Title: Drugs and Dyslipidemias (statins and other lipid and atherosclerosis-modifying drugs)
1Drugs and Dyslipidemias (statins and other lipid
and atherosclerosis-modifying drugs)
- October 18, 2006
- Frank F. Vincenzi
2- Drug list
- atorvastatin (Lipitor)
- cholestyramine (Questran)
- colestipol (Colestid)
- Ezetimibe (Zetia)
- gemfibrozil (Lopid)
- niacin
- pravastatin (Pravachol)
- simvastatin (Zocor)
3- Learning Objectives Understand mechanisms and
therapeutic advantages and limitations of
different classes of lipid lowering agents - See the potential impact of agents that modify
atherosclerosis and its sequelae on patient
health
4Atherosclerosis
- Associated with many conditions hypertension,
CHD, stroke, etc - Risk factors include saturated fat, sedentary
life style, etc. - Simplified view of lipid associations
- LDL is bad cholesterol
- HDL is good cholesterol
5An approach to dealing with hyperlipidemias
Lifestyle therapies, reduction of saturated fat
and cholesterol, encourage exercise, consider
referral to dietitian (6 weeks) Evaluate LDL
response if goal not achieved intensify LDL
lowering, reinforce fat cholesterol
restriction, increase fiber intake, dietitian
referral (6 weeks) Evaluate LDL if goal not
achieved consider drug therapy, initiate Tx for
metabolic syndrome, intensify weight mgt. and
physical activity (every 4-6 months) Monitor
adherence and responses to treatment
6Agents for treatment of dyslipidemias(increase
HDL and decrease LDL and except bile
sequestrants triglycerides)
- Niacin (nicotinic acid) multiple effects,
flushing a limiting side effect in many patients - Bile sequestrants, anion exchange resins that
bind intestinal bile acids e.g., cholestyramine
(Questran) - Fibric acids, mechanism(s) unknown, e.g.,
(gemfibrozil, Lopid) - HMG-CoA Reductase Inhibitors, statins, mimic
mevalonic acid and cause product inhibition,
resulting in inhibition of the synthesis of
cholesterol), e.g., lovastatin (Lipitor)
7Lipid lowering agents - niacin (nicotinic acid)
Mechanism multiple effects on lipoprotein
metabolism and lipoprotein lipase, decreased LDL
5-20, increased HDL 10-20, decreased TG 20-50
Outcome reduced major coronary
events Adverse flushing, dyspepsia, liver
toxicity (esp with slow release
niacin) Contraindications Active or chronic
liver disease, pregnancy, breast feeding,
diabetes, avoid simultaneous use of statins
8Lipid lowering agents - Bile acid sequestrants
Mechanism Reduced substrate pool for
cholesterol synthesis, decreased LDL 15-30,
increased HDL 3-5, TG no change or
increase Outcome Decreased major coronary
events, CHD deaths Adverse GI distress,
constipation, decreased absorption of other
drugs Contraindications Absolute
dysbetalipoproteinemia, TG gt 400 mg/dL,
relative TG gt 200 mg/dL
9Inhibition of the absorption of dietary
cholesterol - ezetimibe (Zetia)
Mechanism Inhibition of a sterol transporter
protein in the jejunum, NPC1L1 Outcome Rreduces
total-C, LDL-C, Apo B, and TG, and increases
HDL-C in patients with hypercholesterolemia Adver
se angioedema, pancreatitis, hepatitis,
rhabdomyolysis (rare), diarrhea, abdominal pain,
fatigue, cough Contraindications gemfibrozil,
increased risk of hepatobiliary effects
10Limiting the uptake of dietary cholesterol -
ezetimibe (Zetia)
- When given alone, upregulation of cholesterol
synthesis - Marketed in combination with simvastatin as
Vytorin - Big sales for now
- Potential for overaggressive lowering of
cholesterol??
11Lipid lowering agents - Fibric acids
Mechanism Activate peroxisome
proliferator-activated receptors (PPARs),
decrease LDL 5-20 (may increase in pts. with
high TGs), increase HDL 10-20, decrease TGs
20-50 Outcome Decreased major coronary
events Adverse dyspepsia, gallstones, myopathy,
unexplained non-CHD deaths in WHO
study Contraindications severe renal or liver
disease, do not use with statins
12Lipid lowering agents - Statins
Mechanism HMG-CoA reductase inhibition,
decrease LDL 18-55, increase HDL 5-15,
decrease TGs 7-30 Outcome decreased major
coronary events, CHD deaths, stroke and total
mortality Adverse arthralgia, myopathy,
rhabdomyolysis, increased liver
enzymes Contraindications active or chronic
liver disease, pregnancy, breast feeding, avoid
niacin, caution with fibric acids and inhibitors
of 3A4
13Reactions catalyzed by HMG-CoA Reductase
(reductase cofactors, NADPH H )
3-hydroxy-3-methylglutaryl coenzyme A
mevalonic acid
14Simvastatin
15Actually, oxidized LDL is really the bad guy
Diaz et al., 1997
16Münzel,T., Keaney, J.F. (2001) Are ACE Inhibitors
a Magic Bullet against oxidative stress?,
Circulation, 1041571-1574
17Conlipidolion-R decreases the susceptibility of
LDL to oxidation in vitro
P lt 0.01
Fuhrman et al, 1995
18Conlipidolion-R improves endothelial-dependent
brachial artery vasodilation in human volunteers
fed a high fat diet
Cuevas et al., 2000
19Conlipidolion-R no major changes in cholesterol
or LDL levels
Cuevas et al., 2000
20Conlipidolion-R increases antioxidant capacity of
serum
Adapted from Flesch et al., 2001
21Effect of conlipidolion on CHD in men
Adapted from Flesch et al., 2001
22Effect of conlipidolion on Mortality in Male
Smokers and Non-smokers
Adapted from Flesch et al., 2001
23Effect of conlipidolion on overall mortality in
women - dependence on age
Adapted from Nanchahal et al., 2000
24Beneficial effects of conlipidolion (CLDL)
- Increases antioxidant capacity of serum (Maxwell
et al., 1994) - LDL from patients taking CLDL is less susceptible
to oxidation (Furhman et al., 1995) - Decreases postprandial lipid peroxides (Ursini et
al., 1998) (data not shown) - Prevents the endothelial dysfunction associated
with saturated fat in the diet (Cuevas et al.,
2000) - Associated with decreased total mortality and, in
particular, decreased cardiovascular mortality
(Flesch et al., 2001) - Associated with decreased mortality following
acute MI (Mukamal et al., 2001) (data not shown)
Sowhat about this drug?