介绍了他汀类药物与其他各类降脂药物在临床上的联合应用和安全性。
Combination Lipid-Altering Drug Therapy with Statins
Harold Bays, MD, FACP
Combination Lipid-Altering Drug Therapy with Statins
Need for combination lipid-altering drug therapy
Ezetimibe and statins
Bile acid sequestrants and statins
PPAR agonists and statins
Fish oils and statins
Niacin and statins
NCEP ATP III LDL-C Treatment Goals
NCEP ATP = National Cholesterol Education Program Adult Treatment Panel.
LDL-C = low-density lipoprotein cholesterol.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.
CHD
All Patients
High Risk
Patients Achieving Goal (%)
Inadequate Achievement of NCEP ATP III Treatment Goals, Especially among Patients at Highest Risk
70%
Adapted from Pearson TA et al. Arch Intern Med 2000;160;459-467.
Low Risk
Drug therapy included statins (fluvastatin, lovastatin, pravastatin, simvastatin), gemfibrozil, bile acid sequestrants, niacin, psyllium fiber, and combination drug therapy.
1,352
4,137
1,924
861
40%
18%
39%
n =
Atorvastatin 10/20/40/80 mg 211 mg/dl*
Simvastatin 10/20/40 mg? 219 mg/dl*
Mean % Change from Baseline
Majority of LDL-C Lowering Occurs at the Lowest Statin Dose
Adapted from Jones P et al. Am J Cardiol 1998;81:582-587.
*Mean baseline LDL-C. ?At the time of this study, the maximum dose for simvastatin was 40 mg.
Daily Dose
16% with 3 Titrations
13%
38%
46%
51%
54%
28%
35%
41%
(1) Peripheral cholesterol synthesis
(3) Intestinal cholesterol absorption
Biliary cholesterol
Dietary cholesterol
(2) Hepatic cholesterol synthesis
HDL
HDL
Liver
SR-B1
LDL/apo B–E
Receptor
Bays H et al. Expert Opin Pharmacother 2003;4:779-790.
Intestinal epithelial cell
Bile acid
CE
Free cholesterol
excretion
uptake
MTP
ACAT
ABC G5 ABC G8
(esterification)
Three Sources of Cholesterol
Luminal cholesterol
Micellar cholesterol
CM
Intestinal Cholesterol Absorption
Bays H et al. Expert Opin Pharmacother 2003;4:779-790.
Intestinal epithelial cell
Biliary cholesterol
Dietary cholesterol
Luminal cholesterol
Micellar cholesterol
Bile acid
Cholesteryl esters
Free cholesterol
excretion
uptake
ABCG5 ABCG8
(esterification)
Through lymphatic system to the liver
Ezetimibe: Mechanism of Action
Ezetimibe selectively inhibits intestinal cholesterol absorption
? intestinal delivery of cholesterol to the liver
? expression of hepatic LDL receptors
? cholesterol content of atherogenic particles
Ezetimibe and its active glucuronide metabolite circulate enterohepatically
Delivers agent back to the site of action
Limits systemic exposure
Bays H. Expert Opin Investig Drugs 2002;11:1587-1604.
Catapano AL. Eur Heart J Suppl 2001;3:E6-E10.
Photo courtesy of Harry R. Davis, PhD
Radiolabeled ezetimibe localized at brush border of small intestine
Placebo (n=52)
Mean % Change in LDL-C from Baseline at Week 12
Ezetimibe: Efficacy Dose–Response Study
Bays HE et al. Clin Ther 2001;23:1209-1230.
*p<0.05 vs placebo.
4.3
–9.9 *
–12.6 *
–16.4 *
–18.7 *
0.25 mg (n=47)
1 mg (n=49)
5 mg (n=49)
10 mg (n=46)
Ezetimibe
Ezetimibe: Efficacy “Added On” to Ongoing Statin Therapy
Gagné C et. al. Am J Cardiol 2002;90:1084-1091.
*40% on atorvastatin (weighted mean baseline dose 34 mg); 31% simvastatin (37 mg), and 29% others combined (pravastatin 29 mg, fluvastatin 35 mg, lovastatin 26 mg, and cerivastatin 0.4 mg)
Patients on ongoing stable statin therapy* not reaching NCEP ATPII LDL-C goal
Week <–6
Open-label statin + placebo
(n=390, mean LDL-C = 139 mg/dl)
Open-label statin + ezetimibe (n=379, mean LDL-C = 138 mg/dl)
0
8
RANDOMIZATION
LDL-C
% Reduction from Baseline at Week 8
Ezetimibe: Efficacy "Add On" Study
Gagné C et al. Am J Cardiol 2002;90:1084-1091.
*p<0.001 ?p<0.05 ?p<0.01
–25.1 *
1.0
–2.9
–14.0 ?
HDL-C
TG
–3.7
2.7 ?
Statin + placebo (n=390)
Statin + ezetimibe 10 mg (n=379)
Statin + Ezetimibe (n=305)
Statin + Placebo (n=322)
Patients at NCEP II Goal* (%)
Ezetimibe: Efficacy—"Add On" Study
*?100 mg/dl in 68% of patients, <130 mg/dl in 23%, <160 mg/dl in 10%.
More patients might have achieved goal if titrated to higher statin doses.
72%
Gagné C et al. Am J Cardiol 2002;90:1084-1091.
19%
Mean LDL-C
139 mg/dl 133 mg/dl
138 mg/dl 102 mg/dl
Statin monotherapy
Statin + placebo or ezetimibe
*p <0.001
Ezetimibe + Atorvastatin 10 mg (n=65)
Atorvastatin
40 mg (n=66)
20 mg (n=60)
10 mg (n=60)
Mean % Change in LDL-C from Untreated Baseline
Ezetimibe: Efficacy (“10 + 10 = 80”)
–53%
Ballantyne CM et al. Circulation 2003;107:2409-2415.
–37%
–42%
–45%
–54%
P<0.01
80 mg (n=62)
Ezetimibe: Metabolism
Ezetimibe undergoes glucuronidation in the intestinal wall and is then metabolized to its active glucuronide metabolite in the liver and delivered back to the intestine for enterohepatic recirculation
The enterohepatic recirculation helps account for ezetimibe’s 22-hour half-life
Ezetimibe is not an inducer or inhibitor of cytochrome P450 enzymes, reducing the risk for potential drug interactions with many common drugs enzymatically affected by cytochrome P450 enzymes
Bays H. Expert Opin Investig Drugs 2002;11:1587-1604.
van Heek M et al. Br J Pharmacol 2000; 129:1748-1754.
Glucuronidation
Intestinal wall
Plasma
Liver
Bile
Intestinal lumen
3H-DPM (x 10–6)
Ezetimibe: Metabolism Low Systemic Exposure to Ezetimibe
van Heek M et al. Br J Pharmacol 2000;129:1748-1754.
3-h post 3H ezetimibe IV dosing
Ezetimibe: Drug Interactions
Statins: No significant pharmacokinetic interactions
Cholestyramine: Decreased the mean AUC of total ezetimibe concentration by 55%. Ezetimibe should be administered ?2 hours before or ?4 hours after a resin
Fibrates: Not currently recommended in combination with ezetimibe, as safety and efficacy has not yet been established by clinical trials.
Cyclosporin: May substantially increase ezetimibe levels
No significant pharmacokinetic interactions with antacids, cimetidine, warfarin, digoxin, ethinyl estradiol, levonorgestrel, glipizide, tolbutamide
Package insert.
Bays H. Expert Opin Investig Drugs 2002;11:1587-1604.
Ezetimibe: Indications
Hypercholesterolemia
Monotherapy
Combination therapy with statins
Homozygous familial hypercholesterolemia
Homozygous sitosterolemia
The effects of ezetimibe (monotherapy or combination therapy) on atherosclerotic coronary heart disease morbidity and mortality have not yet been established.
Package insert.
Bays H. Expert Opin Investig Drugs 2002;11:1587-1604.
Ezetimibe: Contraindications
Hypersensitivity to ezetimibe (rash, etc.)
Unexplained or moderate to severe liver enzyme elevation
Pregnancy C category as monotherapy (no adequate studies in pregnant women)
All statins are contraindicated in pregnant and nursing women
Package insert.
Bays H. Expert Opin Investig Drugs 2002;11:1587-1604.
Ezetimibe: Laboratory Safety Monitoring
Laboratory monitoring is not required for ezetimibe monotherapy. When ezetimibe is added in combination with statins, liver enzyme monitoring is recommended at initiation of ezetimibe therapy and then according to statin recommendations.
Ezetimibe administration is not associated with excess risk for myopathy or rhabdomyolysis.&