Drugs and Dyslipidemias (statins and other lipid and atherosclerosis-modifying drugs) October 18,...
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Transcript of Drugs and Dyslipidemias (statins and other lipid and atherosclerosis-modifying drugs) October 18,...
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)
Mechanismmultiple effects on lipoprotein metabolism and lipoprotein lipase, decreased LDL 5-20%, increased HDL 10-20%, decreased TG 20-50%
Outcomereduced major coronary events
Adverseflushing, dyspepsia, liver toxicity (esp with slow release niacin)
ContraindicationsActive or chronic liver disease, pregnancy, breast feeding, diabetes, avoid simultaneous use of statins
Lipid lowering agents - Bile acid sequestrants
MechanismReduced substrate pool for cholesterol synthesis, decreased
LDL 15-30%, increased HDL 3-5%, TG no change or increase
OutcomeDecreased major coronary events, CHD deaths
AdverseGI distress, constipation, decreased absorption of other drugs
ContraindicationsAbsolute: dysbetalipoproteinemia, TG > 400 mg/dL, relative TG > 200 mg/dL
Inhibition of the absorption of dietary
cholesterol - ezetimibe (Zetia®)
MechanismInhibition of a sterol transporter protein in the jejunum,
NPC1L1
OutcomeRreduces total-C, LDL-C, Apo B, and TG, and increases
HDL-C in patients with hypercholesterolemia
Adverseangioedema, pancreatitis, hepatitis, rhabdomyolysis (rare),
diarrhea, abdominal pain, fatigue, cough
Contraindicationsgemfibrozil, 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%
OutcomeDecreased major coronary events
Adversedyspepsia, gallstones, myopathy, unexplained non-CHD deaths in WHO study
Contraindicationssevere renal or liver disease, do not use with statins
Lipid lowering agents - Statins
MechanismHMG-CoA reductase inhibition, decrease LDL 18-55%, increase HDL 5-15%, decrease TGs 7-30%
Outcomedecreased major coronary events, CHD deaths, stroke and total mortality
Adversearthralgia, myopathy, rhabdomyolysis, increased liver enzymes
Contraindicationsactive or chronic liver disease, pregnancy, breast feeding, avoid niacin, caution with fibric acids and inhibitors of 3A4
Reactions catalyzed by HMG-CoA Reductase
3-hydroxy-3-methylglutaryl
coenzyme A mevalonic acid
(reductase cofactors, NADPH + H+ )
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
0 1 20
100
200
300
Time after conlipidolion (weeks)
Conlipidolion-R improves endothelial-dependent brachial artery vasodilation in human volunteers fed a high fat diet
Cuevas et al., 2000
high fat diet
0 1 2 3 4 5-5
0
5
10
Time (min)
healthy diet
0 1 2 3 4 5-5
0
5
10Control
Conlipidolion
Time (min)
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?