Perspectives on Lipid-Lowering Therapy With HMG-CoA Reductase Inhibitors

1
Perspectives on Lipid-Lowering Therapy With
HMG-CoA Reductase Inhibitors

2
Cholesterol Biosynthetic Pathway
HMG-CoA reductase
Squalene synthase
Dolichol
Acetyl CoA
HMG- CoA
Farnesyl pyrophosphate
Mevalonate
Squalene
Cholesterol
Ras protein
Farnesyl- transferase
E,E,E-Geranylgeranyl pyrophosphate
Farnesylated proteins
Geranylgeranylated proteins
Ubiquinones
3
Metabolic Effects of Lipid-Lowering Agents on
Lipoproteins
Agents LDL-C HDL-C VLDL-C Bile acid
sequestrants Ç clearance (modest Ç) Ç
secretion Niacin È synthesis Ç clearance È
synthesis Fibric acid derivatives (modest È) Ç
synthesis Ç clearance HMG-CoA reductase Ç
clearance (modest Ç) Ç clearanceinhibitors
(statins) È synthesis
with atorvastatin
Adapted from Levy et al. Circulation.
199387III45-III53.
4
Safety Summary for HMG-CoA Reductase Inhibitors

• Excellent patient acceptance
• Few drug-drug interactions
• Few side effects
• most common are gastrointestinal mild to
  moderate
• at high doses, elevated ALT/AST in 1 to 2
• myopathy reported in 0.1 (CK gt10 x ULN)
• Only rare cases of toxicity
• No increases in total or non-CHD mortality

Lovastatin Study Groups I through IV. Arch Intern
Med. 19931531079-1087. Second Report of the
Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults
(ATP II). September 1993 NIH Publication
93-3095.
5
Risk of CHD Events and Level of Cholesterol
Ccontrol Ttreatment Aaggressive
Mmoderate. Yusuf S, Anand S. Circulation.
1996931774-1776.
6
Relation Between CHD Events and LDL-C in Recent
Statin Trials
4S-PI
30
2 Prevention
25
4S-Rx
20
with
LIPID-Rx
15
LIPID-PI
1 Prevention
CHD event
CARE-Rx
CARE-PI
WOSCOPS-PI
10
AFCAPS/TexCAPS-PI
5
WOSCOPS-Rx
AFCAPS/TexCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C level at follow-up (mg/dL)
PIplacebo Rxtreatment Shepherd J et al. N
Engl J Med. 19953331301-1307. 4S Study Group.
Lancet. 19953451274-1275. Sacks FM et al. N
Engl J Med. 19963351001-1009. Downs JR et al.
JAMA. 19982791615-1622. Tonkin A. Presented at
AHA Scientific Sessions, 1997.