Lipidsupdate

Guidelines for Clinical Care
Quality Department Ambulatory
Lipid Therapy Screening and Management of Lipids

Guideline Team
Team Leader Patient population: Adults age 20–79 years without familial or severe dyslipidemias or chronic
Audrey L. Fan, MD kidney disease (CKD). (In patients with CKD, see UMHS Management of Chronic Kidney Disease.)
General Medicine
Objective: Primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD)
Team Members through lipid screening, determining treatment benefit and risk, and providing appropriate treatment.
Jill N. Fenske, MD
Family Medicine
Key Points
R. Van Harrison, PhD
Obtain a screening / baseline lipid profile
Medical Education Patients. Men age ≥ 35 and women age ≥ 45 years. Also men age 20–35 and women age 20–45 who are
Melvyn Rubenfire, MD at increased risk for ASCVD [IC*]. Can also consider a screening or baseline lipid profile in adults
Cardiology age ≥ 20 when assessing traditional ASCVD risk factors (age, sex, total cholesterol, HDL-C, systolic
Marie A. Marcelino, BP, use of antihypertensive therapy, diabetes, and smoking) [IIC*].
PharmD Fasting/non-fasting. Screening lipid profile can be obtained fasting or non-fasting.
Pharmacy Services Prior to considering drug treatment for dyslipidemias at any age exclude secondary causes (Table 1).
Consultant, 2020 revision Assess ASCVD risk. Does the patient have any of the following risk factors?
Trisha D. Wells, PharmD Clinical ASCVD. This includes stroke/TIA, carotid and peripheral arterial disease, and clinical evidence
Pharmacy Services of coronary heart disease.
Initial Release LDL-C ≥ 190 mg/dL and age ≥ 20, not caused by drugs or an underlying medical condition (Table 1).
May 2000 Diabetes mellitus type 1 or 2, and age 40–75 years, with LDL-C 70–189 mg/dL.
Most Recent Major Update 10-year ASCVD risk ≥ 7.5% and age 40–75 years (see Table 2 for calculation information).
May 2014
Interim / Minor Revision
Chronic kidney disease. (See the UMHS CKD guideline for managing lipids in CKD patients.)
May 2016 For additional risk factors (risk enhancers), see Table 3.
July 2020 If no ASCVD and none of the above risk factors
Reinforce healthy lifestyle. Education as appropriate: smoking cessation, healthy diet, regular exercise,
weight loss, reduce excessive alcohol [IA*].
Follow-up. Repeat screening and risk assessment in 4–6 years [IID*]. If borderline, consider repeat in 1–2 years.
Ambulatory Clinical If the patient has ASCVD or any of the above risk factors other than CKD
Guidelines Oversight Treat with lifestyle changes. Educate as appropriate: smoking cessation (reduces coronary event rate by ~
Karl T. Rew, MD 50% within 1-2 years), healthy diet, regular exercise, weight loss, reduce excessive alcohol [IA*].
April L. Proudlock, BBA,
Initiate statin therapy. (Non-statin medications should be considered only in statin-intolerant patients.)
RN
• Discuss with patient: risk reduction benefits, adverse effects, drug interactions, patient preferences.
• Check baseline ALT. (See Table 4 for monitoring if liver function tests are abnormal.)
Literature search service • Choose dosing for % LDL-C reduction: high-intensity statin (≥ 50%), moderate-intensity statin (30–
Taubman Health Sciences
Library 49%). See Table 6-9 for statin “intensity” levels, effects, interactions, and contraindications.
• Four main treatment benefit groups and their dosing intensity (Tables 5 and 6).
Clinical ASCVD: If age ≤ 75 years, use high-intensity [IA*]; if age > 75 years, use moderate-intensity [IIA*].
For more information If at very high-risk for ASCVD, on maximally tolerated statin, and LDL-C is ≥ 70 mg/dL, consider
734-936-9771 adding ezetimibe [IIA*]. If LDL-C remains ≥ 70 mg/dL, consider adding a PCSK9 inhibitor [IIA*].
LDL-C ≥ 190 mg/dL, age ≥ 20, use high-intensity [IA*].
Diabetes (type 1 or 2) and age 40–75 years with LDL-C 70–189 mg/dL, use moderate-intensity [IA*];
© Regents of the consider high-intensity with risk assessment [IID*].
University of Michigan 10-year ASCVD risk ≥ 7.5% and age 40–75 years, use moderate-to-high intensity [IA*].
If other risks (see Table 3), consider statin therapy or increasing statin intensity based on individual
benefit and harm; including younger persons and those with 10-yr ASCVD risk <7.5%, lifetime risk
These guidelines should not be 39% or greater, and particularly an elevated coronary artery calcium score by CT.
construed as including all • In 6–12 weeks:
proper methods of care or − Check lipids to evaluate adherence. Recheck ALT only if baseline was abnormal, or if patient has
excluding other acceptable
methods of care reasonably known liver disease, risk factors for liver disease, or is on other potentially hepatotoxic medications.
directed to obtaining the same Check creatine kinase (CK) only if muscle aches/weakness. If statin-intolerance, address (Table 10).
results. The ultimate judgment − If lipids do not decrease as expected: address adherence, reinforce lifestyle modifications, and
regarding any specific clinical
procedure or treatment must be consider referral to a specialist in lipid management.
made by the physician in light Triglycerides: Important risk enhancer. After excluding secondary causes and initiating healthy lifestyle,
of the circumstances presented
by the patient.
for persons on a statin with TG > 350 mg/dL consider 2 g twice daily of OTC EPA or EPA+DHA. If
fasting TG ≥ 500 mg/dL or if there is a history of pancreatitis, consider referral to a lipid specialist.
Recent evidence demonstrates triglycerides are a marker of risk for ASCVD.
Longer term follow-up. Check lipids annually to assess adherence.
Note: For cholesterol, total = TC, high-density lipoprotein = HDL-C, low-density lipoprotein = LDL-C. Triglycerides = TG
* Strength of recommendation: I = generally should perform; II = reasonable to perform; III = generally should not perform.
Levels of evidence reflect the best available literature in support of an intervention or test: A = randomized controlled trials; B = controlled trials,
no randomization; C = observational trials; D = opinion of expert panel.
1 UMHS Lipid Therapy Guideline, July, 2020

Table 1. Secondary Causes of Hyperlipidemia
Secondary Cause Elevated LDL-C Elevated Triglycerides
Diet Saturated or trans fats, weight Weight gain, very low-fat diets, high intake of refined
gain, anorexia nervosa carbohydrates, excessive alcohol intake
Drugs Diuretics, cyclosporine, Oral contraceptives, estrogens, glucocorticoids, bile acid
glucocorticoids, amiodarone sequestrants, protease inhibitors, retinoic acid, anabolic
steroids, sirolimus, raloxifene, tamoxifen, beta blockers (not
carvedilol), thiazides
Diseases Biliary obstruction, nephrotic Nephrotic syndrome, chronic kidney disease, lipodystrophies,
syndrome, chronic kidney Cushing syndrome
disease
Disorders and altered Hypothyroidism, obesity, Diabetes (poorly controlled), hypothyroidism, obesity, inactivity;
states of metabolism pregnancy* pregnancy*
* Cholesterol and triglycerides rise progressively throughout pregnancy. Note that statins, niacin, and ezetimibe are
contraindicated during pregnancy and lactation.
Adapted from 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol
Table 2. 10-Year Risk Assessment for ASCVD
Ten-year risk is defined as the risk of developing a first ASCVD event (nonfatal MI, CHD death, fatal or nonfatal stroke) over a
10-year period among people free from ASCVD at the beginning of the period.
Pooled Cohort Equations estimate 10-year ASCVD risk in individuals age 40–79 years with and without diabetes. A
downloadable spreadsheet enabling estimation of 10-year and lifetime risk for ASCVD and a web-based calculator are
available at http://my.americanheart.org/cvriskcalculator
Risk is calculated based on: gender, age (40–79 years), race (African American or whites/others), total cholesterol, HDL-
cholesterol, systolic blood pressure, treatment for high blood pressure (Y/N), diabetes (Y/N), and smoker (Y/N).
The Pooled Cohort Equation may be revised in the near future due to concerns of over-estimating risk particularly in those with
a healthy lifestyle, well educated, and higher socioeconomic status. However, a 10-yr risk score cutoff of ≥ 7.5% may be
reasonable to initiate a conversation between clinician and patient regarding ASCVD risk reduction (see text on Assessing
ASCVD Risk Factors).
When compared with non-Hispanic Whites, the estimated 10-year risk for ASCVD is generally lower in Hispanic-American and
Asian-American populations and higher in American-Indian populations. If using equations for non-Hispanic Whites for other
race/ethnic groups, the estimated risks may be over-estimates, especially for Hispanic- and Asian-Americans.

Table 3. Patient Factors that May Enhance Risk for ASCVD or Increase Benefit from Statin Therapy
In selected individuals who are not in the four main statin benefit groups (see Table 5), and for whom a decision to initiate statin
therapy is otherwise unclear, additional factors may be considered to inform treatment decision making:
Risk enhancers include:
Family history of premature ASCVD, with onset < 55 years of age in a first degree male relative, or < 65 years of age in a first
degree female relative
Primary hypercholesterolemia, including LDL-C ≥ 160–189 mg/dL, or non-HDL-C 190–219 mg/dL
Metabolic syndrome. The NCEP ATP III defines metabolic syndrome as a diagnosis of 3 or more of the following risks:
– Waist circumference > 40 inches (102 cm) for men or > 35 inches (88 cm) for women
– HDL-C < 40 mg/dL for men or < 50 mg/dL for women
– Impaired fasting glucose ≥ 100 mg/dL*
– Triglycerides ≥ 150 mg/dL
– Blood pressure ≥ 130/85 mm Hg
Chronic kidney disease (eGFR < 60 mL/min/1.73m2)
Chronic inflammatory conditions, such as psoriasis, SLE, rheumatoid arthritis, human immunodeficiency virus (HIV)
History of preeclampsia
History of premature menopause (age < 40 years)
High-risk ethnic groups (eg, South Asian)
Current tobacco user
Factors associated with increased ASCVD risk:
– Persistent elevations of triglycerides ≥ 175 mg/dL
– High-sensitivity C-reactive protein ≥ 2 mg/L
– Apolipoprotein B ≥ 130 mg/dL
– Lipoprotein (a) > 50 mg/dL or 125 nmol/L, especially at higher values of lipoprotein (a)
– Ankle-brachial index < 0.9
– Coronary artery calcium (CAC) score ≥ 100, or ≥ 75th percentile for age, sex and ethnicity
*The American Diabetes Association defines impaired fasting glucose as ≥ 100 mg/dL. SLE = Systemic lupus erythematosus.
Adapted from: 2018 Guideline on the Management of Blood Cholesterol: Guidelines Made Simple (updated June 2019).
Washington, DC: American College of Cardiology, 2019.
Table 4. Monitoring Abnormal Baseline ALT
Careful follow-up of liver tests is indicated for those with known liver disease, risk factors for liver disease, or who are on other
potentially hepatotoxic medications. When ALT is elevated and TG > 200 mg/dL in patients with diabetes, pre-diabetes, or the
metabolic syndrome, consider hepatic ultrasound for NAFLD/NASH/cirrhosis. For other patients:
• If baseline liver function tests (LFTs) are normal, no further monitoring is required.
• If baseline LFTs are mildly abnormal (over upper limit of normal [ULN] but < 2 times the ULN): reassess LFTs after 6–12
weeks of statin treatment for stability. If ALT > 2 ULN, consider screening for liver disease to clarify the cause of the
elevated ALT, so as not to have to stop statins. Consider monitoring annually for stability if baseline LFTs are abnormal.
Abnormal baseline liver biochemistries can frequently improve with statin therapy.

Table 5. Main Groups Likely to Benefit from Lipid Treatment
Risk Group Treatment
Secondary Prevention
Patients with clinical ASCVD (angina, ACS, PCI, CABG, PVD,

stroke/TIA, evidence of ischemia on stress testing, carotid plaque,
aortic aneurysm)
If very high-risk ASCVD a High-intensity or maximal statin
If on maximal statin and LDL-C ≥ 70 mg/dL Consider adding ezetimibe
If LDL-C still ≥ 70 mg/dL or non-HDL-C ≥ 100 mg/dL Consider adding a PCSK9 inhibitor
If not very high-risk ASCVD
If age > 75 Consider initiating/continuing high-intensity statin
If age ≤ 75 High-intensity statin to reduce LDL-C ≥ 50%
If high-intensity statin not tolerated Moderate-intensity statin
If on maximal statin and LDL-C ≥ 70 mg/dL May consider adding ezetimibe
Primary Prevention (assess ASCVD risk)
LDL-C ≥ 190 mg/dL High-intensity statin
Diabetes mellitus and age 40–75 and LDL-C ≥ 70 mg/dL Moderate-intensity statin
If multiple risk factors Consider high-intensity statin to reduce LDL-C ≥ 50%
If 10-year ASCVD risk of ≥ 20% Consider adding ezetimibe to max tolerated statin to
reduce LDL-C ≥ 50%
Other patients
If Age 40–75 and LDL-C is 70–189 and ASCVD risk is:
≥ 20% (high risk) Statin to reduce LDL-C ≥ 50%
7.5–19.9% (intermediate risk)
If risk enhancers (see Table 3) Moderate-intensity statin to reduce LDL-C 30–49%
If risk decision is uncertain Consider measuring coronary artery calcium (CAC)
score b
If no risk enhancers Emphasize heart-healthy lifestyle
5–7.4% (borderline risk)
If risk enhancers (see Table 3) Discuss moderate-intensity statin therapy
If no risk enhancers Emphasize heart-healthy lifestyle
< 5% (low risk) Emphasize heart-healthy lifestyle
If age 20–39
If family history of premature ASCVD and LDL-C ≥ 160 mg/dL Consider statin
Others Emphasize heart-healthy lifestyle
Adapted from: 2018 Guideline on the Management of Blood Cholesterol: Guidelines Made Simple (updated June 2019).
Washington, DC: American College of Cardiology, 2019.
a Very high-risk for future ASCVD events: Either multiple ASCVD events or 1 major and multiple high-risk conditions.
• Major ASCVD events: acute coronary syndrome within past 12 months, history of myocardial infarction (other than recent
syndrome), history of ischemic stroke, symptomatic peripheral arterial disease.
• High-risk conditions: age ≥ 65, heterozygous familial hypercholesterolemia, history of prior coronary artery bypass surgery or
PCI outside of the major ASCVD events, diabetes mellitus, hypertension, chronic kidney disease (eGFR < 60
mL/min/1.73m2), current smoking, persistently elevated LDL-C (LDL-C ≥ 100 mg/dL) despite maximally tolerated statin
therapy and ezetimibe, history of congestive heart failure.
b Coronary artery calcium (CAC) score: if CAC = 0, lower risk, no statin (unless diabetes, family history of premature ASCVD, or
cigarette smoker); if CAC is 1–99, statin is favored (especially age ≥ 55); if CAC ≥ 100 or ≥ 75th percentile for age, sex, and
ethnicity, initiate a statin.

Table 6. Statin Dose Intensity and Equivalency Chart*
Statin %LDL-C Statin (HMG-CoA Reductase Inhibitor) Options

Intensity Reduction Rosuvastatin Atorvastatin Pitavastatin Simvastatin Lovastatin Pravastatin Fluvastatin
63
62
40 mg
61
($11 gen,
High- 60
$242 br)
Intensity 59
(lowers 58 80mg
LDL-C ≥ 56 20 mg ($8 gen,
50%) ($8 gen, $508 br)
54
$242 br)
52
50 10 mg
($7 gen, 40mg
48 $242 br) ($7 gen,
46 $508 br)
44
42 20mg
($7 gen,
Moderate- 40 40 mg
$508 br) 4 mg
Intensity ($4 gen,
38 (N/A gen,
(lowers $261 br)
36 $293 br) 80 mg
LDL-C
30–49%) 80mg ($13 gen,
34
20 mg ($8 gen, $367 br)
2 mg ($4 gen, $263 br) 40 mg
32 5 mg (N/A gen, $261 br) ($8 gen, 80mg
($10 gen, $293 br) $183 br) ($137 gen,
30 $242 br) 10mg 10 mg 40mg $350 br)
($6 gen, ($4 gen, ($6 gen,
28 $356 br) $150 br) $132 br) 20mg
Low- 26 ($9 gen,
1 mg 20 mg $125 br)
Intensity 24 40mg
(N/A gen, (54 gen,
(lowers 5 mg ($122 gen,
22 $293 br) $79 br)
LDL-C < ($5 gen, $175 br)
30%) 20 $75 br) 10 mg 10mg 20mg
($5 gen, ($7 gen, ($122 gen,
18
$44 br) $63 br ) $88 br)
Note: Consider the similar cost for generics after considering the potential for drug interactions (Tables 8 and 9). The high potency
statins are preferred with dose adjustment, as needed. Avoid simvastatin and lovastatin because of increased drug
interactions and myopathy. The shading reflects doses listed in the ACC/AHA Guideline on Treatment of Blood Cholesterol
(2013) as reflecting high-intensity therapy (≥ 50% reduction in LDL-C, darker shading) and moderate-intensity therapy
(30-49% reduction in LDL-C, lighter shading).

Table 7. Drug Therapy Summary
$/Mo
Drug & Strength Dose Range $/Mo branda LDL-C HDL-C TG General Cautions about Drug Class
generic a
HMG-CoA Reductase Inhibitors (Statins)
High Potency Statins are contraindicated in pregnancy/lactation. Pre-
Atorvastatin (Lipitor) 10−80 mg/d $6-8 $202-290 39−60% ↓ 5−9% ↑ 19−37% ↓ menopausal women should be advised regarding the
10, 20, 40, 80 mg risks of statins on the fetus, the need for birth control
methods, and stopping statins upon missing a menstrual
Rosuvastatin (Crestor)* 5−40 mg/d $10-11 $92 all 45−63 % ↓ 8−14 % ↑ 10−35% ↓ cycle.
5, 10, 20, 40 mg Liver function tests (LFTs) ↑ in 0.1–1.9%. Careful follow-up
is indicated for those with known liver disease, risk
Moderate Potency factors for liver disease, or who are on other potentially
Pitavastatin (Livalo) 1−4 mg/d N/A $335 32−43% ↓ 5−8 ↑ 15−18%↓ hepatotoxic meds. For other patients, if baseline LFTs
1, 2, 4 mg are normal, no further monitoring is required. If baseline
LFTs are mildly abnormal (over the upper limit of normal,
Simvastatin (Zocor)** 5−40 mg/d $5 $76-133 26−47% ↓ 8−16% ↑ 12−33% ↓ but < 3 times the upper limit of normal): monitor LFTs
5, 10, 20, 40 mg during first 6 months of statin treatment for stability.
Myopathy risk very low as monotherapy, but is increased
Low Potency with drugs that inhibit CYP3A4 (see Table 9). Routine
Fluvastatin (Lescol XL) 20−80 mg/d b $70-135 N/A 19−32% ↓ 3−8% ↑ 0−11% ↓ creatine kinase (CK) screening not proven beneficial.
20, 40 mg capsule 80mg XL: Avoid in combination with gemfibrozil.
80 mg ER tablet $348 Dose adjustments are recommended for patients with
80mg ER: eGFR < 60 mL/min/1.73m2. No dose adjustment
$250 necessary for atorvastatin. See UMHS Management of
Chronic Kidney Disease for dose recommendations in
CKD.
Doubling a statin dose reduces LDL-C by about 6-7%.
Lovastatin (Altoprev 24- 10−80 mg/d b $5-8 $1064 24−40% ↓ 5−19% ↑ 3−22% ↓ Specific statin cautions:
hour)*** * Rosuvastatin drug levels are two fold higher in patients
10, 20, 40 mg of Asian descent; use with caution.
Pravastatin (Pravachol) 10−40 mg/d $7-8 $125-129 18−35% ↓ 4−16% ↑ 1−25% ↓ **Simvastatin 80 mg dose is available but should be
0, 20, 40, 80 mg avoided considering other options.
***Strong CYP3A4 inhibitors can increase atorvastatin,
lovastatin, and simvastatin exposure increasing risk for
muscle injury. See Table 10 for dose limitations with
interaction drugs.
There is no established safety data for statins with ALT > 3x the upper limit of normal (ULN); generally, avoid statins when ALT > 3x ULN, unless found to be related to known liver
disease and risk/benefit is appropriate; severe liver disease is rare with statins. If ALT is > 2x ULN at baseline, evaluate for liver disease; if present, monitor; a further moderate
increase in ALT is expected.
Kim H, Kim TM, Yang SJ, Baik SY, Lee SH, Cho JH, Lee H, Yim HW, Choi IY, Yoon KH, Kim HS. Change in ALT levels after administration of HMG-CoA reductase inhibitors to
subjects with pretreatment levels three times the upper normal limit in clinical practice. Cardiovasc Ther. 2018 Jun;36(3):e12324. doi: 10.1111/1755-5922.12324. Epub 2018 Mar 6.

Table 7. Drug Therapy Summary, continued
Drug & Strength Dose Range $/Mo gen a $/Mo br a LDL-C HDL-C TG General Cautions about Drug Class
Absorption Inhibitors
Bile Acid Resins: Effective and safe with statins.
Cholestyramine (Questran, 4−12 g BID $18–48 $48-144 15−30% ↓ 3−5% ↑ 0–20% ↑ Take other meds 1 hour prior or 4 hours after, or take with
Questran Light) dinner.
4 g resin/variable g powder May cause constipation, bloating, altered fat absorption.
Colesevelam (Welchol) May decrease absorption of vitamins.
3.75 g/packet 3.75 g/d or $163 $700 15−18% ↓ 3% ↑ 9−10% ↑ Can increase triglyceride levels, avoid if TG level > 300
625 mg tablet 1.875 g BID mg/dL.
Colestipol (Colestid)
5 g powder/1g tab 5–15 g BID $26-72 $137-409 15−30% ↓ 3−5% ↑ 0–20% ↑
_____________________________________________
Ezetimibe (Zetia) 10 mg/d $9 $373 15−20% ↓ 1−4% ↑ 5−8% ↓ Ezetimibe is effective and safe with statins.
Fibric Acid Derivatives

Fibrates Obtain baseline ALT, monitor at physician discretion, unless
Gemfibrozil (Lopid) 600 mg BID $11 $435 ± 10% 10% ↑ 43% ↓ at increased risk (see text).
600 mg tablet Contraindicated in hepatic disease or severe renal disease
with GFR < 10 mL/min.
Risk of myopathy with statins.
Dosage should be reduced in chronic kidney disease.
Do not use gemfibrozil in conjunction with statins.
Fenofibrates ______________________________________
Antara (micronized) 43−130 mg/d N/A $186-549 17−35% ↓ 2−34% ↑ 32−53% ↓ Use lowest initial starting dose of fenofibrate dosage form in
43, 130 mg capsules elderly.
Fenoglide 40−120 mg/d N/A $400-1200 Increases effect of warfarin.
40, 120 mg tablets Dosage should be reduced in chronic kidney disease. Renal
Lipofen 50−150 mg/d N/A $117-258 function should be checked periodically, particularly when
50, 150 mg capsules it may impact renal function in the cardiorenal syndrome
Tricor 48−145 mg/d $11-12 $18-34 The FDA has concluded that the totality of the scientific
48, 145 mg tablets evidence no longer supports the conclusion that a drug-
Triglide 50−160 mg/d N/A $369 induced reduction in triglyceride levels and/or increase in
50, 160 mg tablets HDL-C levels in statin-treated patients results in a
Fenofibric Acid reduction in the risk of cardiovascular events. Fibrates
Fibricor 35–105 mg/d $69 $533-1064 should not be used in conjunction with statins for
35, 105 mg tablet reduction in cardiovascular risk.
TriLipix 45–135 mg/d $18-33 $98-292
45, 135 mg delayed release
capsule

Niacin c, d
Niacin Immediate Release 500−1500 mg $116-230 $349-698 5−25% ↓ 15−35% ↑ 20−50% ↓ Take with meals to avoid flushing or gastrointestinal upset.
(IR) (Niacor) TID Can pre-medicate with aspirin 325 mg, 30 minutes prior
50, 100, 250, 500 mg to dose to reduce flushing.
Take Niaspan ER at bedtime with a low-fat snack.
Niacin Extended Release (ER) 1000−2000 $24-44 $296-592 7−16% ↓ 14−22% ↑ 16−38% ↓ With Niaspan ER follow titration schedule: weeks 1–4: 500
(Niaspan) mg/d mg at bedtime; weeks 5–8: 1000 mg at bedtime; may
500, 750, 1000 mg increase dose by 500 mg/d every 4 weeks to a max
dose of 2 g/d. Do not crush tablets. Check LFTs at
baseline and 6 weeks after start or dosage change;
monitor every 6–12 months thereafter.
Causes glucose intolerance; caution in established or
borderline diabetes.
May cause gastrointestinal intolerance; caution with
history of complicated active peptic ulcer disease.
Urinary secretion of uric acid, caution with gout.
Contraindicated in hepatic disease.
Caution in renal impairment.
The FDA has concluded that the totality of the scientific
evidence no longer supports the conclusion that a drug-
induced reduction in triglyceride levels and/or increase in
HDL-C levels in statin-treated patients results in a
reduction in the risk of cardiovascular events. Niacin
should not be used in conjunction with statins for
reduction in cardiovascular risk.
PCSK9 Inhibitors (continued on next page)

Alirocumab (Praluent) 75–150 mg N/A $500-1200 43–64% ↓ 4.6–8.9% ↑ 6.5– For LDL-C > 190 mg/dL with family history of premature
75 mg/mL, 150 mg/mL subcutaneously 17.35% ↓ ASCVD or very high LDL-C, consider referring to a lipid
every 2 weeks; specialist for management.
300 mg Used as add on therapy to statins in very high-risk
subcutaneously patients.
every 4 weeks Available in solution prefilled syringe or solution
autoinjector for subcutaneous injection.
Maximum dose of 150 mg every 2 weeks.
No dosing adjustment required for renal or hepatic
impairment.
Can cause diarrhea, hypersensitivity reaction, myalgia,
flu-like symptoms, and cough.
No known significant drug interactions.

PCSK9 Inhibitors, continued
Evolocumab (Repatha) 140 mg N/A $150-490 For LDL-C > 190 mg/dL with family history of premature
140 mg/mL, 420 mg/3.5 mL subcutaneously ASCVD or very high LDL-C, consider referring to a
every 2 weeks; lipid specialist for management.
420 mg Used for add on therapy to statins in very high-risk
subcutaneously patients.
every month Available in solution for subcutaneous injection.
420 mg/3.5 mL dose should be given over 9 minutes or
in 3 separate 140 mg/mL injections consecutively
within 30 minutes.
No dosing adjustment required for renal or hepatic
impairment.
Can cause hypertension, dizziness, gastroenteritis, flu-
like symptoms, injection site reaction, URI, cough, and
myalgia.
No known significant drug interactions.
Combination Products
Ezetimibe and simvastatin 10/10–10/80 $56-74 $302 all 45–60% ↓ 6–10 % ↑ 23–31% ↓ Combination therapy (statin + other lipid agent) improves
(Vytorin) (ezetimibe/ lipids, but may increase myopathy risk, and has not
10/10, 10/20, simvastatin) been shown to result in a reduction in the risk of
10/40, 10/80 mg mg/d cardiovascular events compared to statin monotherapy.
a Cost = Average Wholesale Price minus 10%. AWP from Lexicomp Online 02/2020. For generic drugs, Maximum Allowable Cost plus $3 from BCBS of Michigan MAC List, 02/2020.
b Dose given as 40 mg BID when total is 80 mg/d.
c Generic niacin immediate release (IR) is inexpensive but not federally regulated and not well tolerated. Some OTC niacin SR formulations have been associated with hepatitis,
fulminant hepatitis and death.

d Start IR 50–100 mg BID–TID and ↑ dose by 300 mg/day per week; use titration pack. Usual maximum daily dose IR 3 g/day

Table 8. Common Drug Interactions
Interactive Agent(s) Clinical Manifestations

Statins a,b Fluconazole, itraconazole, ketoconazole, Increased risk of myopathy
posaconazole
Cyclosporine, tacrolimus Increased risk of myopathy c
Clarithromycin, erythromycin Increased risk of myopathy c
Verapamil, diltiazem, amlodipine Increased risk of myopathy c
HIV protease inhibitors (eg, ritonavir) Increased risk of myopathy c
Nefazodone Increased risk of myopathy c
Niacin, fibrates Increased risk of myopathy c
Danazol Increased risk of myopathy c
Ranolazine Increased risk of myopathy c
Niacin Statins Increased risk of myopathy (< 1%) c
Resins Fat soluble vitamins Impaired absorption (though vitamin supplement not
routinely necessary)
All other drugs Impaired absorption. Take all other meds 1 hour
before or 4 hours after resins
Fibrates Statins Increased risk of myopathy
Warfarin Increased INR
Sulfonylureas May increase risk of hypoglycemia
a Pravastatin, fluvastatin, rosuvastatin, and pitavastatin have a lower risk of drug interactions with other medications
metabolized through the CYP3A4 system than other statins. Simvastatin has a higher risk of myopathy compared to other
statins.
b Grapefruit juice increases the risk of myopathy for statins that are metabolized by the cytochrome P450 3A4 system
(atorvastatin, lovastatin, simvastatin). Avoid large quantities of grapefruit juice (> 1 quart daily).
c Consider statins not metabolized by the CYP3A4 enzymes, such as pravastatin, fluvastatin, rosuvastatin, and pitavastatin.
Table 9. Simvastatin and Lovastatin Contraindications and Dose Limitations
Simvastatin Lovastatin
Contraindicated with simvastatin: Contraindicated with lovastatin:

Calcineurin inhibitors (cyclosporine/tacrolimus/sirolimus) Clarithromycin
Clarithromycin Erythromycin
Danazol HIV protease inhibitors
Erythromycin Itraconazole
Gemfibrozil Ketoconazole
HIV protease inhibitors Nefazodone
Itraconazole Posaconazole
Ketoconazole Telaprevir
Posaconazole
Nefazodone Avoid with lovastatin:
Cyclosporine/tacrolimus
Do not exceed 10 mg simvastatin daily with: Gemfibrozil
Diltiazem*
Verapamil* Do not exceed 20 mg lovastatin daily with:
Danazol
Do not exceed 20 mg simvastatin daily with: Diltiazem
Amiodarone Ranolazine
Amlodipine Verapamil
Ranolazine
Do not exceed 40 mg lovastatin daily with:
Amiodarone
*Contraindicated with Simcor® (simvastatin/niacin ER) as Simcor® is only available with 20 mg or 40 mg of simvastatin.
10 UMHS Lipid Therapy Guideline update, July 2020

Table 10. Management of Statin-Intolerant Patients
1. Discontinue statin. For patients with mild to moderate muscle symptoms that develop during statin therapy, stop the statin
until the symptoms can be evaluated. If more than moderate pains or sudden onset of pain or weakness occurs, consider
excluding rhabdomyolysis by evaluating with CK, creatinine, and checking a urinalysis for myoglobinuria.
2. Secondary causes/conditions. Consider other conditions that may increase the risk for muscle aches or myopathy (eg,
hypothyroidism, influenza, exercise, reduced renal or hepatic function, rheumatologic disorders, steroid myopathy, vitamin D
deficiency, or primary muscle diseases). Consider drug interactions, such as concomitant use of certain statins (atorvastatin,
lovastatin, simvastatin) and other agents that are metabolized by the cytochrome P450 3A4 system.
3. Trial without statin. If muscle symptoms or elevated CK do not resolve completely after 2 months without statin treatment,
consider other causes of muscle symptoms listed above. If persistent muscle symptoms are determined to arise from a
condition unrelated to statin therapy, resume statin therapy at the original dose.
4. Consider lower dose statin retrial. If muscle symptoms resolve after 2 months without statin treatment, and no
contraindication exists, consider retrial of the original or a lower dose of the same statin to establish a causal relationship.
5. Alternative statin. If a causal relationship exists, stop the original statin. After muscle symptoms resolve, start an alternative
low dose statin (preferably rosuvastatin or pravastatin, and avoid trials of lovastatin or simvastatin), and titrate up slowly to
maximum tolerable dose.
6. Intermittent statin dosing. If the patient has failed a trial of a second statin, consider a trial of low dose twice weekly or
alternate day dosing of a long-acting statin, such as atorvastatin or rosuvastatin.
7. Consider referral to lipid specialist. If the patient has failed both a second statin and alternate day statin dosing, consider
referring patient to a lipid specialist for further evaluation and treatment.
Polypharmacy is an issue in secondary prevention. Patients

may be hesitant to take another pill, especially one that may
Clinical Background cause muscle aches. Health providers need to provide
patients with information on the indications, proven benefit,
long term use, and small but real risks.
Clinical Problem
Incidence. Coronary heart disease (CHD) and stroke are the
two most important causes of death and disability in Rationale for Recommendations
developed countries. It is estimated that over 50% of first
CHD events and 75% of CHD deaths are preventable with Scope of This Guideline
use of evidence-based strategies, including diet, exercise,
weight and blood pressure control, aspirin, tobacco This guideline makes recommendations on lipid screening
cessation, and lowering lipids. NHANES data show that and treatment for prevention of cardiovascular events and
roughly 33.5% of the US adult population has high LDL-C mortality in patients age 20–79 years. Primary prevention
(> 130 mg/dL). Over the past decade, the percentage of refers to patients without prior CHD or other clinical
American adults with high total cholesterol decreased from atherosclerotic cardiovascular disease (ASCVD). Primary
18.3% to 13.4%. This reduction reflects the increased prevention includes patients with diabetes mellitus, chronic
percentage of adults with high LDL-C who are being treated, kidney disease (CKD stages 1–5), or patients with Pooled
which increased from 28.4% in 1999–2002 to 48.1% in Cohort Equation 10-year ASCVD risk ≥ 7.5%. Secondary
2005–2008. CHD and atherosclerotic cardiovascular disease prevention includes people with known ASCVD, including
(ASCVD) have declined in the past two decades, likely due prior CHD, stroke/TIA, great vessel arterial disease, and
to improvements in blood pressure and cholesterol control, clinical peripheral arterial disease (PAD).
and declines in smoking.
This guideline focuses on the groups that would benefit the
Issues. Many studies have shown that CHD patients are not most from treatment with a statin (HMG-CoA reductase
adequately treated. Less than half of adults with high LDL- inhibitor) in terms of ASCVD risk reduction and treatment
C receive treatment. The situation is likely worse for strategies, in the context of cardiovascular risk. It also
secondary prevention of ASCVD in those without CHD. discusses the importance of triglycerides and the major
Why do we fail to screen and adequately treat cholesterol? classes of medications and their place in therapy. Statins
Cost may be an issue for some patients. Lack of adherence remain the primary treatment of choice.
to treatment recommendations, despite insurance coverage,
is another. Patient education about the benefits and general
need for lifelong treatment may help improve adherence.
In patients with chronic kidney disease, the approach to lipid atorvastatin 80 mg daily), is more effective in reducing
management depends on CKD stage, dialysis treatment, and events than lower intensity statin treatment. A meta-analysis
prior kidney transplant. Lipid management for CKD patients of high versus lower dose statins, including PROVE IT-TIMI
is addressed in the UMHS clinical care guideline for CKD. 22, TNT, IDEAL (Incremental Decrease in End Points
Through Aggressive Lipid-Lowering) and A-Z (Aggrastat-
The guideline does not address the management of severe or to-Zocor), yielded a significant additional 16% reduction in
familial dyslipidemias, which typically involves lipid CHD events. There was no difference in mortality, but a
specialists. trend toward decreased CHD mortality (OR 12%, p=0.054).
Etiology, Treatment Benefit, and Strategy The HPS trial randomized 20,536 secondary prevention
patients with normal cholesterol to simvastatin 40 mg or
Etiology. Many studies support the causal link between placebo. These were patients who had cholesterol levels for
cholesterol and CHD. People with high total cholesterol (> which their doctors had not recommended drug treatment.
240 mg/dL) have approximately twice the risk of heart Treatment resulted in a 24% relative RR for CHD events and
disease as people with optimal levels (< 200 mg/dL). Large a 12% reduction in total mortality. All subgroups benefited,
cohort studies have shown that each 1% increase in LDL-C including women and the elderly (age > 70 years). Notably,
cholesterol is associated with a 1–2% increase in CHD, and patients at all levels of baseline LDL-C benefited to a similar
each 1% increase in HDL-C is associated with a 2–3% drop degree. Treatment of 1,000 patients with simvastatin would
in CHD event rates. Predictive modeling in one study prevent 70–100 patients from having a major vascular event.
suggested that every 10% increase in the prevalence of Even those patients with a baseline LDL-C < 100 mg/dL
treatment among adults with high LDL-C could prevent (about 3,500 patients) had a similar benefit.
approximately 8,000 deaths per year in those age < 80 years.
Benefit of primary prevention. Primary prevention studies
It is important to evaluate for secondary causes of have shown consistent reduction in ASCVD and
hyperlipidemia by history and selected laboratory tests (see revascularization events. Meta-analysis has shown a
Table 1). It is particularly important to identify patients with nonsignificant (22.6%) reduction in CHD mortality and no
familial dyslipidemias, who often have premature CHD and change in total mortality. A large randomized controlled trial
a strong family history. These patients may not achieve lipid (JUPITER study) looking at rosuvastatin in patients with low
goals with standard treatment, and may benefit from referral LDL-C and elevated C-reactive protein was terminated early
to a lipid specialist. due to dramatic CHD event reduction in the statin arm. The
primary endpoint (first-ever myocardial infarction, stroke,
Treatment benefit. Treatment options include diet, lifestyle hospitalization for unstable angina, arterial revascularization,
changes, and medications, with many patients also using or cardiovascular death) was reduced 44% (P<0.00001). All
complementary and alternative therapies. Of these, trial subgroups benefited.
evidence has shown most benefit with medications.
Interpreting treatment benefit in primary prevention requires
Statins have shown the greatest reduction in total cholesterol looking at absolute versus relative risk reduction (RR). As a
and LDL-C, and the most dramatic reduction in CHD events. group, the primary prevention trials showed a 29% relative
In primary prevention studies, every 40 mg/dL decrease in RR. However, primary prevention populations have low
LDL-C is associated with a 20% reduction in cardiovascular CHD risk, translating into low absolute RR. A meta-analysis
event rates, regardless of baseline LDL-C. In secondary looking at low-risk (10-year risk < 6%), intermediate-risk
prevention trials, statins have also reduced CHD and total (10-year risk 6–20%), and high-risk (10-year risk ≥ 20%),
mortality. found that 4.3 years of statin therapy would reduce CHD
events by 0.75%, 1.63%, and 2.51%, respectively, with
Non-statin medications, including niacin, fibrates, and resins NNTs of 133, 61, and 40. Statins are not considered cost
have shown smaller reductions in CHD events. These effective in the low-risk group, but are cost-effective in the
medications are to be considered only in statin-intolerant intermediate-risk group, and as in the high risk group may be
patients who are candidates for statin treatment, particularly cost saving in those with high LDL-C and risk enhancers.
in secondary prevention.
For patients with diabetes and no other ASCVD risk factors,
Benefit of secondary prevention. Secondary prevention trials statin therapy may reasonably be delayed until age 40 since
have shown consistent reductions in ASCVD events, CHD statin use in diabetics under age 40 is only marginally cost-
mortality, and total mortality. Statins have shown reductions effective. (See UMHS clinical care guideline Management of
in different secondary prevention groups, including patients Type 2 Diabetes Mellitus.)
with CHD, acute coronary syndrome, and peripheral and
cerebrovascular disease. All subgroups, including the elderly Statins may not be appropriate in all patients with diabetes.
and females, have benefited. Older trials used statins that Relatively young patients with a recent diagnosis of Type 1
lowered LDL-C 30–40% with approximately 30% event diabetes, patients with diabetes from pancreatic
reduction. Newer trials have convincingly shown that high- insufficiency, especially in the setting of severe malnutrition,
intensity statin treatment (eg, rosuvastatin 40 mg daily or and patients with a limited life expectancy are possible
examples. When deciding whether to start a statin, consider syndromes, history of MI, stable and unstable angina,
the patient's 10-year ASCVD risk, nutritional status, and life coronary or other arterial revascularization, stroke, TIA, as
expectancy. well as those with great vessel and peripheral arterial disease,
all of presumed atherosclerotic origin.
Evidence is insufficient to recommend drug therapy for low
HDL-C or high triglycerides for primary prevention. For primary prevention (in patients with no clinical ASCVD)
the age group for screening remains an area of controversy.
Treatment strategy. Treatment strategy is changing from a National organizations have different age recommendations
“treat-to-target” approach with lipid level goals to a risk- for screening. Some groups have argued for screening at age
based treatment strategy for most patients. 20, because atherosclerosis begins long before clinical
manifestations. Others have argued that there is no evidence
Risk-based treatment. The 2013 ACC/AHA Guideline on the that screening or treating young adults has been shown to be
Treatment of Blood Cholesterol to Reduce Atherosclerotic of benefit, and given their low absolute risk, would not be
Cardiovascular Risk in Adults provided a new perspective cost effective. Much of the argument against early screening
on LDL-C treatment benefit and strategy to achieve it. was prior to the very low cost of statins.
Rather than focusing on targets for LDL-C levels, the
recommendations reflect using the appropriate intensity of Most guidelines agree that there is good evidence for
statin therapy to reduce ASCVD risk in those patient screening men age ≥ 35 years. The optimal age for screening
populations most likely to benefit. The 2018 women is unknown, but relative to men they generally have
ACC/AHA/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ a lower overall risk and a 10-year delay in relative risk.
ASPC/NLA/PCNA Guideline on the Management of Blood Epidemiologic studies indicate the risks of high cholesterol
Cholesterol identified some additional risk subgroups and extend to age 75, though little trial data exist for this older
LDL-C levels relevant to treatment decisions. age group. AFCAPS/TexCAPS showed benefit in older
adults (age 65–73 years). PROSPER looked at older adults
Even though LDL-C levels are independently associated (age 70–82 years), but the primary prevention group (3,239
with risk for atherosclerotic events, the clinical benefits of patients) did not have a significant reduction in CHD events.
statin treatment (including reduction in ASCVD fatal and Screening for lipid disorders, like other primary prevention
non-fatal events) are proportional to total baseline ASCVD efforts, may not be appropriate in individual patients with
risk rather than baseline LDL-C. In order to maximize the reduced life expectancy.
ratio of benefits to harms and costs, statin therapy is
recommended for individuals at increased ASCVD risk who This guideline incorporates 2008 USPSTF recommendations
are most likely to experience a net benefit in terms of the in assessment for screening and treating lipid disorders:
potential for ASCVD risk reduction and the potential for • Benefits substantially outweigh potential harms for all
adverse effects. Focusing on ASCVD risk of patient groups men age 35 and older and for those women age 45 and
facilitates risk assessment and treatment in the clinical older who are at increased risk for CHD.
setting. • Benefits moderately outweigh potential harms for
younger adults (men age 20–35 and women age 20–45)
Main risk groups. The four main patient risk groups (one for who are at increased risk for CHD.
secondary prevention and three for primary prevention) are:
Secondary prevention The 2013 ACC/AHA Guideline on the Assessment of
• Clinical ASCVD (coronary heart disease, stroke and Cardiovascular Risk states it is reasonable to assess
peripheral arterial disease) traditional ASCVD risk factors (age, gender, total and HDL-
C, systolic BP, use of antihypertensive therapy, diabetes, and
Primary prevention
current smoking) every 4–6 years starting at age 20 years.
• LDL-C ≥ 190 mg/dL (age ≥ 20)
• Diabetes mellitus Type 1 or 2 and age 40–75 years Lipid measures. Obtain a baseline screening lipid profile
• Other patients (see Table 5) (total cholesterol, triglycerides, HDL-C, and LDL-C).
Ideally this should be obtained when the patient is fasting for
Table 5 provides more detail regarding each of these groups, a more accurate evaluation of potential dyslipidemias,
their subgroups, and the associated levels of risk. It also including hypertriglyceridemia. However, if patient
shows recommendations, based on potential risk, benefit, convenience or adherence is an issue, a non-fasting lipid
and harm of treatment, for moderate-intensity or high- profile is adequate to assess cardiovascular risk and to
intensity statin treatment and non-statin pharmacological monitor statin adherence. Total cholesterol and HDL-C are
treatment. Healthy lifestyle is recommended for all. needed for cardiovascular risk calculators. While non-fasting
LDL-C is less accurate than fasting LDL-C, non-fasting
Screening / Baseline Lipid Profile values are sufficient for monitoring general statin adherence.
If lipids are obtained non-fasting and are abnormal (ie, total
Target population. Patients with clinical ASCVD should cholesterol > 200 mg/dL, HDL-C < 40 mg/dL, or
have a baseline and annual lipid profile. This secondary triglycerides > 350 mg/dL), consider obtaining a follow up
prevention group includes those with acute coronary fasting lipid panel to better evaluate for dyslipidemias.
• Other risk factors. See Table 3 for other patient risk
LDL-C is typically measured indirectly in a lipid panel. The factors to consider in selected individuals who are not in
indirect measure is less accurate if TG > 400 mg/dL. At the the above statin benefit groups, and for whom a decision
Michigan Medicine, the lab automatically measures the to initiate statin therapy is otherwise unclear.
direct LDL-C when TG > 400 mg/dL. If a local laboratory • In younger adults age 20–39 years, assessing lifetime risk
does not measure LDL-C directly, when non-fasting TG > facilitates the clinician-patient risk discussion and
400 mg/dL, obtain a fasting lipid panel. emphasizes intensive lifestyle efforts.
• Risk-enhancing factors may favor statin therapy in
Since laboratory and biologic variability is considerable (up patients with borderline risk (10-year risk of 5–7.4%).
to 10% for LDL-C, 20–25% TG, and 3–5% HDL-C), at least
2 lipid panels should be obtained before initiating therapy. Controversy currently exists concerning use of the
ACC/AHA Pooled Cohort Equation to calculate 10-year risk
Patients with acute coronary syndrome who have not had a for ASCVD (see Table 2). It may over-estimate risk, and
recent fasting lipid profile should have one drawn by the there is concern regarding the 10-year ASCVD risk score
morning following the event, and treatment with a statin cutoff of ≥ 7.5% resulting in over-treating the primary
should be initiated early and prior to discharge. The prevention patient population. The 7.5% cutoff score is
cholesterol may be artificially low at the time of an acute MI, reasonable to use as an opportunity to initiate a conversation
returning to baseline in four weeks. between clinician and patient regarding potential ASCVD
risk reduction benefits, adverse effects, drug interactions,
Results other than high LDL-C. Some patients will have a and patient preferences.
metabolic syndrome picture, with low HDL-C and high
triglycerides. The American Heart Association/American Due to the more diverse patient population included in the
College of Cardiology (AHA/ACC) guidelines for Pooled Cohort Equation, we recommend using the Pooled
prevention of CAD recommend considering additional Cohort Equation rather than calculating the Framingham
medication directed at these abnormal lipids, including score. The Framingham score is based upon a population that
niacin and fibrates. However, the role of combination is largely composed of middle-aged, non-Hispanic Whites,
therapy is controversial. No studies show combination and calculates CHD risk rather than ASCVD risk (which
therapy reduces CHD events or mortality. Combination includes CVA).
simvastatin/niacin was shown to reduce angiographic
stenosis in one trial. Other options to further reduce Checking a high-sensitivity C-reactive protein (hs-CRP) is
triglycerides or LDL-C would be to add omega-3 fatty acids currently not recommended as a cardiovascular disease
and cholesterol absorption blockers (resins and ezetimibe), screening test for average-risk adults without symptoms, but
respectively. is included as a risk enhancer for those who are at borderline
risk.
For elevated fasting triglyceride levels (> 500 mg/dL), see
the Triglycerides section. Coronary Artery Calcium (CAC) score is most helpful in
intermediate-risk patients to further stratify their risk level.
Data are insufficient to make general treatment Additional considerations in younger persons with first
recommendations on patients with baseline total cholesterol degree relatives with major ASCVD event prior to age 40,
< 135 mg/dL, LDL-C < 40 mg/dL, or HDL-C < 40 mg/dL. elevated Lipoprotein (a), HDL-C < 35mg/dL, smokers,
diabetes with another risk factor, and CKD.
Assess ASCVD Risk Factors
If a decision about statin therapy is uncertain (including
Assess level of ASCVD risk using the four categories of risk statin intolerant or patients reluctant to take statins) in adults
groups likely to benefit. Consider assessment of other risk age 40–75 years, without diabetes mellitus, with LDL-C
factors as clinically indicated. levels from 70–189 mg/dL, who have a 10-year ASCVD risk
of 7.5–19.9%, consider measuring the CAC score.
• Clinical ASCVD present (secondary prevention). • If the CAC score is zero, treatment with statin therapy
• LDL-C ≥ 190 mg/dL not caused by drugs or underlying may be withheld or delayed, except in cigarette
medical condition, and age ≥ 20 years. See Table 1 for smokers, those with diabetes mellitus, and those with a
common secondary causes of lipid disorders and treat as strong family history of premature ASCVD.
appropriate. • If the CAC score is 1–99, statin therapy is favored,
• Diabetes mellitus type 1 or 2, age 40–75 years, and LDL- especially in those age ≥ 55 years.
C 70–189 mg/dL. • If CAC is ≥ 100 or ≥ 75th percentile, statin therapy is
• Calculate 10-year ASCVD risk for those age 40–79 years. indicated unless otherwise deferred by the outcome of
See Table 2 for calculation. clinician-patient risk discussion.
• Chronic kidney disease. Refer to the UMHS Management
of Chronic Kidney Disease clinical care guideline for Carotid Intima-Media Thickness (CIMT) testing as an
lipid management information for this population. additional tool for risk stratification is not clinically useful at
this time due to lack of standardization.
Recommend increasing consumption of fruits and vegetables
Treatment if No ASCVD or Risk Factors rich in fiber, fish, and linolenic acid (canola oil, soy, flax
seed). Whole grains should be substituted for processed
Reinforce lifestyle. For all patients in all age groups, flours and simple sugars. This diet pattern is comparable to
encourage healthy lifestyle activities. These include the Mediterranean diet, which has been shown to reduce
smoking cessation, dietary changes, weight loss if CHD events beyond its impact on serum lipids. A large trial
overweight or obese, and exercise. These interventions have published in 2013 demonstrated that adults at high risk for
been shown to reduce cardiovascular disease risk CVD events who ate a Mediterranean diet supplemented
independent of their influence on lipids. They are discussed with olive oil or mixed nuts had significantly fewer major
in more detail below. cardiovascular events, including myocardial infarction,
stroke, and CVD death, than those in the control group.
Follow-up. Patients with normal screening lipids are
generally rechecked at 4- to 6-year intervals because lipids The plant stanols (sitostanol and sitostanol esters) can lower
may gradually worsen over time, and patients may develop LDL-C by approximately 10% by reducing absorption of
secondary causes later in life. Patients with borderline values cholesterol. These occur naturally in bran cereals, whole
not requiring therapy may be rechecked at 1–2 year intervals. wheat, legumes, and nuts, are available in soft margarine and
can be used as a spread on bread products and vegetables.
Treatment through Lifestyle Changes Caplets are available be taken as 2-3 g daily. While outcome
data (ie, evidence for reduction of CVD events) has not been
Lifestyle changes are a critical component of health demonstrated with plant stanols, dietary studies low in fat
promotion and ASCVD risk reduction in both primary and and high in fiber and vegetables do. Margarines derived by
secondary prevention. Recommend a healthy lifestyle for all hydrogenation to trans-fatty acids should be avoided because
patients, whether they are taking cholesterol lowering drugs they can increase LDL-C. Many patients with
or not. The reductions in total cholesterol and LDL-C hyperlipidemia will benefit from a consultation with a
induced by a combination of dietary therapy and dietitian to help them make appropriate food choices.
pharmacologic therapy are generally greater than for either
approach alone. Recommend smoking cessation, dietary Fish oil supplements. The omega-3 fatty acids
changes, weight loss if overweight or obese, and exercise. eicosapentaenoic acid (EPA) and docosahexaenoic acid
Consider referral to a dietitian for persons age 20-39 years, (DHA), found in dietary fish oil, have been shown to reduce
particularly for those with more than one risk factor and a atherosclerosis in animal models. Increased dietary omega-3
39% or greater lifetime risk by the ACC/AHA risk estimator. fatty acids via dietary change or supplements have been
shown to improve CHD and CHD mortality in some, but not
Smoking cessation. In persons with CHD, smoking all studies. A meta-analysis suggests that supplementation
cessation reduces the coronary event rate by about 50% with omega-3 fatty acids does not reduce the risk for CVD
within one to two years of stopping. Among the benefits of events. They reduce hepatic production of triglycerides and
smoking cessation is a 5–10% increase in HDL-C. CHD is VLDL-C, and lower serum triglycerides by 20–50%. They
not a contraindication to pharmacotherapy for smoking may have other anti-thrombotic and anti-inflammatory
cessation. A meta-analysis found no increase in risk for properties as well. The REDUCE-IT trial evaluated
major adverse events with nicotine therapy, although overall icosapent ethyl (Vascepa™), a prodrug that is converted to
events increased. Nicotine replacement therapy is EPA, taken as 2 g twice daily. The trial showed that in men
contraindicated in unstable angina or acute MI. For more and women with clinical atherosclerosis or diabetes and
information, see the UMHS Tobacco Treatment clinical care other risk factors on statins, with triglycerides 135-499
guideline. mg/dL, icosapent ethyl resulted in a 25% reduction in CV
events when compared to placebo. The benefit was not
Diet and food supplements. The 2013 AHA/ACC related to the level or reduction in triglycerides. Two placebo
Guideline on Lifestyle Management to Reduce controlled studies of EPA and DPA showed no benefit.
Cardiovascular Risk recommends a diet high in fruits,
vegetables, and whole grains. Dairy products should be low Taking 2–4 grams of EPA and DHA per day can lower
fat. Dietary patterns should be adapted to the caloric needs of triglycerides 20–40%. Lovaza and Vascepa are FDA-
the patients. The DASH or Mediterranean dietary pattern and approved fish oil supplements available by prescription.
USDA food pattern were cited as examples of dietary Vascepa contains only an EPA prodrug, while Lovaza
patterns which are in line with current recommendations. A contains both DHA and EPA. In clinical trials evaluating
trial of diet should not delay statin therapy in secondary patients with severe hypertriglyceridemia, Vascepa did not
prevention patients. increase LDL-C levels, whereas an increase in LDL-C was
seen in Lovaza trials. OTC omega-3 fatty acid sources are
The degree of response to various dietary interventions, available at a much lower price, but they are not regulated,
including soluble fiber, soy, and plant stanols, correlates and require more capsules to achieve the same dose.
highly with the amount consumed and baseline LDL-C
levels. Prescribed diets should not be restrictive. Emphasize Fish oil supplements are a reasonable adjunct to secondary
what should be eaten rather than what should not be eaten. prevention in populations with high triglycerides. Unlike
fibrates, they do not increase myopathy risk when added to standard drink daily for women, and 1–2 standard drinks
statins. Fish oil supplements are generally well tolerated, daily for men), reduction is recommended.
with gastrointestinal upset and fishy aftertaste as potential
adverse effects. Clinical significant bleeding has been Pharmacologic Treatment: Statins
reported at higher doses. Caution should be used in patients
on concomitant antiplatelet or anticoagulant therapy. Statins are the first-line agents for lipid management.
They have the advantage of potency, tolerability, safety, and
Weight loss. Excess body weight is associated with higher strong clinical trial data supporting benefit. Bile acid resins
triglycerides, lower HDL-C, and higher total cholesterol. The are generally more expensive per LDL-C reduction, and have
more overweight the patient, the less responsive lipid much higher rates of adverse effects. Fibrates are well
parameters are to dietary therapy if weight loss does not also tolerated, but have minimal impact on LDL-C and have not
occur. Low fat diets not associated with weight loss or shown results in terms of event reduction. Niacin is effective
exercise can raise triglycerides and lower HDL-C. Even at improving metabolic syndrome profiles, ie, low HDL-
modest weight loss counteracts the HDL-C lowering effect C/high triglycerides, but considering the newer options has
of the diet alone, lowers triglycerides, and causes further no role in ASCVD risk reduction. In contrast, ezetimibe
reduction in total cholesterol and LDL-C. (Zetia), a drug that blocks cholesterol ester absorption,
lowers the LDL-C by 15-20% and was effective as an adjunct
Exercise. Regular aerobic physical exercise raises HDL-C to simvastatin in patients with a previous MI and LDL-C ≥
and lowers triglycerides. Exercise alone has little effect on 70 mg/dL.
LDL-C. The Look Ahead Study, which included over 5,000
overweight or obese diabetic adults, showed improvements Individual statins. Statins are the best-studied lipid-lowering
in hemoglobin A1c, but no reductions in LDL-C. The drugs and show the most benefit in terms of absolute LDL-C
primary goal of the intervention was weight loss. CVD reduction and patient outcome. Large clinical event trials
events were similar in the intervention and control groups. have included atorvastatin, lovastatin, pravastatin,
Moderate-intensity exercise, including walking at a simvastatin, and rosuvastatin. Statins are considered to have
moderately brisk pace, done regularly (30 minutes 3–5 times a class effect.
a week) raises HDL-C by an average of approximately 5%.
The increase of HDL-C with exercise training is inversely High intensity statins reduce clinical events more than low
related to the pre-training HDL-C level. Exercise training intensity statins. Rosuvastatin is the most potent agent.
less consistently lowers total cholesterol, triglycerides, and Pravastatin is not metabolized by CYP450 (liver), and has
LDL-C. However, exercise training increases the effect that fewer drug interactions. Atorvastatin, fluvastatin, lovastatin,
reducing dietary fat intake has on lowering total cholesterol, pravastatin, rosuvastatin, and simvastatin are available as
LDL-C, and triglycerides. The non-lipid effects of exercise generics.
are more important and those on lipids.
Table 6 presents dosing equivalents across statins for high-
Decreased dietary fat intake alone causes reduced LDL-C intensity dosing (≥ 50% LDL-C reduction) and moderate-
and HDL-C. However, the addition of exercise training and intensity dosing (30–49% LCL-C reduction). Table 7
polyunsaturated fatty acids and monunsaturated fatty acids presents a summary of information regarding commonly
counteracts the HDL-C lowering effect of reduced dietary used lipid lowering drugs.
fat, and HDL-C levels are maintained or even increased.
Adverse effects. The most common adverse effect from
Age and gender do not appear to influence the effect of statins is myalgias (ie, muscle pain or soreness), weakness,
exercise training on increasing HDL-C. Resistance exercise or cramping without CK elevation, which resulted in
(eg, weight lifting) has also been shown to increase HDL-C dropouts of 5% among trial patients. No evidence confirms
in young and older adults. that myalgias are more common with one statin than another.
Rhabdomyolysis (CK > 10,000 IU/L or CK > 10 times the
For patients with known CHD, exercise must be tailored to upper limit of normal, plus elevation in serum creatinine) is
the degree of disease. Aerobic exercises (walking, cycling, a potentially life-threatening complication of statin therapy,
swimming) should be done at levels that do not precipitate with a 10% mortality rate. For statin monotherapy, the
cardiac ischemia and angina. average incidence of rhabdomyolysis is 0.44 per 10,000
person-years.
Alcohol. Population studies suggest a possible coronary
protective effect of moderate alcohol (1–3 ounces/day) Observed rates of new-onset diabetes vary with statin
intake in men and women including the elderly. Alcohol of intensity, with approximately 0.1 and 0.3 excess cases of
all types is associated with a modest (5–15%) increase in diabetes per 100 statin-treated individuals per year observed
HDL-C. In some there is a modest increase in triglycerides, for moderate- and high-intensity statins, respectively.
which may be profound in patients with diabetes or other Limited evidence associates statin use with reversible
causes of hypertriglyceridemia. The coronary protective cognitive impairment (eg, memory loss, confusion,
effects of alcohol may be offset by increased mortality from forgetfulness, amnesia, memory impairment) and with
other causes. If alcohol intake is more than moderate (1 incidental cases of new-onset diabetes. Statin labeling has
been updated to reflect these potential risks; however, this
evidence remains controversial. For patients at high risk of Intolerance. Statin intolerance is a common problem in
cardiovascular events, the cardiovascular benefits of statins primary and specialty care, generally due to myalgias. Prior
outweigh these increased risks. to initiation of statin therapy, a history of prior or current
muscle symptoms should be obtained to avoid unnecessary
Contraindications and dose limitations for simvastatin and discontinuation of statins. No studies support a particular
lovastatin are presented in Table 9. High dose simvastatin strategy for management of statin intolerance. A suggested
and lovastatin (ie, 80 mg) have a greater risk of muscle injury strategy for managing patients with statin intolerance is
compared to lower doses of these two drugs or with other presented in Table 10.
statins. For simvastatin this risk is greatest during the first
year of treatment and declines afterward. Therefore, only Pregnancy. Statins are contraindicated in pregnancy due to
patients who have been on simvastatin 80 mg for at least risk of teratogenicity and possible risk of delayed fetal
twelve months without evidence of myopathy should development. Women of child bearing potential should
continue to be treated at this dosage. Statin naïve patients generally avoid statins. Do not use statins in women who are
should not be started on simvastatin 80 mg. pregnant or lactating.
Some patients are more likely to have adverse effects from Initiating statin therapy. Once a patient’s risk category has
statins, particularly those individuals who have multiple and been assessed, discuss statin therapy with the patient.
serious co-morbidities. These include impaired renal or Determine the recommended intensity of statin dosing, and
hepatic function, a history of previous statin intolerance or initiate statin therapy. Follow up on the response to statin
muscle disorders, unexplained ALT elevations > 3 times the therapy in terms of patient tolerance and lipid profile
upper limit of normal, concomitant use of drugs affecting response. Monitor ALT in those with known liver disease,
statin metabolism, excess alcohol, and age > 75 years. If any risk factors for liver disease, or who are on other potentially
of these predisposing characteristics are present, moderate- hepatotoxic medications.
intensity statin therapy may be preferred in individuals for
whom high-intensity statin therapy would otherwise be Discussing drug therapy. Before initiating statin therapy,
recommended. High-intensity statin therapy should also be clinicians and patients should discuss:
used cautiously in patients of Asian ancestry or with a history • Benefits for ASCVD risk reduction
of hemorrhagic stroke. • Potential adverse effects
• Drug-drug interactions
Statin interactions. Statins interact with several other • Patient preferences
medications (see Table 8), primarily increasing the risk of
myopathy. For example, adding a fibrate to a statin increases When discussing benefits for ASCVD risk reduction in the
the risk of rhabdomyolysis to 5.98 per 10,000 person-years. primary prevention population (those without clinical
Other drugs that increase risks are inhibitors of cytochrome ASCVD), the ACC/AHA Guideline on the Treatment of
P450 enzymes. Atorvastatin, lovastatin, and simvastatin are Blood Cholesterol suggests using the estimated 10-year
metabolized by CYP3A4, while fluvastatin, rosuvstatin and ASCVD risk and the relative risk reduction of ~30% for
to some extent pitavastatin are metabolized by CYP2C9. moderate-intensity statin or ~45% for high-intensity statin
Pravastatin is not metabolized by the CYP enzymes. therapy in order to estimate the absolute risk reduction from
Inhibitors of CYP enzymes that can affect statin metabolism moderate- or high-intensity statin therapy. The benefit is less
include cyclosporine, azole antifungals, macrolide clear in patients outside of the four main target groups
antibiotics, protease inhibitors, verapamil, diltiazem, identified in the ACC/AHA guideline. For individuals
amiodarone and others. Given the increased risk of muscle outside those groups, clinicians will need to consider other
injury with simvastatin and lovastatin, labeling has been risk factors (see Table 3) when discussing potential benefit.
updated to reflect contraindications and dose limitations with
concomitant use of these statins and specific interaction The ACC/AHA guideline notes that the main adverse
drugs (see Table 9). A large amount of grapefruit juice (> 1 consideration is the excess risk of diabetes, which is about
quart/day) also increases the blood level of the statins that are 0.1 excess case per 100 individuals treated with a moderate-
metabolized by the CYP450 3A4 system. intensity statin for 1 year and about 0.3 excess cases per 100
individuals treated with a high-intensity statin for 1 year.
In immunocompromised patients and those with systemic
illnesses such as diabetes, it may be best to switch from Studies show that both statin-treated and placebo-treated
atorvastatin, simvastatin and lovastatin to drugs not patients seem to experience the same rate of muscle
metabolized by CYP3A4. Whenever possible, avoid using symptoms. The actual rate of statin-related muscle symptoms
the interacting drug rather than modifying the patient’s statin in the clinical population is unclear.
therapy. If an interacting drug cannot be avoided, either
adjust the dose of these statins or consider an alternative with Statins interact with several other drugs (see Table 8). If
less potential for drug-drug interactions. If a patient potential interactions are a concern, the usual approach is to
experiences myopathy on any statin, the statin should be try to avoid using the interacting drug rather than modifying
stopped immediately. statin therapy. The discussion should address the importance
of other medical conditions and potential changes in drug Check for:
therapy for the overall clinical benefit of the patient. • Adverse effects of statin treatment and address as
appropriate.
Patient preferences regarding medications, likely need for • Expected reduction in LDL-C based on intensity of statin
lifetime therapy, and ability to manage costs should also be treatment. If expected reduction does not occur, address
addressed. statin and lifestyle adherence. In ASCVD patients at very
high risk, if patient is on maximal statin therapy and LDL-
Check baseline ALT. A baseline measurement of ALT C level is ≥ 70 mg/dL, consider adding non-statin drug
should be obtained before initiating statin therapy. See Table therapy. (See below.)
4 for monitoring recommendations when ALT is abnormal.
Reinforce lifestyle modifications.
Statin dosing based on risk group. The ACC/AHA
guidelines for dosing (see Table 6 for Statin Dose Intensity Longer term follow-up. Monitor LFTs if indicated. Check
and Equivalency Chart) based on risk group are: lipids annually to assess adherence. Reinforce lifestyle
• Clinical ASCVD modifications.
− Age ≤ 75 years = high-intensity.
An annual lipid profile is recommended to check on statin
− Age > 75 years = moderate-intensity.
adherence and to provide an opportunity to reinforce the
• LDL-C ≥ 190 mg/dL and age ≥ 20 years = high- lifestyle modifications that are the cornerstones of ASCVD
intensity. risk reduction. A study of statin adherence in 2001 found that
on average, patients did not take their statin medication 20%
• Diabetes Mellitus Type 1 or 2, and age 40–75 years,
of the time. Fifty percent of patients stopped statin treatment
with LDL-C 70–189 mg/dL
by one year if their copayment was > $20/month and by 3.9
− If no other ASCVD risk, moderate-intensity.
years if their copayment was < $10/month. Insurance records
− If at higher risk (eg, multiple ASCVD risk factors of statin dispensing are becoming less reliable indicators of
or age 50–75 years), consider a high-intensity statin statin adherence because statin medications are increasingly
to reduce the LDL-C level by ≥ 50%. being filled without an insurance claim, eg, statins obtained
• ≥ 7.5% estimated 10-year ASCVD risk, and age 40–75 through $4 generic programs or free (atorvastatin) through
years, with LDL-C 70–189 mg/dL, without diabetes local pharmacies. An annual lipid profile is a relatively non-
mellitus, without clinical ASCVD = moderate-to-high- invasive test to monitor adherence.
intensity.
For those patients who are already on statin therapy at lower Non-Statin Pharmacologic Treatment
doses, and LDL-C had been at previously recommended goal
values, we recommend clinicians and patients engage in a Treatment with statin and non-statin combinations.
discussion which considers the potential for ASCVD risk Limited evidence exists to support the routine use of non-
reduction benefits, potential for adverse effects, and patient statin drugs in combination with statin therapy to further
preferences regarding intensifying statin therapy. reduce ASCVD events. Adding non-statin therapy may be
considered in high-risk patients who:
Check in 6–12 weeks. Careful follow-up of liver function • Are completely statin intolerant.
tests is indicated only for those with abnormal baseline ALT, • Have an inadequate response to statins (high-intensity
known liver disease, risk factors for liver disease, or those therapy should show ≥ 50% reduction in LDL-C,
who are on other potentially hepatotoxic medications. Liver moderate-intensity therapy should show 30–49%
function tests (LFTs) should be measured if symptoms reduction in LDL-C).
suggesting hepatotoxicity arise (eg, unusual fatigue or • Are not able to tolerate the recommended statin
weakness, loss of appetite, abdominal pain, dark-colored intensity.
urine or yellowing of the skin or sclera). For other patients • Have severe hypertriglyceridemia (> 500 mg/dL)
with abnormal baseline LFTs, see Table 4 for monitoring necessitating the use of fibrates or fish oil to prevent
based on level of abnormality. If there are no concerns over pancreatitis.
liver function, and LFTs are normal, no further monitoring is
required. Adherence to statin therapy and lifestyle should be
reassessed and re-emphasized before addition of a non-statin
Routine CK monitoring is not recommended in individuals drug. Combination therapy of statins with fibrates
receiving statin therapy. Moderate CK elevations (< 800 IU) significantly increases the risk of myopathy and
do not necessarily indicate toxicity or increased risk of rhabdomyolysis.
myopathy. Baseline CK measurement is reasonable for those
individuals believed to be at increased risk of adverse events, In patients at very high-risk for ASCVD and on maximally
and during statin therapy for individuals experiencing muscle tolerated statin, if LDL-C is ≥ 70 mg/dL, consider addition
symptoms. of non-statins to statin therapy. Very high-risk includes a

history of multiple major ASCVD events or 1 major ASCVD PCSK9 inhibitors. PCSK9 inhibitors include alirocumab
event and multiple high-risk conditions. (Praluent) and evolocumab (Repatha). PCSK9 inhibitors are
• Consider adding ezetimibe. human monoclonal antibodies that bind to the PCSK9
• If on ezetimibe therapy and LDL-C level remains ≥ 70 inhibitor and decrease the degradation of the LDL receptor.
mg/dL, consider adding a PCSK9 inhibitor. (Note: for Both alirocumab and evolocumab are given as subcutaneous
PCSK9 inhibitors, long-term safety [> 3 years] is injections either every 2 weeks or every 4 weeks. Potential
uncertain and cost effectiveness is low at mid-2018 list LDL-C reduction with these medications is 43–64% when
prices.) added to highest tolerated dose of statins. Consider PCSK9
inhibitors in secondary ASCVD prevention or in patients
In patients with severe primary hypercholesterolemia (LDL- with severe hypercholesterolemia (LDL-C ≥ 190 mg/dL) if
C level ≥ 190 mg/dL), without calculating 10-year ASCVD they do not achieve the desired LDL-C lowering on
risk, begin high-intensity statin therapy. If the LDL-C level maximum tolerated statin therapy along with ezetimibe.
remains ≥ 100 mg/dL: PCSK9 inhibitors decrease LDL-C levels further when added
• Consider adding ezetimibe. to statin therapy. PCSK9 inhibitors also improve
• If on statin plus ezetimibe and the LDL-C level remains cardiovascular outcomes when added to statin therapy. These
≥ 100 mg/dL and the patient has multiple factors that medicines are generally well tolerated. The most common
increase subsequent risk of ASCVD events, consider adverse effects include injection site reactions, stomach
adding a PCSK9 inhibitor. (Note: for PCSK9 upset, cough, dizziness, and myalgias. No clinically
inhibitors, long-term safety [> 3 years] is uncertain and significant drug interactions have been reported with either
cost effectiveness is uncertain at mid-2018 list prices.) evolocumab or alirocumab. PCSK9 inhibitors are expensive
and can be cost-prohibitive for patients.
Bile acid resins. Cholestyramine, colestipol, and
colesevelam are generally considered second line because of Fibrates. Fibrates available in the US include gemfibrozil
poor patient tolerability to their adverse effects and difficult and fenofibrate. Safety and efficacy of fenofibric acid
dosing/administration time. These drugs have been shown to (Fibricor and TriLipix), the active metabolite of fenofibrate,
reduce LDL-C cholesterol 15–30%, depending on dose. has not been extensively studied in clinical trials, and
They are available in powder and tablet form. Resins work approval was largely based on the fenofibrate studies. The
by binding cholesterol in the gut and interfering with FDA has concluded that the totality of the scientific evidence
absorption. They may increase triglycerides and should not no longer supports the conclusion that a drug-induced
be initiated in individuals with baseline fasting triglycerides reduction in triglyceride levels and/or increase in HDL-C
≥ 300 mg/dL or type III hyperlipoproteinemia. If levels in statin-treated patients results in a reduction in the
triglycerides exceed 400 mg/dL, resin therapy should be risk of cardiovascular events. Therefore fibrates should not
discontinued. be used in conjunction with statins for reduction in
cardiovascular events.
Adverse effects are common with resins and are dose
dependent. The most common adverse effects are bloating, Fibrates activate the nuclear transcription factor peroxisome
nausea, constipation, and abdominal pain. Non- proliferator-activated receptor-alpha (PPAR-alpha), which
gastrointestinal side effects are uncommon. Resins interfere regulates genes that control lipid metabolism. Gemfibrozil
with absorption of fat-soluble vitamins and many drugs. has no significant effect on LDL-C. Fenofibrate has been
With the exception of colesevelam, they should be taken 1 shown to lower LDL-C by 20% in patients with
hour before or 4 hours after other medications. Adverse hypercholesterolemia, and 12% in patients with combined
effects can be reduced somewhat by titrating up slowly. hyperlipidemia, metabolic syndrome, and type 2 diabetes.
Colesevelam has been shown to have a lower incidence of Angiographic studies have shown benefit. Fibrates have been
gastrointestinal side effects, similar to placebo, and does not shown to reduce CHD events in primary and secondary
interfere with absorption of statins, digoxin, metoprolol, prevention trials, but have had no effect on mortality, and in
quinidine, valproic acid, or warfarin. Colesevelam improves some instances have been associated with increased adverse
glycemic control in type 2 diabetes. events. For this reason, they are considered second-line
medications for CHD prevention and are primarily reserved
Ezetimibe. Ezetimibe inhibits intestinal absorption of for patients who have severe triglyceride elevation (> 500
cholesterol by blocking cholesterol transport at the intestinal mg/dL) despite lifestyle changes, to help prevent
brush border. It can lower LDL-C by 15–20% alone. pancreatitis.
Ezetimibe should be considered for patients who are statin
intolerant or who are not meeting statin LDL-C percent Adverse effects of fibrates are generally gastrointestinal,
reduction goals with maximal tolerated statin therapy alone. including nausea, dyspepsia, and changes in bowel habits.
See the UMHS Management of Chronic Kidney Disease for The risk of cholestasis and need for cholecystectomy is
role of ezetimibe in patients with CKD. Baseline ALT should increased. Fibrates carry a small risk of myopathy as
be measured prior to initiation of therapy and as clinically monotherapy. Fibrates may cause a small reversible increase
indicated. Ezetimbe should be discontinued if persistent ALT in creatinine, and dose adjustment in chronic kidney disease
elevations > 3 times the upper limit of normal occur. patients is recommended. Contraindications include severe

renal or liver disease, preexisting gallbladder disease, and studies, independent of statin treatment. However, current
pregnancy. evidence is insufficient to support drug therapy for elevated
triglycerides in primary prevention. The focus for primary
Niacin. Niacin improves all aspects of the lipid profile prevention patients should be on lifestyle changes and
(HDL-C increases 15–35%, triglycerides decreases 20–50%, treating secondary causes of elevated triglycerides (see Table
LDL-C decreases 5–25%). The mechanism is not known. 1 for secondary causes).
Niacin has been shown to reduce coronary events and total
mortality, though results are less dramatic than statins. LDL- For secondary prevention patients, based on expert opinion,
C reductions are minimal compared to the statins, and many ACC/AHA guidelines for secondary prevention of CHD
patients are unable to tolerate the adverse effects of niacin. recommend drug therapy for elevated triglycerides,
The greatest benefit for niacin alone would be in patients regardless of HDL-C and LDL-C, in addition to aggressive
with a low HDL-C and moderate elevation of triglycerides, lifestyle management.
or for those intolerant to statins. The FDA has concluded that
the totality of the scientific evidence no longer supports the Patients with severe fasting triglyceride elevation (> 500
conclusion that a drug-induced reduction in triglyceride mg/dL) despite lifestyle modifications can be considered for
levels and/or increase in HDL-C levels in statin-treated drug therapy to prevent acute pancreatitis. Fenofibrate is the
patients results in a reduction in the risk of cardiovascular preferred fibrate for triglyceride lowering. Fish oil
events. Therefore niacin should not be used in conjunction supplements containing DHA and/or EPA can alternatively
with statins for reduction in cardiovascular events. Rare be used for triglyceride lowering. Gemfibrozil should not be
cases of rhabdomyolysis have been associated with initiated for triglyceride lowering on patients taking statins
concomitant use of statins and niacin in doses > 1 g. due to the increased risk for muscle symptoms and
rhabdomyolysis. The FDA has concluded that the totality of
Patients on niacin should have baseline testing of ALT, the scientific evidence no longer supports the conclusion that
glucose, and uric acid, with follow up ALT at 3 months or at a drug-induced reduction in triglyceride levels and/or
dose escalations, and periodically thereafter. increase in HDL-C levels in statin-treated patients results in
a reduction in the risk of cardiovascular events.
Niacin is available over the counter (OTC) as a dietary
supplement in both immediate release (IR) and sustained Complementary and Alternative Treatment
release (SR) formulations. Prescription niacin products
include Niacor (IR), and Niaspan, an extended-release Complementary and alternative therapies may affect lipid
formulation taken at bedtime, which is associated with better levels, although evidence is limited. Some of the therapies
side-effect tolerance and adherence. “Flush-free” and “no for which evidence is available are reviewed below.
flush” preparations are also marketed OTC, but contain very
little to no active niacin and should not be used. Dietary Estrogen and progestins. The benefits to the lipid profile
supplements are not subject to the same FDA regulations as attributable to oral estrogens include a 10–15% reduction in
prescription products; OTC niacin products may not be LDL-C, a 10–20% increase in HDL-C, and a decrease in
therapeutically equivalent to the prescription-only products. lipoprotein (a) by up to 25%. Hormone replacement therapy
may increase triglycerides by 10–15%. However, two large
Adverse effects of niacin include flushing, pruritus, trials assessed hormone replacement therapy in post-
gastrointestinal disturbances, fatigue, glucose intolerance, menopausal women with and without coronary disease,
and gout. The vasoactive symptoms are reduced by pre- finding an increased risk of coronary disease,
medicating with aspirin 325 mg by mouth 30 minutes prior, thromboembolism, and stroke. Hormone replacement is not
slow titration of the niacin dose, or use of extended release indicated for primary or secondary prevention of
formulations. Hepatotoxicity has been reported, particularly cardiovascular disease. Therapy should instead be based on
with SR products at doses > 2 g/day. Niacin should not be direct indications (eg, relief of hot flashes), and not for lipid
used if ALT is > 2–3 times the upper limit of normal. Niacin management.
should be discontinued in patients experiencing persistent
severe cutaneous symptoms, persistent hyperglycemia, acute Red yeast rice. Red yeast rice products contain several
gout, unexplained abdominal pain or gastrointestinal naturally occurring substances related to the statins; the
symptoms, or if new-onset atrial fibrillation or weight loss predominant is mevinolin, the major component of
occurs. Niacin ER has fewer adverse effects than IR niacin. lovastatin. Potential adverse effects are the same as statins,
Niacin ER is generally considered twice as potent. When including a risk of myopathy and hepatotoxicity. The FDA
switching from IR to ER, the dose should be reduced in half, considers red yeast rice products containing mevinolin to be
and use no more than 2 g/day. unapproved drugs, and illegal. However, the products are
still available in stores and on the internet. Many
Triglycerides manufacturers do not list the amount of mevinolin contained
in the products. Other products labeled as red yeast rice may
High triglycerides have been associated with an increase in contain alternative ingredients such as policosanol (a sugar
coronary events in population studies, and an increase in cane derivative), flavonoids, EPA, or DHA. Commercial
event rate and mortality in CHD secondary prevention preparations vary substantially and one study found
supplements containing nephrotoxins. Advise patients not to potential ASCVD risk reduction benefits, risk of adverse
use red yeast rice products due to lack of effectiveness and effects, drug-drug interactions, and patient preferences
the lack of manufacturing standards leading to concerns for should precede the initiation of statin therapy for primary
safety. prevention in older individuals. In patients with increasing
co-morbidities, or patients with a limited life expectancy, it
Plant stanols/sterols. Plant stanols/sterols are available as is reasonable to consider stopping statin treatment.
spreads or capsules. They work by helping to prevent
cholesterol absorption and can reduce LDL-C by 5–17%.
There is no evidence that stanols or sterols reduce the risk of Related National Guidelines
cardiovascular disease. Long term safety has not been
established. The UMHS Clinical Guideline on Lipid Therapy is
consistent with the following national guidelines concerning
Garlic. Many patients use garlic for hyperlipidemia, but lipid screening and treatment.
evidence suggests that it is less effective than initially
thought. The Natural Medicines Comprehensive Database American College of Cardiology/American Heart
downgraded garlic to a rating of “possibly ineffective.” Association Task Force report: 2018 ACC/AHA
Garlic can cause drug interactions and increase the risk of /AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC
bleeding. /NLA/PCNA Guideline on the Management of Blood
Cholesterol (2019)
Others. Even less proof exists regarding efficacy or safety in American Diabetes Association: Standards of medical care
cholesterol lowering for several other products that are in diabetes (2020)
widely available in health food stores and pharmacies. These
US Preventive Services Task Force: Screening for lipid
include policosanol, chitosan, and gugulipid (extract from
disorders in adults (2016)
the resin of Indian thorny tree). They should be avoided.
Special Populations for Preventive Therapy

Measures of Clinical Performance
Women. Studies have shown a significant treatment benefit
in women. A meta-analysis on the effect of statins on risk of National programs that have clinical performance measures
CHD found a similar benefit in women as in men. Surrogate for lipid screening and management include the following.
endpoints, such as atherosclerotic progression, have shown
Centers for Medicare & Medicaid Services:
benefit from statins in women. Premenopausal women are at
• Physician Quality Reporting Measures for Group
low CHD risk, with approximately a 10-year delay in risk
Practice Reporting Option (GPRO)
compared to their male counterparts. For this reason,
• Clinical Quality Measures for financial incentives for
USPSTF recommends starting screening in women age 45
Meaningful Use of certified Electronic Health Record
and older who are at increased risk for CHD and in all men
technology (MU)
age 35 and older. The American College of Physicians
• Quality measures for Accountable Care Organizations
(ACP) has a somewhat similar age difference,
(ACO)
recommending screening of women age 45–65 years and
men age 35–65 years.
Regional programs that have clinical performance measures
for lipid screening and management include the following.
End Stage Renal Disease. Evidence is insufficient to make
recommendations regarding statin therapy for patients with • Blue Cross Blue Shield of Michigan: Physician Group
end stage renal disease. For these patients, an individualized Incentive Program clinical performance measures
approach is recommended that takes into consideration (PGIP)
possible risk reduction, adverse effects, and • Blue Care Network [HMO]: clinical performance
contraindications. For lipid management in patients with measures (BCN)
ESRD, see UMHS CKD guideline.
These programs' clinical performance measures for lipid
Individuals Age > 75 Years. Randomized controlled trials screening and management are summarized below. When
support the continuation of statins beyond age 75 years in programs have measures, the measures are generally similar,
those who are already taking and tolerating these drugs, as although specific details vary (eg, population inclusions and
well as the use of moderate-intensity statin therapy for exclusions).
secondary prevention in individuals age > 75 years who have
clinical ASCVD. However limited data are available Preventive care and screening: fasting LDL-C test. The
regarding primary prevention among individuals age > 75 percentage of patients age 20–79 years whose risk factors
years. Initiation of statins for primary prevention in have been assessed and a fasting LDL-C test performed for
individuals age > 75 years requires consideration of those at risk. High risk = CHD or CHD risk equivalent; test
additional factors, including increasing comorbidities, safety performed in preceding year. Moderate risk = 2 or more of
considerations, and priorities of care. Discussion of the cigarette smoking, hypertension, low HDL-C, family history
of premature CHD, men age ≥ 45, women age ≥ 55; test lipoproteins, HDL cholesterol), consensus development
performed in preceding year. Low risk = 0 or one of: cigarette conferences, practice guidelines, guidelines, outcomes and
smoking, hypertension, low HDL-C, family history or process assessment (health care); clinical trials, controlled
premature CHD, men age ≥ 45, women age ≥ 55; test clinical trials, multicenter studies, randomized controlled
performed in preceding 5 years (MU). trials, cohort studies; adults; English language; and
published from 1/1/2011 to 4/30/2013. In addition to the
Preventive care and screening: risk-stratified fasting LDL-C overall terms, for primary prevention a major search term
control. The percentage of patients age 20–79 years who had was primary prevention of coronary artery disease with
a fasting LDL-C test performed and whose risk-stratified specific topic searches for: screening, pharmacotherapy, diet,
fasting LDL-C is at or below the recommended goal: high exercise, alternative or complementary medicines, and other
risk < 100 mg/dL, moderate risk < 130 mg/dL, low risk < 160 treatment. In addition to the overall terms, for secondary
mg/dL (see preceding measure for risk definitions) (MU). prevention a major search term was secondary prevention
(treatment only) of coronary artery disease, peripheral
CAD and lipid screening. The percentage of patients age 18– vascular disease, or cerebral vascular disease/stroke with
75 years with coronary artery disease who had an LDL-C test specific topic searches for pharmacotherapy, diet, exercise,
during the measurement year (BCN, PGIP). alternative or complementary treatment, and other treatment.
An additional search using the overall terms was performed
CAD and lipid lowering drug. The percentage of patients age for statins and drug interactions and for individual
18 years or older with a diagnosis of coronary artery disease differences and class effects of statins.
who were prescribed lipid lowering therapy. (MU, ACO,
PGIP). The search was conducted in components each keyed to a
specific causal link in a formal problem structure (available
Diabetes and lipid profile. The percentage of patients age 18– upon request). The search was supplemented with very
75 years with diabetes who received at least one lipid profile recent clinical trials known to expert members of the panel.
within 12 months (MU, GPRO, PGIP age 40–75 years). Negative trials were specifically sought. The search was a
single cycle. Conclusions were based on prospective
Diabetes and LDL-C control. The percentage of patients age randomized controlled trials if available, to the exclusion of
18–75 years with diabetes mellitus who had most recent other data; if randomized controlled trials were not available,
LDL-C in control (less than 100 mg/dL) (MU, ACO observational studies were admitted to consideration. If no
composite, GRPO, BCN, PGIP). such data were available for a given link in the problem
formulation, expert opinion was used to estimate effect size.
Heart failure and LDL-C screening. The percentage of
patients age 18–75 years with congestive heart failure who
had an LDL-C test in the measurement year (PGIP).
Disclosures
Ischemic vascular disease (IVD) and lipid profile and LDL-
C control. The percentage of patients age 18 years and older The University of Michigan Health System endorses the
discharged with acute myocardial infarction, coronary artery Guidelines of the Association of American Medical Colleges
bypass graft, or percutaneous transluminal coronary and the Standards of the Accreditation Council for
angioplasty in the year before the most recent year or who Continuing Medical Education that the individuals who
had a diagnosis of ischemic vascular disease during the past present educational activities disclose significant
two years who had a complete lipid profile performed during relationships with commercial companies whose products or
the past year and whose LDL-C was less than 100 mg/dL services are discussed. Disclosure of a relationship is not
(MU, ACO) intended to suggest bias in the information presented, but is
made to provide readers with information that might be of
potential importance to their evaluation of the information.
Strategy for Literature Search Team Member Relationship Company
Audrey L. Fan, MD (none)
The literature search for this update began with results of the Jill N. Fenske, MD (none)
literature searches performed in 1999 for the 2000 version of R. Van Harrison, PhD (none)
this guideline, and in 2007 for the 2009 update of this Melvyn Rubenfire (none) Pfizer
guideline. Since that time the American Association of Marie A. Marcelino, PharmD (none)
Clinical Endocrinologists performed a search of relevant Trisha D. Wells, PharmD (none)
literature through early 2011 in developing its guidelines for
management of dyslipidemia and prevention of
atherosclerosis (see references). Those results were used for Review and Endorsement
the literature through 12/31/10. For more recent literature, a
search similar to those previously performed for this Drafts of this guideline were reviewed in clinical conferences
guideline was conducted on Medline prospectively using the and by distribution for comment within departments and
overall keywords of: cholesterol (including hyperlipidemia, divisions of the University of Michigan Medical School to
which the content is most relevant: Family Medicine, Lowering with Atorvastatin in Patients with stable Coronary
General Medicine, and Cardiology. The final version was Disease (treating to new targets (TNT). NEJM 2005; 352:
endorsed by the Clinical Practice Committee of the 1425-35
University of Michigan Faculty Group Practice and the
Executive Committee for Clinical Affairs of the University Marjoribanks J, Farquhar C, Roberts H, et al. Long term
of Michigan Hospitals and Health Centers. hormone therapy for perimenopausal and postmenopausal
women. Cochrane Database Syst Rev. 2012 Jul
11;7:CD004143. doi: 10.1002/14651858.CD004143.pub4
Acknowledgments
Natural medicines in the clinical management of
Listed on the first page are members of the team that hyperlipidemia. Natural Medicines Comprehensive
reviewed the previous version of this guideline and produced Database; Therapeutic Research Center, 2013. Available at
this update. The following individuals developed earlier http://naturaldatabase.therapeuticresearch.com/ce/ceCourse.
versions of this guideline, parts of which continue to be used aspx?pm=5&pc=10-
in this updated guideline: 105&AspxAutoDetectCookieSupport=1 Accessed 1/6/14.
2000 (May): William E. Barrie, MD; R. Van Harrison, PhD;
Ridker PM, Danielson E, Fonseca F. Rosuvastatin to Prevent
Ujjaini B. Khanderia, PharmD; Robert B. Kiningham,
Vascular Events in Men and Women with Elevated C-
MD; Shawna D. Nesbitt, MD; Melvyn Rubenfire, MD.
Reactive Protein (JUPITER). N Engl J Med 2008;359:2195-
2003 (April): William E. Barrie, MD; R. Van Harrison, PhD; 207.
Ujjaini B. Khanderia, PharmD; Robert B. Kiningham,
MD; Melvyn Rubenfire, MD. Rizos EC, Ntzani EE, Bika E, Kostapanoes MS, Elisaf MS.
2009 (February): William E. Barrie, MD; R. Van Harrison, Association between omega-3 fatty acid supplementation
PhD; Ujjaini B. Khanderia, PharmD; Robert B. and risk of major cardiovascular disease events: a systematic
Kiningham, MD; Robert S. Rosenson, MD. review and meta-analysis. JAMA, 2012; 308(10): 1024-
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LaRosa JC, Grundy SM, Waters DD. Intensive Lipid


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Guidelines for Clinical Care

Quality Department Ambulatory

Lipid Therapy Screening and Management of Lipids

1 UMHS Lipid Therapy Guideline, July, 2020

Secondary Cause Elevated LDL-C Elevated Triglycerides

Table 2. 10-Year Risk Assessment for ASCVD

2 UMHS Lipid Therapy Guideline, July, 2020

Table 4. Monitoring Abnormal Baseline ALT

3 UMHS Lipid Therapy Guideline, July, 2020

Risk Group Treatment

Patients with clinical ASCVD (angina, ACS, PCI, CABG, PVD,

Primary Prevention (assess ASCVD risk)

LDL-C ≥ 190 mg/dL High-intensity statin

4 UMHS Lipid Therapy Guideline, July, 2020

Statin %LDL-C Statin (HMG-CoA Reductase Inhibitor) Options

5 UMHS Lipid Therapy Guideline, July, 2020

6 UMHS Lipid Therapy Guideline, July, 2020

Fibric Acid Derivatives

7 UMHS Lipid Therapy Guideline, July, 2020

PCSK9 Inhibitors (continued on next page)

8 UMHS Lipid Therapy Guideline, July, 2020

fulminant hepatitis and death.

9 UMHS Lipid Therapy Guideline, July, 2020

Interactive Agent(s) Clinical Manifestations

Table 9. Simvastatin and Lovastatin Contraindications and Dose Limitations

Contraindicated with simvastatin: Contraindicated with lovastatin:

10 UMHS Lipid Therapy Guideline update, July 2020

Polypharmacy is an issue in secondary prevention. Patients

18 UMHS Lipid Therapy Guideline update, July 2020

19 UMHS Lipid Therapy Guideline update, July 2020

Special Populations for Preventive Therapy

Heart Protection Study Collaborative Group. MRC/BHF

LaRosa JC, Grundy SM, Waters DD. Intensive Lipid

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