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 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:

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 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?