Management & Medications  Diet, weight loss and drug therapy are the mainstay of treatment, while exercise training is used as adjunctive therapy  Lipid-lowering medications  Nicotinic acid – niacin suppresses VLDL synthesis  Bile acid-binding resins – lowers LDL (Lipitor, Metaprol, Cholestyramine)  Fibric acid derivatives – increase enzyme activity (Gemfibrozil)

Management & Medications  Lipid-lowering medications:  HMG CoA inhibitors – inhibit cholesterol synthesis (Lovostatin, Provostatin)  Other medications to be aware of  Beta blockers – increase TG, decrease HDL  Diuretics – increase Chol, VLDL, LDL & TG  Insulin therapy – decrease TG and increase HDL  Estrogens – increase HDL, VLDL, TG

Mechanisms of action of drugs  bind to bile acids/cholesterol  inhibit absorption/reabsorption  increase peroxisomal FA oxidation  stimulate lipoprotein lipase  inhibit triglyceride lipase  inhibit HMG CoA reductase  stimulates microsomal 7-alpha hydroxylase

Drug Classification  systemic/non-sytemic  cholesterol lowering agents  bile acid sequestrants  sitosterols*  probucol*  d-thyroxin*  HMG Co-A reductase inhibitors * No longer available commercially in the U.S

Drug Classification  mixed activity (nicotinic acid)  triglyceride lowering  clofibrate (Atromid-S)  gemfibrosil (Lopid)  fenofibrate (Tricor)

Mechanism of Action of Statins, Cholesterol Synthesis Pathway acetyl CoA HMG-CoA mevalonic acid mevalonate pyrophosphate isopentenyl pyrophosphate geranyl pyrophosphate farnesyl pyrophosphate squalene cholesterol dolicholsubiquinones HMG-CoA synthase HMG-CoA reductase Squalene synthase X Statins

Statin lovastatin pravastatin simvastatin atorvastatin cerivastatin fluvastatin Protein binding (%) >95% ~50% 95–8% >98% >99% >98% Metabolised by CYP450 Yes No Yes Lipophilic Yes No Yes No Half- life (h) ~2 ~3 ~15 ~3 Pharmacokinetics of Statins (Adapted from Horsmans 1999, Vaughan et al, 2000)

HMG CoA reductase inhibitors  Precautions:  mild elevation of serum aminotransferase (should be measured at 2 to 4 month intervals)  minor increases in creatine kinase (myopathy, muscle pain and tenderness)  do not give during pregnancy

CLOFIBRATE  Primary activity on triglycerides  MOA:  increases lipoprotein lipase  lowers VLDL  increases peroxisomal FFA oxidation  inhibits cholesterol biosynthesis  increases biliary secretion of cholesterol  ancillary:  decreases platelet adhesiveness/fibrinogen

Clofibrate (Atromid-S)  Precautions  enhances coumarin activity  renal/hepatic injury contraindication  pregnancy/nursing  cholelithiasis  most commonly reported ADR are GI related  liver malignancies (not very common; but has led to scant usage)

Fenofibrate (Tricor)  a relatively new fibric acid derivative (micronized form of the drug)  lowers plasma TG  inhibits TG synthesis  stimulates catabolism of VLDL  indicated primarily for hypertriglyceridemia  same side effects and precaution as in other fibric acid compounds  half-life: 20 hours  Dose: mg/day with meals

Gemfibrosil (Lopid)  MOA  stimulates lipoprotein lipase  interact with PPAR  (peroxisome proliferator-activated receptors)  inhibits triglyceride lipolysis in adipose tissue  decreases FFA uptake by the liver  decreases hepatic VLDL/TG synthesis  slight cholesterol lowering effect  precautions  similar to clofibrate  myositis (voluntary muscle inflammation)  GI (indigestion, abdominal pain, diarrhea)  cholelithiasis (increased cholesterol biliary secretion)  half life: 1.1 hours

NICOTINIC ACID (Niacin) A water soluble vitamin of the B family; nicotinamide is not active Once converted to the amide, it is incorporated into NAD In order to be effective, it has to be dosed at the rate of 1.5 to 3.5 gm daily. A sustained release dosage form is available adverse effects: GI disturbances (erosion and ulceration) red flush especially in the face and neck area caused by vasodilation of capillaries

Nicotinic acid (Niacin)  MOA  dual plasma triglyceride and cholesterol lowering  decreases VLDL and LDL  decreases TG lipase in adipose tissue  increases lipoprotein lipase in adipose tissue  precaution  transient cutaneous flush  histamine release  potentiates BP effect of antihypertensives

Advicor®  niacin-extended-release and lovastatin tablets  reduces LDL-C, TC, TG and increases HDL-C  available as 500/20, 750/20 and 100/20 mg tablets

16 HDL-C=High-density lipoprotein cholesterol, LDL-C=Low-density lipoprotein cholesterol, TC=Total cholesterol, TG=Triglycerides *Daily dose of 40mg of each drug, excluding rosuvastatin. TherapyTCLDLHDLTG Patient tolerability Statins*  19-37%  25-50%  4-12%  14-29% Good Ezetimibe  13%  18%  1%  9% Good Bile acid sequestrants  7-10%  10-18%  3%Neutral or  Poor Nicotinic acid  10-20%  14-35%  30-70% Reasonable to Poor Fibrates  19%  4-21%  11-13%  30% Good Lipid Management Pharmacotherapy

Investigational drugs  acylCoA: cholesterol acyltransferase inhibitors  Orphan nuclear receptors:  LXR – “oxycholesterol receptor” --- enhanced cholesterol efflux  FXR – “bile acid receptor” ---- decreased cholesterol conversion to bile salts

Squalene synthase inhibitors  squalestin 1, a fermentation product derived from Phloma species (Coelomycetes)  a potent inhibitor of squalene synthase  produces a marked decrease in serum cholesterol and apoB levels  may represent an alternative clinical therapy to hypercholesterolemia