Non-Statin Lipid-Lowering Agents

Full update March 2020

Statins are the lipid-lowering agents of choice because they have by far the most, and most robust, evidence for reducing cardiovascular events, including death.39,49 Non-statins have a more limited role.39,49 When deciding to start or continue a non-statin, consider the following:

  • The addition of a non-statin to a statin has not been proven to further reduce cardiovascular mortality.30,61,68
  • Despite IMPROVE-IT, the FDA denied the expanded indication for morbidity and mortality benefits for ezetimibe.65
  • Reinforce statin adherence and lifestyle changes, and check for secondary cause of LDL or triglyceride elevation before adding a non-statin.49
  • For patients who cannot tolerate the recommended statin dose or who do not achieve the expected statin response (e.g., 50% LDL reduction with high-intensity statin, LDL ≤70 mg/dL [1.8 mmol/L]) and are very high-risk at baseline, consider adding a non-statin.39,49
    • Consider adding ezetimibe to a statin in very high-risk patients.30,49 Ezetimibe is the preferred add-on for most patients not meeting lipid goals with a statin.39,49
    • Consider PCSK9 inhibitor as last-line add-on for familial hypercholesterolemia or high-risk clinical CVD requiring additional LDL reduction.49,52-54,61,67,68 See our charts, Lipid Treatment FAQs (U.S.) and Canadian Dyslipidemia Recommendations and FAQs (Canada) for help identifying candidate patients based on guidelines.
    • Consider a bile acid sequestrant, ezetimibe, or PCSK9 inhibitor for patients who cannot tolerate a statin but need LDL reduction.49
    • Do not add gemfibrozil to a statin due to myopathy risk.49
  • It is reasonable to use omega-3 fatty acids, fenofibrate, or niacin for TG ≥500 mg/dL (~5 mmol/L) to prevent pancreatitis (with lifestyle changes).38 (Niacin not preferred in 2018 U.S. lipid guidelines.49) TG-lowering effects of niacin, omega-3-ethyl esters, and fibrates is greatest in patients with higher baseline TG levels.43-45
  • Canada: subgroup analysis suggests that fibrates (e.g., bezafibrate, fenofibrate, gemfibrozil) might benefit patients with high triglycerides and low HDL.39

The chart below provides lipid effects, outcomes, and cost information for the non-statins. Information in the chart may differ from product labeling.

Abbreviations: AAA = abdominal aortic aneurysm; CKD = chronic kidney disease; CrCl = creatinine clearance; CV = cardiovascular; CVD = cardiovascular disease; GI = gastrointestinal; HDL = high-density lipoprotein HeFH = heterozygous familial hypercholesterolemia; HoFH = homozygous familial hypercholesterolemia; IR = immediate release; LDL = low-density lipoprotein; MI = myocardial infarction; PCSK9 = proprotein convertase subtilisin/kexin type 9 TG = triglycerides.

Drug/Approx. Cost for 30-day Supplya

Lipid Effects

Lipid Effects in Combination with Statin

Outcomes Data (monotherapy unless otherwise specified)



(PCSK9 inhibitor)

75 mg/two weeks (pens):
U.S.: ~$450
Canada: ~$550

75 mg/two weeks:
LDL ↓: ~45% to 48%.52,56,67

(When added to a statin.)

See Lipid Effects column.

Post-hoc analysis suggests alirocumab in combination with maximally tolerated statin doses may reduce major CV events in high-risk patients. Further data are needed to confirm

[Level B-1].55

Consider with max tolerated statin for: primary hyperlipidemia (e.g., HeHF) for further LDL reduction, or clinical CVD requiring additional risk reduction.52,67,68

Canadian guidelines: second-line statin add-on option for AAA, diabetes, or CKD.39

No dose adjustment needed with mild to moderate renal or hepatic impairment. No safety data available with severe renal or hepatic impairment.52,67

Subcutaneous injection.52,67

No long-term safety data.

Bempedoic acid
(U.S. only)

(adenosine triphosphate-citrate lyase inhibitor)

180 mg/day: U.S. $330

180 mg/day:
LDL ↓: 21.2%.71

HDL ↓: 0.6%.71

TG: no effect.71

Note: ~40% of patients were taking low-dose statin or nonstatin.71

180 mg/day:69 Further LDL ↓: 18%.


Consider for patients with familial hypercholesterolemia or cardiovascular disease who need additional LDL reduction despite ezetimibe and maximally tolerated statin.70,72

Avoid with simvastatin >20 mg/day or pravastatin >40 mg/day due to increased risk of myopathy.70

May cause tendon rupture. Avoid in patients with a history of tendon problems.70

Monitor for signs and symptoms of hyperuricemia (e.g., gout flare).70

Also available in combination with ezetimibe (Nexlizet).

(Bezalip SR, generic);
(Canada only)

(Fibric acid)

400 mg/day:
Canada: ~$75

400 mg/day:35,36
LDL ↓: 6% to 21%.

HDL ↑: 15% to 25%.

TG ↓: 25.1% to 42%.

400 mg/day:36
Further LDL ↓: 1.1%.

Further HDL ↑: 21.6%.

Further TG ↓:


Secondary prevention: prevents composite endpoint of MI and sudden death in a subgroup with TG

200 mg/dL (~2.3 mmol/L) or higher. No increase in non-CV death.37

Reversible increase in serum creatinine.33

Requires renal dose adjustment.33,b

Limited data with statins.

(generics only [U.S.]; Olestyr, generics [Canada]

(Bile acid sequestrant)

16 g/day (packets):
U.S.: ~$245
Canada: ~$50

LDL ↓:62
9% (4 to 8 g/day); 21% (16 to 20 g/day);23% to 28% (>20 g/day).

HDL ↑: 4% to 8% (16 to 24 g/day).62


TG ↑: 11% to 28% (4 to 24 g/day).62

Further LDL ↓:4,5
~10% (8 g/day); ~20% (24 g/day).

Further HDL ↑:3,4 0% to 10%.

Primary prevention, men: reduces need for bypass, and combined endpoint of coronary heart disease, death, and nonfatal MI (NNT = 59 for

7 years) [Level A-1].6,14

Secondary prevention, men: with diet, reduces cardiac events vs usual care (not placebo-controlled; events not a primary outcome) [Level B-1].7 Slows progression and increases regression of atherosclerosis.7,34

Can be difficult to tolerate due to GI side effects such as constipation and gas.8

Canadian guidelines: statin add-on option in patients not meeting lipid goals (ezetimibe preferred in primary prevention, clinical CVD, diabetes, AAA, or CKD).39

(Welchol, generic [U.S.], Lodalis [Canada])

(Bile acid sequestrant)

3.8 g/day (tablets):
U.S.: ~$100
Canada: ~$225

3.8 g/day:
LDL ↓: 15% to 19.1%.2,8

HDL ↑: 3% to 8.1%.2,8

TG ↑: 10% (about 20% when used with insulin or sulfonylureas).2

3.8 g/day:2
Further LDL ↓: 10% to 16%.

Further HDL ↑: 3% to 7%.


Limited data with statins.

Studied in combination with atorvastatin, lovastatin, pravastatin, and simvastatin.2,10

Canadian guidelines: statin add-on option in patients not meeting lipid goals (ezetimibe preferred in primary prevention, clinical CVD, AAA, diabetes, or CKD).39

Potential lower risk of GI side effects compared to cholestyramine and colestipol.8,64

FDA-approved for glycemic control in type 2 diabetes.2

(Colestid, generic [U.S.])

(Bile acid sequestrant)

10 g/day (packets):
U.S.: ~$190
Canada: ~$75

LDL ↓: 5% (2 g/day) to 26% (16 g/day).62

HDL: no effect.62

TG ↑: 10% to 15% (2 to 16 g/day).62

Further LDL ↓: 10% (5 g/day) to 12% (10 g/day).11

Reduces progression of atherosclerosis and events when combined with niacin or lovastatin (events not a primary outcome).50

Can be difficult to tolerate due to GI side effects such as constipation and gas.8

Canada: statin add-on option in patients not meeting lipid goals (ezetimibe preferred in primary prevention, clinical CVD, diabetes, AAA, or CKD).39


(PCSK9 inhibitor)

140 mg every two weeks:
U.S.: ~$560
Canada: ~$545

140 mg every two weeks:58,59,61,63
LDL ↓: 42% to 65%.
(Regardless of statin use.)

See Lipid Effects column.

Lowered LDL 34% to 38.5% more compared to ezetimibe.58,60

Added to a high- or moderate-dose statin, prevents one CV death, MI, or stroke for every 67 high-risk CVD patients treated for about two years (FOURIER study). CV death as a stand-alone outcome not affected. Most patients had a prior MI, and about one third had diabetes and/or smoked.61

Consider with max tolerated statin for: HeHF or HoFH for further LDL reduction, or clinical CVD requiring additional risk reduction.53,54,61

Subcutaneous injection.53,54

No dosage adjustment needed with mild to moderate hepatic impairment. No data in severe hepatic impairment.53,54 Canada: use caution in severe renal or hepatic impairment.53

No long-term safety data.

(Zetia, generics [U.S.], Ezetrol, generics [Canada])

(Cholesterol absorption inhibitor)

10 mg/day:
U.S.: ~$20
Canada: <$10

10 mg/day:12,13
LDL ↓: 18%.

HDL ↑: 1%.

TG ↓: 8%.

Further LDL ↓: 25%.13


Further HDL ↑: 3%.13


Further TG ↓: 14%.13

With simvastatin 20 mg, reduces first major atherosclerotic event in chronic renal disease [Level A-1].29

Adding ezetimibe to simvastatin 40 mg post-acute coronary syndrome (ACS) prevents one CV event for every 50 patients treated for
7 years vs simvastatin alone [Level A-1].30

See our chart, Lipid Treatment FAQs, for details on the role of ezetimibe from the U.S. lipid guidelines.

Canada: preferred statin add-on for primary prevention, AAA, diabetes, clinical CVD, or CKD. A statin-add-on option in genetic dyslipidemia.39

U.S.: ezetimibe/simvastatin [Vytorin, generics]). $25 [10 mg/20 mg/day]).

U.S.: Antara, generics; Fenoglide, generics; Fibricor; Lipofen; Tricor, generic Triglide; Trilipix, generics; Lofibra (generic only)
Canada: Lipidil EZ, generics; Lipidil Supra, generics

(Fibric acid)

130 mg/day
U.S.: ~$165

145 mg/day:
U.S.: ~$20
Canada: ~ $30

200 mg/day
Canada: <$10

145 mg/day:15
LDL ↓: 20.6%.

HDL ↑: 11%

TG ↓: 23.5% to 54.5% (greatest drop in patients with highest triglycerides).

200 mg/day:16-18
Further LDL ↓: 0% to 6%.

Further HDL ↑: 13% to 17%.

Further TG ↓: 20% to 32%.

Prevention of CV events in type 2 diabetes: did not reduce primary composite outcome (non-fatal MI or CV death). Improved outcomes included non-fatal MI (24%↓), coronary revascularization (21%↓), progression to albuminuria, and reduced laser treatments for retinopathy. Non-significant increase in CV death.31

As statin add-on, did not lower risk of non-fatal MI, non-fatal stroke, or CV death more than statin alone in patients with type 2 diabetes at high risk for CV disease.32

Option for TG ≥500 mg/dL (~5 mmol/L).38

Consider for patients with high CV risk and high TG/low HDL despite statin.39

Requires renal dose adjustment.33,b

Associated with reversible increase in serum creatinine.33

Unclear risk of cholelithiasis.51

In the U.S., FDA indication for fenofibric acid (Trilipix) use with statins revoked in April 2016 due to lack of CV benefit.57

Fenofibrate is still indicated as adjunct to diet to improve lipids.66

Preferred over gemfibrozil for use with statins for safety.33

(Lopid [U.S.], generics)

(Fibric acid)

1,200 mg/day:
U.S.: <$10
Canada: ~$60

1,200 mg/day:
LDL: No effect.21

HDL ↑: 6%.21

TG ↓: 33% to 50%.21,41

Further TG ↓: 41%.19

Further HDL ↑: 9%.19

Primary prevention, men: reduced sudden cardiac death plus fatal/nonfatal MI
(NNT = 71 over 5 years) [Level A-1].20

Secondary prevention of nonfatal MI plus cardiac death in men with low HDL (NNT = 23 over 5 years) [Level A-1].21

Option for TG ≥500 mg/dL (~5 mmol/L).38

Requires renal dose adjustment.33,b

Avoid with statin.33

No mortality benefit.20,21

Unclear risk of cholelithiasis.51

Icosapent ethyl

(EPA about 1 g omega-3s/capsule)

(4 g/day)
U.S.: ~$330
Canada: ~$315

4 g/day:46
LDL: No effect.

HDL: No effect.

TG ¯: 27%.

Further TG ↓: 10.1% (2 g/day), 21.5% (4 g/day).47

Further LDL ↓: 6.2% (4 g/day).47

As a statin add-on, reduces a composite of CV death, nonfatal MI or stroke, revascularization, or unstable angina in a high-risk, mostly secondary prevention, population (NNT=21 over 5 years). Higher incidence of A Fib seen in icosapent group (NNH=71) [Level B-1].48

Option for TG ³500 mg/dL (~5 mmol/L).46

Patients in statin add-on study had a mean TG of 216 mg/dL

(2.4 mmol/L).48

Safe for use with statin.47

Use caution with fish or shellfish allergy.23,46

(Niacor, [IR; U.S. only], Niaspan, generics [U.S.]

Niacin 1 g/day:
U.S.: ~$215 (Niacor)
U.S.: ~$15 (Niaspan)

Monotherapy at usual doses:38
TG ↓: 20% to 50%.

Niaspan 2 g/day:24
LDL ↓: 14% to 17%.
HDL ↑: 22% to 26%.

Niacin IR or Niaspan 1.5 g/day:
LDL ↓: 12%.28
HDL ↑: 17% (Niacin IR).28
HDL ↑: 19% to 22% (Niaspan).24

Further LDL ↓:
(Niaspan 1 g/day); 31%
(Niaspan 2 g/day).9

Further HDL ↑:
(Niaspan 1 g/day);
(Niaspan 2 g/day).9

Further TG ↓:
(Niaspan 1 g/day);
(Niaspan 2 g/day).9

As statin add-on, reduces carotid intima-media thickness (surrogate marker) as compared to ezetimibe as statin add-on in patients with lower HDL.29

Secondary MI prevention: one less MI for every 30 patients treated for five years (Coronary Drug Project) [Level B-1].24

No CV event benefit from combo of niacin + statin vs statin alone in patients with well-controlled LDL, low HDL, and high TG.40

Option for TG ≥500 mg/dL (~5 mmol/L).38

Raises HDL more than any other agent.

Dose-dependent risk of hyperglycemia (especially in patients with type 2 diabetes) and liver toxicity.24

No mortality benefit.24

May increase risk of statin myopathy.24

FDA indication for niacin extended-release (ER) use with statins revoked in April 2016 due to lack of CV benefit/safety.57

Niacin is indicated as monotherapy or for use with bile acid sequestrants.22,24

Omega-3 ethyl esters
(Lovaza, generics)
(U.S. only)

(EPA/DHA about 1 g omega-3s/capsule).

U.S.: ~$300
(4 g/day)

4 g/day:27
LDL ↑: 44.5%.

HDL ↑: 9.1%.

TG ↓: 45%.

4 g/day:25
LDL ↑: 0.7%.

Further HDL ↑: 3.4%.

Further TG ↓: 29.5%.

Secondary prevention: reduces cardiovascular death, sudden death, and combined endpoint of death, non-fatal MI, and non-fatal stroke [Level B-1].26

Secondary prevention in patients with, or at risk for, type 2 diabetes: did not reduce CV events. About half of patients were taking a statin.42

Primary prevention: no benefit for composite of MI, stroke, or CV death
[Level A-1].1

Option for TG ≥500 mg/dL (~5 mmol/L).38

Safe for use with statin.25

Associated with an increase in risk for recurrence of symptomatic atrial fibrillation or flutter, especially within first three months of therapy.27

Use with caution with fish or shellfish allergy.27

  1. Pricing based on wholesale acquisition cost (WAC) of specified dose of lowest priced generic (if available). U.S. medication pricing by Elsevier, accessed February 2020.
  2. Maximum daily dose if CrCl <60 mL/min: bezafibrate 200 mg, gemfibrozil 600 mg, and fenofibrate 67 mg. Avoid if CrCl <15 mL/min.33

Levels of Evidence

In accordance with our goal of providing Evidence-Based information, we are citing the LEVEL OF EVIDENCE for the clinical recommendations we publish.



Study Quality


Good-quality patient-oriented evidence.*

  1. High-quality RCT
  2. SR/Meta-analysis of RCTs with consistent findings
  3. All-or-none study


Inconsistent or limited-quality patient-oriented evidence.*

  1. Lower-quality RCT
  2. SR/Meta-analysis with low-quality clinical trials or of studies with inconsistent findings
  3. Cohort study
  4. Case control study


Consensus; usual practice; expert opinion; disease-oriented evidence (e.g., physiologic or surrogate endpoints); case series for studies of diagnosis, treatment, prevention, or screening.

*Outcomes that matter to patients (e.g., morbidity, mortality, symptom improvement, quality of life).

RCT = randomized controlled trial; SR = systematic review [Adapted from Ebell MH, Siwek J, Weiss BD, et al. Strength of Recommendation Taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature. Am Fam Physician 2004;69:548-56.]

Project Leader in preparation of this clinical resource (360314): Melanie Cupp, Pharm.D., BCPS


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Cite this document as follows: Clinical Resource, Non-Statin Lipid-Lowering Agents. Pharmacist’s Letter/Prescriber’s Letter. March 2020.

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