The Issue of Treating

Cholesterol

in the Elderly

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

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 statins treatment in the elderly 2

Clipped From the Headlines

statins treatment in the elderly 3

The Real World

“I’m Old But I’m Not Dead Yet”

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 statins treatment in the elderly 4

Today’s Goal

• Should I Treat • Why • Which Statin

statins treatment in the elderly 5

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,

CRP Myeloperoxidase

proliferative, thrombotic

Fibrinogen PAI disease that occurs in response to

risk factor activation

of the

endothelium

.

Nitrous Oxide

Cholesterol

and specifically

oxidized LDL

forms the bulk of the plaque 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

8 statins treatment in the elderly

Development of Atherosclerotic Plaques

Fatty streak Normal Lipid-rich plaque Foam cells Fibrous cap Lipid core Thrombus statins treatment in the elderly 9

statins treatment in the elderly 10

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Vulnerable vs. Stable Atherosclerotic Plaques Lumen Fibrous Cap Lipid Core

Like Diabetic

Vulnerable Plaque

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

Stable Plaque

by statins

Lumen Lipid Core Fibrous Cap

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

statins treatment in the elderly • Thick fibrous cap • Smooth muscle cells: more extracellular matrix • Lipid-poor plaque Lot of Plaque before occlude lumen 12

Lower Cholesterol Levels Associated With Lower CHD Risk 150 125 100 75 50 The Framingham Heart Study 25 0



204 205-234 235-264 265-294



295 Serum Cholesterol (mg/100 mL)

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

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statins treatment in the elderly 14

What is the molecular basis for use of a statin?

How is the statin working?

15 statins treatment in the elderly

statins treatment in the elderly

Statin Biochemistry

16

HMG-CoA Reductase

Zoomed in view active site most highly regulated enzymes positive hole 2) All statins are false substrates tetrameric complex hydrophobic binding site Tetramic complex F CH 4 N H O CH 3 CH 3 OH O ONa

statins treatment in the elderly 18

You are what you eat

Be Afraid, Be Very Afraid First step of therapy is always diet

statins treatment in the elderly 19

All the Players

• Cholesterol can’t dissolve in water (blood) • Cholesterol only comes from animals–

none in plants

• • To dissolve and move Lipoproteins •

Bad cholesterol = LDL

• • Bad cholesterol = LDL

A good (apoA) B bad (apoB)

•

Big good Small / dense bad

LDL 20

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

21 statins treatment in the elderly

All the Players

To dissolve and move Lipoproteins 5 complexes 4 key proteins groups

apo-proteins A BCE B 22 statins treatment in the elderly

A lot of studies in elderly, statins benefited ~30% statins treatment in the elderly 23

statins treatment in the elderly 24

statins treatment in the elderly

Benefit seen by

1 year

25

Primary Endpoint

CHD death, Nonfatal MI, Fatal or Nonfatal Stroke 20 15 Placebo Events = 473/2913 (16.2%) 15% RRR (P = 0.014) % With Event 10 5 Pravastatin Events = 408/2891 (14.1%) NNT = 48 0 0 1 2 Years 3

statins treatment in the elderly

Prosper

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

27 statins treatment in the elderly

Improvement at all levels of LDL

• If divide patients by high, medium, and low LDL Event reduction similar for each group • Seen in Prosper • Seen in ALLHAT • ALSO TREAT THE LOW LDL PATIENT ASCOT TRIAL statins treatment in the elderly 28

Pravachol and Aspirin = Pravigard 0.100

combination -- more than additive Fatal or Non-Fatal MI

Placebo

(158/1460)

ASA

(626/5833)

Prava

(125/1436)

0.075

31%* RRR 0.050

Prava+ASA

(445/5888)

0.025

0.000

0 * Relative Risk Reduction 1

statins treatment in the elderly

2 Year 3 4 5

Meta-analysis 29

statins treatment in the elderly 30

Pharmacokinetics of HMG-CoA Reductase Inhibitors HMG-CoA Octanol/H 2 O Coefficient CYP450 Increased Conc.

With Inhibitors Simvastatin Lovastatin Pravastatin Atorvastatin Fluvastatin 65.0

16.0

0.2

15.0

22.0

3A4/2D6 3A4 No 3A4 2C9 Yes Yes No Yes Yes

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statins treatment in the elderly 32

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statins treatment in the elderly (cardiziem) (sporanox) 34

Effects of CYP 3A4 Inhibitors on Statin Serum Concentrations Simvastatin 15 10 x Elevations in Serum Concentrations Versus Placebo* 10 5 3.9 x 5.0 x 0 Verapamil Itraconazole Erythromycin * Area under the concentration-time curve (AUC) of active simvastatin acid

Kantola T et al.

Clin Pharmacol Ther

. 1998;64:177-182. Neuvonen PJ et al.

Clin Pharmacol Ther.

1998;63:322-341.

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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.

statins treatment in the elderly 38

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 statins treatment in the elderly 39

Plavix

pro-drug activated by 3A4 Lipitor may diminish Plavix’s antiplatelet effect at least in the lab 1) Circulation 2003; 107: 1568-1569 2) Circulation 2003; 107: 32-37 3) Euro Heart J 24 (19) October 2003, 1744-1749 4) Circulation 2003;108:921-924 40 statins treatment in the elderly

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) statins treatment in the elderly 41

Statin Pleiotropic Effects or non-Cholesterol Effects

1. Decrease inflammation– decrease CRP 2. Decrease lipid oxidation 3. Decrease thrombosis 4. Decrease transplant rejection (routinely use with transplants) 5. Increase endothelial medial vasodilation increased nitrous oxide production 6. Increased osteoblastic activity (reduced hip fx) statins treatment in the elderly 42

statins treatment in the elderly

Statin Biochemistry

GTP enzyme anchors cell signaling proliferation production cytokines

thrombosis, inflammation, nitrous oxide production

43

So Many Choices, So Little Time

■ statins treatment in the elderly 44

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 statins treatment 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 statins treatment in the elderly 46

The Real World

80 y/o woman drives to office for yearly checkup controlled hypertension on med, BP 130/80 fixed income, never smoked, A-Fib on diltiaziem & coumadin weighs 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 statins treatment in the elderly 47

statins treatment in the elderly 48

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Risk Assessment: FHS Score for Men

Risk Factor 1) Age 2) Total C 3) HDL-C Points 13 0 1 4) BP 5) Smoking Point Total 2 0 16 www.nhlbi.nih.gov

statins treatment in the elderly

Point Total <0 11 12 13 14 15 16



17 8 9 10 5 6 7 0 1 2 3 4 10-Year CHD Risk (%) <1 8 10 12 16 20 25



30 1 1 1 1 1 2 2 3 4 5 6 Low Moderate High

50

Pros and Cons of a Statin in Elderly PRO:

Clinically Demonstrated 1. 19%  2. 15%  MI all key vascular events 7.

8.

9.

   osteoporosis FX dementia 3.

# to treat for benefit < 50 diabetes 4.

 CRP 10.

 similar all tertiles of LDL

(even low LDL levels benefited)

5. benefit seen by year

1 11.

 transplant rejection 51 statins treatment in the elderly

Pros and Cons of a Statin in Elderly PRO

: Demonstrated in Lab 1.

2.

3.

   thrombosis endothelial function osteoblasts  clasts

4. Stabilize plaque

7. Inhibit PAI-1

which is primary inhibitor of fibrinolysis

8.

 Vasodilation  NO 52 statins treatment in the elderly

Pros and Cons of a Statin in Elderly CON

1. Adverse drug-drug rxn 7. Quality of life 2. Cost 8. > 1 year see benefit 3. One more pill 9. Overall death rate = 4. Muscle problem 5.

 T killer cells 10.Life expectancy 6. Liver / kidney insufficiency 53 statins treatment in the elderly

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

JC Brocklehurst. The Atlas of Geriatric Medicine

Goals of Treating the Elderly



Prevent Heart Disease



Prevent Stroke



Increase length of life



Improve quality of life

statins treatment in the elderly 55

Clinical example RX age 80

Less time in nursing home ($57k / yr) VS Cost & supervision Selection: drug-drug / proven / cost statins treatment in the elderly 56

Prevention always the best treatment 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) statins treatment in the elderly 57