Steven D. Atwood, M.D., FACP Internal Medicine, Springfield, MO [email protected] The Issue of...

Steven D. Atwood, M.D., FACP Internal Medicine, Springfield, MO [email protected]

The Issue of Treating

Cholesterol in the Elderly

The Issue of Treating

Cholesterol in the Elderly

statins treatment in the elderly 2

Clipped From the Headlines

• Statin therapy associated with reduced mortality across all age groups, including very elderly

• Statin therapy in the elderly—the evidence mounts

• Statins safe for elderly patients. New findings offer reassurance about cholesterol drugs


Clipped From the Headlines


The Real World

80 y/o woman drives to office for yearly checkup controlled hypertension, fixed income, weighs 110 A-Fib on diltiazem and coumadin

2 children in the area

LDL=190 HDL=60 TG=180

10 years on a statin vs. the cost of losing 2 years of good life to a nursing home

“I’m Old But I’m Not Dead Yet”


Today’s Goal

• Should I Treat

• Why

• Which Statin

Atherosclerosis

Is an inflammatory,

proliferative,

thrombotic

disease that occurs in response to risk factor activation of the endothelium.

Cholesterol and specifically oxidized LDL forms the bulk of the plaque

Atherosclerosis

Is an inflammatory,

proliferative,

thrombotic

disease that occurs in response to risk factor activation of the endothelium.

Cholesterol and specifically oxidized LDL forms the bulk of the plaque

CRPMyeloperoxidase

FibrinogenPAI

Nitrous Oxide

anti-oxidants


Normal Arterial Wall

Tunica adventitia

Tunica media

Tunica intima

Endothelium

Subendothelial connective tissue

Internal elastic membrane

Smooth muscle cells

Elastic/collagen fibers

External elastic membrane


Development of Atherosclerotic Plaques

Normal

Fatty streak

Foam cells

Lipid-rich plaque

Lipid core

Fibrous cap

Thrombus


LumenFibrous Cap

Lipid Core

Lipid Core

Fibrous Cap

Lumen

Vulnerable Plaque

Stable Plaque

• Thick fibrous cap• Smooth muscle cells: more extracellular matrix• Lipid-poor plaque

• Thin fibrous cap• Inflammatory cell infiltrates: proteolytic activity• Lipid-rich plaque

Libby P. Circulation. 1995;91:2844-2850.

Vulnerable vs. Stable Atherosclerotic Plaques Like

Diabetic

Enhanced by statins

Lot of Plaque before occlude lumen


Lower Cholesterol Levels Associated With Lower CHD Risk

0

25

50

75

100

125

150

204 205-234 235-264 265-294 295

Castelli WP. Am J Med. 1984;76:4-12.

CH

D I

ncid

en

ce p

er

1000

Serum Cholesterol (mg/100 mL)

The Framingham Heart Study


What is the molecular basis for use of a statin?

How is the statin working?


Statin Biochemistry

HMG-CoA Reductase

HMG CoA binding domain

tetrameric complex

Zoomed in view active site

positive hole

hydrophobicbinding site N

ONa

O

F

CH3

CH3

OH OH

CH4

1) One of the body’s most highly regulated enzymes

2) All statins are false substrates

Tetramic complex


You are what you eat

Be Afraid, Be Very Afraid

First step of therapy is always diet

20

All the Players• Cholesterol can’t dissolve in water (blood)

• Cholesterol only comes from animals– none in plants

• To dissolve and move Lipoproteins

5 complexes 4 key protein groups

• Good cholesterol = HDL• Bad cholesterol = LDL• A good (apoA) B bad (apoB)• Big good Small / dense bad

LDL

• Good cholesterol = HDL

• Bad cholesterol = LDL

• A good (apoA) B bad (apoB)

• Big good Small / dense bad


All the Players

• Cholesterol can’t dissolve in blood• Cholesterol only comes from

animals– none in plants

• To dissolve and move Lipoproteins 5 complexes 4 key protein groups• Good cholesterol Bad cholesterol• A good B bad• Big good Small / dense bad

• Bad fat Good fat

omega-3

cold water fish SMASH

plant, Olive , Canola unsaturated short chains

animal fat = bad trans fat


All the Players To dissolve and move Lipoproteins 5 complexes 4 key proteins groups

apo-proteins A BCE B


A lot of studies in elderly, statins benefited ~30%


Benefit seen

by 1 year


Primary EndpointPrimary EndpointPrimary EndpointPrimary Endpoint

CHD death, Nonfatal MI, Fatal or Nonfatal StrokeCHD death, Nonfatal MI, Fatal or Nonfatal Stroke

YearsYears

00

55

1010

1515

2020

PlaceboPlaceboEvents = 473/2913 (16.2%)Events = 473/2913 (16.2%)

PlaceboPlaceboEvents = 473/2913 (16.2%)Events = 473/2913 (16.2%)

PravastatinEvents = 408/2891 (14.1%)

PravastatinEvents = 408/2891 (14.1%)

% With Event

% With Event

15% RRR(P = 0.014)15% RRR(P = 0.014)

00 11 22 33

NNT = 48NNT = 48

PROSPER Study Group. Lancet. 2002; 360:1623-30.PROSPER Study Group. Lancet. 2002; 360:1623-30.


Prosper

The benefit of treatment in the elderly was the same as the benefit in the young


Improvement at all levels of LDL

• If divide patients byhigh, medium, and low LDLEvent reduction similar for each group

• Seen in Prosper• Seen in ALLHAT

• ALSO TREAT THE LOW LDL PATIENT ASCOT TRIAL


Fatal or Non-Fatal MI

Placebo (158/1460)

Cu

mu

lati

ve P

rop

ort

ion

of

Ev

ents

0.000

0.025

0.050

0.075

0.100

0 1 2 3 4 5

Year

Prava (125/1436)ASA (626/5833)

Prava+ASA(445/5888)

31%*RRR

*Relative Risk Reduction

Meta-analysis

Pravachol and Aspirin = Pravigard combination -- more than additive


Pharmacokinetics of HMG-CoA Reductase InhibitorsPharmacokinetics of HMG-CoA Reductase Inhibitors

Increased Conc. With Inhibitors Increased Conc. With Inhibitors HMG-CoAHMG-CoA

Octanol/H2OCoefficient

Octanol/H2OCoefficient CYP450CYP450

YesYesSimvastatinSimvastatin 65.065.0 3A4/2D63A4/2D6

NoNoPravastatinPravastatin 0.20.2 NoNo

YesYesAtorvastatinAtorvastatin 15.015.0 3A43A4

YesYesFluvastatinFluvastatin 22.022.0 2C92C9

YesYesLovastatinLovastatin 16.016.0 3A43A4


(cardiziem) (sporanox)


Effects of CYP 3A4 Inhibitors on Statin Serum ConcentrationsEffects of CYP 3A4 Inhibitors on Statin Serum Concentrations

00

55

1010

1515

VerapamilVerapamil ItraconazoleItraconazole ErythromycinErythromycin

3.9 x3.9 x5.0 x5.0 x

10 x10 xElevations in

Serum Concentrations

Versus Placebo*

Elevations in Serum

Concentrations Versus

Placebo*

Kantola T et al. Clin Pharmacol Ther. 1998;64:177-182. Neuvonen PJ et al. Clin Pharmacol Ther. 1998;63:322-341. Kantola T et al. Clin Pharmacol Ther. 1998;64:177-182. Neuvonen PJ et al. Clin Pharmacol Ther. 1998;63:322-341.

* Area under the concentration-time curve (AUC) of active simvastatin acid* Area under the concentration-time curve (AUC) of active simvastatin acid

SimvastatinSimvastatin


Effects of Advancing Age on Drug

Distribution and Metabolism

• Decreased protein binding• Increased volume of distribution

for lipophilic drugs• Decreased phase 1 (CPY 450) oxidation

Mayersohn M. Special Pharmacokinetic Considerations in the Elderly in: Evans WE et.al. Eds.Applied Pharmacokinetics: Principles of Therapeutic Drug Monitoring, 2nd edition.


MYOPATHY 1) lipid solubility

2) increase serum levels via 3A4 up to 20 x increase e.g.. 5x with verapamil 5 125

3) damage to the needed cholesterol, ubiquinone prenalated proteins myopathy muscle cell death

1) for elderly known risk factors include: 1) age 2) muscle mass 3) obesity 4) female 5) impaired renal status


Plavix

pro-drug activated by 3A4

Lipitor may diminish Plavix’s antiplatelet effect at least in the lab

1) Circulation 2003; 107: 1568-15692) Circulation 2003; 107: 32-37

3) Euro Heart J 24 (19) October 2003, 1744-1749 4) Circulation 2003;108:921-924


Pleiotropic Effects or non-Cholesterol effects

1. Unstable angina (stabilize plaque)

2. DM 30% less (Pravachol woscops )

3. Osteoporosis (reduced hip fractures)

4. Stroke (Vasodilation - NO) 5. Less dementia (maybe-conflicting data)


Statin Pleiotropic Effects or non-Cholesterol Effects

1. Decrease inflammation– decrease CRP2. Decrease lipid oxidation3. Decrease thrombosis4. Decrease transplant rejection

(routinely use with transplants)5. Increase endothelial medial vasodilation

increased nitrous oxide production6. Increased osteoblastic activity (reduced hip fx)


Statin Biochemistry

GTP enzyme anchors cell signaling proliferation production cytokines

thrombosis, inflammation, nitrous oxide production


So Many Choices, So Little Time

• 6 types options for present statins39

■


Prescription Options list

• 39 statin combinations• Statins vary by 1. Side effects

2. Potency for lipids 3. Potency for Plieotropic effects

4. Cost

• Geriatric– side effects may be the major issue how is it metabolized does it have the best pleiotropic effect cost is the statin proven to help in the elderly


Issues of Crestor in Elderly

1. lack of data

2. long half life

3. rhabdomyolysis

4. trouble clearing FDA

5. triple level in Asians

6. proteinuria

7. hematuria

8. to much suppression

9. 2C9

10. superpower in most fragile


The Real World

80 y/o woman drives to office for yearly checkup controlled hypertension on med, BP 130/80fixed income, never smoked, A-Fib on diltiaziem & coumadinweighs 110

2 children in the area

LDL=190 TC=260 HDL=60 TG=180

10 years on a statin vs. the cost of losing 2 years of good life to a nursing home


Risk Assessment: FHS Score for Men

<0 <10 11 12 13 14 15 26 27 38 49 5

10 611 812 1013 1214 1615 2016 25

17 30

Point Total10-Year

CHD Risk (%)

Low

Moderate

High

Risk Factor Points

1) Age 13

2) Total C 0

3) HDL-C 1

4) BP 2

5) Smoking 0

Point Total 16

www.nhlbi.nih.gov


PRO: Clinically Demonstrated

Pros and Cons of a Statin in Elderly

1. 19% MI

2. 15% all key vascular events

3. # to treat for benefit < 50

4. CRP

5. benefit seen by year 1

7. osteoporosis FX

8. dementia

9. diabetes 10. similar all tertiles of LDL

(even low LDL levels benefited)

11. transplant rejection


PRO: Demonstrated in Lab


1. thrombosis

2. endothelial function

3. osteoblasts clasts

4. Stabilize plaque

7. Inhibit PAI-1 which is primary inhibitor of fibrinolysis

8. Vasodilation NO


CON


1. Adverse drug-drug rxn

2. Cost

3. One more pill

4. Muscle problem

5. T killer cells

6. Liver / kidney insufficiency

7. Quality of life

8. > 1 year see benefit

9. Overall death rate =

10.Life expectancy

“Probably the most important single pathological process underlying disability in old age is atherosclerosis”

JC Brocklehurst. The Atlas of Geriatric Medicine


Prevent Heart Disease

Prevent Stroke

Increase length of life

Improve quality of life

Goals of Treating the Elderly


Clinical example RX age 80

Less time in nursing home ($57k / yr) VSCost & supervision

Selection: drug-drug / proven / cost

57statins treatment in the elderly

Superior doctors prevent the disease. Mediocre doctors treat the disease before evident. Inferior doctors treat the full-blown disease. --Huang Lee Nai-Ching (2600 BC, First Chinese Medical Text)

Prevention always the best treatment

Steven D. Atwood, M.D., FACP Internal Medicine, Springfield, MO [email protected] The Issue of...

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