1. Applied Therapeutics Dr. Riyadh Mustafa Al-Salih
Dyslipidemia
Applied Therapeutics
Dr. Riyadh Mustafa Al-Salih

2. DEFINITION
Dyslipidemia is defined as elevated total cholesterol, low-density lipoprotein (LDL) cholesterol, or triglycerides; low high-density lipoprotein (HDL) cholesterol; or a combination of these abnormalities.

3. PATHOPHYSIOLOGY
Cholesterol, triglycerides, and phospholipids are transported in blood as complexes of lipids and proteins (lipoproteins). Elevated total and LDL cholesterol and reduced HDL cholesterol are associated with development of coronary heart disease (CHD).
Risk factors such as oxidized LDL, mechanical injury to endothelium, and excessive homocysteine can lead to endothelial dysfunction and cellular interactions culminating in atherosclerosis. Eventual clinical outcomes may include angina, myocardial infarction (MI), arrhythmias, stroke, peripheral arterial disease, abdominal aortic aneurysm, and sudden death.

4. PATHOPHYSIOLOGY
Atherosclerotic lesions arise from transport and retention of plasma LDL through the endothelial cell layer into the extracellular matrix of the subendothelial space.
Once in the artery wall, LDL is chemically modified through oxidation and nonenzymatic glycation.
Mildly oxidized LDL recruits monocytes into the artery wall, which transform into macrophages that accelerate LDL oxidation. Oxidized LDL provokes an inflammatory response mediated by chemoattractants and cytokines.
Repeated injury and repair within an atherosclerotic plaque eventually lead to a fibrous cap protecting the underlying core of lipids, collagen, calcium, and inflammatory cells.
Maintenance of the fibrous plaque is critical to prevent plaque rupture and coronary thrombosis.

5. CLINICAL PRESENTATION
Most patients are asymptomatic for many years. Symptomatic patients may complain of chest pain, palpitations, sweating, anxiety, shortness of breath, or abdominal pain. They may also experience difficulty with speech or movement or loss of consciousness.
Depending on the lipoprotein abnormality, signs on physical examination may include cutaneous xanthomas, peripheral polyneuropathy, high blood pressure, and increased body mass index or waist size.

6. DIAGNOSIS
Measure fasting (preferred) lipoprotein profile (total cholesterol, LDL, HDL, and triglycerides) in all adults 20 years of age or older at least once every 5 years.
Measure plasma cholesterol, triglyceride, and HDL levels after a 12-hour fast because triglycerides may be elevated in nonfasting individuals; total cholesterol is only modestly affected by fasting.

7. Goals of Treatment
Goals of Treatment: Lower total and LDL cholesterol to reduce the risk of first or recurrent events such as MI, angina, heart failure, ischemic stroke, or peripheral arterial disease.

8. TREATMENT GENERAL PRINCIPLES
In 2013, the American College of Cardiology/American Heart Association (ACC/AHA) published revised treatment guidelines that supersede the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III).
Rather than recommending specific lipid level targets, the guidelines identify four patient groups who quality for treatment with statins to reduce the 10-year risk of atherosclerotic cardiovascular disease (ASCVD) in secondary and primary intervention

10. Intensity of Statin Therapy by Drug and Dose
High-Intensity Statin Therapy
Moderate-Intensity Statin Therapy
Low-Intensity Statin Therapy
Daily dose lowers LDL on average by ≥50%
Daily dose lowers LDL on average by 30 to <50%
Daily dose lowers LDL on average by <30%
Atorvastatin (40) 80 mg
Rosuvstatin (20) 40 mg
Atorvastatin 10 (20) mg
Rosuvastatin (5) 20 mg
Simvastatin 20–40 mg
Pravastatin 40 (80) mg
Lovastatin 40 mg
Fluvastin XL 80 mg
Fluvastatin 40 mg twice daily
Pitavastatin 2–4 mg
Simvastatin 10 mg
Pravastatin 10–20 mg
Lovastatin 20 mg
Fluvastatin 20–40 mg
Pitavastin 1 mg

11. NONPHARMACOLOGIC THERAPY
Begin therapeutic lifestyle changes (TLCs) on the first visit, including dietary therapy, weight reduction, and increased physical activity.
Advise overweight patients to lose 10% of body weight.
Encourage physical activity of moderate intensity 30 minutes a day for most days of the week. Assist patients with smoking cessation and control of hypertension.
The objectives of dietary therapy are to progressively decrease intake of total fat, saturated fat, and cholesterol and to achieve a desirable body weight.
Increased intake of soluble fiber (oat bran, pectins, and psyllium) can reduce total and LDL cholesterol by 5% to 20%.

12. PHARMACOLOGIC THERAPY
Bile Acid Resins (Cholestyramine, Colestipol, Colesevelam)
Niacin
HMG-CoA Reductase Inhibitors (Atorvastatin, Fluvastatin, Lovastatin, Pravastatin, Rosuvastatin, Simvastatin)
Fibric Acids (Gemfibrozil, Fenofibrate, Clofibrate)
Ezetimibe
Fish Oil Supplementation
Mipomersen: an antisense oligonucleotide inhibitor of apolipoprotein B-100 synthesis.
Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors

13. Effects of Drug Therapy on Lipids and Lipoproteins
 Mechanism of Action
Effects on Lipids
Effects on Lipoproteins
Cholestyramine, colestipol, and colesevelam
↑ LDL catabolism
↓ Cholesterol absorption
↓ Cholesterol
↓ LDL
↑ VLDL
 Niacin
↓ LDL and VLDL synthesis
↓ Triglyceride
↓ cholesterol
↓ VLDL, ↓ LDL, ↑ HDL
Gemfibrozil, fenofibrate, clofibrate
↑ VLDL clearance
↓ VLDL synthesis
Lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin rosuvastatin
 ↑ LDL catabolism
 ↓ LDL synthesis
 ↓ Cholesterol

14. Effects of Drug Therapy on Lipids and Lipoproteins
 Mechanism of Action
Effects on Lipids
Effects on Lipoproteins
Ezetimibe
Blocks cholesterol absorption across the intestinal border
 ↓ Cholesterol
 ↓ LDL
 Mipomerson
Inhibits apolipoprotein B-100 synthesis
↓ Cholesterol
 ↓ LDL, non-HDL
 Lomitapide
Inhibits microsomal triglyceride transfer protein
 Alirocumab
 Evolocumab
 PCSK9 inhibitor
↓ Cholesterol, ↓ Lpa
 ↓ Cholesterol and LDL

15. Combination Drug Therapy
Combination therapy may be considered after adequate trials of monotherapy and for patients documented to be adherent to the prescribed regimen. Two or three lipoprotein profiles at 6-week intervals should confirm the lack of response prior to initiation of combination therapy.
In general, a statin plus a BAR or niacin plus a BAR provides the greatest reduction in total and LDL cholesterol.
Regimens intended to increase HDL levels should include either gemfibrozil or niacin, bearing in mind that statins combined with either of these drugs may result in a greater incidence of hepatotoxicity or myositis.
Familial combined dyslipidemia may respond better to a fibrate and a statin than to a fibrate and a BAR.