Refractory dyslipoproteinemia

Pr dr M A. BADR

ALEX FAC OF MED

Pr Dr M A BADR

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.

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.

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

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.

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)

III- In Exercise:

basal – working – sports .

IV- In Other Behaviours:

( smoking--alcohol –drugs addictions--

contraindicated medications (eg. B Blockers).

Grades of Non adherence Uncompliance :

- Minor and major

- Continuous or interrupted

- Single or multiple aspects

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.

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 .

( 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

How to help patients managetheir dyslipidemia: A primary carephysician–pharmacist teaminterventionJulie 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

Training of all team members: An 8-hourworkshop was developed to familiarize pharmacistswith:1. The Canadian dyslipidemia treatment recom -mendations and dyslipidemia pharmaco therapy26,272. The physician-pharmacist team interventionand the clinical tools3. The monitoring and interpretation of laboratorytests4. Adherence intervention strategies

Technical tools to facilitate adherenceDevices , I phone , reminder…….

Asthma Drugs 40-70%Beta-2-agonists

Hypertension Drugs 10-30%ACE Inhibitors

Heart Failure Drugs 15-25% Beta Blockers

Anti Depressants 20-50%SSRIs

Cholesterol Drugs 30-70% Statins

Major drugs ineffective for many…

Source: Amy Miller, Personalized Medicine Coalition

Quantitative medicine is the key to reducing healthcare costs and improving

healthcare outcomes

Patients with same diagnosis

Misdiagnosed

Non-responders,toxic responders

Non-toxic responders

PharmacogenomicsThe 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

Affymetrix Microarrays

50um

1.28cm

~107 oligonucleotides,half Perfectly Match mRNA (PM), half have one Mismatch (MM)Gene expression computed from PM and MM

Affymetrix Microarray Raw Image

Gene ValueD26528_at 193D26561_cds1_at -70D26561_cds2_at 144D26561_cds3_at 33D26579_at 318D26598_at 1764D26599_at 1537D26600_at 1204D28114_at 707

Scannerenlarged section of raw image

raw data

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

The influence of SLCO1B1 (OATP1B1) genepolymorphisms on response to statin therapy

SPR Romaine1, KM Bailey1,AS Hall2 and AJ Balmforth11Division of Cardiovascular and DiabetesResearch, Leeds Institute of Genetics, Health andTherapeutics, University of Leeds, Leeds, UK and2Multidisciplinary Cardiovascular ResearchCentre (MCRC), Leeds Institute of Genetics,Health and Therapeutics, University of Leeds,

Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) arewell established in the treatment of hypercholesterolaemia and theprevention of coronary artery disease.

hepatocytes and recent interest has focused on genetic variation in hepaticinflux and efflux transporters for their potential to explain these differences.In this review we explore current literature regarding the pharmacokineticand pharmacodynamic influence of the common c.388A4G and c.521T4Csingle-nucleotide polymorphisms (SNPs) within the solute carrier organicanion transporter 1B1 (SLCO1B1) gene, encoding the organic aniontransporter polypeptide 1B1 (OATP1B1) influx transporter. We discuss theirpotential to predict the efficacy of statin therapy and the likelihood thatpatients will experience adverse effects.The Pharmacogenomics Journal (2010)

SNP

ABSTRACTVariation in individual response to statin therapy has been widely studied fora potential genetic component. Multiple genes have been identified aspotential modulators of statin response, but few study findings havereplicated.

An association study of 43 SNPs in 16 candidategenes with atorvastatin response

The Pharmacogenomics Journal (2005) 5, 352–358& 2005 Nature Publishing Group All rights reserved 1470-269X/05 $30.00www.nature.com/tpj

Pharmacogenomics blames the patient, NOT the drugs…

• Treatment failure• Toxicity• Adverse events

Don’t blame my genes!!!

• Make a good drugNew paradigm of research should focus on molecular

targetsDrug structure

• Focus on lifestyle changes

• Therapeutic drug monitoring

• Patient counseling, error reporting

• Increase healthcare availability first

What are effective medication combinations for dyslipidemia?

Joseph Saseen, PharmD, FCCP; Elizabeth Tweed, BSN, MLIS University of Colorado at Denver and Health Sciences

LDL - HYPERCHOLEST

TARGETACHIEVED AND

TOLERATED

STATIN

NOT TOLERATED

EZETEMIBE

BILE ACIDBINDING RESIN

FIBRATE/NIACIN

TARGET VALUES NOTACHIEVED

COMBINATION WITHEZETIMIBE

ADDITITIONALBILE ACID BINDING

LDL-APHERESISCAD

HYPERTRIGLICEREDEMIA

LIFE STYLE MODIFICATION SECONDARY CAUSES; ALCOHOL,DIABETES,OBESITY

TARGET VALUES

ACHIEVEDAND WELL

TOLERATED

FIBRATE

NOT TOLERATED

STATIN

NIACIN

TARGET VALUES NOT ACHIEVED

CONSIDER COMBINATIONWITH NIACIN

COMBINED HYPERLIPOPROT

LIFE STYLE MODIFICATION

STATIN

TARGET NOT ACHIEVED

FIBRATE

POSIBLE COMBINATION

STATIN WITH NICOTINIC

FIBRATE WITHG NICOTINIC

FIBRATE WITH EZETIMIBEAND

STATIN WITH FIBRATE

Lp(a) hyperlipoproteinemia

OPTIMIZE CARDIOVASCULAR RISK FACTORS

NOATHEROSCLEROSIS

STATIN

ATHEROSCLEROSIS

STATIN

COMBINATION WITH NIACIN

CAD WORSEN CONSIDERAPHERESIS

DIABETIC DYSLIPOPROTEINEMIA

GLUCOSE CONTROL

ISOLATED HYPERTRIGLYCERIDEMIA

FIBRATE

COMBINED HLPLDL-HYPERCHOLEST

STATIN

TARGET NOT ACHIEVED

INCREASESTATIN

STATIN +EZETEMIBE

STATIN + NIACIN

STATIN+fibrate

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

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

HMG CoA Reductase Inhibitors (Statins)

Statin Dose Range

Lovastatin 20–80 mgPravastatin 20–40 mgSimvastatin 20–80 mgFluvastatin 20–80 mgAtorvastatin 10–80 mgCerivastatin 0.4–0.8 mg

APHERESIS

APHERESIS

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

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

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

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

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

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.