Drugs for lipids

Statin Combination Products Page 5 CLINICAL STUDIES — Primary Prevention – When taken by patients with risk factors, such as high LDL-C, low HDL-C, elevated CRP, hypertension, or diabet

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Treatment Guidelines

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Drugs for Lipids

Tables

3 Adverse Effects of Cholesterol-Lowering Drugs Page 4

4 Statin Combination Products Page 5

CLINICAL STUDIES — Primary Prevention –

When taken by patients with risk factors, such as high LDL-C, low HDL-C, elevated CRP, hypertension, or diabetes, but no previous coronary heart disease, statins can reduce the risk of a cardiovascular event.2

with cardiovascular disease have shown that lowering

of LDL-C with high-intensity statin therapy (defi ned as reducing LDL-C by 50%) decreases the incidence of cardiac events, stroke, and coronary death signifi cantly more than less intensive regimens Each additional

1 mmol/L (18 mg/dL) decrease in LDL-C reduces all-cause mortality by 10% and major vascular events by 20%.3

ADVERSE EFFECTS — Statins are generally well

tolerated Some patients who cannot tolerate one statin may tolerate another

Muscle effects ranging from myalgia (soreness, cramps,

weakness, or tenderness with or without increased serum creatine kinase [CK]) to myositis (pain and tenderness with increased CK) are common Rarely, rhabdomyolysis and myoglobinemia leading to renal failure can occur In one randomized trial (SEARCH) in 12,064 patients, the incidence of myopathy (muscle pain or weakness and a CK

>10 times the upper limit of normal [ULN]) was 0.9% (53

of 6031) in  patients taking 80 mg of simvastatin daily and 0.03% (2 of 6033) in   those taking 20 mg of simvastatin daily (the maximum daily dose of simvastatin has since been lowered from 80 mg to 40 mg).4,5 A similar dose-related effect has not been reported with atorvastatin in clinical trials CK levels should be measured if the patient develops myalgia; if levels exceed 3-5 times the ULN and are unrelated to unusual or excessive exercise, most expert clinicians would lower the dose or discontinue the drug

An increase in plasma aminotransferase activity to

>3 times ULN occurs in 1-2% of patients taking high doses of statins such as 80 mg of atorvastatin Patients who develop mild-to-moderate transaminase elevations with one statin may be able to tolerate another statin

STATINS

HMG-CoA reductase inhibitors (statins) inhibit

the enzyme that catalyzes the rate-limiting step in

cholesterol synthesis The subsequent reduction in

hepatic cholesterol leads to increased expression of

LDL receptors, which in turn increases uptake and

clearance of LDL-C from the blood Statins also lower

very low-density lipoprotein cholesterol (VLDL-C)

and triglycerides Most statins increase high-density

lipoprotein cholesterol (HDL-C), but only modestly

Statins also have other effects that may be direct effects

of the drug or indirect effects of lowering cholesterol:

they improve endothelial function, decrease platelet

aggregation, and reduce infl ammation Statins also

decrease serum concentrations of C-reactive protein

(CRP), a marker for circulating infl ammatory cytokines

New guidelines from the American College of

Cardiology and American Heart Association no

longer recommend using specifi c cholesterol targets

in the treatment of hyperlipidemia.1 HMG-CoA

reductase inhibitors (statins) are the lipid-lowering

drugs of fi rst choice for treatment of most patients

with atherosclerotic cardiovascular disease They

can decrease the incidence of major coronary events

and death in such patients Taken as an adjunct to

diet, exercise, and smoking cessation, statins can

also reduce the risk of fi rst cardiovascular events and

death in patients with risk factors such as elevated

levels of low-density lipoprotein cholesterol

(LDL-C) and diabetes Their  benefi ts in these patients

clearly outweigh their adverse effects Combining

a statin with another LDL-C lowering drug, such

as colesevelam, niacin, or ezetimibe, can reduce

LDL-C levels further than a statin alone, but studies

demonstrating that such combinations improve

clinical outcomes are lacking Lipid-lowering drugs

must be taken indefi nitely; when they are stopped,

plasma lipoproteins return to pretreatment levels

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Drugs for Lipids

Treatment Guidelines from The Medical Letter • Vol 12 (Issue 137) • January 2014

2

1000 patients treated for a minimum of 2 years, found

no increase in cancer incidence or deaths due to non-vascular causes with statin therapy.3

DRUG   INTERACTIONS — Statin-induced

myop-athy is often caused by drug interactions Simvastatin and lovastatin undergo extensive fi rst-pass metabolism

by CYP3A4 in the liver; their plasma concentrations can be increased dramatically with concurrent use of strong CYP3A4 inhibitors.10 Atorvastatin undergoes less fi rst-pass metabolism by CYP3A4 and most 3A4 inhibitors produce only small increases in its plasma concentrations, but rhabdomyolysis has occurred Fluvastatin is metabolized primarily by CYP2C9 Pravastatin, pitavastatin, and rosuvastatin are not metabolized by the cytochrome P450 enzymes to a clinically signifi cant extent and are least affected by other drugs

Concurrent administration of cyclosporine (Neoral,

and others) increases serum concentrations of all statins and the risk of rhabdomyolysis, probably through inhibition of drug transporters such as OATP

and P-glycoprotein Gemfi brozil (Lopid, and generics)

also increases serum concentrations of statins, possibly

or lower doses of the same one Statin treatment is

safe in patients with mild to moderate elevations of

transaminase levels (≤3 times ULN) and can reduce

cardiovascular morbidity and improve liver function in

patients with mild fatty liver.6

A meta-analysis of 13 statin trials, each including >1000

patients, found an increased risk of diabetes mellitus

in men and women treated with statins compared to

placebo.7 Another meta-analysis found a higher risk of

new-onset diabetes with more intensive statin therapy

than with moderate-dose therapy.8 The 2013 ACC/AHA

guidelines estimate that the risk of new-onset diabetes

is about 0.1 cases/100 patients/year with

moderate-intensity statin therapy (defi ned as reducing LDL-C by

30-<50%) and about 0.3 cases/100 patients/year with

high-intensity therapy (reduction of LDL-C by >50%).1

An observational study has suggested a rare association

of statin use with polyneuropathy.9 Other reports have

described memory loss, sleep disturbances, erectile

dysfunction, gynecomastia, a lupus-like syndrome,

and acute pancreatitis, but with all of these, the

cause-and-effect relationship is not clear A meta-analysis of

26 randomized controlled trials, each including at least

Table 1 Statins

FDA-Approved Usual Adult Usual Decrease in

Atorvastatin – generic 10, 20, 40, 80 mg tabs Initial: 10-20 mg once 35–40% $10.50

Fluvastatin – generic 20, 40 mg caps Initial: 40 mg bid 20–25% 163.20

extended-release –

Lovastatin – generic 10, 20, 40 mg tabs Initial: 20 mg once 25–30% 10.80

Maximum: 80 mg once 4 35–40%

extended-release – Initial: 20 mg once 20–25%

Altoprev (Watson/Actavis) 20, 40, 60 mg tabs Maximum: 60 mg once 40–45% 463.30

Pitavastatin – Livalo 1, 2, 4 mg tabs Initial: 2 mg once 35–40% 150.00

Pravastatin – generic 10, 20, 40, 80 mg tabs Initial: 40 mg once 5 30–35% 26.10

Rosuvastatin – Crestor 5, 10, 20, 40 mg tabs Initial: 10-20 mg once 6,7 45–50% 171.30

Simvastatin – generic 5, 10, 20, 40, 80 mg tabs Initial: 10-20 mg once 9 35–40% 4.20

1 Some expert clinicians use lower doses for initial treatment of patients with only modest elevations of LDL-C or a history of poor tolerance to these drugs For patients who require a large reduction in LDL-C, some would use higher doses initially Statins are generally most effective when taken in the evening Dosage adjustment may be needed for patients with renal or hepatic impairment.

2 Statins in doses that lower LDL-C by >50% are considered high-intensity therapy Those that lower LDL-C by 30-<50% are considered moderate-intensity therapy (NJ Stone et al J Am Coll Cardiol 2013 Nov 7 [epub]) The ranges listed here correspond to the initial and maximum daily doses

3 Approximate wholesale acquisition cost (WAC) of 30 days’ treatment with the lowest initial dose Source: Analy$ource® Monthly (Selected from FDB

MedKnowledge™) December 5, 2013 Reprinted with permission by FDB, Inc All rights reserved ©2013 www.fdbhealth.com/policies/drug-pricing-policy Actual retail prices may be higher.

4 Or 40 mg bid

5 10 mg initially for patients with signifi cant renal impairment.

6 Higher serum concentrations of rosuvastatin have been reported in Asian patients; an initial dose of 5 mg once daily is recommended.

7 Patients with severe renal impairment not on hemodialysis should begin with 5 mg and not exceed 10 mg/day.

8 Not to exceed 20 mg/day in Asian patients (E Lee et al Clin Pharmacol 2005; 78:330).

9 Patients with severe renal impairment should start with 5 mg.

10 Patients taking 80 mg for >12 months without evidence of myopathy can continue at this dose.

11 The maximum dose of simvastatin should be 10 mg daily in patients also taking diltiazem (Cardizem) or verapamil (Calan) and 20 mg daily if taken with

amiodarone (Cordarone), amlodipine (Norvasc), or ranolazine (Ranexa).

CHOLESTEROL ABSORPTION INHIBITOR

Ezetimibe inhibits intestinal absorption of both dietary and biliary cholesterol by blocking its transport at the brush border of the small intestine The recommended dose of 10 mg/day reduces LDL-C by about 18% A

fi xed-dose combination of ezetimibe plus simvastatin

(Vytorin) or atorvastatin (Liptruzet) lowers LDL-C

levels more than a statin alone No convincing data are available to date showing that ezetimibe alone or

in combination with a statin improves cardiovascular outcomes

ADVERSE EFFECTS — Ezetimibe has generally been

well tolerated Diarrhea, arthralgia, rhabdomyolysis,

through inhibition of drug transporters such as OATP,

increasing the risk of rhabdomyolysis

CHOICE OF A STATIN — Lovastatin, pravastatin,

simvastatin, and atorvastatin are available generically,

and all have been shown to reduce cardiovascular risk

Of these, atorvastatin is the most effective in lowering

LDL-C and has a well-documented benefi cial effect

on clinical outcomes Rosuvastatin may be slightly

more effective than atorvastatin in lowering LDL-C,

and has also been shown to improve clinical outcomes

Pitavastatin has not been shown to decrease LDL-C

more than recommended doses of other statins with

longer safety records and, unlike other statins, no data

are available on clinical outcomes with pitavastatin.11

Table 2 Non-Statins

Some Available Usual Adult

Bile Acid Sequestrants

Colesevelam 3 – Welchol tablets (Daiichi Sankyo) 625 mg tabs 6 tabs once or 3 tabs bid $325.80

Welchol packets 3.75 g/packet 3.75 g once or 1.875 g bid 325.80 Colestipol – generic 1 g tabs, 5 g packet, 5 g/scoop 10 g once or 5 g bid 120.20

Colestid tablets (Pfi zer) 1 g tabs 2-16 g once or divided 60.30

Cholestyramine – generic (packets) 4 g/packet 8 g once or 4 g bid 123.00

Cholesterol Absorption Inhibitor

Ezetimibe – Zetia (Merck) 10 mg tabs 10 mg once 163.60

Fibrates

Fenofi brate – non-micronized

Fenoglide (Santarus)3 40, 120 mg tabs 120 mg once 265.80

Lipofen (Kowa)3 50, 150 mg caps 150 mg once 130.10

Lofi bra (Gate)3 54, 160 mg tabs 160 mg once 109.50

Tricor (AbbVie) 48, 145 mg tabs 145 mg once 174.90

Triglide (Shionogi) 160 mg tabs 160 mg once 199.80 micronized – generic 3 67, 134, 200 mg caps 200 mg once 66.20

Antara (Lupin) 30, 43, 90, 130 mg caps 130 mg once 192.30

Lofi bra (Gate)3 67, 134, 200 mg caps 200 mg once 109.50

Fenofi bric acid – generic 45, 135 mg delayed-release 135 mg once 143.90

Niacin

Niacin immediate-release – OTC 500 mg tabs 1000 mg tid 3.74 extended-release 4 – generic 500, 750, 1000 mg ER tabs 1000 mg once 163.50

sustained-release – Slo-Niacin (Upsher-Smith) 250, 500, 750 mg SR tabs 1000 mg bid 14.50

Fish Oil Capsules

Vascepa (Amarin)3 1000 mg caps 5 2 caps bid 6 184.00

Lovaza (GSK) 1000 mg caps 7 4 caps once or 2 caps bid 6 210.80 USP-verifi ed fi sh oil capsules 8 1, 1.2 g caps 9 4 caps tid 18.00 10

1 Dosage adjustment may be needed for renal or hepatic impairment.

2 Approximate wholesale acquisition cost (WAC) for 30 days’ treatment with the lowest usual adult dosage Source: Analy$ource® Monthly (Selected from FDB MedKnowledge™) December 5, 2013 Reprinted with permission by FDB, Inc All rights reserved ©2013 www.fdbhealth.com/policies/drug-pricing-policy Actual retail prices may be higher.

3 Should be taken with food

4 Taken with a low-fat snack at bedtime.

5 Each 1-gram capsule contains 1000 mg EPA.

6 FDA-approved dose for treating hypertriglyceridemia (>500 mg/dL).

7 Each 1-gram capsule contains about 465 mg EPA and 375 mg DHA (total 900 mg polyunsaturated fatty acids [PUFAs]).

8 USP-verifi ed fi sh oil products are manufactured by Berkley & Jensen, Kirkland, and Nature Made.

9 Most 1-gram capsules contain 300 mg PUFAs (180 mg EPA and 120 mg DHA); Nature Made Capsules are 1.2 g containing 360 mg PUFAs (216 mg EPA and 144

mg DHA) Three capsules are approximately equal to one Lovaza capsule.

10 Cost of 2 bottles containing 400 Nature Made capsules based on retail price at Costco.com Accessed December 10, 2013.

Drugs for Lipids

Treatment Guidelines from The Medical Letter • Vol 12 (Issue 137) • January 2014

4

statins, possibly through inhibition of drug transporters such as OATP, increasing the risk of rhabdomyolysis Fenofi brate is eliminated renally and should be used with caution in patients taking cyclosporine or other nephrotoxic drugs

NIACIN (NICOTINIC ACID)

Niacin modifi es all plasma lipoproteins and lipids favorably It increases HDL-C by 15-35% and decreases triglycerides by 10-50% It decreases total plasma LDL-C by 5-25%, changing small, dense LDL particles

to lower-risk large, buoyant forms It also decreases plasma levels of lipoprotein(a), another marker of cardiovascular risk.Niacin is available in immediate-

and extended-release (Niaspan) formulations Most of

the data relating to reductions in cardiovascular disease with niacin comes from studies with immediate-release niacin.17 When patients received intensive therapy

(40-80 mg/day of simvastatin), with or without ezetimibe (10 mg/day), to lower LDL-C to the range of 40-80 mg/dL, the addition of extended-release niacin 1500-2000 mg/ day did not reduce cardiovascular and cerebrovascular clinical events.18

ADVERSE EFFECTS  —  Niacin can cause skin fl ushing

and pruritus, gastrointestinal distress, blurred vision, fatigue, glucose intolerance, hyperuricemia, hepatic toxicity, exacerbation of peptic ulcer and, rarely, dry eyes

or hyperpigmentation Some adverse effects, particularly

fl ushing, are more common with the immediate-release formulation Cutaneous reactions can be diminished by starting with a low dose of niacin, by taking it after meals, and by taking aspirin (81-325 mg) 30 minutes before niacin

BILE ACID SEQUESTRANTS

The resins cholestyramine (Questran, and others) and colestipol (Colestid, and others) and the hydrophilic

hepatitis, pancreatitis, and thrombocytopenia have

been reported Patients with moderate-to-severe hepatic

impairment should not take ezetimibe

DRUG INTERACTIONS — Ezetimibe may increase

the anticoagulant effect of warfarin Bile acid sequestrants

interfere with the absorption of ezetimibe; they should be

taken at least several hours apart Cyclosporine increases

plasma levels of ezetimibe and ezetimibe increases

cyclosporine levels; the clinical signifi cance of these

effects is unknown

FIBRIC ACID DERIVATIVES

Fibrates activate the nuclear transcription factor

PPAR-alpha (peroxisome proliferator-activated

receptor-alpha), which regulates genes that control lipid and

glucose metabolism, infl ammation, and endothelial

function Gemfi brozil, fenofi brate, fenofi bric acid,

and bezafi brate (Bezalip – available in Canada, not in

the US) lower triglycerides and VLDL-C, usually by

25-50%, and may increase HDL-C They may lower

LDL-C, but when they decrease elevated triglycerides,

LDL-C may increase Fibrates are indicated for patients

with hypertriglyceridemia severe enough to be at risk

for pancreatitis.12

EFFICACY — Gemfi brozil is the only fi brate with

demonstrated benefi cial effects on cardiovascular

outcomes,13 but drug interactions with statins are

a major problem with its use Fenofi brate may be

more effective than gemfi brozil in lowering plasma

LDL-C and triglycerides, but a randomized trial

(ACCORD) in 5518 patients with type 2 diabetes

found that combination therapy with fenofi brate and

simvastatin did not improve cardiovascular outcomes

more than simvastatin alone.14 Fenofi bric acid, the

active metabolite of fenofi brate, is the only fi brate

approved by the FDA for use with a statin to reduce

triglyceride levels and raise HDL-C,15 but there is

no evidence that it is more effective than any other

fi bric acid derivative in lowering triglyceride levels

or increasing HDL-C and, as with other fenofi brates,

addition of fenofi bric acid to a statin has not been

shown to improve cardiovascular outcomes.16

ADVERSE EFFECTS — Fibrates are generally

well tolerated Gastrointestinal problems are the most

common complaint Cholelithiasis, hepatitis, and

myositis can occur Fibrates are contraindicated in

patients with liver or gall bladder disease A paradoxical

severe decrease in HDL-C has been reported; if this

occurs, the fi brate should be stopped Aminotransferase

elevations have occurred with fi brate therapy

Fenofi brate can cause elevations in serum creatinine;

the clinical signifi cance of this fi nding is unknown

DRUG INTERACTIONS — Fibrates may potentiate

the effects of oral anticoagulants and oral hypoglycemic

drugs Gemfi brozil can increase serum concentrations of

Table 3 Adverse Effects of Cholesterol-Lowering Drugs

STATINS

GI disturbances, headache, rash, fatigue, myalgia and muscle weakness leading to rhabdomyolysis, elevated hepatic enzymes, hepatic dysfunction, and increased risk of diabetes mellitus

Rare: Polyneuropathy, memory loss, sleep disturbances,

impotence, gynecomastia, lupus-like syndrome, and pancreatitis

FIBRIC ACID DERIVATIVES

GI disturbances, cholelithiasis, hepatitis, and myositis

NIACIN

Skin fl ushing, pruritus, GI disturbances, blurred vision, fatigue, glucose intolerance, hyperuricemia, hepatic toxicity, and exacer-bation of peptic ulcers (adverse effects, especially fl ushing, are more frequent with immediate-release products)

Rare: Dry eyes and hyperpigmentation

EZETIMIBE

Diarrhea, arthralgia, rhabdomyolysis, hepatitis, pancreatitis, and thrombocytopenia

BILE ACID SEQUESTRANTS

Constipation, heartburn, nausea, eructation, and bloating (adverse effects are more common with colestipol and choles- tyramine and may diminish over time)

FISH OIL

Eructation, dyspepsia, and unpleasant aftertaste

LDL-C Although concurrent use of ezetimibe and a

fi brate might normalize plasma lipids in patients with combined dyslipidemia, it might also cause gallbladder disease because both drugs increase biliary cholesterol excretion In severe hypertriglyceridemia not adequately controlled by diet, fi brates and niacin could be used together, possibly in combination with omega-3 PUFAs Since treatment of hypertriglyceridemia with a fi brate may increase LDL-C, it sometimes becomes necessary

to add a statin as well

HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA

Two drugs have recently been approved for homozygous familial hypercholesterolemia (HoFH).23 This inherited condition is most commonly caused by defects in the low-density lipoprotein receptor gene, causing very high levels of LDL-C Without treatment, cardiovascular disease and death can occur in childhood The prevalence

of HoFH is about one per million persons; it affects about

300 people in the US Both mipomersen (Kynamro),

which must be injected subcutaneously, and lomitapide

(Juxtapid), which is taken orally, can lower LDL-C in

patients with HoFH already taking maximum dosages

of other lipid-lowering drugs Whether either one could eliminate the need for apheresis remains to be determined

polymer colesevelam hydrochloride (Welchol) are not

absorbed from the gastrointestinal tract These drugs

can lower LDL-C by up to 20% and increase HDL-C,

but may raise plasma triglyceride concentrations in

patients with hypertriglyceridemia Cholestyramine

and colestipol have been shown to reduce the number

of cardiovascular events, but no clinical outcome data

are available for colesevelam

ADVERSE EFFECTS — Constipation occurs

fre-quently with colestipol and cholestyramine and may

be accompanied by heartburn, nausea, eructation, and

bloating Colesevelam is much better tolerated

DRUG INTERACTIONS — Bile acid sequestrants can

interfere with the absorption of other drugs, including

statins Colesevalam does not appear to interfere with

the absorption of most statins

FISH OIL

Long-chain omega-3 polyunsaturated fatty acids

(PUFAs), which are present in cold-water fi sh such as

herring or salmon and are commercially available in

capsules, can decrease fasting triglyceride concentrations

20-50% by reducing hepatic triglyceride production

and increasing triglyceride clearance.19 With long-term

intake, they may increase HDL-C

EFFICACY — The results of recent studies do not offer

any convincing evidence that fi sh oil supplements either

prevent cardiovascular disease or improve outcomes in

patients who already have it.20,21

Lovaza (formerly Omacor), a combination of

eico-sapentaenoic acid (EPA) and docosahexaenoic acid

(DHA), was the fi rst omega-3 PUFA product to be approved

by the FDA for treatment of severe hypertriglyceridemia

Daily doses of 3-12 g can lower triglycerides by 20-50%,

but have not been shown to prevent pancreatitis, which is

a major concern in patients with very high triglycerides

Vascepa, the second FDA-approved omega-3 PUFA

product for treatment of severe hypertriglyceridemia, is

the ethyl ester of EPA In controlled trials, it has reduced

triglyceride levels by 22-33% compared to placebo.22

ADVERSE EFFECTS — DHA can increase LDL-C

levels, but EPA apparently does not Fish oil supplements

are generally well tolerated Adverse effects have

included eructation, dyspepsia, and an unpleasant

after- taste Worsening glycemic control has been

reported in diabetic patients taking large doses Fish oil

in large doses can also inhibit platelet aggregation and

increase bleeding time; whether it could cause clinically

signifi cant bleeding has not been established

COMBINATIONS

Statins can be used in combination with fenofi brate,

niacin, colesevelam, or omega-3 fatty acids to lower

triglycerides and increase HDL-C in addition to lowering

Table 4 Statin Combination Products*

Niacin ER/lovastatin

Advicor (AbbVie)2 500/20 mg $153.00

Niacin ER/simvastatin

Simcor (AbbVie)3 500/20 mg 107.10

Ezetimibe/simvastatin

Vytorin (Merck)4 10/10 mg 165.80

10/80 mg 165.80

Ezetimibe/atorvastatin

Liptruzet (Merck)5 10/10 mg 165.00

* In addition to the combinations listed in the table, some statins are also available in combination with drugs used to treat other indications Atorvastatin is available in combination with the calcium channel blocker

amlodipine (Caduet, and generics) and simvastatin is available with the antidiabetic drug sitagliptin (Juvisync).

1 Approximate wholesale acquisition cost (WAC) of 30 tablets Source: Analy$ource® Monthly (Selected from FDB MedKnowledge™) December 5,

2013 Reprinted with permission by FDB, Inc All rights reserved ©2013 www fdbhealth.com/policies/drug-pricing-policy Actual retail prices may be higher.

2 Usual daily dosage is 1-2 tablets Maximum daily dosage is 2000/40 mg Take with a low-fat snack at bedtime.

3 Usual daily dosage is 1000/20 mg to 2000/40 mg taken at bedtime with a low-fat snack Maximum daily dosage is 2000/40 mg.

4 Usual daily dosage is 10/10 mg to 10/40 mg in the evening Maximum daily ezetimibe dosage is 10 mg.

5 Usual daily dosage is 10/10 mg to 10/80 mg once daily.

Treatment Guidelines from The Medical Letter • Vol 12 (Issue 137) • January 2014

6

Drugs for Lipids

Treatment Guidelines

from The Medical Letter ®

EDITOR IN CHIEF: Mark Abramowicz, M.D

EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School EDITOR: Jean-Marie Pfl omm, Pharm.D

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CONSULTING EDITORS: Brinda M Shah, Pharm.D., F Peter Swanson, M.D CONTRIBUTING EDITORS:

Carl W Bazil, M.D., Ph.D., Columbia University College of Physicians and Surgeons Vanessa K Dalton, M.D., M.P.H., University of Michigan Medical School Eric J Epstein, M.D., Albert Einstein College of Medicine

Jane P Gagliardi, M.D., M.H.S., F.A.C.P Duke University School of Medicine Jules Hirsch, M.D., Rockefeller University

David N Juurlink, BPhm, M.D., Ph.D., Sunnybrook Health Sciences Centre Richard B Kim, M.D., University of Western Ontario

Hans Meinertz, M.D., University Hospital, Copenhagen Sandip K Mukherjee, M.D., F.A.C.C., Yale School of Medicine Dan M Roden, M.D., Vanderbilt University School of Medicine Esperance A.K Schaefer, M.D., M.P.H., Harvard Medical School

F Estelle R Simons, M.D., University of Manitoba Neal H Steigbigel, M.D., New York University School of Medicine Arthur M F Yee, M.D., Ph.D., F.A.C.R., Weill Medical College of Cornell University SENIOR ASSOCIATE EDITOR: Amy Faucard

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Copyright and Disclaimer: The Medical Letter is an independent nonprofi t organization that provides health care professionals with unbiased drug prescribing recommendations The editorial process used for its publications relies on a review of published and unpublished liter-ature, with an emphasis on controlled clinical trials, and on the opinions of its consultants The Medical Letter is supported solely by subscription fees and accepts no advertising, grants or donations No part of the material may be reproduced or transmitted by any process in whole

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PREGNANCY

Statins are contraindicated (category X) for use

during pregnancy; congenital anomalies have been

reported with lovastatin in some animal species and in

a few human infants Gemfi brozil and fenofi brate are

classifi ed as category C (risk cannot be ruled out) for

use during pregnancy and are teratogenic in animals

Cholestyramine and colestipol might interfere with

absorption of important nutrients Colesevelam appears

to be safe in animal reproductive studies Ezetimibe has

caused skeletal defects in some animal studies and is

classifi ed as category C for use during pregnancy Niacin

and the omega-3 PUFAs are also classifi ed as category C

for use during pregnancy

1 NJ Stone et al 2013 ACC/AHA guideline on the treatment of blood

cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report

of the American College of Cardiology/American Heart Association Task

Force on Practice Guidelines J Am Coll Cardiol 2013 November 7 (epub).

2 PM Ridker and PW Wilson A trial-based approach to statin guidelines

JAMA 2013; 310:1123.

3 Cholesterol Treatment Trialists’ (CTT) Collaboration Effi cacy and safety

of more intensive lowering of LDL cholesterol: a meta-analysis of data

from 170,000 participants in 26 randomised trials Lancet 2010; 376:1670.

4 SEARCH Collaborative Group Intensive lowering of LDL cholesterol

with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of

myocardial infarction: a double-blind randomised trial Lancet 2010;

376:1658.

5 FDA drug safety communication: new restrictions, contraindications,

and dose limitations to Zocor (simvastatin) to reduce the risk of muscle

injury Available at www.fda.gov/drugs/drugsafety/ucm256581.htm

Accessed December 4, 2013.

6 MJ Tikkanen et al Effect of intensive lipid lowering with atorvastatin on

cardiovascular outcomes in coronary heart disease patients with

mild-to-moderate baseline elevations in alanine aminotransferase levels Int J

Cardiol 2013; 168:3846.

7 N Sattar et al Statins and risk of incident diabetes: a collaborative

meta-analysis of randomised statin trials Lancet 2010; 375:735.

8 D Preiss et al Risk of incident diabetes with intensive-dose compared with

moderate-dose statin therapy: a meta-analysis JAMA 2011; 305:2556.

9 D Gaist et al Statins and risk of polyneuropathy: a case-control study

Neurology 2002; 58:1333.

10 Inhibitors and inducers of CYP enzymes and P-glycoprotein Med Lett

Drugs Ther 2013; 55:e44.

11 Pitavastatin (Livalo) – the seventh statin Med Lett Drugs Ther 2010;

52:57.

12 Drugs for hypertriglyceridemia Med Lett Drugs Ther 2013; 55:17.

13 L Tenkanen et al Gemfi brozil in the treatment of dyslipidemia: an

18-year mortality follow-up of the Helsinki Heart Study Arch Intern Med

2006; 166:743.

14 ACCORD Study Group Effects of combination lipid therapy in type 2

diabetes mellitus N Engl J Med 2010; 362:1563.

15 Fenofi bric acid (Trilipix) Med Lett Drugs Ther 2009; 51:33.

16 AB Goldfi ne et al Fibrates in the treatment of dyslipidemias – time for

a reassessment N Engl J Med 2011; 365:481.

17 E Bruckert et al Meta-analysis of the effect of nicotinic acid alone

or in combination on cardiovascular events and atherosclerosis

Atherosclerosis 2010; 210:353.

18 What about niacin? Med Lett Drugs Ther 2011; 53:93.

19 Fish oil supplements Med Lett Drugs Ther 2012; 54:83.

20 Risk and Prevention Study Collaborative Group N-3 fatty acids in patients

with multiple cardiovascular risk factors N Engl J Med 2013; 368:1800.

21 SM Kwak et al Effi cacy of omega-3 fatty acid supplements

(eicosapentaenoic acid and docosahexaenoic acid) in the secondary

prevention of cardiovascular disease: a meta-analysis of randomized,

double-blind, placebo-controlled trials Arch Intern Med 2012; 172:686.

22 Icosapent ethyl (Vascepa) for severe hypertriglyceridemia Med Lett

Drugs Ther 2013; 55:33.

23 Two new drugs for homozygous familial hypercholesterolemia Med

Lett Drugs Ther 2013; 55:25.

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Treatment Guidelines from The Medical Letter • Vol 12 (Issue 137) • January 2014

ACPE UPN: 0379-0000-14-137-H01-P; Release: December 2013, Expire: December 2014

7 Adverse effects of niacin include:

a skin fl ushing

b blurred vision

c fatigue

d all of the above

8 Which of the following drugs has not been shown to improve cardiovascular outcomes when taken in combination with a statin?

a ezetimibe

b fenofi bric acid

c niacin

d all of the above

9 Which of the following drugs can decrease fasting triglyceride concentrations by 20-50%?

a Lovaza

b cholestyramine

c colestipol

d Juxtapid

10 Adverse effects of fi sh oil supplements include:

a eructation

b dyspepsia

c an unpleasant aftertaste

d all of the above

11 Mipomersen and lomitapide have recently been approved for treatment of:

a homozygous familial hypercholesterolemia

b hypertriglyceridemia

c myopathy associated with use of statins

d all of the above

12 Which of the following drugs is contraindicated (category X) for use during pregnancy?

a ezetimibe

b niacin

c simvastatin

d gemfi brozil

1 Which one of the following would be the best choice for treatment

of patients with atherosclerotic cardiovascular disease?

a colesevelam

b ezetimibe

c niacin

d atorvastatin

2 A 68-year-old man has been taking 200 mg of amiodarone and

40 mg of simvastatin daily for several months He complains of

muscle pain and is concerned that the soreness and tenderness

in his muscles is getting worse Which of the following would you

recommend?

a reducing the dose of simvastatin to 20 mg

b increasing the dose of amiodarone to 400 mg

c increasing the dose of simvastatin to 60 mg

d continuing both drugs as originally prescribed

3 Adverse effects of statins include:

a myopathy

b polyneuropathy

c new-onset diabetes

d all of the above

4 In recommended doses, ezetimibe reduces LDL-C by about:

a 30%

b 10%

c 18%

d 40%

5 A 72-year-old woman with low HDL-C levels and

hypertriglyceridemia severe enough to be at risk for pancreatitis

asks her physician to recommend a lipid-regulating drug Which

of the following would be the best choice for this patient?

a pitavastatin

b niacin

c fenofi bric acid

d ezetimibe

6 Which of the following statins are available generically and have

been shown to reduce cardiovascular risk?

a atorvastatin

b lovastatin

c pravastatin

d all of the above