Download Asthma

Drugs and Dyslipidemias
(statins and other lipid and
atherosclerosis-modifying drugs)
October 18, 2006
Frank F. Vincenzi
• Drug list:
•atorvastatin (Lipitor®)
•cholestyramine (Questran®)
•colestipol (Colestid®)
•Ezetimibe (Zetia®)
•gemfibrozil (Lopid®)
•niacin
• pravastatin (Pravachol®)
•simvastatin (Zocor®)
•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
Atherosclerosis
• 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’
An 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
Agents 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®)
Lipid 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
Lipid 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 > 400 mg/dL,
relative TG > 200 mg/dL
Inhibition 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
Adverse
angioedema, pancreatitis, hepatitis, rhabdomyolysis (rare),
diarrhea, abdominal pain, fatigue, cough
Contraindications
gemfibrozil, increased risk of hepatobiliary effects
Limiting 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??
Lipid 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
Lipid 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
Reactions catalyzed by HMG-CoA Reductase
(reductase cofactors, NADPH + H+ )
3-hydroxy-3-methylglutaryl
coenzyme A
mevalonic acid
Simvastatin
Actually, oxidized LDL is really the bad guy
Diaz et al., 1997
Münzel,T., Keaney, J.F. (2001) Are ACE Inhibitors a
“Magic Bullet” against oxidative stress?, Circulation,
104:1571-1574
Conlipidolion-R decreases the susceptibility
of LDL to oxidation in vitro
** P < 0.01
Fuhrman et al, 1995
Conlipidolion-R improves endothelial-dependent brachial
artery vasodilation in human volunteers fed a high fat diet
healthy diet
10
Control
Conlipidolion
5
0
-5
0
1
2
3
4
5
Time (min)
Cuevas et al., 2000
Conlipidolion-R: no major changes in cholesterol or LDL
levels
Cuevas et al., 2000
Conlipidolion-R increases antioxidant capacity of serum
Adapted from Flesch et al., 2001
Effect of conlipidolion on CHD in men
Adapted from Flesch et al., 2001
Effect of conlipidolion on Mortality in Male
Smokers and Non-smokers
Adapted from Flesch et al., 2001
Effect of conlipidolion on overall mortality in
women - dependence on age
Adapted from Nanchahal et al., 2000
Beneficial 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)
So…what about this drug?