Top Ten Things Every Clinician Should Know About the 2018 Cholesterol Guidelines

Author(s)
Dawn Fuke, PharmD, BCPS
Zach Conroy, PharmD, BCACP

Reviewed By
Lily Van Cheng, PharmD
Courtney Davis, PharmD, BCACP

Citation
Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guidelines on the Management of Blood Cholesterol. Circulation. 2018 [Epub ahead of print] doi:10.1016/j.chest.2018.07.040

The American Heart Association / American College of Cardiology (AHA/ACC) Task Force recently published the 2018 Guideline on the Management of Blood Cholesterol. The guidelines writing committee had representation from 12 organizations, including the National Lipid Association, American Diabetes Association, and the American Pharmacists Association — all of whom endorsed the guidelines. The previous guidelines (published in 2013) were intended to answer some specific clinical questions and significantly changed our approach to treatment. The 2018 guidelines provide a more comprehensive set of recommendations, akin to the (older) National Heart, Lung, and Blood Institute Adult Treatment Panel (ATP) guidelines last published in 2002! Listen to the podcast for additional insights and perspectives.

1. Breakfast lovers rejoice! It’s OK to measure cholesterol in (most) patients at any time, even after eating. Lipid profiles are still recommended in order to determine atherosclerotic cardiovascular disease (ASCVD) risk and provide a baseline low-density lipoprotein cholesterol (LDL-C) level. With the new guidelines, most patients are not required to fast prior to obtaining a cholesterol panel; however they should avoid extremely high-fat meals in the 8 hours prior to the lab draw. If the nonfasting triglyceride level is 400 mg/dL or higher, then a fasting lipid profile should be obtained. Additionally, if the calculated LDL-C is below 70 mg/dL, a direct LDL-C is recommended based on data that shows the Friedewald calculation isn’t very reliable when the LDL-C is below 70 mg/dL.

2. LDL-C targets are back… sort of. Similar to the 2013 guidelines, the 2018 guidelines continue to recommend the use of moderate- or high-intensity statins based on risk stratification to achieve LDL-C lowering of at least 30% for intermediate risk patients and greater than 50% for high risk/very high patients. What is new is using LDL-C targets to help clinicians decide when it’s time to intensify or add non-statin therapy.

Patient Management Group	Risk Stratification	Statin Recommendation	Consider additional therapy if not at LDL-C target
Clinical ASCVD	Very high-risk*	High intensity	<70 mg/dL
	Not at very high-risk	High intensity	<70 mg/dL
Severe hypercholesterolemia		High intensity	<100 mg/dL
Diabetes	High-risk†	High intensity	<50% reduction in LDL-C on maximally tolerated statin
	Not high-risk	Moderate intensity	N/A
Primary prevention	High-risk†	High intensity	N/A
	Intermediate-risk‡	Moderate intensity

^{*Very high-risk includes a history of multiple major ASCVD events or 1 major ASCVD event plus multiple high-risk conditions
†10-year ASCVD risk ³20%    ‡ 10-year ASCVD risk ³7.5 – <20%}

3. Is LDL-C lowering with statin enough? Look to IMPROVE-IT. While statins remain the cornerstone lipid-lowering therapy, the 2018 guidelines do recommend consideration of certain non-statin LDL-C lowering medications in specific scenarios. In very high-risk patients with clinical ASCVD or severe hypercholesterolemia, combination therapy can be considered when the LDL-C remains above target or maximally tolerated statin therapy yields suboptimal LDL-C lowering.

This guideline makes a strong recommendation to add ezetimibe to maximally tolerated doses of statin first and then consider adding a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor next if further LDL-C reduction is needed. Both ezetimibe and PCSK9 inhibitors have been shown to reduce ASCVD events when used in combination with statin therapy in very high-risk patients, but ezetimibe is far more affordable and has a longer safety and tolerability track record. At mid-2018 prices, most economic models have classified PCSK9 inhibitors as “low value” (≥$150,000 per quality-adjusted life years added).

The 2018 guidelines continue to advise against the addition of triglyceride-lowering drugs (fibrates and niacin) unless the clinician is also treating severe hypertriglyceridemia (fasting triglycerides ³500 mg/dL and especially if ³1000 mg/dL) to reduce risk of acute pancreatitis.

Non-statin options	Expected LDL-C reduction	Consider for	Comments
Ezetimibe	13-20%	Clinical ASCVD on a maximally tolerated statin with LDL-C ≥70 mg/dL   Severe hypercholesterolemia on a maximally tolerated statin with LDL-C level of ≥100 mg/dL	-1st line evidence-based add-on to statin therapy -Available as a generic formulation -Generally well tolerated
PCSK9 inhibitors	43-64%	Clinical ASCVD on maximally tolerated statin + ezetimibe with LDL-C ≥70 mg/dL   Severe hypercholesterolemia on maximally tolerated statin + ezetimibe with LDL-C ≥100 mg/dL	-2nd line evidence-based add-on to statin therapy -Long-term safety and cost-effectiveness are uncertain
Bile acid sequestrants	15-30%	Severe hypercholesterolemia on maximally tolerated statin + ezetimibe who still have not achieved ≥50% reduction of LDL-C	-Lack of ASCVD outcomes data – Drug-drug interactions and GI side effects common -Not recommended if fasting TG >300 mg/dL

4. Clinician intuition should be factored into treatment decisions! Risk qualifiers (aka enhancers) are added to the guidelines. Every clinician has probably considered “unofficial” patient factors that likely increase the inherent ASCVD risk, but have not been supported by guidelines. These 2018 risk enhancers may or may not independently confer additional ASCVD risk, but may influence total risk and thereby treatment decisions. Some of these enhancers had been included in the old Framingham calculation, but not the 2013 and 2018 ASCVD risk calculators. The updated risk calculator can be accessed here. https://tools.acc.org/ASCVD-Risk-Estimator-Plus/#!/calculate/estimate/

Very High Risk of Future ASCVD Events in Patients with Clinical ASCVD

Major ASCVD Events
ACS within the past 12 months	History of MI (other than ACS in the past 12 months)
History of ischemic stroke	Symptomatic PAD (claudication with ABI <0.85 or previous revascularization / amputation)
High-Risk Conditions
65 years or older	CKD (eGFR 15-59 ml/min/1.73 m2)
Current smoking	Diabetes mellitus
Hypertension	Heterozygous familial hypercholesterolemia
LDL-C >100 despite maximum tolerated statin and ezetimibe	Heart failure
Prior CABG or PCI outside of the major ASCVD event

Primary Prevention Risk Enhancers

Family history of premature ASCVD	Males < 55 years Females < 65 years
Primary hypercholesterolemia	Ideally 3 measurements: LDL-C, 160–189 mg/dL non–HDL 190–219 mg/dL
Metabolic syndrome	At least 3 of the following: Increased waist circumference Triglycerides > 175 mg/dL Elevated blood pressure Elevated glucose Low HDL (<40 mg/dL in men; <50 in women mg/dL) Asians may have metabolic syndrome with lower waist circumference
Chronic kidney disease	eGFR 15–59 mL/min/1.73 m2 with or without albuminuria Not treated with dialysis or kidney transplantation
Chronic inflammatory conditions	Examples: Psoriasis Rheumatoid Arthritis HIV/AIDS
History of premature menopause and pregnancy-associated conditions that increase later ASCVD risk	Menopause before 40 years Preeclampsia Gestational diabetes mellitus Preterm deliveries Small for gestational age infants Hypertension in pregnancy
High-risk race/ethnicities	South Asian Native American/Alaskan Black women
Lipid/biomarkers	Ideally 3 measurements to determine primary hypertriglyceridemia (≥175 mg/dL) Elevated hsCRP (≥2.0 mg/L), not routinely measured Elevated Lp(a) (≥50 mg/dL or ≥125 nmol/L), not routinely measured Elevated apoB (≥130 mg/dL), can be considered if triglycerides >200 mg/dL (apoB ≥130 mg/dL corresponds to an LDL-C >160 mg/dL) ABI <0.9

5. Sharing is caring! Utilize shared decision-making techniques. Similar to the 2013 guideline, the guidelines continue to emphasize the importance of clinician-patient shared decision-making discussions before starting statin therapy for primary prevention. This discussion should review the potential for statin benefit versus the potential for adverse effects, drug-drug interactions, and should include the patient’s calculated 10-year risk of ASCVD, presence or absence of risk-enhancing factors, the potential benefit of lifestyle modifications, and patient preference. If the benefit-to-risk ratio remains unclear, clinicians can consider measuring coronary artery calcium (CAC) to provide additional information to base the decision to start a statin.

6. Still can’t decide whether or not to start statin? CACulate their risk further. The decision to start a statin for primary prevention is not always clear-cut. For intermediate-risk adults (10-year ASCVD risk 7.5% to 20%), there is moderate quality evidence to consider measuring CAC to refine the risk assessment when either ASCVD risk is unclear or there are hesitations about initiating statin therapy. The CAC score further stratifies ASCVD risk and is independent of many risk factors included in the pooled cohort equation (e.g. age, sex, and ethnicity). If the patient is not a smoker, does not have diabetes, or does not have a strong family history of premature ASCVD, a CAC score of zero indicates a low 10-year risk of ASCVD and benefits of statins may not outweigh risks. Therefore, it may be reasonable to withhold statin therapy and reassess risk in 5-10 years for these lower-risk patients.

NOTE:  There is no utility in measuring CAC in patients already treated with a statin as statins themselves increase CAC scores.

CAC Score	ASCVD Risk	Comments
0	Low	Statin therapy may be withheld or delayed*
1-99	Intermediate	Favors starting statin (especially if ³55 years of age or older)
³100	High	Statin therapy indicated

^{*Except in smokers, those with diabetes, or strong family history of premature ASCVD}

 

7. No more “waiting until you’re older.” Specific recommendations for adults younger than 40 years old with type 1 or 2 diabetes. The CARDS trial is the landmark study that supports statin therapy in patients with diabetes plus an additional cardiovascular risk factor who are 40 years or older. However, the incidence of diabetes in younger adults has been increasing. The guidelines do acknowledge that there is limited evidence regarding the benefits of statin therapy in younger adults with diabetes but the estimated risk is anticipated to rise as these patients age. Patients in whom statin therapy should be considered and discussed (using a shared decision-making approach) are those between 20-39 years of age, with type 2 diabetes for > 10 years or type 1 diabetes for > 20 years; albuminuria; eGFR <60 ml/min/1.73 m2; retinopathy; neuropathy; or ankle-brachial index (ABI) <0.9.

Independent Risk Enhancers Specific to Diabetes

ABI <0.9	Albuminuria >30 mcg albumin/mg creatinine
DM duration (years) 10 or more for type 2 20 or more for type 1	eGFR <60 ml/min/1.73 m2
Neuropathy	Retinopathy

8. Sex-based cholesterol recommendations. A few newer considerations for statin use in women include premature menopause (< 40 years) and a history of pregnancy-associated disorders. While these factors should not automatically result in statin therapy initiation, they should be factored into the overall ASCVD risk calculation and shared decision-making discussion. Additionally, for the first time, there are specific recommendations for statin use in women of childbearing age. Rather than avoiding statin therapy, the guidelines call for contraceptive counseling and a clear recommendation to stop statin therapy 1-2 months before pregnancy is attempted, with immediate discontinuation if an unplanned pregnancy occurs. Statin therapy should not be restarted until after pregnancy and breastfeeding are completed.

9. Chronic inflammatory disorders and human immunodeficiency virus (HIV) are acknowledged as ASCVD risk enhancing factors. Observational studies have demonstrated that inflammatory conditions, such as rheumatoid arthritis, systemic lupus erythematosus, and psoriasis increase the risk of ASCVD events and death. Additionally, HIV, even when the viral load is undetectable, increases the risk of myocardial infarction. The guidelines now recommend taking these conditions into account as risk enhancers and to consider moderate to high intensity statin therapy in these patients.

10. Think of the children (and adolescents). While the guidelines do not recommend universal cholesterol screening for children, it does recommend checking a lipid panel (fasting or nonfasting) in children as young as 2 years of age with a family history of early CVD or familial hypercholesterolemia. Those without familial risk factors but who are obese or have other metabolic risk factors should also have a screening lipid panel obtained. Additionally, statin therapy can be considered in those 8 years or older who have not responded to 3 to 6 months of lifestyle therapy and LDL-C levels remain above 190 mg/dL (or >160 mg/dL in those with familial hypercholesterolemia).

These recommendations will have a significant impact on how we treat patients with elevated cholesterol and ASCVD risk. In some ways, the decision to start therapy is made easier by allowing nonfasting cholesterol levels, incorporating risk enhancers, and clearer recommendations for women, younger adults, and those with HIV or a chronic inflammatory disorder.  What are your thoughts?  Are there any recommendations you feel can’t be justified or perhaps will be misconstrued or misused?  Tell us what you think.

 

NOTE:  This program will be available for recertification credit through the American Pharmacists Association (APhA) Ambulatory Care Review and Recertification Program.  To learn more, visit https://www.pharmacist.com/ambulatory-care-review-and-recertification-activities.