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Sharma M, Ansari MT, Soares-Weiser K, et al. Comparative Effectiveness of Lipid-Modifying Agents [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2009 Sep. (Comparative Effectiveness Reviews, No. 16.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

Appendix CDrugs Included in the Review and Label Information

DrugTrade namePharmacokineticsLabelled indications* Contraindications (in addition to considerations common to the class)DosingDose adjustments for special populations
HMG-CoA reductase inhibitors (Statins) inhibit conversion of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate, an early step in the cholesterol biosynthetic pathway
Contraindications: active liver disease; unexplained persistent ↑ transaminases; pregnancy; lactation
Withhold therapy if patient is experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy.
Atorvastatin CalciumLipitor®Plasma peak: 1–2 h
Biovailability: 14% systemic; 30%
Absorption ↓ with food but LDL-c reduction similar regardless of food
Highly plasma protein- bound ½-life: Plasma ~14h;
Activity 20–30 h
Fecal excretion
In liver ↓ LDL receptors on the cell-surface
↑ cellular uptake and catabolism of LDL
Metabolized by CYP450 3A4
↓ TC, LDL-c, Apo B, and TG levels and ↑ HDL-c in FH, nFH, and mixed dyslipidemia (Types IIa and IIb)
↓ serum TG levels (Type IV) Primary dysbetalipoproteinemia (Type III)
↓ total-C, LDL-C in HoFH
↓ risks of myocardial infarction, stroke, angina, need for revascularization, and hospitalization for congestive heart failure, in CHD
Contraindications: ↑ CPK
10, 20, 40, 80 mg tablets
Initially 10 mg/d; max 80 mg/d
Titrate q 2–4 wks as appropriate
May be combined with bile acid sequestrants; maximize time between agents
Do not combine with fibrates
Ator levels, myopathy and/or rhabdomyelitis risk ↑ with concurrent cyclosporine, fibrates, niacin, CYP450 3A4 substrates §
↑ Cmax, ↑ AUC in people > 65y compared to younger adults
↑ Cmax, ↓AUC in women compared to men (no significant difference in LDL↓)
↑ AUC of concomitant norethindrone and ethinyl estradiol contraceptives
Fluvastatin sodium
or
Fluvastatin sodium
Extended-Release
Lescol®
or
Lescol® XL
Plasma Peak Lescol < 1h; Lescol XL ~ 3h
Absorption slower but not decreased with food
↑ Cmax, AUC with hepatic insufficiency
Highly variable pharmocokinetics [with doses > 20mg, enantiomer differences at peak]
Highly plasma protein-bound
Metabolism by CYP450 2C9 (75%), 2C8 (~5%), 3A4 (~20%)
Excretion: 90% feces; primarily metabolites
↓ TC, LDL-c, Apo B, and TG levels and ↑ HDL-c in HeFH, nFH, and mixed dyslipidemia (Types IIa and IIb)
↓ need for revascularization procedures, slow coronary atherosclerosis in CHD
20, 40 mg Lescol® capsules and 80 mg Lescol® XL tablets
Initial dose 20 mg, titrate q 6- wks as indicated by lipid levels and liver function
For LDL-c ↓>25%, or initial LDL- c>190mg/dL, consider initial dose of 40–80 mg/d
Adolescents >1y post- menarche with HeFH, LDL- c>190 mg/dL, family history of CVD and 2+ risk factors
Interactions: ↑ Fluv Cmax, AUC with cyclosporine
↓ Fluv Cmax, AUC, ↑ plasma clearance with Rifampicin
↑ Fluv Cmax, AUC, ↓ plasma clearance with Cimetidine, Ranitidine, Omeprazole
↑ phenytoin and Fluv Cmax and AUC when used concomitantly
↑ Diclofenac Cmax, AUC with Fluv
↑ Glibenclamide (Glyburide) Cmax, AUC, t½, with Fluv – monitor carefully
Renal insufficiency – no adjustment necessary
Hepatic insufficiency – caution with history of liver disease or heavy alcohol ingestion
Monitor prothrombin times with warfarin
LovastatinALTOCOR
Extended release
Inactive lactone metabolized to beta- hydroxyacid and further active metabolites
Absorption: ~ 30%
Excretion: primarily feces; ~10% urine
Crosses placenta and blood-brain barrier
Highly plasma protein- bound
CYP450 3A4 substrates§ ↑ drug exposure, myopathy risks
↓ LDL-C, Total-C, TG; ↑ HDL- C in HeFH, nFH, mixed dyslipidemia (Type IIa, IIb)
Less effective, more incidents of ↑ transaminases in HoFH
10, 20, 40, 60 mg tablets 1 tab at bedtime; start low, titrate q 4 wks
≤ 20 mg if taken with niacin ↑myopathy with fibrates, >1g/day niacin, cyclosporine, CYP450 3A4 substrates§
↓ LDL-C, Total-C, variable
↓ TG, variable ↑ HDL-C drug exposure ↓ with food
Pravastatin sodiumPRAVACHOL®Drug in active form Elimination ½ life 77 h Highly variable plasma peak and AUC for healthy and cirrhotic subjects
Evening dose ↓ systemic bioavailability; ↑ efficacy ~20% plasma protein-bound
~50:50 renal:fecal excretion
Not metabolized by CYP450 3A4
↓ risk of MI, need for revascularization, death from cardiac events, with HC, with and without clinically evident CHD
↓ risk of stroke, slow coronary atherosclerosis in CHD
↓ LDL-C, Total-C, Apo-B, VLDL-c, TG; ↑ HDL-C in HeFH, nFH, mixed dyslipidemia (Type IIa, IIb)
↓ TG (Type IV)
Primary dysbetalipoproteinemia (Type III)
[labelled for children >8]
10, 20, 40, 80 mg tablets
Initial 40 mg/d od; max 80 mg/d
Administer 1h before or 4h after bile acid sequestrant
No ↑ risk myopathy with concurrent therapy with niacin, fibrates, CYP450 3A4 substrates §
Renal insufficiency 10 mg/d
Rosuvastatin calciumCRESTOR®Peak plasma concentration 3–5h; Primarily plasma protein- bound
Bioavailability: ~20%
Elimination half-life: ~19hrs
Excretion: 90% in feces
Unknown transfer to milk ~ 2X exposure in Asian patients compared to Caucasian
Metabolized “minimally” by CYP 450-2C9; no effect on CYP 450 3A4
↓ Total-c, LDL-c, ApoB, non- HDL-c, TG, and ↑ HDL-C in Primary hypercholesterolemia (HeFH and nonfamilial) and mixed dyslipidemia (Types IIa and IIb)
↓ TG (Type IV) HoFH
Not studied in Type I, III and V
Slow progression of atherosclerosis in adults
5, 10, 20, 40 mg tablets Initial dose 10 mg/d except as noted.
≤ 5 mg/d with cyclosporin
≤ 10 mg/d with Lopinavir/Ritonavir
≤ 10 mg/d in combination with gemfibrozil
Use Mg or Al containing antacids 2h before or after Rosuvastatin
↑ risk myopathy and/or rhabdomyelitis, acute renal failure with higher dose, concurrent lipid lowering therapy, cyclosporine, lopinavir/ritonavir
HoFH and/or LDL-c >190 mg/d: 20–40 mg/d
Asian: 5 mg/d initially
Elderly: use with caution
Severe renal impairment not on dialysis: 5–10 mg/d (~ 3X ↑ plasma concentration)
Prolongs INR with coumarin anti-coagulant - monitor INR frequently
Use with caution with drugs that reduce endogenous steroid hormones (e.g. ketoconazole, spironolactone, and cimetidine)
↓ dose with warfarin
SimvastatinZOCOR®Plasma peak: ~ 2–4h
Plasma half-life: 4–12 h
Lactone hydrolyzed to β-hydroxyacid
Low bio-availability in the circulation (<5%)
↑ levels with age, and renal and hepatic insufficiency
Extensive first-pass extraction in the liver
Highly plasma protein- bound
Excretion: ~ 60% feces; ~ 13% urine
No CYP450 3AC inhibition
CYP450 3AC substrate
↓ risk of MI, need for revascularization, death from cardiac events, risk of stroke, TIA in HC patients with clinically evident CHD; ↓ TC, LDL-c, Apo B, non- HDL-c-c, TG; ↑ HDL-c in primary Hypercholesterolemia (HeFH and nonfamilial) Mixed dyslipidemia (Types IIa and IIb)
Dysbetalipoproteinemia (Type III)
Hypertriglyceridemia (Type IV hyperlipidemia)
HoFH
Also labeled for pediatric uses
5, 10, 20, 40, 80 mg tablets
20 mg/d od in evening; titrated monthly as indicated clinically
HoFH: 40 mg/d in evening or 80 mg/d in 3 divided doses
↑ myopathy with fibrates, >1g/day niacin, cyclosporin, CYP450 3A4 substrates § , HIV protease inhibitors
With concomitant lipid lowering therapy: ≤ 10 mg/d
With cyclosporine or
Danzol: initially 5 mg/d; ≤ 10 mg/d maximum
With Amiodarone or
Verapamil: ≤ 20 mg/d
Renal insufficiency: 15 mg/d initially with close monitoring
Contraindications: hypersensitivity, active liver disease; unexplained persistent ↑ transaminases; pregnancy; lactation
Ezetimibe selective inhibitor of intestinal cholesterol and related phytosterol absorption by the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), in the brush border of the small intestine
EzetimibeZetia®Plasma peak: 4–12 h
Plasma half-life: ~ 22 hrs
Highly plasma protein- bound
Absorption: High inter- subject variability; unaffected by food
Glucuronide conjugation ↑ levels in geriatric patients
Excretion: ~ 80% feces Neither inhibitor nor inducer of CYP450 isozymes
50–80% ↓ AUC with cholestyramine bid
↓ Total-c, LDL-c, ApoB in primary hypercholesterolemia (HeFH and nonfamilial) - monotherapy and in combination with HMG-CoA inhibitors
↓ Total-c, LDL-c, ApoB, non- HDL-c-c in mixed hyperlipidemia - combination therapy with FF
HoFH: in combination with Ator or Sim *
↓ sitosterol and campesterol in HoFS
As appropriate upon hospitalization for an acute coronary event
10 mg tablets
10 mg od
May be administered with HMG-CoA reductase inhibitor or fibrate, with awareness that monotherapy risks of other medications are magnified with co-therapy
Hepatic insufficiency: no adjustments required
Renal insufficiency: no adjustments required ≥ 2 h before or ≥ 4 h after bile acid sequestrant
None for race
Contraindications: hypersensitivity, active liver disease; unexplained persistent ↑ transaminases; pregnancy; lactation
Rhabdomyelysis and myopathy are rare on monotherapy; generally associated with concomitant use of HMG-CoA reductase inhibitor
Ezetimibe/SimvastatinVytorinSame as individual drugs above
55% ↓ AUC with bile acid sequestrant
↓ Total-c, LDL-c, ApoB, non- HDL-c, TG, and ↑ HDL-C in primary HC or mixed hyperlipidemia. (HeFH and nonfamilial)
↓ Total-c, LDL-c in primary or mixed hypercholesterolemia HoFH *
10/10, 10/20, 10/40, 10/80 mg ezitimibe/mg Sim od evening, with or without food
Primary HC initially 10/10 or 10/20, titrated monthly as clinically appropriate
HoFH: 10/40 – 10/80 mg/d 10/10 max with gemfibrate; caution with other fibrates, ≥1 g/d niacin
With bile sequestrants, dose ≥2 h before or ≥4 h after sequestrant
risk of myopathy and/or rhabdomyelitis ↑ with dose, CYP450 3A4 substrates § 55% ↓ AUC with cholestryamine – not recommended Monitor with concomitant digoxin, warfarin
Hepatic insufficiency: not recommended
Renal insufficiency: use only if Sim ≥5 mg is tolerated.
≤10/10 mg/d with cyclosporine or Danazol only if Sim ≥5 mg tolerated ≤ 10/20 mg/d with
Amiodarone or Verapamil Other concomitant lipid lowering therapy: avoid - lack of safety and effectiveness data. If used, dose ≤ 10/10 mg/d
Contraindications: hypersensitivity, active liver disease; unexplained persistent ↑ transaminases; pregnancy; lactation
Fibrates
FenofibrateTRICOR®Insoluble in water, but readily absorbed from GI tract; ↑ absorption with food
Plasma Peak fenofibric acid 6–8h
Elimination t½ 20h
Steady-state after 5 days dosing
Highly plasma protein-bound
Glucuronide conjugation
Elimination: 60% of a dose in urine; 25% feces
Insignificant oxidative metabolism (e.g. CYP450)
Finobrate and finofibric acid do not inhibit CYP450 3A4, 2D6, 2E1, 1A2; are weak inhibitors of 2C19, 2A6; mild-to-moderate inhibitors of 2C9
↓ Total-c, LDL-c, TG, ApoB; ↑ HDL-c in primary HC (HeFH and nFH; Types IIa and IIb) - monotherapy and with statins
↓ TG in Types IV and V hyperlipidemia
Contraindications: hypersensitivity; severe renal or hepatic dysfunction; unexplained persistent liver function abnormality; preexisting gallbladder disease
54, 160 mg tablets
Initial dose 160 mg/d with normal renal function; reduce dose if lipid targets met
Limit dose to 54 in those with moderate renal impairment, and in elderly
Coumarin-type anticoagulants potentiated – monitor prothrombin times
Immunosuppressants (e.g. cyclosporine) may elicit synergistic nephrotoxicity
Bile acid sequestrants 1–2h after or 4–6h before fenofibrate
Combine with HMG-CoA reductase inhibitors only if benefit outweighs increased risk including myopathy and/or rhabdomyelitis
Micronized fenofibrateLofibra®30% ↑ absorption compared to TRICOR,® so lower once-daily dose is effectiveAs above134, 200 mg tablets
GemfibrozilLOPID®Completely absorbed
↑ Cmax with dose 0.5h before meal; unchanged AUC
↓ AUC with dose after meal
Highly plasma protein- bound
6% excreted in feces
70% excreted in urine; glucuronide conjugation
Oxidative metabolism
↓ TG in Types IV and V hyperlipidemia at risk of pancreatitis
Not indicated for Type I hyperlipoproteinemia, ↓ risk of developing CHD only in Type IIb patients with low HDL-c, high LDL-c and TG
Contraindications: combination with cerivastatin (↑ risk myopathy and/or rhabdomyelitis ); hepatic or severe renal dysfunction, including primary biliary cirrhosis; gallbladder disease; hypersensitivity
600 mg tablets
1200 mg/d; 600 bid, 0.5h before morning and evening meals
Coumarin-type anticoagulants potentiated – monitor prothrombin times
Patients taking repaglinide or gemfibrozil should not start the other; patients taking both already should carefully monitor blood glucose, and should not take itraconazole.
Discontinue if lipid response not significant
Caution in pregnancy – only if potential benefit outweighs risks to fetus
Unknown transfer to breast milk
Niacin
Niacin (NIR)Niacor®Water-soluble B-complex vitamin (note: nicotinamide not effective)
Plasma peak: 30–60 min
Plasma t½: 20–45 min
Excretion: 88% in urine as niacin and nicotinuric acid
↓ Total-c, LDL-c in primary HC (Types IIa and IIb)
↓TG in hyperlipidemia (Types IV and V), ↑ HDL-c
Not indicated in Type I hyperlipoproteinemia
Contraindications: hypersensitivity; significant/unexplained hepatic dysfunction; active peptic ulcer; arterial bleeding
500 mg tablets
1–2 g, bid or tid
Start with 250 mg following evening meal, increase every 4–7 days until 2 g/d. If lipid goals are not met, increase at 2–4 wk intervals to 3g/d. May increase further, generally 6g/day max.
Flushing may be decreased by slowly increasing dose, pre-treatment with aspirin or other NSAID.
Use with caution: substantial alcohol consumption; history of peptic ulcer; hepatitis; hepatobiliary disease; diabetes or potential diabetes; unstable angina/MI (esp. with nitrate, calcium channel blockers or adrenergic blocking agents); increased risk R/M with HMG-CoA reductase inhibitors
Pregnancy: discontinue Tx for Types IIa or IIb; assess individually for Types IV or V
Nursing: transfers to milk - assess individually
Niacin extended-release (NER)NIASPAN®Plasma half-life: NR
Absorption: 60 to 76 % of dose
Excretion: 60 to 76 % of dose recovered in urine; little in feces
Distribution: In mice niacin and metabolites concentrate in the liver, kidney and adipose tissue.
Complex metabolism
↓ Total-c, LDL-c, Apo-B and TG in primary hypercholesterolemia (HeFH and nonfamilial) and mixed dyslipidemia (Types IIa and IIb)
↓ TC in Types IV and V hyperlipidemia
↓ risk recurrent MI with history of MI and HC
In combination with Lov (see below) In combination with bile acid sequestrant to slow or reverse atherosclerotic disease; ↓ Total-c, LDL-c in primary hypercholesterolemia (Type IIa)
Contraindications: hypersensitivity; significant, unexplained hepatic dysfunction; active peptic ulcer; arterial bleeding
500, 750, 1000 mg
Tablets swallowed whole, according to a titration schedule, at bedtime, after a low-fat snack
Flushing a common side- effect - reduced with aspirin or other NSAID, avoidance of hot drinks. If awakened by flushing rise carefully, esp. if taking blood-pressure medication
Retitrate after extended discontinuation
Maximize time between bile acid sequestrants and niacin
May be added for patients on stable dose Lov, max Lov 20 mg/d, and Niaspan 2 g/d
Caution, monitor closely: hepatic insufficiency; history of jaundice, hepatobiliary disease, peptic ulcer; renal insufficiency; diabetes/potential diabetes – monitor for dose-related ↑ glucose intolerance; unstable angina/MI (esp. with nitrate, calcium channel blockers or adrenergic blocking agents); predisposition to gout May potentiate effects of anticoagulants Monitor for hypophosphatemia
Pregnancy: discontinue Tx for Types IIa or IIb; assess individually for Types IV or V
Niacin extended-release/lovastatinAdvicor®Plasma peak: Niacin 5h; Lov 2–4h
Plasma half-life: Niacin 20 to 48 min; Lov 4.5 h
Absorption: Niacin ~72%; systemic concentrations dose-dependent and variable; Lov
Bioavailability of Niacin and Lov varies with food; tablets not interchangeable
Distribution: Niacin <20% serum protein-bound, distributes into milk; Lov highly serum protein- bound
Lov bioavailability ↑ with CYP450 3A4 substrates §
Excretion: >60% Niacin in urine; ~83% Lov in feces [check to make consistent with 2 ingredients above]
Not for initial therapy
Primary hypercholesterolemia (HeFH and nonfamilial) and mixed dyslipidemia (types IIa and IIb)
Patients treated with Lov needing lower TG or higher HDL; and Patients treated with niacin who require further LDL- lowering
Contraindications – see niacin and Lov
500/20, 750/20, 1000/20 mg niacin/mg Lov
Add Lov to existing niacin therapy, or titrate niacin
Warning: do not substitute with equivalent dose used of crystalline niacin – possible severe hepatotoxicity
Caution: alcohol consumption, history of liver disease
Avoid concomitant use of fibrates unless benefit likely to outweigh potential harm (e.g. hepatotoxicity, myopathy and/or rhabdomyelitis)
See also Lov, niacin
No dose adjustments reported for special populations.
Bile acid sequestrants - Strong acid ion exchange resins that are not bioabsorbed, to remove bile acids from hepatic re-circulation Contraindicated with bowel obstruction or hypersensitivity to agent
CholestryamineCholestryamineHydrophilic In patients with partial biliary obstruction, ↓ dermal deposition lessens pruritis??↓ LDL-c in HC
Not indicated for TG only
9 g/dose (packet or scoop) mixed with liquid
1 dose od; titrated to bid after 1wk; recommended maintenance 2–4, max 6g/d as appropriate
May reduce absorption of many medications and nutrients (vitamins, phosphate) – use caution when titrating dose and when discontinuing
Caution re. constipation, possible bowel obstruction; tooth discoloration, damage
Caution in pregnancy/nursing due to possible nutrient deficiencies
ColestipolCholestidNot applicable5 g/scoop granules 1g tablets
ColesevelamWelcholHydrophylic, insoluble in water, not degraded by digestive enzymes
Binds bile acids, including glycholic acid
Alone or with a statin to ↓ LDL-c in primary hypercholesterolemia (Type IIa)625 mg tablets
6 tablets od or 3 bid with meals, with liquid; max 7/d
No ↓ bioavailability of digoxin, Lov, metopropol, quinidine, valproic acid and warfarin
Slight ↓ bioavailability verapamil
Caution re. susceptibility to vitamin K or fat-soluble vitamin deficiencies
Caution re. dysphagia, swallowing disorders, severe gastrointestinal motility disorders, or major gastrointestinal tract surgery
Consult physician if intending conception, pregnant or nursing
Omega-3 fatty acids
Omega-3-acid ethyl estersOMACOR®Highly absorbed
Mechanism poorly understood
Dose-dependent ↑ serum phospholipid EPA; less marked ↑ DHA not dose-dependent
Human CYP450 unknown; ↑P450 enzyme concentrations in rats
↓ very high TG (≥ 500 mg/dL)
Contraindications: hypersensitivity, allergy or hypersensitivity to fish
1 g capsules (900 mg ethyl esters of omega-3 fatty acids)
~ 465 mg EPA
~ 375 mg DHA
Dose: 4 g od or 2 g bid
Discontinue after 2 mo if response is inadequate
Pregnancy: not studied – discontinue if pregnant or nursing
Anticoagulants: monitor for increased bleeding
ALT may increase in isolation - monitor

Abbreviations: ALT = Alanine transaminase, AST = aspartate transaminase, AUC = area under the curve in pharmacokinetic study, Apo A = Apo B, Cmax = maximum plasma concentration, CHD = coronary heart disease, CPK = creatine phosphokinase, d = day, DHA = docosahexaenoic acid, EPA, eicosapentaenoic acid, FH = Familial hypercholesterolemia, GI = gastrointestinal, HC = hypercholesterolemia, HoFH = Homozygous familial hypercholesterolemia, HeFH = Heterozygous familial hypercholesterolemia, HoFS = Homozygous familial sitosterolemia, LDL –c low density lipoprotein cholesterol, max = maximum, MI = myocardial infarction, mo = month, NAR = no adjustments required, nFH = Non-familial hypercholesterolemia, NR = not reported, NSAID = non-steroidal anti-inflammatory drug, od = once daily, t½ = half-life (time for concentration to decrease to half the initial level), TG = triglycerides, TIA = transient ischemic attack, Tx = treatment

Footnotes:

*

Every attempt should be made to control serum lipids with appropriate diet, exercise, weight loss in obese patients, and control of any medical problems such as diabetes mellitus and hypothyroidism that are contributing to the lipid abnormalities. Medications known to exacerbate hypertriglyceridemia (beta-blockers, thiazides, estrogens) should be discontinued or changed if possible prior to consideration of triglyceride-lowering drug therapy.

Hypersensitivity is a contraindication for all medications.

as an adjunct to or in place of other treatments (e.g., LDL-c apheresis)

§

e.g. itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, or large quantities of grapefruit juice.

Cover of Comparative Effectiveness of Lipid-Modifying Agents
Comparative Effectiveness of Lipid-Modifying Agents [Internet].
Comparative Effectiveness Reviews, No. 16.
Sharma M, Ansari MT, Soares-Weiser K, et al.

AHRQ (US Agency for Healthcare Research and Quality)

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