Guidelines in refractory dyslipidemia treatment

1. Refractory dyslipoproteinemia
Pr dr M A. BADR
ALEX FAC OF MED
Pr Dr M A BADR

2. Six Aims for Improvement
• Safe – avoiding injuries to patients from the care that is intended to
help them.
• Effective – providing services based on scientific knowledge to all
who could benefit and refraining from providing services to those not
likely to benefit (avoiding underuse and overuse)
• Patient-centered – providing care that is respectful of and
responsive to individual patient preferences, needs and values and
ensuring that patients values guide all clinical decisions.
• Timely – reducing waits and sometimes harmful delays for both
those who receive and those who give care.
• Efficient – avoiding waste, including waste of equipment, supplies,
ideas and energy.
• Equitable – providing care that does not vary in quality because of
personal characteristics such as gender, ethnicity, geographic
location, and socio-economic status.

3. Persistence of Use of Lipid-Lowering
Medications A Cross-National Study
Jerry Avorn, MD; Johanne Monette, MD, MSc; Anne
Lacour, PhD; Rhonda L. Bohn, MPH; Mark Monane,
MD, MS; Helen Mogun, MS; Jacques LeLorier, MD,
PhD
JAMA. 1998;279:1458-1462.
Context.— Although clinical trials have
demonstrated the benefits of lipid-lowering therapy,
little is known about how these drugs are prescribed
Conclusion.— In all populations studied, patients who were
prescribed lipid-lowering drug regimens remained without
filled prescriptions for over a third of the study year on
average. Rates of persistence varied substantially with choice
of agent prescribed, comorbidity, and socioeconomic status,
despite universal coverage of prescription drug costs. After 5
years, about half of the surviving original cohort in the
United States had stopped using lipid-lowering therapy
altogether.

4. Types and Fields of adherence:
(simple or combinations)
I- In Medication
- total stop ( of one or more medicines)
- diminish or exceed dose
- change type - interrupted treatment.

5. II- In Dieting
- unrestricted (exceed total intake)
- errors in caloric distribution , number of meals
snacks, skip meals, irregular timing ,etc.
- Type: Over- intake of Fat , Sugar, etc (salt)

6. III- In Exercise:
basal – working – sports .
IV- In Other Behaviours:
( smoking--alcohol –drugs addictions--
contraindicated medications (eg. B Blockers).

7. Grades of Non adherence
Uncompliance :
- Minor and major
- Continuous or interrupted
- Single or multiple aspects

8. Diagnostic Approach to Uncompliance
A- Patient Factors :
1- Psychological state after recent discovery
( at stages of denial , revolt , despair ….)
2- Having wrong concepts and belief ( health locus , cause of
illness , distorted information.)
3- Nonspecific totalitarian lovers of opposing stand.
4- Slaves of their habits ( e.g. smoking , diet, exercise )
5- Transient depression from failing to achieve goals .
6- Transient stress : social , economic , inter-current illness.

9. B- Inadequate Education at Management
I- unclear objectives
Knowledge :,unsuitable,wrong priorities.
Skills : psychomotor , communication and cognitive .
Attitudes and Behaviors.
II- Inadequate methods :
(a) In providing knowledge :
- Too much , or unsuitable content in a presentation.
- Poor performance at the one-to-one education ( listen,
motivate, encourage, etc. ).
- In small group education: ( ignorance of group dynamics )
- In large group presentation: ( Inability to ensure active
participation of audience.)
- In mass media education: (inducing panic and confusion).
- Inadequate use of AV- aids ,and education facilities .

10. ( b) In teaching skills,
inadequate description--demonstration and exercise .
(c) Neglect of attitudes changes
through model inspiration (good & bad) , contacts ,
discussions. etc.
III- Absence of follow-up evaluation:
- pre and post testing
- follow up records of control parameters and compliance
- check lists of performance of skills
- rating scales for attitude changes

11. How to help patients manage
their dyslipidemia: A primary
care
physician–pharmacist team
intervention
Julie Villeneuve, MSc; Diane Lamarre,
MSc; Marie-Claude Vanier, MSc; Marie-
Thérèse Lussier,
MD, MSc; Jacques Genest Jr., MD,
FRCP(C); Eveline Hudon, MD, MClSc;
Lucie Blais, PhD;
Sylvie Perreault, PhD; Lyne Lalonde, PhD
C P J / R P C • S E P T E M B E R / OCTO B E R 2 0 0 7 • VOL 1 4 0 , N O 5

12. Training of all team members: An 8-hour
workshop was developed to familiarize
pharmacists
with:
1. The Canadian dyslipidemia treatment
recom -
mendations and dyslipidemia pharmaco
therapy26,27
2. The physician-pharmacist team
intervention
and the clinical tools
3. The monitoring and interpretation of
laboratory
tests
4. Adherence intervention strategies
Technical tools to facilitate adherence
Devices , I phone , reminder…….

13. Major drugs ineffective for many…
Hypertension Drugs 10-30%
ACE Inhibitors
Heart Failure Drugs 15-25%
Beta Blockers
Anti Depressants 20-50%
SSRIs
Cholesterol Drugs 30-70%
Statins
Asthma Drugs 40-70%
Beta-2-agonists
Source: Amy Miller, Personalized Medicine Coalition

14. Quantitative medicine is the key to
reducing healthcare costs and improving
healthcare outcomes
Non-responders,
toxic responders
Patients with same diagnosis Non-toxic responders
Misdiagnosed

15. Pharmacogenomics
The study of genome-derived data to predict a
body’s response to a drug or susceptibility to a
disease:
• Human genetic variation in DNA
– Single nucleotide polymorphisms (SNPs)
– Copy number differences
– Insertions
– Deletions
– Duplications
– Rearrangements
• RNA and protein expression differences

16. Affymetrix Microarrays
1.28cm
50um
~107 oligonucleotides,
half Perfectly Match mRNA (PM),
half have one Mismatch (MM)
Gene expression computed from
PM and MM

17. Affymetrix Microarray Raw
Image
Gene Value
D26528_at 193
D26561_cds1_at -70
D26561_cds2_at 144
D26561_cds3_at 33
D26579_at 318
D26598_at 1764
D26599_at 1537
D26600_at 1204
D28114_at 707
Scanner raw data
enlarged section of raw image

18. SNPs
• Occur when a single nucleotide (A,T,C,or G) in the
genome sequence is altered, e.g., AAGGCTAA to
ATGGCTAA
• Comprise 90% of all human genetic variation
• Exist every 100 to 300 bases along the 3-billion-base
human genome
• Found in both coding (i.e., gene) and noncoding regions
of the genome.
• Usually have no effect on cell function, but some could
predispose people to disease or influence their response
to a drug

19. The influence of SLCO1B1 (OATP1B1)
gene
polymorphisms on response to statin
therapy
SPR Romaine1, KM Bailey1,
AS Hall2 and AJ Balmforth1
1Division of Cardiovascular and Diabetes
Research, Leeds Institute of Genetics, Health and
Therapeutics, University of Leeds, Leeds, UK and
2Multidisciplinary Cardiovascular Research
Centre (MCRC), Leeds Institute of Genetics,
Health and Therapeutics, University of Leeds,
Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are
well established in the treatment of hypercholesterolaemia and the
prevention of coronary artery disease.

20. SNP
hepatocytes and recent interest has focused on genetic variation in hepatic
influx and efflux transporters for their potential to explain these differences.
In this review we explore current literature regarding the pharmacokinetic
and pharmacodynamic influence of the common c.388A4G and c.521T4C
single-nucleotide polymorphisms (SNPs) within the solute carrier organic
anion transporter 1B1 (SLCO1B1) gene, encoding the organic anion
transporter polypeptide 1B1 (OATP1B1) influx transporter. We discuss their
potential to predict the efficacy of statin therapy and the likelihood that
patients will experience adverse effects.
The Pharmacogenomics Journal (2010)

21. An association study of 43
SNPs in 16 candidate
genes with atorvastatin
response
ABSTRACT
Variation in individual response to statin
therapy has been widely studied for
a potential genetic component. Multiple
genes have been identified as
potential modulators of statin response, but
few study findings have
replicated.
The Pharmacogenomics Journal (2005) 5,
352–358
& 2005 Nature Publishing Group All rights
reserved 1470-269X/05 $30.00
www.nature.com/tpj

22. Pharmacogenomics blames the
patient, NOT the drugs…
• Treatment failure
• Toxicity
• Adverse events

23. Don’t blame my genes!!!
• Make a good drug
New paradigm of research should focus
on molecular targets
Drug structure
• Focus on lifestyle changes
• Therapeutic drug monitoring
• Patient counseling, error reporting
• Increase healthcare availability first

24. What are effective medication combinations for dyslipidemia?
Joseph Saseen, PharmD, FCCP; Elizabeth Tweed , BSN, MLIS University of Colorado at Denver and Health Sciences

25. LDL - HYPERCHOLEST
TARGET VALUES NOT
STATIN
ACHIEVED
NOT COMBINATION WITH
TOLERATED EZETIMIBE
TARGET
ACHIEVED AND
TOLERATED EZETEMIBE
ADDITITIONAL
BILE ACID BINDING
BILE ACID
BINDING RESIN
LDL-APHERESIS
FIBRATE/
CAD
NIACIN

26. HYPERTRIGLICEREDEMIA
LIFE STYLE MODIFICATION
SECONDARY CAUSES; ALCOHOL,DIABETES,OBESITY
FIBRATE TARGET VALUES NOT
ACHIEVED
TARGET
VALUES NOT
ACHIEVED TOLERATED
AND WELL
TOLERATED CONSIDER
STATIN
COMBINATION
WITH NIACIN
NIACIN

27. COMBINED HYPERLIPOPROT
LIFE STYLE MODIFICATION
STATIN
POSIBLE COMBINATION
STATIN WITH NICOTINIC
TARGET NOT ACHIEVED
FIBRATE WITHG NICOTINIC
FIBRATE FIBRATE WITH EZETIMIBE
AND
STATIN WITH FIBRATE

28. Lp(a) hyperlipoproteinemia
OPTIMIZE CARDIOVASCULAR RISK FACTORS
ATHEROSCLEROSIS
NO
ATHEROSCLEROSIS
STATIN
COMBINATION
STATIN
WITH NIACIN
CAD WORSEN CONSIDER
APHERESIS

29. DIABETIC
DYSLIPOPROTEINEMIA
GLUCOSE CONTROL
ISOLATED COMBINED HLP
HYPERTRIGLYCERIDEMIA LDL-HYPERCHOLEST
STATIN
FIBRATE
TARGET NOT ACHIEVED
INCREASE STATIN + STATIN + STATIN+
STATIN EZETEMIBE NIACIN fibrate

30. Apheresis
• What can transfusion medicine offer to
patients with hypercholesterolemia?
Recent advances in affinity column
technology now enable the efficient
removal of LDL-cholesterol directly from
the bloodstream by apheresis. This new
therapeutic tool may reduce the risk of
progressive atherosclerotic disease in
hypercholesterolemic patients who are
resistant to diet and drugs

31. Non-HDL Cholesterol
(Non-HDL Chol = TC - HDL)
• Known predictor of CHD in
epidemiology
• Equivalent to total apo B-100, and
TC/HDL
• Represents the sum of LDL, Lp(a),
IDL, and VLDL: All atherogenic apo B
containing lipoproteins
• Accounts for 50% of the CHD risk
reduction provided by HDL

32. HMG CoA Reductase
Inhibitors (Statins)
Statin Dose Range
Lovastatin 20–80 mg
Pravastatin 20–40 mg
Simvastatin 20–80 mg
Fluvastatin 20–80 mg
Atorvastatin 10–80 mg
Cerivastatin 0.4–0.8 mg

34. APHERESIS

35. APHERESIS

36. AUTOLOGOUS DELIPIDATED HDL
• HDL Therapy Via Plasmapheresis
• A First-In-Man, Randomized, Placebo-
Controlled Study to
• Evaluate the Safety
• and Feasibility of Autologous
Delipidated HDL Plasma Infusions
• in Patients with Acute Coronary
Syndrome

37. WASHINTON HOSPITAL CENTER
• Ron Waksman, MD; Kenneth Kent, MD, PhD;
Augusto Pichard,
• MD; William Suddath, MD; Lowell Satler, MD;
Dianne Martin,
• RN; Timothy Perlman; Dale Richardson, MBA;
Jo-Ann Maltais,
• PhD; Patricia Landry, MBA; Rebecca Torguson,
MPH; Neil J.
• Weissman, MD; Peter Fitzgerald, MD; H. Bryan
Brewer, MD

38. Delipidated" HDL
• Delipidated" HDL: A new option for plaque
regression?
Other studies have established that increasing
pre-beta HDL increases cholesterol efflux and
that pre-beta HDL is the most effective form of
HDL for lipid removal from arterial plaque via
reverse cholesterol transport. Plasma
delipidation, through apheresis, converts alpha
HDL to pre-beta HDL and in theory may lead to
regression of atherosclerosis

39. Table: Change in IVUS parameters, Post delipidation treatments minus baseline ACS presentation.

40. Principle of LDL apheresis
• . LDL apheresis works by leading
venous blood through a collumn coated
with antibodies to apolipoprotein B (the
main protein of LDL particles), dextran
sulphate or polyacrylate , or by
precipitating LDL with heparin at low pH

41. Autologous plasma delipidation
using a continuous flow
• Autologous plasma delipidation using a continuous flow
system
• United States Patent 4895558
• A method and apparatus for autologous plasma delipidation of
animals (including humans). The method comprises drawing blood
from the animal, separating the plasma from the red blood cells,
delipidating the plasma with a lipid solvent, remixing the delipidated
with the red blood cells and re-introducing the delipidated blood into
the animal. A preferred apparatus which utilizes the above method
comprises a needle for drawing blood from the animal and the blood
is then fed into a centrifugal separator where the blood is separated
into the plasma and red blood cells. The plasma is then mixed with a
biphase solvent and passed through a separator where the
delipidated plasma (in an aqueous phase) is drawn off from the lipid
components (in an organic phase). After removal of solvent, the
delipidated plasma is remixed with the red blood cells and re-
introduced to the animal by a re-infusion needle.