Lipid-regulators
(Agents Used in Hyperlipidemia)
Yun-Bi Lu, PhD
卢韵碧
Dept. of Pharmacology,
School of Medicine, Zhejiang University
yunbi@zju.edu.cn
Lipids include:
• Triglyceride (TG)
• Cholesterol (TC)
Free cholesterol
Cholesterol ester
• Others, e.g. phospholipids
Lipids + apolipoprotein (apoprotein, apo) = lipoprotein
LIPOPROTEINS
0.95
VLDL
VLDL
Remnants
IDL
Density (g/ml)
1.006
Chylomicron
Remnants
1.02
LDL
1.06
HDL2
1.10
HDL3
1.20
5
10
20
40
60
Diameter (nm)
80
1000
Correlation Between Cholesterol Levels and
Coronary Heart Disease Events
18
16
14
12
Age-adjusted
6-year
10
CHD death rate
per 1000 men 8
RULE:
For every 1% increase
in LDL-C, there is a 1%
increase in CHD events
6
4
2
0
140
n=325,000 men
160
180
200
220
240
260
280
300
Serum total cholesterol (mg/dL)
Martin MJ et al. Lancet. 1986;II:933-936.
TC
TG and TC
LPL
TG
Low-Density Lipoprotein (LDL)
apo B-100
Phospholipid
Unesterified
cholesterol
Cholesterol
ester
Triglyceride
Diameter 225-275 Å
• Physiologic Role of Cholesterol
– Component of all cell membranes
– Precursor of other steroids
• Cortisol(糖皮质激素)
• Progesterone(孕酮)
• Estrogen(雌激素)
• Testosterone(睾酮)
• Bile acids(胆酸)
• Excess cholesterol and/or triglyceride
– Hyperlipmia (高脂血症) or
hyperlipoproteinemia (高脂蛋白血症)
– Atherosclerosis (动脉粥样硬化)
– Coronary heart disease (CHD)
– Xanthomas (黄瘤)
Simple Classification of Hyperlipidemias
TC
Hypercholestrolemia
TG
↑
高胆固醇血症
↑
Hypertriglyceridemia
高甘油三酯血症
Mix Hyperlipidemia
混合型高脂血症
↑
↑
LDL (low density lipoprotein)
• LDL is associated with increased heart disease
“lousy cholesterol” “bad cholesterol”
• The major carrier of cholesterol in the blood
• Role: transport cholesterol to peripheral tissues
• Half-life: ~ 24 hrs (every day about half of the
circulating LDL is removed via receptor mediated
endocytosis)
LDL receptor
•The LDL receptor is central to cholesterol homeostasis
(1970’s Brown and Goldstein)
• When LDL binds to its receptor (via recognition of the
apoprotein B100) the entire LDL molecule is taken up
(engulfed) by the cell in clatherin coated pits
endosomes
lysosomes
Pharmacotherapy:
Effect on Serum Lipids
Pharmacotherapy
• 他汀类(Statins)：羟甲基戊二酸单酰辅酶A还原酶抑制剂 (HMG-CoA
Reductase Inhibitors) – 洛伐他汀(lovastatin)、辛伐他汀
(simvastatin)、普伐他汀(pravastatin) 、氟伐他汀(fluvastatin) 、
阿伐他汀(atovastatin)
• 胆固醇吸收抑制药(Cholesterol absorption inhibitors) –依泽替米贝
(ezetimibe)
• 胆酸结合树脂 (Bile Acid-Binding Resins, RESINS) – 考来替泊
(Colestipol), 考来烯胺 (cholestyramine)
• 烟酸 (NICOTINIC ACID, NIACIN)
• 苯氧酸类(贝特类) FIBRIC ACID DERIVATIVES (FIBRATES) – 氯贝
特(clofibrate)、吉非贝齐(gemfibrozil)、苯扎贝特(benzafibrate)、
非诺贝特(fenofibrate)、环丙贝特(ciprofibrate)
Cholesterol Synthesis Pathway
NATURAL PRODUCT HMG CoA
REDUCTASE INHIBITORS
6,000 microbial extracts screened
HO
R = H, mevastatin
R = CH3, lovastatin
O
O
O
Penicillium citrinum (mevastatin)
H3C
H3C
H
CH3
Aspergillus terreus (Lovastatin, Merck)
R
IC50 = ~ 2 nM
Required 600 L of culture to be solvent extracted
NATURAL PRODUCT
INHIBITORS
Pravastatin
HO
COONa
OH
O
First isolated as metabolite in dog urine
H3C
H3C
H
CH3
Currently produced by microbial
transformation of mevastatin
Hydrophilic in nature
HO
Administered in active form
Summary of Pharmacological
Properties of Statins
Rosuvastatin
5.4
~20%
20
No
Atorvastatin
8.2
~14%
14
Yes
Cerivastatin
10.0
60%
2–3
Yes
Simvastatin
11.2
 5%
1–2
Yes
Fluvastatin
27.6
24%
1–2
No
Pravastatin
44.1
17%
1–2
No
McTaggart F et al. Am J Cardiol 2001;87(suppl):28B-32B;
Knopp RH. N Engl J Med 1999;341:498-511.
Pharmacologic Therapy:
Statins—Dose Response
Response to Minimum/Maximum Statin Dose
% Reduction in LDL-C
Fluvastatin Pravastatin Lovastatin Simvastatin Atorvastatin
10/80 mg
20/80 mg
20/80 mg
20/80 mg
20/80 mg
0
10
19
27
28
20
35
37
12
30
31
40
10
37*
12
40
50
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
12
18
47
55
Statins - Mechanism of Action
• Structural analogs of the HMG-CoA intermediate
• Increase in high-affinity LDL receptors
• Increase catabolic rate of LDL and the liver's
extraction of LDL precursors (VLDL remnants),
thus reducing plasma LDL.
• Due to the first pass hepatic extraction, the major
effect is on liver.
Statins - Clinical Use
– Most Effective for ↓ LDL
– Some ↑ HDL and good ↓ VLDL
– Used alone to ↓ LDL
– Used with resins, CAIs to ↓ LDL
– Used with niacin to ↓ LDL, ↓ VLDL, and ↑
HDL
– Enhanced if taken with food (except for
pravastatin – taken without food)
– Give in the evening(Cholesterol synthesis
highest at night)
Statins – Benefits
• Demonstrated therapeutic benefits
– Reduce major coronary events
– Reduce CHD mortality
– Reduce coronary procedures (PTCA/CABG)
– Reduce stroke
– Reduce total mortality
NCEP ATP III. JAMA 2001;285:2486-2497.
Statins – Adverse Effects
– Rash, GI disturbances (dyspepsia(消化不良), cramps,
flatulence(肠胀气), constipation(便秘), abdominal
pain)
– Hepatotoxicity
– Myopathy (肌病)(0.5% of pts)
» Risk highest with lovastatin and especially in
combination with Fibrates
– Cyp3A4 or CYP2C9 drug interactions with many
statins
Hepatotoxicity ?
Hepatic transaminase elevations; occur in
0.5-2% and are dose dependant
• Whether transaminase elevation with statin
therapy constitutes true hepatotoxicity has not
been established
• Progression to liver failure specifically due to
statins is exceedingly rare, if it ever occurs
• No evidence exists showing exacerbation of
liver disease when statins are given to patients
with cholestasis and active liver disease
• Statins may actually improve transaminase
elevations in individuals with fatty liver
Pasternak RC et al. Circulation. 2002;106:1024-1028.
Risk Factors for Myopathy
• Advanced age
• Metabolic acidosis
– > 80 yo
• Hypoxia
– Women > men
• Infection
• Multisystem disease
– thyroid, liver
• Perioperative period
• Large quantities of
grapefruit juice
– > 1 qt./day
• Major trauma
• Alcohol abuse
• Electrolyte imbalance
• Drug interactions
Jacobson TA. Expert Opin Drug Saf 2003;2:269-86
Davidson MH. Am J Cardiol 2002;90 (suppl):50K-60K
CHOLESTEROL
ABSORPTION INHIBITORS
Ezetimibe
Net Cholesterol Balance
in Humans
Cholesterol Absorption Inhibitor
(ezetimibe)
• Mechanisms:
– Blocks cholesterol absorption at the intestinal
brush border
– No effect on absorption of lipid-soluble vitamins
• Indications:
High LDL (Additive in combination with statin )
• Pharmacology
– Intestinal wall localization
– Enterohepatic circulation
– Minimal systemic exposure (Very well tolerated)
Ezetimibe+ Statin
vs. Statin Titration
5%-6% 5%-6% 5%-6%
Statin – starting dose
1st
2nd
3rd
3-STEP
TITRATION
Doubling
15%-18%
Statin – starting dose
+ Zetia
10 mg
% Reduction in LDL-C
1-STEP
COADMINISTRATION
Bile Acid-Binding Resins (Resins)
Cholestyramine
Colesevelam
Polymer
Backbone
Hydrophobic
Side Chain
Primary Amines
Bound Bile Acid
Quaternary
Amine Side
Chains
Resins - Colestipol, cholestyramine, and colesevelam
• Mechanisms:
─ Binds to bile acid in the intestines, interrupting enterohepatic
circulation and increasing fecal excretion of the acid
─  LDL receptors(外源性的吸收减少，内源性代谢进入胆酸，导致肝
内受体代偿性表达)
• Efficacy: LDL  20-30%
• Indications: High LDL
• Uses: be used to relieve pruritis(瘙痒症) in patients who have
cholestasis and bile salt accumulation; and/or to relieve
diarrhea in post-cholecystectomy(胆囊切除术后) patients
Resins

Adverse effects
– Constipation(便秘)
– Bloating(腹胀), indigestion, nausea
– Large doses may impair absorption of fats
or fat soluble vitamins (A, D, E, and K)
– Drug Interactions
• Resins bind digoxin, warfarin, thiazide diuretics, tetracycline,
thyroxine, iron salts, pravastatin, fluvastatin, folic acid,
phenylbutazone(保泰松), aspirin, ascorbic acid (these agents
should be given 1 hour before the resin or 4 hours after)
• may be useful in digitalis toxicity.
Nicotinic Acid (NIACIN)
apo B-100
Decreased VLDL
Production
apo E
 VLDL
apo C
 VLDL
Liver
Remnant
CONVERSION
Other sites
 LDL
Increased VLDL
Clearance through LPL
Nicotinic Acid (Niacin, Vitamin B3)
• Mechanism
─ Increase clearance of VLDL via the LPL pathway,  TG
catabolism
─ Suppress synthesis of TG,VLDL, IDL, & LDL in the liver.
─ May  HDL catabolism (via  apoA-I catabolism )
• Efficacy:
– TC  25%
– HDL  10-40%
LDL  10-25%
TG  20-50%
• Indications:
– High LDL-C and/or high TG
– Combined hyperlipidemia
 Start with low dose and gradually increase
 Give at night with food.
Nicotinic Acid (Niacin, Vitamin B3)

–
–
–
–
–
–
–
Adverse effects
Flushing(潮红)
» Harmless cutaneous vasodilation
» VERY Uncomfortable
» Occurs after drug is started or ↑ dose
» Lasts for the first several weeks
» Can give aspirin 30 minutes before dose
Pruritis, rashes, dry skin
Nausea and abdominal discomfort
» Peptic disease
Hepatotoxicity
» Rare true hepatotoxicity occur
» Monitor liver functions regularly
» Liver injury is less likely with Niaspan
Hyperuricemia
» Occurs in about 1/5 of pts
» Occasionally precipitates gout
Carbohydrate tolerance may be moderately impaired (hyperglycemia)
» Reversible
» Can be given to diabetics receiving insulin
contraindicates use
» Pregnancy
Fibrates (贝特类)
• Mechanisms
• Act as PPAR ligands (peroxisome proliferator-activated
receptor-alpha)
• a nuclear receptor that regulates lipid metabolism and
glucose homeostasis
•  FA oxidation in muscle and liver
• Reduced expression of Apo CII is key to  VLDL catabolism
•  clearance of VLDL by  action of lipoprotein lipase.  VLDL
production
• ↓ Intracellular lipolysis in adipose tissue
• Efficacy:
LDL + 10%
HDL  10-25%
TG  40-55%
• Indications:
•  TG and/or  HDL
Fibrates
• Adverse effects
– Rashes
– GI upset
– Gallstones (upper abdominal discomfort, intolerance
of fried food, bloating)
» ↑ biliary cholesterol saturation
» Use with caution in pts with biliary tract disease
– Highly protein binding.
– Will increase risk of statin-induced myopathy when
used together (rhabdomyolysis has occurred rarely)
– Avoid in patients with hepatic or renal dysfunction
Summary of Clinical Effects
Summary of Side Effects
Drug Class
Side Effects
Resins
Unpalatability, bloating,
constipation, heartburn
Nicotinic acid
Flushing, nausea, glucose
intolerance, abnormal liver
function tests
Fibrates
Nausea, skin rash
Statins
Myositis, myalgia, elevated
hepatic transaminases
Thanks!