Antihyperlipidemic DrugsEdson Mutandwa MBBS v

HYPERLIPIDEMIA

• Hyperlipidemia refers to increased levels of lipids (fats) in the blood, including cholesterol and triglycerides. (uptodate)• hyperlipidemia significantly increase your risk of developing

cardiovascular disease, coronary artery disease, cerebrovascular disease, and peripheral vascular disease.

LIPID METABOLISM

RISK FACTORS FOR HYPERLIPIDEMIA

• Family history of early heart disease (father before the age of 55 years and mother before the age of 55 years)• Cigarette smoking• High blood pressure• Age (men older than 45 years and women olderthan 55 years) • Low HDL levels• Obesity• Diabetes• etc

DIAGNOSIS OF HYPERLIPIDEMIA

• Diagnosis is typically based on medical history, physical examination and blood test done after overnight fasting

WHEN TO CHECK LIPID PANEL

Two different Recommendations Adult Treatment Panel (ATP III) of the National Cholesterol Education

Program (NCEP) • Beginning at age 20: obtain a fasting (9 to 12 hour) serum lipid profile consisting of total

cholesterol, LDL, HDL and triglycerides• Repeat testing every 5 years for acceptable values

United States Preventative Services Task Force• Women aged 45 years and older, and men ages 35 years and older undergo screening with a

total and HDL cholesterol every 5 years.• If total cholesterol > 200 or HDL <40, then a fasting panel should be obtained• Cholesterol screening should begin at 20 years in patients with a history of multiple

cardiovascular risk factors, diabetes, or family history of either elevated cholesterol levels or premature cardiovascular disease

Management of hyperlipidemia

Management of hyperlipidemia start with therapeutic life changes (TLC) which includes;• a cholesterol-lowering diet (TLC diet), • physical activity, • quitting smoking (if applicable), • weight management,• and antihyperlipidemia drugs

Antihyperlipidemic drugs classification

• HMG-CoA reductase inhibitors• Bile acid sequestrants• Fibrates• Nicotinic acid (Niacin)• cholesterol absorption inhibitors• PCSK9 inhibitors

HMG-CoA reductase inhibitors Examples; Lovastatin, atorvastatin, rosuvastatin (5 to 40 mg/day) Mechanism of action

• Analogs of HMG (3-hydroxy-3 methylglutaryl-CoA)• HMG-CoA reductase catalyzes synthesis of mevalonic acid from HMG-CoA and is the rate

limiting step in cholesterol biosynthesis• Leads to up-regulation of LDL receptors in liver

Therapeutic Uses• Great for all hyperlipidemias involving increased levels of LDL or cholesterol• Atherosclerosis; stroke prevention• Primary prevention of CAD

Major side effect and drug interactions

Side effects• Headache• nausea• sleep disturbance• elevations in hepatocellular enzymes and alkaline phosphatase. CI in hepatic

dysfunction• Myositis and rhabdomyolysis, primarily when given with gemfibrozil or cyclosporine;

myositis is also seen with severe renal insufficiency (CrCl <30 mL/min).• CI in pregnancyDrug interactions; Lovastatin, atorvastatin, rosuvastatin, and simvastatin potentiate effect of warfarin; this interaction is not seen with pravastatin, fluvastatin, or pitavastatin. Most statins can also affect digoxin metabolism and levels

Bile acid sequestrants Examples; Cholestyramine (4 to 24 g/day), Colestipol (5 to 30 g/day),

Colesevelam (3.75 g/day) Mechanism of action• Anion-exchange resin – binds bile acids in intestinal lumen preventing

enterohepatic circulation (this increases excretion of bile which is made from cholesterol),this causes an up-regulation of hepatic LDL receptors and increased production of cholesterol

Therapeutic Uses• Uses Hyperlipidemias involving ISOLATED INCREASES OF LDL

Major side effect and drug interactionsSide effects• Constipation• Flatulence• Dyspepsia• Hypertriglyceridemia• Hyperchloremic acidosis (since they exchange Cl)• Bind many things (drugs, vitamins, toxins, anything fat soluble) which limits their absorption • Prexisting coagulopathy is a contraindication since they prevent absorption of vit K • Drug interactions Impaired absorption of fat soluble vitamins and co-administered medications

including: Amiodarone, digoxin, warfarin, thiazides, β-blockers, levothyroxine, others; interaction can be minimized by taking other medications at least 1 hour before or 4 hours after bile acid sequestrant.

Fibrates• Examples; Gemfibrozil (600 mg BID), Fenofibrate (Nanocrystal 145 mg/dayMicronized 160 to 200 mg/day0 Mechanism of action• activation of nuclear transcription receptor to increase LPL synthesis (removes

TGs from lipoproteins); enhanced removal of VLDL from plasma

Theurapitic use• DOC fro type III lipoproteinemia (familial dysbetalipoproteinemia)• Hypertriglyceridemias • useful for Pruritus in biliary obstruction (↑ bile acids)

Major side effect and drug interactions• Side effects• Skin rash, • gastrointestinal (nausea, bloating, cramping) • myalgia; • lowers blood cyclosporine levels; potentially nephrotoxic in

cyclosporine treated patients. Avoid in patients with CrCl <30 mL/min. (Fenofibrate)• Potentiates warfarin action. Absorption of gemfibrozil diminished by

bile acid sequestrants. (Gemfibrozil)

Nicotinic acid (Niacin) Examples; Niacin (IR: 1 to 6 g/day or XR 0.5 to 2 g/day) Mechanism of action• It is a potent inhibitor of lipolysis in adipose tissues which decreases

mobilization of FFAs (major precursor of TGs) to the liver which in turn decreases VLDL (after few hours)• Increases HDL levels

Theraupetic use• Uses Hyperlipidemias with very high VLDL and LDL• Patients with very low HDL

Major side effect and drug interactionsSide effects• dry skin• myositis • Prostaglandin-mediated cutaneous flushing, warm sensation• Headache• Pruritus, Nausea, Vomiting, diarrhea• hyperpigmentation (particularly in intertriginous regions); acanthosis nigricans; • Decreased glucose tolerance• Hepatotoxicity (check AST, ALT levels)• Rhabdomyolysis • Hyperuricemia (inhibits tubular secretion of uric acid)

Cholesterol absorption inhibitors Examples; Ezetimibe (10 mg/day) Mechanism of action• Localizes at the brush border, selectively inhibits intestinal absorption

of cholesterol and related sterols (only blocks exogenous sterol intake)

Therapeutic use• Used in hypercholesterolemia together with statins & diet regulation

Major side effect and drug interactionsSide effects• Diarrhea • Abdominal pain• CI liver dysfunction

PCSK9 inhibitors• Examples; Alirocumab (75 to 150 mg 2/7 w), Evolocumab (140 mg 2/7

w or 420 mg 1/12 m)• Proprotein convertase subtilisin kexin 9 (PCSK9) is a serine protease

produced predominantly in the liver that leads to the degradation of hepatocyte LDL receptors and increased LDL-C levels• This category of lipid lowering therapy appears promising in a range

of clinical situations.• They are given subcutaneously• The major side effect is injectin site reaction

DRUG THERAPY

• If no improvement within 6 weeks with a single drug therapy, the dose should be increased. If no improvement after 3 months change the drug or consider combination therapy:• Bile acid resins can be safely combined with statins or nicotinic acid

(↓ LDL, VLDL cholesterol levels respectively).• Ezetimibe + statins → synergistic effects.• Fibrates and statins are CI because of myopathy.• Nicotinic acid and statins (must be cautiously used) because of

myopathy.

EFFECTS OF ANTIHYPERLIPIDEMIC DRUGS

REFERENCES

• http://www.mayoclinic.org/diseases-conditions/high-blood-cholesterol/in-depth/cholesterol-medications/art-20050958• Uptodate; Treatment of lipids (including hypercholesterolemia) in

secondary prevention; Robert S Rosenson, MD, This topic last updated: Sep 11, 2015

Thank you