Pharmacotherapy of Dyslipidemias

Pharmacotherapy of
Dyslipidemias
Dr. Aditi M. Panditrao
July 1st 2015
2Dr. Aditi M. Panditrao

Terms
• Lipids
• Neutral Lipids – Cholesterol, Triglyceride
• Lipoproteins – Spherical particles of water-soluble proteins,
that transport neutral lipids through body fluids.
• Chylomicrons
• VLDL
• LDL
• HDL
• LP(a)
• Lipoprotein (a) – additional Apo-A with Apo-B 100.

Terms
• Apolipoproteins – Provide structural stability to the
lipoproteins and also may function as ligands in lipoprotein–
receptor interactions or as cofactors in enzymatic processes
that regulate lipoprotein metabolism
• Lipoprotein Lipase – hydrolyses triglycerides in the
lipoproteins to release FFA for the energy requirements of the
muscle and deposition in the adipose tissue

Types of Cholesterol
LDL- (“bad” cholesterol) The major cholesterol carrier in the blood. Excess
most likely to lead to plaque formation. Goal: LOW
HDL- (“good” cholesterol) Transports cholesterol away from arteries and
back to the liver to be eliminated. Removes excess cholesterol from
plaques, slowing growth. Goal: HIGH
Triglycerides- the chemical form in which most fat exists in foods as
well as in the body. Made in the body from other energy sources like
carbohydrates. Calories ingested in a meal and not immediately used by
tissues are converted to triglycerides.

Small Dense LDL
• Longer residence time in plasma than normal sized LDL due to
decreased recognition by receptors in liver
• More susceptible to oxidation due to decreased antioxidants in the
core
• Enter and attach more easily to arterial wall
• Endothelial cell dysfunction

Lipoprotein Transport
• Regulation of lipids in body
• Liver – center
• Cholesterol derived from –
• Diet (Intestines)
• VLDL, LDL (Liver)
• HMG Co A reductase pathway (Liver)
• Transport of CH from intestines – Exogenous
• Transport of CH from liver – Endogenous

..Lipids and Lipoproteins - Part 2 (Exogenous Pathway).flv
12
Apo B-48

..Lipids and Lipoproteins - Part 3 (Endogenous Pathway).flv
13
Apo B-100

..HDL & Reverse Cholesterol Transport [HD].flv 15
Apo A-1

HMG Co A Reductase Pathway

Dyslipidemias
• Disorders of metabolism of lipoproteins,
including lipoprotein over production and
deficiency
• Manifests as –
• Elevated Total Cholesterol (TC)
• Elevated Low-density lipoproteins (LDL)
• Elevated triglycerides (TG)
• Decreased High-density lipoproteins (HDL)

Etiology
• Primary –
• single or multiple gene mutation –resulting in
disturbance of LDL, HDL and Trigylceride,
production or clearance
• Should be suspected in patients with
• premature heart disease
• family hx of atherosclerotic dx.
• serum cholesterol level >240mg/dl.
• Physical signs of hyperlipidemia

Etiology
• Secondary –
• Sedentary lifestyle
• Excessive consumption of cholesterol – saturated
fats and trans-fatty acids.
• Most adult cases of dyslipidemia are secondary in
nature in western civilizations

Selected Causes of Secondary Dyslipidemia
Increased LDL cholesterol
level
Diabetes mellitus
Hypothyroidism
Nephrotic syndrome
Obstructive liver disease
Drugs
Anabolic steroids
Progestins
Beta-adrenergic blockers
(without intrinsic
sympathomimetic action)
Thiazides
Increased triglyceride level
Alcoholism
Diabetes mellitus
Hypothyroidism
Obesity
Renal insufficiency
Drugs
(without intrinsic
Bile acidbinding resins
Estrogens
Ticlopidine
Decreased HDL cholesterol
level
Cigarette smoking
Diabetes mellitus
Hypertriglyceridemia
Menopause
Obesity
Puberty (in males)
Uremia
Drugs
Anabolic steroids
(without intrinsic
Progestins
LDL=low-density lipoprotein; HDL=high-density lipoprotein.
Adapted with permission from Schaefer EJ. Diagnosis and management of lipoprotein disorders. In: Rifkind BM, ed. Drug

Consequences
• Coronary Artery Disease
• Cerebrovascular disease
• Peripheral Vascular Disease
• Renal Artery Disease
• Liver Diseases
• Dermatological manifestations

Classification

Drugs
• HMG Co A Reductase Inhibitors
• The Statins
• Bile Acid Sequestrants (Resins)
• Cholestyramine, Colestipol
• Lipoprotein Lipase Activators
• Fibrates
• Lipolysis and TG synthesis inhibitor
• Nicotinic Acid
• Sterol Absorption Inhibitors
• Ezetimibe
• CETP Inhibitors
• Others

Statins
HMG Co A
Mevalonate
HMG Co A Reductase
Cholesterol
↓ Cholesterol
Sterol Regulatory Element
binding Proteins (ER)
↑ expression of LDL receptors
↑ endocytosis of LDL
↓ Serum LDL, (↑ HDL), ↓ TG

• Dose dependant effects on plasma lipids –
• Atorvastatin –
• 10 mg – LDL ↓ 30-35%,
• 20 mg – LDL ↓ 40%
• 40 mg – LDL ↓ 45%
• 80 mg – LDL ↓ 55%
• Peak LDL lowering – 1-2 weeks after initiation
• Effective in all types of hyperlipidemias

Adverse Effects
• Muscle pain/spasms
• Rhabdomyolysis
• Rashes
• GI upset
• ↑ serum transaminases
• Sleep disturbances – Lovastatin
• C/I - Pregnancy
Fluvastatin, Rosuvastatin

Bile Acid Binding Resins
Liver – Bile Acids
Duodenum
Absorption of
dietary fats
Reabsorbed Bile Acid Binding Resins
Bile Acid + Resin complex
excreted
↑ BA Synthesis from CH
Hepatic CH depletion
Endocytosis of LDL
↓ Serum LDL, ↑ HDL and TG

Individual Agents
• Cholestyramine, Colestipol, Colesevelam
• Granular form – unpalatable
• A/E – Constipation, hemorrhoids, GI distress

Fibrates
32
Activation PPAR – α
↑ Lipoprotein Lipase
Synthesis
↓ expression of
Apo C III
↑ expression of
Apo A I
↑ Hydrolysis and
removal of TG from
VLDL
↑ LPL Activity
(Apo C III – LPL
inhibitor)
↑ Reverse Cholesterol
Transport (HDL)
↑ Hepatic Fatty Acid
Oxidation - ↓ TG
Convert SD-LDL to
less dense LDL

• Gemfibrozil, Benzafibrate, Fenofibrate
• A/E -
• GI symptoms like nausea, dyspepsia & abdominal
pain
• Myositis & rhabdomyolysis: more common with
gemfibrozil specially combination with statins
• Gallstones

Nicotinic Acid

• Comes in 3 forms:
• Immediate release crystalline form: Causes flushing
• Sustained release: less flushing but maximum dose 2
gm to prevent liver toxicity
• Extended release: New drug, Niaspan is extended
release formula better than other forms due to less
side effects
• A/E –
• Cutaneous flush
• GI discomfort, dryness of skin, blurred vision,
cholestasis, hyperuricemia, hepatic dysfunction

Ezetimibe

CETP Inhibitors

• Anacetrapib, Torcetrapib
• Anacetrapib –
• Clinical trial IIB Merck
• 8 week trial, ↓ LDL, ↑ HDL
• 44% (10 mg), 86% (40 mg), 139% (150 mg),
133% (300 mg)
• Clinical trial III (DEFINE) Merck
• LDL ↓ – 39.8%
• Lp (a) ↓ – 36.4%
• HDL ↑ – 138%

Others
• Gugulipid – guggul gum
• ↓ CH biosynthesis, ↑ excretion
• Omega-3 Fatty acids –
• PUFA – eicosa-pentanoic and docosa hexanoic acid
• Anti-inflammatory and antioxidant action
• Walnut, edible seeds and nuts, clary sage seed oil, algal
oil, flaxseed oil, Sacha Inchi oil, Echium oil, and hemp oil,
fish oils, egg oil, squid oils, and krill oil

CH and CAD
• Higher Cholesterol = Higher Risk
• US National Cholesterol Education Programme
(NCEP)

• Lifestyle Modification
• Treatment based on
• LDL level
• HDL level
• TG level
• Associated CAD risk factor(s) or existing CAD
or its equivalent

Therapeutic Life Style Changes
Nutrient Recommended intake
Total fat 25-35% of total calories
Saturated fat < 7% of total calories
Polyunsaturated fat Up to 10% of total calories
Monounsaturated fat Up to 20% of total calories
Carbohydrates 50-60% of total calories
Fiber 20-30 g/day
Cholesterol < 200 mg/day
Protein 15% of total calories

Other life style changes include:
• Weight reduction specially in overweight
patients (reduce 10% in the first 6 months)
• Increase physical activity
• Smoking, Alcohol cessation

Hyperlipidemia Diet
• Whole Grain diet
• Fiber –
• Beans, legumes, barley and lentils
• Fruits - strawberries or cantaloupe
• Tomatoes
• Salt and Sugar avoidance
• Alcohol avoidance
• Omega 3 rich fish meals per week – salmon, trout, sardines
• Vitamin B supplements

Risk Assessment
• To decide how aggressively to treat the
patient
• CHD or CHD risk equivalent (regardless of number
of risk factors) using NCEP ATP III definition of CHD
& CHD risk equivalent
• ≥ 2 risk factors with no CHD & no CHD risk
equivalent using NECP ATP III major risk factors
that modify LDL goals
• Assess CHD risk with Framingham Point Score

High LDL

Drugs implemented
• Drug of Choice – Statins
• Alternative - Niacin, Resins or Ezetimibe
• Combination –
• Statin + Niacin
• Statin + Ezetimibe
• Statin + Resin

High LDL and TG
• Drug of Choice – Statins
• Combination –
• Statin + Niacin
• Statin + Ezetimibe
• Statin + Resin

High TG
• Drug of Choice –
Fibrates or Niacin
• Combination –
• Fibrate + Statin
• Niacin + Statin
• Fish oil

Normal LDL, Low HDL
• CH:HDL - ≤ 3.5 If > 4.5 -
• Drug of Choice – None (Niacin)
• Combination –
• Niacin + Fibrate
• Niacin + Fibrate + Statin

ATP IV
• Persistent questions in ATP III –
– How reliable is FPS?
– Special populations – Children, Pregnant Females,
Kidney disease, Patients with organ transplants
– Inclusion of Inflammatory markers in risk
assessment
– CETP Inhibitors?

Recent Advances
• CETP Inhibitors
• Proprotein convertase subtilisin/kexin type 9
(PCSK9) Inhibitors
• Mipomersen - an apolipoprotein B (ApoB)
synthesis inhibitor
• Lomitapide - inhibitor of microsomal triglyceride
transfer protein

Thank You!!

References
• Papadakis, Maxine. Current Medical Diagnosis & Treatment 2014. Ed.
Stephen J. McPhee. McGraw-Hill Education, 2014
• KD Tripathi; Essentials of Medical Pharmacology (7th ed), JP Medical
Publishers, New Delhi (2014), pp. 282-295
• Yamamoto, E., Nishimura, H., & Hirono, Y. (1987). 2014 AHA/ACC/HRS
Guideline for the Management of Patients With Atrial Fibrillation:
Executive Summary 104(S446), 93-96.
• Sullivan FM, Swan IR, Donnan PT, et al 2013 ACC/AHA Guideline on the
Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular
Risk in Adults N Engl J Med. 2007;357:1598–1607.
• Giri P, Garg RK, Singh MK, Verma R, Malhotra HS, Sharma PK.
Cardiovascular risk assessment and the modification of blood lipids for the
primary and secondary prevention of cardiovascular disease: Indian J
Pharmacol 2015;47:143-7.
• Baugh, RF; Basura, GJ; Ishii, LE; Schwartz, SR; Drumheller, CM; Burkholder,
R; Deckard, NA; Dawson, C; Driscoll, C; Gillespie, MB; Gurgel, RK; Halperin,
J; Khalid, AN; Kumar, KA; Micco, A; Munsell, D; Rosenbaum, S; Vaughan, W
(November 2013). Cholesterol Synthesis, Absorption, Metabolism,
Fate: 149 (5): 656–63.doi:10.1177/0194599813506835

References
• Ahmed A (2005 2014 AHA/ACC/HRS Guideline for the Management of
Patients With Atrial Fibrillation: Cleve Clin J Med 72 (5): 398–401, 405.
doi:10.3949/ccjm.72.5.398
• Peitersen E (1982). " Pharmacotherapy of Dyslipidemia ". Am J Otol 4(2):
107–11. PMID 7148998. quoted in Roob G, Fazekas F, Hartung HP; Fazekas;
Hartung (1999).
• Lee HY, Byun JY, Park MS, Yeo SG. 2014 AHA/ACC/HRS Guideline for the
Management of Patients With Atrial Fibrillation: Executive Summary Am J
Med 2013;126:336-41.
• Nicastri M, Mancini P, De Seta D, Bertoli G, Prosperini L, Toni D, et al. Effi
cacy of early physical therapy CAD: A randomized controlled trial.
Neurorehabil Neural Repair 2013;27:542-51.

Pharmacotherapy of Dyslipidemias

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