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+ )

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

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)

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?