选择正确的降脂治疗方案
Selecting Successful Lipid-Lowering Treatments James M. McKenney, Pharm.D.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.
Treatment Categories, LDL-C Goals and Cutpoints
* 100–129 mg/dL = after TLC, consider statin, niacin, or fibrate therapy
Treatment of Hyperlipidemia
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.
High LDL-C
Therapeutic Lifestyle Change
Drug Therapy
Therapy of Choice: Statin
Alternative: Resin or niacin
Statins: Mechanism of Action
LDL receptor–mediated hepatic uptake of LDL and VLDL remnants
Serum VLDL remnants
Serum LDL-C
Cholesterol synthesis
LDL receptor
(B–E receptor)
synthesis
Intracellular Cholesterol
Apo B
Apo E
Apo B
Systemic Circulation
Hepatocyte
Reduce hepatic cholesterol synthesis, lowering intracellular cholesterol, which stimulates upregulation of LDL receptor and increases the uptake of non-HDL particles from the systemic circulation.
Serum IDL
VLDL
The LDL-C–Lowering Efficacy of the Currently Available Statins
Physician’s Desk Reference. 55th ed. Montvale, NJ: Medical Economics, 2001.
The Triglyceride-Lowering Effects of Statins
Stein EA et al. Am J Cardiol 1998;81:66B-69B.
*Nonfatal MI or CHD death; **ischemic events
Downs JR et al. JAMA 1998;279:1615-1622. | Shepherd J et al. N Engl J Med 1999;333:1301-1307. | Scandinavian Simvastatin Study Group. Lancet 1994;344:1383-1389. | Sacks FM et al. N Engl J Med 1996;335:1001-1009. | LIPID Study Group. N Engl J Med 1998;339:1349-1357. | Schwartz GG et al. JAMA 2001;285:1711-1718. | Pitt B et al. N Engl J Med 1999;341:70-76.
Endpoint Trials with the Statins
CHD Risk Reduction with Statin Therapy
La Rosa JC et al. JAMA 1999;282:2340-2346. | Crouse JR III et al. Arch Intern Med 1997;157:1305-1310. | Pedersen TR et al. Am J Cardiol 1998;81:333-335.
Endpoints
+20
–35
–30
–25
0
–5
–10
–15
–20
Relative Risk Reduction (%)
–40
–45
–50
Major coronary events
Coronary deaths
Cardiovascular deaths
Noncardiovascular events
Total mortality
Strokes
Intermittent claudication
Angina
Potential Time Course of Statin Effects
* Time course established
Days
Years
LDL-C lowered*
Inflammation reduced
Vulnerable plaques stabilized
Endothelial function restored
Ischemic episodes reduced
Cardiac events reduced*
Statin Adverse Events
Common side effects
Headache – Myalgia – Fatigue
GI intolerance – Flu-like symptoms
Increase in liver enzymes
Occurs in 0.5 to 2.5% of cases in dose-dependent manner
Serious liver problems are exceedingly rare
Manage by reducing statin dose or discontinue until levels return to normal
Myopathy
Occurs in 0.2 to 0.4% of patients
Rare cases of rhabdomyolysis
Reduce by
Cautiously using statins in patients with impaired renal function
Using the lowest effective dose
Cautiously combining statins with fibrates
Avoiding drug interactions
Careful monitoring of symptoms
Presence of muscle toxicity requires the discontinuation of the statin
Bile Acid Resins: Mechanism of Action
Net Effect: ? LDL-C
LDL Receptors
VLDL and LDL removal
? Cholesterol 7-? hydroxylase
Conversion of cholesterol to BA
BA Secretion
BA Excretion
Terminal Ileum
Bile Acid
Enterohepatic Recirculation
Reabsorption of bile acids
Effect of Colesevelam on LDL-C
Davidson MH et al. Expert Opin Investig Drugs 2000;9:2663-2671.
Reprinted with permission from Ashley Publications.
Change in LDL-C
Placebo
3.8 g/d
4.5 g/d
(N=494 patients with baseline LDL-C of 130–220 mg/dL and TG <300 mg/dL; after 24 weeks of therapy)
0%
–15%
–18%
Clinical Features of BARs
Products available:
Cholestyramine (Questran), 4–16 g/d
Colestipol (Colestid), 5–20 g/d
Colesevelam (WelChol) 625 mg tablets, 6–7 tablets/d
Reduce coronary events (LRC-CPPT)
Adverse effects
GI intolerance: constipation, bloating, abdominal pain, flatulence
Lack systemic toxicity
Drug interactions (colestipol and cholestyramine)
Bind other negatively charged drugs
Impede the absorption of drugs and/or fat-soluble vitamins
Must give other drugs 1 hour before or 4–6 hours after
Nicotinic Acid: Mechanism of Action
Liver
Circulation
HDL
Serum VLDL results in reduced lipolysis to LDL
Serum LDL
VLDL
Decreases hepatic production of VLDL and of apo B
VLDL secretion
Apo B
Hepatocyte
Systemic Circulation
Mobilization of FFA
TG synthesis
VLDL
Effect of Niacin on Lipoproteins
Adapted from Knopp RH. N Engl J Med 1999;341:498-511.
?1999 Massachusetts Medical Society. All rights reserved.
0 1 g/d 2 g/d 3 g/d
Baseline
-15%
12.5%
25%
-30%
HDL-C with Niaspan?
TG with Niaspan?
TG with crystalline niacin
LDL-C with Niaspan?
LDL-C with crystalline niacin
35%
HDL-C with crystalline niacin
Clinical Features of Nicotinic Acid
Products available (daily dose)
Immediate-release, 2–4 g/d
Extended-release (Niaspan?), 1–2 g/d
OTC products, sustained-release, ?2 g/d
Best agent to raise HDL-C
Reduces coronary events (Coronary Drug Project)
Adverse effects
Flushing, itching, headache (immediate-release, Niaspan?)
Hepatotoxicity, GI (sustained-release)
Activation of peptic ulcer
Hyperglycemia and reduced insulin sensitivity
Contraindications
Active liver disease or unexplained LFT elevations
Peptic ulcer disease
Progression of Drug Therapy for LDL-C Lowering
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.
Visit 1
Visit 2
Visit 3
F/U Visits
Start statin or bile acid resin or nicotinic acid
Consider higher dose of the statin or add a bile acid resin or nicotinic acid
6 wks
Initiate LDL-lowering drug therapy
6 wks
q 4–6 mo
If LDL goal not achieved, intensify LDL-lowering therapy
If LDL goal not achieved, drug therapy or refer to a lipid specialist
Monitor response and adherence to therapy
If LDL goal has been achieved, treat other lipid risk factors
Simvastatin Alone and with Colesevelam: Percent Change in LDL-C
Knapp HH et al. Am J Med 2001;110:352-360.
Reprinted with permission from Excerpta Medica Inc.
Mean Percent Change
Placebo
Simvastatin 10 mg
Simvastatin 20 mg
Colesevelam 2.3 g + Simvastatin 20 mg
Colesevelam 3.8 g + Simvastatin 10 mg
(n=258 patients with baseline LDL-C 160–220 mg/dL; treated for 6 weeks)
–4%
* p<0.05 vs placebo
–26%
–34%
–42%
–42%
*
*
*
*
Wolfe ML et al. Am J Cardiol 2001;87:476-479.
The Effect of Adding Niaspan? to a Stable Dose of a Statin
Percent Change
1 gram daily
2 grams daily
LDL-C
HDL-C
TG
LDL-C
HDL-C
TG
27%
–23%
–30%
-8%
–24%
24%
Brown BG et al. Am J Cardiol 1997;80:111-115.
Triple-Drug Regimen
Lovastatin 40 mg/d
Niaspan 2 g/d
Colesti