 2011;77:556-563.

21

Objective To determine if the lipid-lowing agent simvastatin slows the progression of symptoms in Alzheimer disease

Trial Design Randomized, multicenter, double-blind, placebo-controlled study

Population

Inclusion Criteria

Age ≥ 50 years

Probable AD meeting NINCDS-ADRDA criteria that were medically stable

MMSE score between 12 and 26

Exlusion Criteria

Other neurologic or psychiatric diagnosis that could interfere with cognitive function

Taking lipid-lowering drugs or conditions requiring cholesterol lowering treatment as defined by ATP III guidelines

LDL <80 mg/dL or TG >500 mg/dL

Drug taken recently with significant central anticholinergic effects, sedatives, antiparkinsonian medications, or any investigational treatment for AD

Taking medications that were contraindicated with simvastatin & those that could interact with CYP-3A4 to ↑ or ↓the levels of simvastatin

Intervention Simvastatin 20 mg daily X 6 wks, then 40 mg daily X 16.5 months (n=204) vs. placebo (n=202)

Outcomes Primary outcome: Rate of change on the cognitive portion of the ADAS-cog score

Secondary outcome: Rate of change on ADCS-CGIC, MMSE, dependence scale, ASCS-ADL, and NPI

Results

Baseline Characteristics Average age of both groups: 74.6

Average duration of disease of both groups: 4.13 years

Mean total cholesterol of both groups: 211.9 mg/dL

Mean ADAS-cog score slightly higher in placebo vs. simvastatin: 68.6 vs. 67.2 (respectively, p=0.0414)

Mean MMSE score for both groups: 20.4

Primary Outcome No significant difference in rate of change in ADAS-cog score between placebo and simvastatin (95% CI -0.0462-0.1680,

P=0.25)

(A). Total Score (B). Change in Score

Critique

Strengths

Randomized, double-blind, placebo-controlled study design

Assessed for baseline ADAS-cog and ADCS-CGIC scores at 3 month intervals

Statin used in the study was lipophilic

Limitations

Excluded patients with significant CV, cerebrovascular, and peripheral vascular disease

Allowed selected atypical antipsychotics, antidepressants, and low-dose benzodiazepines if stable for 3 months before baseline visit

Primary endpoints were not met and withdrawal phase was not reported

Short follow-up time period of 18 months

Take Home Points

Therapy with atorvastatin as a treatment for mild to moderate AD was not associated with significant clinical benefit over 18 months

Sanchez 14

Results

Cognitive Exam & Functional Measures

Placebo (n=202) Simvastatin (n=204)

Change in score from baseline

ADAS-cog

3 months 6 months 12 months 18 months

Placebo 1.11 ± 5.32 2.32 ± 5.90 5.36 ± 6.95 8.18 ± 8.70

Simvastatin 1.89 ± 5.35 2.51 ± 5.61 5.79 ± 7.76 9.51 ± 9.48

Secondary Outcome

No significant differences in rate of change in MMSE, dependence scale, ADSC-ADL & NPI scores between placebo and simvastatin

Cognitive Exam & Functional Measures

Placebo (n=202) Simvastatin (n=204)

Change in score from baseline

MMSE

3 months 6 months 12 months 18 months

Placebo

-0.10 ± 3.10 -0.89 ± 3.23 -2.28 ±4.08 -3.75 ±4.28

Simvastatin -0.52 ± 2.74 -0.72 ±3.26 -2.47 ± 3.80 -4.23 ± 4.77

Dependence Scale Placebo -0.15 ± 0.87 -0.21±0.83 -0.36 ± 0.96 -0.53 ± 1.10

Simvastatin -0.04 ± 0.85 -0.10 ± 1.04 -0.26 ± 1.02 -0.48 ± 1.09

ADAS-ADL Placebo -1.20 ± 6.09 -3.95 ± 8.42 -6.21 ± 10.94 -9.62 ± 12.86

Simvastatin -1.54 ±7.44 -3.66 ± 8.18 -7.45 ± 10.18 -10.47 ±13.37

NPI Placebo 0.21 ± 8.02 1.26 ± 9.16 3.60 ± 10.38 3.78 ± 10.73

Simvastatin -0.64 ± 8.61 -0.09± 9.61 1.95 ± 10.64 3.21 ± 12.71

Lipids/Cholesterol Total cholesterol [simvastatin vs. placebo]: ↓ 23% (p<0.001)

LDL [simvastatin vs. placebo]: ↓ 37% (p<0.001)

Safety Data One or more adverse events

Placebo: 181/202 (89.6%)

Simvastatin: 189/204 (92.7%) p=0.30

Symptom Placebo group (n=202) Treatment group (n=204)

Agitation 47 (23.3%) 50 (24.5%)

Asthenia 43 (21.3%) 43 (21.1%)

Diarrhea 28 (13.9%) 40 (19.6%)

Arthralgia 24 (11.9%) 25 (10.3%)

Myalgia 10 (4.9%) 11 (5.4%)

Author’s Conclusions

Treatment with simvastatin for 18 months had no effect on the progression of symptoms based upon ADAS-cog assessment in individuals with mild to moderate AD & no noted change in the secondary outcomes including MMSE or ADAS-CGIC

Critique

Strengths

Primary and secondary outcomes measured at 3, 6, 12, and 18 months

Screened for ApoE4 genotype for those consenting

Baseline ADAS-cog assessment score

Baseline ADAS-cog score was significantly higher in the placebo group

Allowed for the use of acetylcholinesterase inhibitors (AChEi) and memantine

Sample size was met

Adjusted for covariates

Stated compliance of medication (no significant difference between groups)

Statins used in the study was lipophillc

Limitations

ApoE4 allele was not included in the primary analysis

Short follow-up time with of median of 17.9 months

Take Home Point

Simvastatin had no additional benefit to slowing the progression of symptoms of AD based on the ADAS-cog exam over 18 months in mild to moderate AD

Sanchez 15

I. Are statins beneficial for the prevention of vascular dementia?

a. Review of the literature does not support the use of statins for the clinical indication of prevention of dementia associated with vascular disease to help prevent cognitive impairment, possible due to short study durations

i. However, the use of statins in primary and secondary prevention of cardiovascular and cerebrovascular events still remains beneficial in elderly patients

II. Are statins beneficial for the treatment of Alzheimer’s Disease?

a. Review of the literature does not support the use of statins for the clinical indication of treatment of dementia associated with Alzheimer’s disease to help slow progression of cognitive impairment

b. Studies, including patients with high cardiovascular or cerebral vascular disease, does not support the use of statins for the clinical indication of treatment of dementia associated with Alzheimer’s disease

III. Do statins worsen Alzheimer’s disease or vascular dementia?

a. The 2012 FDA safety warning was developed using case-reports, adverse drug event reporting from consumers and health care professions and observational studies, which should warrant further investigation

b. Review of randomized clinical trials with primary, secondary and tertiary endpoints did not slow the progression of Alzheimer’s or vascular dementia with an overall low incidence of side effects

Clinical Recommendation/Summary

Sanchez 16

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3. American Psychiatric Association. Diagnostic and statistical manual of mental disorders (5th

edition). Arlington, VA; American

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8. American Psychiatric Association. Diagnostic and statistical manual of mental disorders (4th

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10. Folsetin MF, Folstein SE, and McHugh PR. “Mini-mental state.” A practical method for grading the cognitive state of patient for

the clinician. J Psychiatr Res 1975;12(3):189-98.

11. Royall DR, Cordes JA, and Polk M. CLOX: an executive drawing task. J Neurol Neurosurg Psychiatry 1998;64:588-94.

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19. Exelon Patch (rivastigmine transdermal system) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals; Revised July 2013.

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DOI: 10.1002/14651858.CD007514.pub2.

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pathways. Angew Chem Int Ed Engl 2013;52(4):1110-21.

27. Shobab LA, Hsiung GYR, and Feldman HH. Cholesterol in Alzheimer’s disease. Lancet Neurol 2005;4:841-52.

28. Jones RW, Kivipelto M, Feldman H, et al. The atorvastatin/donepezil in Alzheimer’s disease study (LEADe): design and baseline

characteristics. Alzhimer Dement 2008;4:145-53.

29. Feldman HH, Doody RS, Kivipelto M, et al. Randomized controlled trial of atorvastatin in mild to moderate Alzheimer

disease(LEADe Study). Neurology 2010;74(12):956-64.

References

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Sanchez 18

Specific Neurocognitive

Disorders

Diagnostic Criteria

1

Dementia with Lewy Bodies

(DLB)

A. Meet criteria for major or mild neurocognitive disorder B. Insidious onset and gradual progression C. The disorder meets a combination of core diagnostic features and suggestive diagnostic features for either

probable or possible neurocognitive disorder with Lewy bodies For probable major or mild neurocognitive disorder with Lewy bodies, the individual has two core features, or one suggestive feature with one or more core features. For possible major or mild neurocognitive disorder with Lewy bodies, the individual has only one core feature, or one or more suggestive features.

1. Core diagnostic features: a. Fluctuating cognition with pronounced variations in attention and alertness b. Recurrent visual hallucinations that are well formed and detailed c. Spontaneous features of parkinsonism, with onset subsequent to the development of

cognitive decline 2. Suggestive diagnostic features:

a. Meets criteria for rapid eye movement sleep behavior disorder b. Severe neuroleptic sensitivity

3. The disturbance is not better explained by cerebrovascular disease, another neurodegenerative disease, the effects of a substance, or another mental, neurological, or systemic disorder

Frontotemporal Dementia (FTD)

A. Meet criteria for major or mild neurocognitive disorder B. Insidious onset and gradual progression C. Either (1) or (2):

1. Behavioral variant: a. Three or more of the following behavioral symptoms:

i. Behavioral disinhibition ii. Apathy or inertia

iii. Loss of sympathy or empathy iv. Perseverative, stereotyped or compulsive/ritualistic behavior v. Hyperorality and dietary changes

b. Prominent decline in social cognition and/or executive abilities 2. Language variant:

a. Prominent decline in language ability, in the form of speech production, word finding, object naming, grammar, or word comprehension

D. Relative sparing of learning and memory and perceptual-motor function E. The disturbance is not better explained by cerebrovascular disease, another neurodegenerative disease,

the effects of a substance, or another mental, neurological, or systemic disorder. Probable frontotemporal neurocognitive disorder is diagnosed if either of the following is present; otherwise, possible frontotemporal neurocognitive disorder should be diagnosed:

1. Evidence of a causative frontotemporal neurocognitive disorder genetic mutation, from either family history or genetic testing

2. Evidence of disproportionate frontal and/or temporal lobe involvement from neuroimaging

Parkinson’s Disease

Dementia (PDD)

A. Meet criteria for major or mild neurocognitive disorder B. Disturbance occurs in the setting of established Parkinson’s disease C. Insidious onset and gradual progression of impairment D. The neurocognitive disorder is not attributable to another medical condition and is not better explained by

another mental disorder Major or mild neurocognitive disorder probably due to Parkinson’s disease should be diagnosed if 1 and 2 are both met. Major or mild neurocognitive disorder possibly due to Parkinson’s disease should be diagnosed if 1 or 2 is met:

1. There is no evidence of mixed etiology (i.e., absence of other neurodegenerative or cerebrovascular disease or another neurological, mental, or systemic disease or condition likely contributing to cognitive decline)

2. The Parkinson’s disease clearly precedes the onset of the neurocognitive disorder

Appendix 1