Lipid- Lowering Medica0ons. Drugs for Med Students Presented by Eric Campbell & Jen Chen

Transcription

1 Lipid- Lowering Medica0ons Drugs for Med Students Presented by Eric Campbell & Jen Chen

2 Rela0ve Effects of Lipid- Lowering Medica0ons Drug LDL HDL TG Sta0ns Fenofibrate Niacin Resins * Eze0mibe *Bile acid sequestrants should not be used in pa0ents with baseline fas0ng triglyceride levels 300 mg/dl or type III hyperlipoproteinemia since severe triglyceride eleva0ons may occur.

3 Choice of Agent LDL LDL & TG LDL & HDL Normal LDL & TG Normal LDL & HDL Sta0n +/- resin +/- eze0mibe Sta0n Sta0n +/- fibrate/niacin Fibrate/niacin/omega 3 or combo Fibrate/niacin or combo

4 HMG- CoA Reductase Inhibitors (Sta0ns) Drug Atorvasta5n (Lipitor ) USUAL Dose Range mg QD (once daily) Rosuvasta5n (Crestor ) 5-40 mg QD Simvasta5n (Zocor ) mg QD Pravasta0n (Pravachol ) mg QD Lovasta0n (Mevacor ) mg QD Fluvasta0n (Lescol ) mg QD

5 HMG- CoA Reductase Inhibitors (Sta0ns) Therapeu0c benefits/uses Cholesterol (esp LDL) Atherosclerosis Coronary heart disease Stroke Mortality Pediatric dyslipidemia MOA Inhibitor of HMG- CoA reductase, the rate- limi0ng enzyme in cholesterol synthesis In general, doubling the sta0n dose LDL by a further 6%.

6 HMG- CoA Reductase Inhibitors (Sta0ns) Adverse effects Generally well tolerated, befer than other lipid- lowering meds Similar incidence of SE with all sta0ns GI (diarrhea, nausea, cons0pa0on, gas, abdo pain) Headache, rash, dizziness Neuropathy (rare) Diabetes (rare, NNH = 255/4 yr, dose- related) Myopathy (<1%) Mechanism unknown Concern if pain + weakness present; check CK, concern if 3-5x May lead to rhabdomyolysis (<0.2%), myoglobinuria, acute renal failure risk with higher doses, combo, drug interac0on, elderly, women, low BMI, Asians, hypothyroidism, impaired renal func0on, diabe0cs Mortality 10% Asymptoma0c increase in liver func0on tests (0.3-2%) AST & ALT > 3x Normal = concerning Dose- related Reversible if stop sta0n

7 HMG- CoA Reductase Inhibitors (Sta0ns) Drug interac0ons myopathy with CYP3A4 or p- gp inhibitors (eg. gemfibrozil, ketoconazole, itraconazole, amiodarone, dil0azem, protease inhibitors, niacin, clarithyromycin, erythromycin) Hold sta0n therapy Reduce sta0n dose for prolonged concurrent therapy Switch to non- interac0ng sta0n Use azithromycin if tx with macrolide is unavoidable; less likely to interact Increased monitoring for muscle- related adverse events absorp0on with bile acid resin effect of warfarin Food interac0ons Grapefruit juice (inhibits CYP3A4 & p- gp) Safe with rosuvasta0n, pravasta0n, fluvasta0n

8 HMG- CoA Reductase Inhibitors (Sta0ns) Contraindica0ons Liver disease Pregnancy/lacta0on Monitoring LFT: 0, 3, 6, 12 months & annually if high dose/ combo or at risk Rou0ne LFT s & CK NOT indicated for all pts

9 Therapeu0c Considera0ons Which sta5n should I prescribe? Select a sta0n based on: pa0ent tolerability, poten0al for drug interac0ons, and cost. Insufficient evidence to support the superior clinical efficacy or safety of one sta0n over another.

10 Therapeu0c Considera0ons Is there any evidence for the treat- to- target LDL- C (or percent LDL- C reduc5on ) approach? Evidence supports the use of fixed sta0n doses, but not the treat- to- target LDL- C (or percent LDL- C reduc0on ) approach. There is a lack of prospec0ve clinical data to support a defini0ve LDL- C level or % LDL- C reduc0on as therapeu0c targets. Pivotal sta0n trials typically used fixed doses, and LDL- C changes were the observed surrogate outcomes but not the variables being manipulated.

11 Fibrates Drug Fenofibrate (Lipidil Micro ) (Lipidil Supra ) (Lipidil EZ ) Gemfibrozil (Lopid ) Benafibrate (Bezalip ) USUAL Dose Range Micro 200 mg QD with food Supra 160 mg QD with food EZ 145 mg QD without regard for food 300 mg BID before meals 600 mg BID before meals 200 mg BID to TID with food 400 mg SR QD

12 Fibrates Therapeu0c benefits/uses Cholesterol TG HDL Atherosclerosis MOA Agonist for the nuclear transcrip0on factor peroxisome proliferator- ac0vated receptor- alpha (PPAR- alpha), downregulates apoprotein C- III (an inhibitor of lipoprotein lipase) and upregulates the synthesis of apolipoprotein A- I, fafy acid transport protein, and lipoprotein lipase

13 Fibrates Adverse effects GI upset, rash, abdominal pain, headache, asymptoma0c increase in LFT Myopathy (rare) Hyperglycemia (rare) Decreased renal func0on (rare) Gallstones (increase by 1-2%) Contraindica0ons Liver disease, gallbladder dz, severe renal dysfunc0on, primary biliary cirrhosis

14 Fibrates Drug interac0ons toxicity/levels with sta0ns, colchicine, cyclosporin effect by cholestyramine (space by 2 hours), rifampin effect of insulin, oral hypoglycemics, warfarin Monitoring CBC, Scr, Glucose in pts taking insulin or oral hypoglycemics, LF Every 3-6 months

15 Bile Acid Sequestrants (Resins) Drug Cholestyramine (Questran ) USUAL Dose Range 4g BID before meals Max 16-24g/day Coles0pol (Coles0d ) 2g BID before meals Max 20-30g/day Colesevelam (Lodalis ) g daily Max g/day

16 Bile Acid Sequestrants (Resins) Therapeu0c uses/benefits Cholesterol LDL Pruritus esp with certain biliary/liver disease Bile- acid induced diarrhea MOA Forms a nonabsorbable complex with bile acids in the intes0ne, releasing Cl- in the process; inhibits enterohepa0c reuptake of intes0nal bile salts and thereby increases the fecal loss of bile salt- bound LDL

17 Bile Acid Sequestrants (Resins) Adverse effects Cons5pa5on, nausea, bloa0ng Contraindica0ons Severe hypertriglyceridemia, biliary obstruc0on Administra0on Mix with juice/milk/water/applesauce Metamucil may be required for cons0pa0on Space other meds (by at least 2 hours) with resins Monitoring LFT, TG

18 Nico0nic Acid Drug Nico5nic Acid (Niacin ) (Niaspan ) USUAL Dose Range Regular release products require 0tra0on. Start mg BID- TID. Increase weekly by 100 mg/ week. With meals. Niaspan ER 500mg- 2g daily 2g/niacin/day helps HDL & TG, but only higher doses affect LDL.

19 Nico0nic Acid Therapeu0c uses/benefits Cholesterol TG HDL Niacin deficiency (Pellagra) MOA Niacin (nico0nic acid) is bioconverted to nico0namide which is further converted to NAD+ and NADH which are coenzymes necessary for 0ssue metabolism, lipid metabolism, and glycogenolysis. The mechanism by which niacin affects plasma lipoproteins is not fully understood.

20 Nico0nic Acid Adverse effects Flushing Flushing thought to be related to rate of rise of niacin Tolerance occurs with 0me Pre- tx with ASA/Advil 30 minutes prior may reduce flushing Take with meals and avoid hot liquids and alcohol to minimize flushing If niacin is missed for more than 2-3 days, it may be necessary to repeat dose 0tra0on to prevent severe flushing Some flush- free products may not contain any free nico0nic acid, so they are INEFFECTIVE at trea0ng hyperlipidemia Hyperglycemia Increased uric acid Headache, GI upset, dry eyes, pruritus, macular edema (rare), postural hypotension

21 Nico0nic Acid Contraindica0ons Severe pep0c ulcer dz, chronic liver dz, overt diabetes, severe gout, hypotension Monitoring LFT, glucose, uric acid

22 Eze0mibe Drug Eze5mibe (Ezetrol ) USUAL Dose Range 10 mg daily (When added to sta0n, may allow sta0n dose) Predominantly used in combina0on with sta0n therapy. May be used as monotherapy in pa0ents intolerant of other therapies.

23 Eze0mibe Therapeu0c uses/benefits Cholesterol (+/- sta0n or fenofibrate) MOA Surrogate data shows addi0onal LDL lowering of 10-20% in combina0on with sta0n Inhibits absorp0on of cholesterol at the brush border of the small intes0ne via the sterol transporter

24 Eze0mibe Adverse effects Fa0gue, abdo pain, diarrhea, pharyngi0s, arthralgia In combina0on with sta0ns similar to sta0n monotherapy Contraindica0ons Hepa0c dysfunc0on, diarrhea Drug interac0ons Cyclosporine and fibrates increase eze0mibe levels Resins interfere with absorp0on Monitoring LFT (greater risk of asymptoma0c enzyme eleva0on than with sta0n alone)

25 Rela0ve Effects of Lipid- Lowering Medica0ons Drug LDL HDL TG Sta0ns Fenofibrate Niacin Resins * Eze0mibe *Bile acid sequestrants should not be used in pa0ents with baseline fas0ng triglyceride levels 300 mg/dl or type III hyperlipoproteinemia since severe triglyceride eleva0ons may occur.

26 Toward Op0mised Prac0ce Guidelines Lipid Algorithm hfp://