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AACE/ACE Guidelines

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND


AMERICAN COLLEGE OF ENDOCRINOLOGY
GUIDELINES FOR MANAGEMENT OF DYSLIPIDEMIA AND PREVENTION
OF CARDIOVASCULAR DISEASE - EXECUTIVE SUMMARY

Complete Appendix to Guidelines available at http://journals.aace.com

Paul S. Jellinger, MD, MACE, Chair1; Yehuda Handelsman MD, FACP, FACE, FNLA, Co-Chair2;
Paul D. Rosenblit, MD, PhD, FNLA, FACE14; Zachary T. Bloomgarden, MD, MACE4;
Vivian A. Fonseca, MD, FACE8; Alan J. Garber, MD, PhD, FACE9;
George Grunberger, MD, FACP, FACE10; Chris K. Guerin, MD, FNLA, FACE11;
David S. H. Bell, MD, FACP, FACE3; Jeffrey I. Mechanick, MD, FACP, FACE, FACN, ECNU12;
Rachel Pessah-Pollack, MD, FACE13; Kathleen Wyne, MD, PhD, FNLA, FACE16;
Donald Smith, MD, MPH, FACE15; Eliot A. Brinton, MD, FAHA, FNLA5;
Sergio Fazio, MD, PhD7 and Michael Davidson, MD, FACC, FACP, FNLA6

American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice are systematically
developed statements to assist health care professionals in medical decision-making for specific clinical conditions but are
in no way a substitute for a medical professional’s independent judgment and should not be considered medical advice.

Most of the content herein is based on literature reviews. In areas of uncertainty, professional judgment was
applied. These guidelines are a working document that reflects the state of the field at the time of publication. Because
rapid changes in this area are expected, periodic revisions are inevitable. Medical professionals are encouraged to
use this information in conjunction with, and not as a replacement for, their best clinical judgment. The presented
recommendations may not be appropriate in all situations. Any decision by practitioners to apply these guidelines must be
made in light of local resources and individual circumstances.

From the 1Professor of Clinical Medicine, University of Miami, Miller School Chancellor of the American College of Endocrinology; 11Clinical Assistant
of Medicine, Miami, Florida, The Center for Diabetes & Endocrine Care, Professor of Medicine, University of California San Diego, San Diego,
Hollywood, Florida; 2Medical Director & Principal Investigator, Metabolic California, Immediate Past-President of the California Chapter of AACE;
Institute of America, Chair, AACE Diabetes Scientific Committee, Tarzana, 12Clinical Professor of Medicine, Director, Metabolic Support, Division of

California; 3Clinical Professor, University of Alabama, Director, Southside Endocrinology, Diabetes, and Bone Disease, Icahn School of Medicine at
Endocrinology, Birmingham, Alabama; 4Clinical Professor, Mount Sinai Mount Sinai, New York, New York; 13Assistant Clinical Professor, Mount
School of Medicine, Editor, the Journal of Diabetes, New York, New York; Sinai School of Medicine, New York, ProHealth Care Associates, Division
5Director, Atherometabolic Research, Utah Foundation for Biomedical of Endocrinology, Lake Success, New York; 14Clinical Professor, Medicine,
Research, Salt Lake City, Utah; 6Professor, Director of the Lipid Clinic, Division of Endocrinology, Diabetes, Metabolism, University California
University of Chicago Pritzker School of Medicine, Chicago, Illinois; 7The Irvine School of Medicine, Irvine, California, Co-Director, Diabetes Out-
William and Sonja Connor Chair of Preventive Cardiology, Professor of Patient Clinic, UCI Medical Center, Orange, California, Director & Principal
Medicine and Physiology & Pharmacology, Director, Center for Preventive Investigator, Diabetes/Lipid Management & Research Center, Huntington
Cardiology, Knight Cardiovascular Institute, Oregon Health and Science Beach, California; 15Endocrinologist, Clinical Lipidologist, Associate
University, Portland, Oregon; 8Professor of Medicine and Pharmacology, Professor of Medicine, Icahn School of Medicine Mount Sinai, Director
Tullis Tulane Alumni Chair in Diabetes, Chief, Section of Endocrinology, Lipids and Metabolism, Mount Sinai Heart, New York, New York; 16Director,
Tulane University Health Sciences Center, New Orleans, Louisiana; Adult Type 1 Diabetes Program, Division of Endocrinology, Diabetes and
9Professor, Departments of Medicine, Biochemistry and Molecular Biology, Metabolism, The Ohio State University Wexner Medical Center, Columbus,
and Molecular and Cellular Biology, Baylor College of Medicine, Houston, Ohio.
Texas; 10Chairman, Grunberger Diabetes Institute, Clinical Professor, Internal Address correspondence to American Association of Clinical
Medicine and Molecular Medicine & Genetics, Wayne State University School Endocrinologists, 245 Riverside Avenue, Suite 200, Jacksonville, FL 32202.
of Medicine, Professor, Internal Medicine, Oakland University William E-mail: [email protected]. DOI: 10.4158/EP171764.GL
Beaumont School of Medicine, Visiting Professor, Internal Medicine, First To purchase reprints of this article, please visit: www.aace.com/reprints.
Faculty of Medicine, Charles University, Prague, Czech Republic, Immediate Copyright © 2017 AACE
Past President of the American Association of Clinical Endocrinologists,

ENDOCRINE PRACTICE Vol 23 No. 4 April 2017 479


480 CPG for Managing Dyslidemia and Prevention of CVD, Endocr Pract. 2017;23(No. 4)

Writing Committee for the AACE/ACE Clinical Practice


Guidelines for the Management of Dyslipidemia and rotic cardiovascular disease; ATP = Adult Treatment
Prevention of Cardiovascular Disease Panel; apo = apolipoprotein; BEL = best evidence
level; CKD = chronic kidney disease; CPG = clinical
Chair practice guidelines; CVA = cerebrovascular accident;
Paul S. Jellinger, MD, MACE EL = evidence level; FH = familial hypercholesterol-
emia; HDL-C = high-density lipoprotein cholesterol;
Co-Chair HeFH = heterozygous familial hypercholesterolemia;
Yehuda Handelsman, MD, FACP, FACE HIV = human immunodeficiency virus; HoFH = homo-
zygous familial hypercholesterolemia; hsCRP = high-
Task Force Members sensitivity C-reactive protein; LDL-C = low-density
David S. H. Bell, MB, FACP, FACE lipoprotein cholesterol; Lp-PLA2 = lipoprotein-asso-
Zachary T. Bloomgarden, MD, MACE ciated phospholipase A2; MESA = Multi-Ethnic Study
Eliot Brinton, MD of Atherosclerosis; MetS = metabolic syndrome; MI =
Michael Davidson, MD, FACC, FACP, FNLA myocardial infarction; NCEP = National Cholesterol
Sergio Fazio, MD, PhD Education Program; PCOS = polycystic ovary
Vivian A. Fonseca, MD syndrome; PCSK9 = proprotein convertase subtilisin/
Alan J. Garber, MD, PhD, FACE kexin type 9; T1DM = type 1 diabetes mellitus; T2DM
George Grunberger, MD, FACP, FACE = type 2 diabetes mellitus; TG = triglycerides; VLDL-C
Chris K. Guerin, MD, FNLA, FACE = very low-density lipoprotein cholesterol
Paul D. Rosenblit, MD, PhD, FNLA, FACE
Donald A. Smith, MD, MPH, FACE
Kathleen Wyne, MD, PhD, FNLA, FACE ABSTRACT

Objective: The development of these guidelines


Task Force for the AACE/ACE Clinical Practice is mandated by the American Association of Clinical
Guidelines for the Management of Dyslipidemia and Endocrinologists (AACE) Board of Directors and American
Prevention of Cardiovascular Disease College of Endocrinology (ACE) Board of Trustees and
adheres with published AACE protocols for the standard-
Chair ized production of clinical practice guidelines (CPGs).
Yehuda Handelsman, MD, FACP, FACE Methods: Each Recommendation is based on a dili-
gent review of the clinical evidence with transparent incor-
Task Force Members poration of subjective factors.
David S. H. Bell, MB, FACP, FACE Results: The Executive Summary of this document
Zachary T. Bloomgarden, MD, MACE contains 87 Recommendations of which 45 are Grade A
Eliot Brinton, MD (51.7%), 18 are Grade B (20.7%), 15 are Grade C (17.2%),
Sergio Fazio, MD, PhD and 9 (10.3%) are Grade D. These detailed, evidence-based
Vivian A. Fonseca, MD, FACE recommendations allow for nuance-based clinical deci-
Alan J. Garber, MD, PhD sion making that addresses multiple aspects of real-world
George Grunberger, MD, FACP, FACE medical care. The evidence base presented in the subse-
Chris K. Guerin, MD, FNLA, FACE quent Appendix provides relevant supporting information
Paul S. Jellinger, MD, MACE for Executive Summary Recommendations. This update
Paul D. Rosenblit, MD, PhD, FNLA, FACE contains 695 citations of which 202 (29.1 %) are evidence
Donald A. Smith, MD, MPH, FACE level (EL) 1 (strong), 137 (19.7%) are EL 2 (intermediate),
Kathleen Wyne, MD, PhD, FNLA, FACE 119 (17.1%) are EL 3 (weak), and 237 (34.1%) are EL 4
Michael Davidson, MD, FACC, FACP, FNLA, Advisor (no clinical evidence).
Conclusion: This CPG is a practical tool that endocri-
Reviewers nologists, other healthcare professionals, regulatory bodies
Farhad Zangeneh, MD, FACP, FACE and health-related organizations can use to reduce the risks
Michael A. Bush, MD and consequences of dyslipidemia. It provides guidance
on screening, risk assessment, and treatment recommenda-
Abbreviations tions for a range of patients with various lipid disorders.
A1C = hemoglobin A1C; ACE = American College of These recommendations emphasize the importance of
Endocrinology; ACS = acute coronary syndrome; AHA treating low-density lipoprotein cholesterol (LDL-C) in
= American Heart Association; ASCVD = atheroscle some individuals to lower goals than previously recom-
mended and support the measurement of coronary artery
CPG for Managing Dyslidemia and Prevention of CVD, Endocr Pract. 2017;23(No. 4) 481

calcium scores and inflammatory markers to help stratify This CPG is unique in that it supports the use of apoli-
risk. Special consideration is given to patients with diabe- poprotein (apo) B level and/or LDL particle concentra-
tes, familial hypercholesterolemia, women, and pediatric tion to refine efforts to achieve effective LDL-C lower-
patients with dyslipidemia. Both clinical and cost-effec- ing, provide screening recommendations for individuals
tiveness data are provided to support treatment decisions. of different ages, and identify special issues for children
(Endocr Pract. 2017;23:479-497) and adolescents. This CPG also discusses the challenges
associated with atherosclerosis and heart disease that are
I. INTRODUCTION specific to women. It continues to emphasize the impor-
tance of LDL-C lowering and supports the measurement of
In 2016, approximately 660,000 U.S. residents will inflammatory markers to stratify risk in certain situations.
have a new coronary event (defined as a first hospitalized Finally, this CPG presents an evaluation of the cost-effec-
myocardial infarction [MI] or atherosclerotic cardiovascu- tiveness of lipid-lowering management.
lar disease [ASCVD] death), and approximately 305,000 This document is organized based on discrete clini-
will have a recurrent event. The estimated annual incidence cal questions, with an Executive Summary of key recom-
of MI is 550,000 new and 200,000 recurrent attacks. The mendations followed by the supporting evidence base. The
average age at first MI is 65.1 years for men and 72.0 years objectives of this CPG are to provide:
for women (1 [EL 4; NE]). Dyslipidemia is a primary, major • An overview of the screening recommendations,
risk factor for ASCVD and may even be a prerequisite for assessment of risk, and treatment recommenda-
ASCVD, occurring before other major risk factors come tions for various lipid disorders;
into play. Epidemiologic data also suggest that hypercho- • Special consideration for individuals with diabe-
lesterolemia and perhaps coronary atherosclerosis itself are tes, women, and children/adolescents with dyslip-
risk factors for ischemic cerebrovascular accident (CVA) idemia; and
(2 [EL 4; NE]). According to data from 2009 to 2012, >100 • Cost-effectiveness data to support therapeutic
million U.S. adults ≥20 years of age have total cholesterol decision making
levels ≥200 mg/dL; almost 31 million have levels ≥240 mg/
dL (1 [EL 4; NE]). Increasing evidence also points to insu- II. METHODS
lin resistance—which results in increased levels of plasma
triglycerides (TG) and low-density lipoprotein cholesterol This CPG was developed in accordance with the
(LDL-C) and a decreased concentration of high-density AACE Protocol for Standardized Production of Clinical
lipoprotein cholesterol (HDL-C)—as an important risk Practice Guidelines (9 [EL 4; NE]). Reference citations
factor for peripheral vascular disease (3 [EL 2; PCS]), in the text of this document include the reference number,
CVA, and ASCVD (4 [EL 2; PCS]). numerical descriptor (EL 1-4), and semantic descriptor
Analysis of 30-year national trends in serum lipid (explained in Table 1) (9 [EL 4; NE]).
levels shows improvements in total cholesterol and LDL-C All primary writers have made disclosures regarding
levels. This may in part be explained by the steady increase multiplicities of interests and have attested that they are
in the use of lipid-lowering drug therapy (self-reported not employed by industry. In addition, all primary writ-
rate of lipid medication use, 38%). However, 69% of U.S. ers are AACE members and credentialed experts. Primary
adults have LDL-C concentrations above 100 mg/dL. writers submitted contributions to specific clinical ques-
Furthermore, the doubling in prevalence of individuals tions, which were subsequently reviewed, discussed, and
who are obese, the high percentage with elevated TG levels integrated into the final document. This valuable input
(33%), and the correlation between obesity and elevated provides the basis for the recommendations herein. The
TG point to the need for continued vigilance on the part of format of this CPG is based on specific and relevant clini-
physicians to reduce ASCVD risk (5 [EL 3; SS]). cal questions (labeled “Q”).
This clinical practice guideline (CPG) is for the diag- Recommendations (labeled “R”) are assigned Grades
nosis and treatment of dyslipidemia and prevention of that map to the best evidence level (BEL) ratings based on
atherosclerosis. The mandate for this CPG is to provide the highest quality supporting evidence level (EL) (Tables
a practical guide for endocrinologists to reduce the risks 1 and 2; Fig. 1) (9 [EL 4; NE]), all of which have also been
and consequences of dyslipidemia. This CPG extends and rated based on scientific substantiation (Table 3) (9 [EL 4;
updates existing CPGs available in the literature, such as NE]). Recommendation Grades are designated “A,” “B,” or
the American Association of Clinical Endocrinologists “C” when there is scientific evidence available, or “D” when
(AACE) Medical Guidelines for Clinical Practice for the there is only expert opinion or a lack of conclusive scientific
Diagnosis and Treatment of Dyslipidemia and Prevention evidence. Technically, the BEL follows the recommenda-
of Atherosclerosis (6 [EL 4; NE]), and complements the tion Grade in the Executive Summary. Briefly, there are 4
AACE Diabetes Mellitus Comprehensive Care Plan intuitive levels of evidence: 1 = strong, 2 = intermediate, 3
CPG (7 [EL 4; NE]). The landmark National Cholesterol = weak, and 4 = no evidence (Table 3). Comments may be
Education Program (NCEP) guidelines (8 [EL 4; NE]) appended to the recommendation Grade and BEL regarding
serve as the backbone of these lipid recommendations. any relevant subjective factors that may have influenced the
482 CPG for Managing Dyslidemia and Prevention of CVD, Endocr Pract. 2017;23(No. 4)

grading process (Table 4) (9 [EL 4; NE]). Details regard- ultimate clinical management is based on what is in the best
ing each recommendation may be found in the upcoming interest of the individual and involves the individual’s input
corresponding section of the CPG Evidence Base Appendix (“patient-centered care”) and reasonable clinical judgment
and will include a complete list of supporting References. by treating clinicians.
Thus, the process leading to a final recommendation and This CPG has been reviewed and approved by
grade is not rigid, but rather incorporates complex expert the primary writers, other invited experts, the AACE
integration of objective and subjective factors meant to Publications Committee, the AACE Board of Directors,
reflect optimal real-life clinical decision making, options, and the ACE Board of Trustees before submission for peer
and individualization of care. This document is a guideline, review by Endocrine Practice. The efforts of all those
and since individual circumstances and presentations differ, involved are greatly appreciated.

Table 1
2014 American Association of Clinical Endocrinologists Protocol
for Production of Clincal Practice Guidelines - Step I: Evidence Ratinga
Numerical descriptor
(evidence level)b Semantic descriptor
1 Meta-analysis of randomized controlled trials (MRCT)
1 Randomized controlled trial (RCT)
2 Meta-analysis of nonrandomized prospective or case-controlled trials
2 Nonrandomized controlled trial (NRCT)
2 Prospective cohort study (PCS)
2 Retrospective case-control study (RCCS)
3 Cross-sectional study (CSS)
Surveillance study (registries, surveys, epidemiologic study, retrospective
3
chart review, mathematical modeling or database) (SS)
3 Consecutive case series (CCS)
3 Single case report (SCR)
4 No evidence (theory, opinion, consensus, review, or preclinical study) (NE)
a Adapted from: Endocr Pract. 2014;20:692-702 (9 [EL 4; NE]).
b 1 = strong evidence; 2 = intermediate evidence; 3 = weak evidence; 4 = no evidence.

Fig. 1. 2014 American Association of Clinical Endocrinologists Clinical Practice Guideline


Methodology. Current American Association of Clinical Endocrinologists Clinical Practice
Guidelines have a problem-oriented focus that results in a shortened production timeline,
middle-range literature searching, emphasis on patient-oriented evidence that matters,
greater transparency of intuitive evidence rating and qualifications, incorporation of subjec-
tive factors into evidence level to recommendation grade mapping, cascades of alternative
approaches, and an expedited multilevel review mechanism (9 [EL 4; NE]).
CPG for Managing Dyslidemia and Prevention of CVD, Endocr Pract. 2017;23(No. 4) 483

Table 2
2014 American Association of Clinical Endocrinologists Protocol for Production of
Clinical Practice Guidelines—Step II: Evidence Analysis and Subjective Factorsa
Study design Data analysis Interpretation of results
Premise correctness Intent-to-treat Generalizability
Allocation concealment (randomization) Appropriate statistics Logical
Selection bias Incompleteness
Appropriate blinding Validity
Using surrogate endpoints (especially in
“first-in-its-class” intervention)
Sample size (beta error)
Null hypothesis vs. Bayesian statistics
a Reprinted from: Endocr Pract. 2014;20:692-702 (9 [EL 4; NE]).

Table 3
2014 American Association of Clinical Endocrinologists Protocol for
Production of Clinical Practice Guidelines—
Step III: Grading of Recommendations; How Different
Evidence Levels Can Be Mapped to the Same Recommendation Gradea,b
Best evidence Subjective Two-thirds
level factor impact consensus Mapping Recommendation grade
1 None Yes Direct A
2 Positive Yes Adjust up A

2 None Yes Direct B


1 Negative Yes Adjust down B
3 Positive Yes Adjust up B

3 None Yes Direct C


2 Negative Yes Adjust down C
4 Positive Yes Adjust up C

4 None Yes Direct D


3 Negative Yes Adjust down D

1, 2, 3, 4 NA No Adjust down D
a Starting with the left column, best evidence levels (BELs), subjective factors, and consensus map to
recommendation grades in the right column. When subjective factors have little or
no impact (“none”), then the BEL is directly mapped to recommendation grades. When subjective factors
have a strong impact, then recommendation grades may be adjusted up (“positive” impact) or down
(“negative” impact). If a two-thirds consensus cannot be reached, then the recommendation grade is D.
NA, not applicable (regardless of the presence or absence of strong subjective factors, the absence of a
two-thirds consensus mandates a recommendation grade D).
b Reprinted from Endocr Pract. 2014;20:692-702 (9 [EL 4; NE]).
484 CPG for Managing Dyslidemia and Prevention of CVD, Endocr Pract. 2017;23(No. 4)

Table 4
2014 American Association of Clinical Endocrinologists
Protocol for Production of Clinical Practice Guidelines—
Step IV: Examples of Qualifiers That May Be
Appended to Recommendationsa
Cost-effectiveness
Risk-benefit analysis
Evidence gaps
Alternative physician preferences (dissenting opinions)
Alternative recommendations (“cascades”)
Resource availability
Cultural factors
Relevance (patient-oriented evidence that matters)
a Reprinted from Endocr Pract. 2014;20:692-702 (9 [EL 4; NE]).

3Q1. HOW SHOULD INDIVIDUALS BE SCREENED high, very high, or extreme risk for ACSVD (Table 6)
FOR THE DETECTION OF DYSLIPIDEMIA? (Grade B; BEL 3; upgraded due to high relevance).

3Q1.1. Global Risk Assessment • R3. Based on epidemiologic and prospective cohort
• R1. Identify risk factors that enable personalized and studies, individuals with type 1 diabetes (T1DM) and
optimal therapy for dyslipidemia (Table 5) (Grade A; duration more than 15 years or with 2 or more major
BEL 1). cardiovascular (CV) risk factors (e.g., albuminuria,
chronic kidney disease [CKD] stage 3/4, initiation
• R2. Based on epidemiologic studies, individuals with of intensive control >5 years after diagnosis), poorly
type 2 diabetes (T2DM) should be considered as controlled hemoglobin A1C (A1C) or insulin resis-

Table 5
Major Atherosclerotic Cardiovascular Disease Risk Factors
Major risk factors Additional risk factors Nontraditional risk factors
Advancing agea-d Obesity, abdominal obesityc,d Lipoprotein (a)
 Total serum Family history of  Clotting factors
cholesterol levela,b,d hyperlipidemiad  Inflammation markers
 Non–HDL-Cd  Small, dense LDL-Cd (hsCRP; Lp-PLA2)
 LDL-Ca,d  Apo Bd Homocysteine levels
Low HDL-Ca,d,e LDL particle concentration Apo E4 isoform
Diabetes mellitusa-d Fasting/post-prandial  Uric acid
Hypertensiona-d hypertriglyceridemiad  TG-rich remnants
Chronic kidney disease 3,4h PCOSd
Cigarette smokinga-d Dyslipidemic triadf
Family history of ASCVDa,d,g
Abbreviations: apo = apolipoprotein; ASCVD = atherosclerotic cardiovascular disease; HDL-C = high-density
lipoprotein cholesterol; hsCRP = high-sensitivity C-reactive protein; LDL = low-density lipoprotein; LDL-C = low-
density lipoprotein cholesterol; Lp-PLA2 = lipoprotein-associated phospholipase; PCOS = polycystic ovary syndrome.
a Risk factors identified in the Framingham Heart study.
b Risk factors identified in the MRFIT study (Multiple Risk Factor Intervention Trial).
c Risk factors identified in the INTERHEART study.
d Risk factors identified in guidelines and position statements (National Cholesterol Education Program Adult Treatment

Panel III, American Association of Clinical Endocrinologists Polycystic Ovary Syndrome Position Statement,
American Association of Clinical Endocrinologists Insulin Resistance Syndrome Position Statement, American
Diabetes Association Standards of Care 2009, American Diabetes Association/American College of Cardiology
Consensus Statement on Lipoprotein Management in Patients with Cardiometabolic Risk, National Lipid
Association, Clinical Utility of Inflammatory Markers and Advanced Lipoprotein Testing).
e Elevated HDL-C is a negative risk factor.
f Hypertriglyceridemia; low HDL-C; and an excess of small, dense LDL-C.
g Definite myocardial infarction or sudden death before age 55 years in father or other male first-degree relative or

before age 65 years in mother or other female first-degree relative.


h Based on a pooled analysis of community-based studies (N = 22,634).
CPG for Managing Dyslidemia and Prevention of CVD, Endocr Pract. 2017;23(No. 4) 485

tance with metabolic syndrome should be considered event using the Reynolds Risk Score (www.
to have risk-equivalence to individuals with T2DM reynoldsriskscore.org) or the Framingham Risk
(Table 7, see online Appendix/Evidence Base) (Grade Assessment Tool (www.framinghamheartstudy.org/
B; BEL 2). risk-functions/coronary-heart-disease/hard-10-year-
risk.php) (Table 8) (Grade C; BEL 4, upgraded due
• R4. The 10-year risk of a coronary event (high, inter- to cost-effectiveness).
mediate, or low) should be determined by detailed
assessment using 1 or more of the following tools • R6. Dyslipidemia in childhood and adolescence
(Table 8) (Grade C; BEL 4, upgraded due to cost- should be diagnosed and managed as early as pos-
effectiveness): sible to reduce the levels of LDL-C that may eventu-
• Framingham Risk Assessment Tool (https:// ally increase risk of CV events in adulthood (Table 9)
www.framinghamheartstudy.org/risk-functions/ (Grade A; BEL 1).
coronary-heart-disease/hard-10-year-risk.php)
• Multi-Ethnic Study of Atherosclerosis (MESA) • R7. When the HDL-C concentration is >60 mg/dL, 1
10-year ASCVD Risk with Coronary Artery risk factor should be subtracted from an individual’s
Calcification Calculator (https://www.mesa- overall risk profile (Grade B; BEL 2).
nhlbi.org/MESACHDRisk/MesaRiskScore/
RiskScore.aspx) • R8. A classification of elevated TG should be incor-
• Reynolds Risk Score, which includes high-sensi- porated into risk assessments to aid in treatment deci-
tivity CRP (hsCRP) and family history of prema- sions (Table 10) (Grade B; BEL 2).
ture ASCVD) (http://www.reynoldsriskscore.org)
• United Kingdom Prospective Diabetes Study 3Q1.2. Screening
(UKPDS) risk engine to calculate ASCVD risk in Familial Hypercholesterolemia
individuals with T2DM) (https://www.dtu.ox.ac. • R9. Individuals should be screened for familial hyper-
uk/riskengine) cholesterolemia (FH) when there is a family history of:
• Premature ASCVD (definite MI or sudden death
• R5. Special attention should be given to assessing before age 55 years in father or other male first-
women for ASCVD risk by determining the 10-year degree relative, or before age 65 years in mother
risk (high, intermediate, or low) of a coronary or other female first-degree relative) or

Table 6
Atherosclerotic Cardiovascular Disease Risk Categories and LDL-C Treatment Goals
Treatment goals
LDL-C Non-HDL-C Apo B
Risk category Risk factorsa/10-year riskb (mg/dL) (mg/dL) (mg/dL)
– Progressive ASCVD including unstable angina in patients
after achieving an LDL-C <70 mg/dL
Extreme risk – Established clinical cardiovascular disease in patients with <55 <80 <70
DM, CKD 3/4, or HeFH
– History of premature ASCVD (<55 male, <65 female)
– Established or recent hospitalization for ACS, coronary,
carotid or peripheral vascular disease, 10-year risk >20%
Very high risk <70 <100 <80
– Diabetes or CKD 3/4 with 1 or more risk factor(s)
– HeFH
– ≥2 risk factors and 10-year risk 10-20%
High risk <100 <130 <90
– Diabetes or CKD 3/4 with no other risk factors
Moderate risk ≤2 risk factors and 10-year risk <10% <100 <130 <90
Low risk 0 risk factors <130 <160 NR
Abbreviations: ACS = acute coronary syndrome; ASCVD = atherosclerotic cardiovascular disease; CKD = chronic kidney
disease; DM = diabetes mellitus; HDL-C = high-density lipoprotein cholesterol; HeFH = heterozygous familial hypercholes-
terolemia; LDL-C = low-density lipoprotein cholesterol; MESA = Multi-Ethnic Study of Atherosclerosis; NR = not recom-
mended; UKPDS = United Kingdom Prospective Diabetes Study.
a Major independent risk factors are high LDL-C, polycystic ovary syndrome, cigarette smoking, hypertension (blood pressure

≥140/90 mm Hg or on hypertensive medication), low HDL-C (<40 mg/dL), family history of coronary artery disease (in male,
first-degree relative younger than 55 years; in female, first-degree relative younger than 65 years), chronic renal disease (CKD)
stage 3/4, evidence of coronary artery calcification and age (men ≥45; women ≥55 years). Subtract 1 risk factor if the person
has high HDL-C.
b Framingham risk scoring is applied to determine 10-year risk.

Reproduced with permission from Garber et al. Endocr Pract. 2017;23:207-238.


486 CPG for Managing Dyslidemia and Prevention of CVD, Endocr Pract. 2017;23(No. 4)

• Elevated cholesterol levels (total, non-HDL and/ Young Adults (Men Aged 20-45 Years, Women Aged
or LDL) consistent with FH (Grade C; BEL 4, 20-55 Years)
upgraded due to cost-effectiveness). • R11. Evaluate all adults 20 years of age or older for
dyslipidemia every 5 years as part of a global risk
Adults With Diabetes assessment (Grade C; BEL 4, upgraded due to cost-
• R10. Annually screen all adult individuals with T1DM effectiveness).
or T2DM for dyslipidemia (Grade B; BEL 2).

Table 8
Key Cardiovascular Risk Scoring Tools: Framingham, MESA, Reynolds, and UKPDS
Risk group/
Framingham Global
Risk
Framingham Global Risk (10-year absolute
Risk factors included/questions ASCVD risk) Clinical examples
Risk assessment tool for calculating 10-year risk of having High • Established coronary artery disease
a heart attack for adults 20 and older who do not have heart >20% • Cerebrovascular disease
disease or diabetes (using data from the Framingham Heart • Peripheral arterial disease
Study): • Abdominal aortic aneurysm
• Diabetes mellitus
• Chronic kidney disease
Age: years
Sex: Female Male Intermediate • Subclinical coronary artery disease
Total cholesterol: mg/dL 10-20% • MetS
HDL cholesterol: mg/dL • Multiple risk factorsa
Smoker (in last month): No Yes • Markedly elevated levels of a single
Systolic blood pressure: mm Hg risk factorb
Are you currently on any • First-degree relative(s) with early onset
medication to treat high No Yes coronary artery disease
blood pressure:
Lower • May include women with multiple risk
<10% factors, MetS, or 1 or no risk factors
Calculate
Optimal • Optimal levels of risk factors and heart-
<10% healthy lifestyle
• High risk: A greater than 20% risk that you will develop a heart attack or die from coronary disease in the next 10 years.
• Intermediate risk: A 10-20% risk that you will develop a heart attack or die from coronary disease in the next 10 years.
• Low risk: Less than 10% risk that you will develop a heart attack or die from coronary disease in the next 10 years.
a Patients with multiple risk factors can fall into any of the 3 categories by Framingham scoring.
b Most women with a single, severe risk factor will have a 10-year risk ≤10%.
Multi-Ethnic Study of Atherosclerosis (MESA)
Risk factors included/questions Risk calculation outcomes
• External validation provided evidence
MESA 10-Year ASCVD risk with coronary artery calcification: of very good discrimination and
Sex: Male Female calibration
Age (45-85 years): years • Harrell’s C-statistic ranged from 0.779
Coronary artery calcification: Agatston to 0.816 in validation against existing
Race/ethnicity (choose one): studies
Caucasian Chinese • The difference in estimated 10-year
African American Hispanic risk between events and nonevents
Diabetes: Yes No was approximately 8-9%, indicating
Currently smoke: Yes No excellent discrimination
• Mean calibration found average
Family history of heart attack: Yes No
predicted 10-year risk within 1/2 of a
Total cholesterol: mg/dL percent of the observed event rate
HDL cholesterol: mg/dL • The test predicts 10-year risk of a
Systolic blood pressure: mm Hg ASCVD event
Lipid-lowering medication: Yes No
Hypertension medication: Yes No
Calculate 10-year ASCVD risk
CPG for Managing Dyslidemia and Prevention of CVD, Endocr Pract. 2017;23(No. 4) 487

Table 8 Continued
Reynolds Risk Score
Risk factors included/questions Risk calculation outcomes
Reynolds Risk Score predicts 10-year risk of heart attack, CVA, or other major heart • Compared to ATP III/Framingham 10-
diseases in healthy people without diabetes. year risk categorization:
Age Years (≤80) o Very little change in categorization
of individuals with very low (<5%)
Currently smoke? Yes No risk
o 30% reclassification of those
Systolic blood pressure mm Hg classified as 5% to <10% risk
Total cholesterol mg/dL or mmol/L according to ATP III
o 29% reclassification of those
HDL cholesterol mg/dL or mmol/L classified as 10% to <20% risk
according to ATP III
hsCRP mg/L o 25% reclassification of those
classified as ≥20% risk according
Mother or father have heart attack Yes No to ATP III
before age 60? • Risk is classified as low (<5%), low to
moderate (5% to <10%), moderate to
Calculate 10-year risk high (10% to <20%), and high (≥20%)
ASCVD Risk
UKDPS Risk Score
Risk factors included/questions Risk calculation outcomes
UKPDS risk engine is a model for estimating risk of ASCVD in persons with T2DM • Survival rates predicted by UKPDS
(this risk is up to 3x greater than for the general population) Risk Score model were similar to rates
Age years observed in the UKPDS trial, well
within non-parametric confidence
Weight kg intervals
• Predicted survival rates adjust for A1C,
Height cm
blood pressure, and lipid risk factors
Sex Male Female • The UKPDS Risk Engine provides risk
estimates and 95% confidence intervals
HDL cholesterol mmol/L
in individuals with T2DM not known
Total cholesterol mg/L to have heart disease for:
- Nonfatal and fatal coronary heart
Systolic blood pressure mm Hg disease
Smoker Yes No - Fatal coronary heart disease
- Nonfatal and fatal CVA
Afro-Caribbean ethnicity? Yes No - Fatal CVA
A1C %
Time period (duration of years: (4, 5, 6, 7, 8, 9, 10, 15, 20)
diabetes)
Regular exercise per week: # of times (1, 2, 3, 4, >5)

Calculate risk
Abbreviations: A1C = hemoglobin A1C; ATP III = Adult Treatment Panel III; ASCVD = atherosclerotic cardiovascular disease; A1C =
glycated hemoglobin; CVA = cerebrovascular accident; HDL = high-density lipoprotein; hsCRP = high-sensitivity C-reactive protein;
ln = natural logarithm; MetS = metabolic syndrome; MI = myocardial infarction; T2DM = type 2 diabetes mellitus; UKPDS = United
Kingdom Prospective Diabetes Study.
488 CPG for Managing Dyslidemia and Prevention of CVD, Endocr Pract. 2017;23(No. 4)

Middle-Aged Adults (Men Aged 45-65 Years, Women • R18. Screen adolescents older than 16 years every 5
Aged 55-65 Years) years or more frequently if they have ASCVD risk
• R12. In the absence of ASCVD risk factors, screen factors, are overweight or obese, have other elements
middle-aged individuals for dyslipidemia at least once of the insulin resistance syndrome, or have a fam-
every 1 to 2 years. More frequent lipid testing is rec- ily history of premature ASCVD (Grade B; BEL 3,
ommended when multiple global ASCVD risk factors upgraded due to cost-effectiveness).
are present (Grade A; BEL 1).
3Q2. WHICH SCREENING TESTS ARE
• R13. The frequency of lipid testing should be based on RECOMMENDED FOR THE DETECTION OF
individual clinical circumstances and the clinician’s CARDIOVASCULAR RISK?
best judgment (Grade C; BEL 4, upgraded due to
cost-effectiveness). 3Q2.1. Fasting Lipid Profile
• R19. Use a fasting lipid profile to ensure the most pre-
Older Adults (Older Than 65 Years) cise lipid assessment; this should include total choles-
• R14. Annually screen older adults with 0 to 1 ASCVD terol, LDL-C, TG, and non-HDL-C (Grade C; BEL
risk factor for dyslipidemia (Grade A; BEL 1). 4, upgraded due to cost-effectiveness).

• R15. Older adults should undergo lipid assessment if • R20. Lipids including TG can be measured in the non-
they have multiple ASCVD global risk factors (i.e., fasting state if fasting determinations are impractical
other than age) (Grade C; BEL 4, upgraded due to (Grade D).
cost-effectiveness).
3Q2.2. LDL-C
• R16. Screening for this group is based on age and • R21. LDL-C may be estimated using the Friedewald
risk, but not sex; therefore, older women should be equation: LDL-C = (total cholesterol – HDL-C) –
screened in the same way as older men (Grade A; TG/5; however, this method is valid only for values
BEL 1). obtained during the fasting state and becomes increas-
ingly inaccurate when TG levels are greater than 200
Children and Adolescents mg/dL and invalid when TG levels are greater than
• R17. In children at risk for FH (e.g., family history 400 mg/dL (Grade C; BEL 3).
of premature cardiovascular disease or elevated cho-
lesterol), screening should be at 3 years of age, again • R22. LDL-C should be directly measured in certain
between ages 9 and 11, and again at age 18 (Grade B; high-risk individuals such as those with fasting TG
BEL 3, upgraded due to cost-effectiveness). levels greater than 250 mg/dL or those with diabetes
or known vascular disease (Grade C; BEL 3).
Table 9
Classification of LDL-C Levels in 3Q2.3. HDL-C
Children and Adolescents • R23. Measurement of HDL-C should be included in
Category LDL-C, mg/dL screening tests for dyslipidemia (Grade B; BEL 2).
Acceptable <100
3Q2.4. Non-HDL-C
Borderline 100-129 • R24. The non-HDL-C (total cholesterol – HDL-C)
High ≥130 should be calculated to assist risk stratification in indi-
Abbreviation: LDL-C = low-density lipoprotein cholesterol viduals with moderately elevated TG (200 to 500 mg/
dL), diabetes, and/or established ASCVD (Grade B;
BEL 2).
Table 10
Classification of Elevated TG Levels • R25. If insulin resistance is suspected, the non-HDL-C
should be evaluated to gain useful information regard-
TG category TG concentration, mg/dL Goal
ing the individual’s total atherogenic lipoprotein bur-
Normal <150 den (Grade D).
Borderline-high 150-199
<150 mg/dL
High 200-499 3Q2.5. Triglycerides
• R26. TG levels should be part of routine lipid screen-
Very high ≥500
ing: moderate elevations (≥150 mg/dL) may identify
Abbreviation: TG = triglycerides individuals at risk for the insulin resistance syndrome,
CPG for Managing Dyslidemia and Prevention of CVD, Endocr Pract. 2017;23(No. 4) 489

and levels ≥200 mg/dL may identify individuals at sub- • R31. Measure lipoprotein-associated phospholipase
stantially increased ASCVD risk (Grade B; BEL 2). A2 (Lp-PLA2), which in some studies has demon-
strated more specificity than hsCRP, when it is nec-
3Q2.6. Apolipoproteins essary to further stratify an individual’s ASCVD
• R27. Apo B and/or an apo B/apo A1 ratio calculation risk, especially in the presence of hsCRP elevations
and evaluation may be useful in at-risk individuals (Grade A; BEL 1).
(TG ≥150, HDL-C <40, prior ASCVD event, T2DM,
and/or the insulin resistance syndrome [even at target • R32. The routine measurement of homocysteine,
LDL-C levels]) to assess residual risk and guide deci- uric acid, plasminogen activator inhibitor-1, or other
sion making (Grade A; BEL 1). inflammatory markers is not recommended because
the benefit of doing so is not sufficiently proven
• R28. Apo B measurements (reflecting the particle con- (Grade D).
centration of LDL and all other atherogenic lipopro-
teins) may be useful to assess the success of LDL-C- • R33. Coronary artery calcification measurement has
lowering therapy (Grade A; BEL 1). been shown to be of high predictive value and is use-
ful in refining risk stratification to determine the need
3Q2.7. Secondary Causes of Dyslipidemia for more aggressive treatment strategies (Grade B;
• R29. Rule out secondary causes of dyslipidemia (Table BEL 2).
11) (Grade B; BEL 2).
• R34. Carotid intima media thickness may be consid-
3Q2.8. Additional Tests ered to refine risk stratification to determine the need
• R30. Use hsCRP to stratify ASCVD risk in individu- for more aggressive ASCVD preventive strategies
als with a standard risk assessment that is borderline, (Grade B; BEL 2).
or in those with an intermediate or higher risk with an
LDL-C concentration <130 mg/dL (Grade B; BEL 2).

Table 11
Common Secondary Causes of Dyslipidemia
Affected lipids Conditions
↑ Total cholesterol and LDL-C • Hypothyroidism
• Nephrosis
• Dysgammaglobulinemia (systemic lupus erythematosus, multiple myeloma)
• Progestina or anabolic steroid treatment
• Cholostatic diseases of the liver due to abnormal lipoproteins, as in primary biliary cirrhosis
• Protease inhibitors for treatment of HIV infectionb
↑ TG and VLDL-C • Chronic renal failure
• T2DMc
• Obesity
• Excessive alcohol intake
• Hypothyroidism
• Antihypertensive medications (thiazide diuretics and b-adrenergic blocking agents)
• Corticosteroid therapy (or severe stress that increases endogenous corticosteroids)
• Orally administered estrogensd, oral contraceptives, pregnancy
• Protease inhibitors for treatment of HIV infectionb
Abbreviations: HIV = human immunodeficiency virus; LDL-C = low-density lipoprotein cholesterol; T2DM = type 2 diabetes
mellitus; TG = triglycerides
a Progestational agents, especially those with androgenic activity, can increase LDL-C and decrease HDL-C.
b Protease inhibitors can induce peripheral lipodystrophy, increased visceral fat, insulin resistance, and diabetes. Protease inhibitor-

induced dyslipidemia may include elevated LDL-C and/or the atherogenic dyslipidemia pattern of high TG; small, dense, LDL-C; and
low HDL-C. However, newer generation protease inhibitors may have improved lipid profiles.
c Diabetic dyslipidemia is often similar to atherogenic dyslipidemia: high TG, small, dense LDL-C, and low HDL-C.
d Transdermally administered estrogens are not associated with increased TG levels.
490 CPG for Managing Dyslidemia and Prevention of CVD, Endocr Pract. 2017;23(No. 4)

3Q3. WHAT ARE THE TREATMENT tobacco cessation), and if risk factors are present (e.g.,
RECOMMENDATIONS IN INDIVIDUALS WITH borderline elevated LDL-C levels, a family history of
DYSLIPIDEMIA AND ASCVD RISK? premature ASCVD, or a personal history of ASCVD),
but also through the use of pharmacotherapy primarily
3Q3.1. Treatment Goals focused on reducing LDL-C (Grade A; BEL 1).
• R35. Treatment goals for dyslipidemia should be per-
sonalized according to levels of risk (Tables 6 and 12) • 3Q3.1.3. Non-High-Density Lipoprotein Cholesterol
(Grade A; BEL 1). • R43. For most individuals, a non-HDL-C goal (total
cholesterol – HDL-C) 30 mg/dL higher than the indi-
• 3Q3.1.1. Risk Categories and LDL-C Goals (Table 6) vidual’s specific LDL-C goal is recommended (Table
• R36. For individuals at low risk (i.e., with no risk fac- 12) (Grade D).
tors), an LDL-C goal <130 mg/dL is recommended
(Grade A; BEL 1). • R44. For individuals at extreme risk, a non-HDL-C
goal 25 mg/dL higher than the individual-specific
• R37. For individuals at moderate risk (i.e., with 2 or LDL-C goal is recommended (Table 12) (Grade A;
fewer risk factors and a calculated 10-year risk of less BEL 1).
than 10%), an LDL-C goal <100 mg/dL is recom-
mended (Grade A; BEL 1). • 3Q3.1.4. Apolipoproteins
• R45. For individuals at increased risk of ASCVD,
• R38. For individuals at high risk (i.e., with an including those with diabetes, an optimal apo B goal
ASCVD equivalent including diabetes or CKD stage is <90 mg/dL, while for individuals with established
3 or 4 with no other risk factors or individuals with 2 ASCVD or diabetes plus 1 or more additional risk
or more risk factors and a 10-year risk of 10%-20%), factor(s), an optimal apo B goal is <80 mg/dL, and for
an LDL-C goal <100 mg/dL is recommended (Grade individuals at extreme risk, an optimal apo B goal is
A; BEL 1). <70 mg/dL (Table 12) (Grade A; BEL 1).

• R39. For individuals at very high risk (i.e., with • 3Q3.1.5 Triglycerides
established or recent hospitalization for ACS, coro- • R46. TG goals <150 mg/dL are recommended (Table
nary, carotid or peripheral vascular disease; diabetes 12) (Grade A; BEL 1).
or CKD stage 3 or 4 with 1 or more risk factors; a
calculated 10-year risk greater than 20%; or hetero- 3Q3.2. Treatment Recommendations
zygous familial hypercholesterolemia [HeFH]), an • R47. A comprehensive strategy to control lipid lev-
LDL-C goal <70 mg/dL is recommended (Grade A; els and address associated metabolic abnormalities
BEL 1). and modifiable risk factors is recommended primarily
using lifestyle changes (Grade A, BEL 1) and patient
• R40. For individuals at extreme risk (i.e., with pro- education with pharmacotherapy as needed to achieve
gressive ASCVD, including unstable angina that per- evidence-based targets (Grade A, BEL 1).
sists after achieving an LDL-C <70 mg/dL, or estab-
lished clinical ASCVD in individuals with diabetes, • 3Q3.2.1. Physical Activity
CKD stage 3 or 4, and/or HeFH, or in individuals with • R48. A reasonable and feasible approach to fitness
a history of premature ASCVD (<55 years of age for therapy (i.e., exercise programs that include at least
males or <65 years of age for females), an LDL-C 30 minutes of moderate-intensity physical activity
goal <55 mg/dL is recommended (Grade A; BEL 1). [consuming 4-7 kcal/min] 4 to 6 times weekly, with an
expenditure of at least 200 kcal/day) is recommended;
• R41. An LDL-C goal <100 mg/dL is considered suggested activities include brisk walking, riding a
“acceptable” for children and adolescents, with 100 to stationary bike, water aerobics, cleaning/scrubbing,
129 mg/dL considered “borderline” and 130 mg/dL or mowing the lawn, and sporting activities (Grade A;
greater considered “high” (based on recommendations BEL 1).
from the American Academy of Pediatrics) (Table 9)
(Grade D). • R49. Daily physical activity goals can be met in a
single session or in multiple sessions throughout the
• 3Q3.1.2. HDL-C course of a day (10 minutes minimum per session); for
• R42. HDL-C should be >40 mg/dL, but also as high some individuals, breaking activity up throughout the
as possible, primarily through the use of lifestyle day may help improve adherence with physical activ-
interventions (e.g., weight loss, physical activity, and ity programs (Grade A; BEL 1).
CPG for Managing Dyslidemia and Prevention of CVD, Endocr Pract. 2017;23(No. 4) 491

Table 12
Lipid Goals for Patients at Risk for Atherosclerotic Cardiovascular Diseasea
Lipid parameter Goal (mg/dL)
TC <200
<130 (low risk)
<100 (moderate risk)
LDL-C <100 (high risk)
<70 (very high risk)
<55 (extreme risk)
Non-HDL-C 30 above LDL-C goal; 25 above LDL-C goal (extreme risk patients)
TG <150
<90 (patients at high risk of ASCVD, including those with diabetes)
<80 (patients at very high risk with established ASCVD or diabetes plus ≥1
Apo B
additional risk factor)
<70 (patients at extreme risk)
Abbreviations: apo = apolipoprotein; ASCVD = atherosclerotic cardiovascular disease; HDL-C = high-
density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; TC = total cholesterol; TG =
triglycerides
a See text for references and evidence levels.

• R50. In addition to aerobic activity, muscle-strength- on the basis of morbidity and mortality outcome trials
ening activity is recommended at least 2 days a week (Grade A; BEL 1).
(Grade A; BEL 1).
• R57. For clinical decision making, mild elevations in
• 3Q3.2.2. Medical Nutrition Therapy blood glucose levels and/or an increased risk of new-
• R51. For adults, a reduced-calorie diet consisting of onset T2DM associated with intensive statin therapy
fruits and vegetables (combined ≥5 servings/day), do not outweigh the benefits of statin therapy for
grains (primarily whole grains), fish, and lean meats ASCVD risk reduction (Grade A; BEL 1).
is recommended (Grade A; BEL 1).
• R58. In individuals within high-risk and very high-
• R52. For adults, the intake of saturated fats, trans- risk categories, further lowering of LDL-C beyond
fats, and cholesterol should be limited, while LDL- established targets with statins results in additional
C-lowering macronutrient intake should include plant ASCVD event reduction and may be considered
stanols/sterols (~2 g/ day) and soluble fiber (10-25 g/ (Grade A; BEL 1).
day) (Grade A; BEL 1).
• R59. Very high-risk individuals with established coro-
• R53. Primary preventive nutrition consisting of nary, carotid, and peripheral vascular disease or diabe-
healthy lifestyle habits is recommended in all healthy tes who also have at least 1 additional risk factor should
children (Grade A; BEL 1). be treated with statins to target a reduced LDL-C treat-
ment goal of <70 mg/dL (Grade A; BEL 1).
• 3Q3.2.3. Smoking Cessation
• R54. Tobacco cessation should be strongly encour- • R60. Extreme risk individuals should be treated with
aged and facilitated (Grade A; BEL 2; upgraded due statins to target an even lower LDL-C treatment goal
to potential benefit). of <55 mg/dL (Table 6) (Grade A; BEL 1).

• 3Q3.2.4. Pharmacologic Therapy Fibrates


• R55. In individuals at risk for ASCVD, aggressive lipid-
modifying therapy is recommended to achieve appro- • R61. Fibrates should be used to treat severe hypertri-
priate LDL-C goals (Table 13) (Grade A; BEL 1). glyceridemia (TG >500 mg/dL) (Table 13) (Grade A;
BEL 1).
Statins
• R62. Fibrates may improve ASCVD outcomes in pri-
• R56. Statin therapy is recommended as the primary mary and secondary prevention when TG concentra-
pharmacologic agent to achieve target LDL-C goals tions are ≥200 mg/dL and HDL-C concentrations <40
mg/dL (Grade A; BEL 1).
492 CPG for Managing Dyslidemia and Prevention of CVD, Endocr Pract. 2017;23(No. 4)

Table 13
Primary Lipid-Lowering Drug Classes
a b
Drug class Metabolic effect Main considerations
HMG-CoA reductase Primarily ↓ LDL-C 21-55% by Liver function test prior to therapy and as clinically indicated
inhibitors (statins: competitively inhibiting rate- thereafter.
lovastatin, limiting step of cholesterol synthesis Myalgias and muscle weakness in some patients
pravastatin, in the liver, leading to upregulation Potential for drug-drug interaction between some
fluvastatin, of hepatic LDL receptors statins and CYP450 3A4 inhibitors, cyclosporine,
simvastatin, warfarin, and protease inhibitors.
atorvastatin, Effects on TG and HDL-C are less Myopathy/rhabdomyolysis in rare cases; increased risk
rosuvastatin, pronounced (↓ TG 6-30% and ↑ with co-administration of some drugs (see product
pitavastatin) HDL-C 2-10%) labeling).
Simvastatin dosages of 80 mg are no longer recommended.
Do not exceed 20 mg simvastatin daily with amlodipine or
ranolazine.
Plasma elevations of rosuvastatin may be higher among
Asian persons than other ethnic groups.
New-onset diabetes is increased in patients treated with
statins; however, it is dose-related, occurs primarily
in patients with MetS, appears to be less common
with pravastatin and possibly pitavastatin, and occurs
overall to a lesser extent than the associated decrease in
ASCVD.
Cholesterol absorption Primarily ↓ LDL-C 10- Myopathy/rhabdomyolysis (rare) Myopathy/
inhibitors (ezetimibe) 18% by inhibiting intestinal rhabdomyolysis (rare)
absorption of cholesterol and When co-administered with statins or fenofibrate, risks
decreasing delivery to the liver, associated with those drugs remain (e.g., myopathy/
leading to upregulation of hepatic rhabdomyolysis, cholelithiasis)
LDL receptors
↓ Apo B 11-16%
In combination with statins,
additional ↓ LDL-C 25%,
total ↓ LDL-C 34-61%
In combination with
fenofibrate, ↓ LDL-C 20-22% and
↓ apo B 25-26% without reducing
↑ HDL-C
PCSK9 (Proprotein ↓LDL-C 48-71%, ↓ non-HDL-C 49- Requires subQ self-injection, and refrigeration is generally
convertase subtilisin/kexin 58%, ↓Total-C 36-42%, ↓Apo B 42- needed.
type 9) inhibitors 55% by inhibiting PCSK9 binding Adverse reactions resulted in discontinuation in 2.2% overall,
(alirocumab, evolocumab) with LDLRs, increasing the number 1.2% more than placebo for evolocumab, and 5.3% overall,
of LDLRs available to clear LDL, 0.2% more than placebo for alirocumab. Overall levels of
and lowering LDL-C levels adverse reactions and discontinuation very low.
Adverse reactions with significantly different rates between
drug and placebo were: local injection site reactions
(1.9% greater for alirocumab vs. placebo, 0.7% greater for
evolocumab vs. placebo) and influenza (1.2% greater for
alirocumab vs. placebo, 0.2% for evolocumab vs. placebo). The
most common adverse reactions with similar rates for drug vs.
placebo were for:
Alirocumab (4-12%; most common to least common):
nasopharyngitis, influenza, urinary tract infections, diarrhea,
bronchitis, and myalgia.
Evolocumab (2-4%; most common to least common):
Nasopharyngitis, back pain, and upper respiratory tract
infection.
CPG for Managing Dyslidemia and Prevention of CVD, Endocr Pract. 2017;23(No. 4) 493

Table 13 Continued
Fibric acid derivatives Primarily ↓ TG 20-35%, Gemfibrozil may ↑ LDL-C 10-15%.
(gemfibrozil, fenofibrate, ↑ HDL-C 6-18% by GI symptoms, possible cholelithiasis.
fenofibric acid) stimulating lipoprotein lipase May potentiate effects of orally administered
activity anticoagulants. c
Fenofibrate may ↓ TC and Gemfibrozil may ↑ fibrinogen level .
LDL-C 20-25% Gemfibrozil and fenofibrate can ↑ homocysteine
d
Lower VLDL-C and LDL-C; independent of vitamin concentrations .
reciprocal rise in LDL-C Myopathy/rhabdomyolysis when used with statin
transforms the profile into a less (uncommon with gemfibrozil, but increased risk
atherogenic form by shifting with all statins except fluvastatin); interaction
fewer LDL particles to larger size less likely with fenofibrate or fenofibric acid (no
Fenofibrate ↓ fibrinogen level apparent difference by statin).
Fibrates are associated with increased serum creatinine
levels, which may not reflect renal dysfunction.
Fenofibrate dose should be cut by two-thirds and
gemofibrozil by one-half when eGFR is 15-60, and
fibrates should be avoided when eGFR is <15.
May cause muscle disorders.
Can improve diabetic retinopathy.
Niacin (nicotinic acid) ↓ LDL-C 10-25%, ↓ TG Potential for frequent skin flushing, pruritus, abdominal
20-30%, ↑ HDL-C 10- discomfort, hepatotoxicity (rare but may be severe),
35% by decreasing hepatic nausea, peptic ulcer, atrial fibrillation.
synthesis of LDL-C and Deleterious effect on serum glucose at higher dosages.
VLDL-C Increases uric acid levels; may lead to gout.
↓ Lipoprotein (a)
Transforms LDL-C to less
atherogenic form by
increasing average particle size
and also decreases LDL particle
concentration
Bile acid sequestrants Primarily ↓ LDL-C 15-25% by May ↑ serum TG
(cholestyramine, binding bile acids and preventing Frequent constipation and/or bloating, which can reduce
colestipol, colesevelam their reabsorption in the ileum adherence
hydrochloride) (causing hepatic cholesterol Many potential drug interactions (decreased drug
depletion and LDLR upregulation) absorption), less so with colesevelam (see product
labeling)
Colesevelam ↓ glucose and May reduce absorption of folic acid and fat-soluble
hemoglobin A1C (~0.5%); is FDA vitamins such as vitamins A, D, and K
approved to treat T2DM
MTP inhibitor (lomitapide) ↓ Up to LDL-C 40%, TC 36%, Can cause increases in transaminases (ALT,
apo B 39%, TG 45%, and non- AST). Monitoring of ALT, AST, alkaline phosphatase,
HDL-C 40% (depending on dose) and total bilirubin prior to initiation, and of ALT and AST
in patients with HoFH by binding during treatment, is required per FDA REMS.
and inhibiting MTP, which inhibits Causes increases in hepatic fat (steatosis) with or without
synthesis of chylomicrons and concomitant elevated transaminases, which may be a risk
VLDL for progressive liver diseases. 
Also causes steatosis of the small intestine with resulting
abdominal pain and steatorrhea unless a very-low-fat
diet is followed. May also cause fat-soluble vitamin
deficiency unless vitamin supplements are taken.
Caution should be exercised when used with other drugs
with potential hepatotoxicity. Because of hepatotoxicity
risk, only available through REMS program.
494 CPG for Managing Dyslidemia and Prevention of CVD, Endocr Pract. 2017;23(No. 4)

Table 13 Continued
Antisense apolipoprotein ↓ LDL-C 21%, TC 19%, apo B Can cause increases in transaminases (ALT,
B oligonucleotide 24%, and non-HDL-C 22% in AST). Monitoring of ALT, AST, alkaline phosphatase,
(mipomersen via subQ patients with HoFH by degrading and total bilirubin prior to initiation, and of ALT and AST
injection) mRNA for apo B-100, the principal during treatment is recommended.
apolipoprotein needed for hepatic Causes increases in hepatic fat (steatosis) with or without
synthesis of VLDL (and subsequent concomitant elevated transaminases, which may be a risk
intraplasma production of IDL and for progressive liver diseases. 
LDL) Caution should be exercised when used with other drugs
with potential hepatotoxicity. Because of hepatotoxicity
risk, only available through REMS program.
Omega-3 fatty acids ↓ TG 27-45%, TC 7-10%, VLDL-C TG levels should be carefully assessed prior to initiating
(icosapent ethyl, omega-3- 20-42%, apo B 4%, and non- therapy and periodically during therapy.
acid ethyl esters) HDL-C 8-14% in individuals with Omega-3-acid ethyl esters can increase LDL-C levels.
severe hypertriglyceridemia, most Monitoring of LDL-C levels during treatment is
likely by reducing hepatic VLDL- recommended.
TG synthesis and/or secretion May prolong bleeding time. Periodic monitoring of coagulation
and enhancing TG clearance from status should be undertaken in patients receiving treatment
circulating VLDL particles. Other with omega-3 fatty acids and other drugs affecting
potential mechanisms of action coagulation.
include: increased ß-oxidation; Periodic monitoring of ALT and AST levels during treatment
inhibition of acyl-CoA; is recommended for patients with hepatic impairment. Some
1,2-diacylglyceral acyltransferase; patients may experience increases in ALT levels only.
decreased hepatic lipogenesis; Caution should be exercised when treating patients with a
and increased plasma lipoprotein known hypersensitivity to fish and/or shellfish.
activity The effect of omega-3 fatty acids on cardiovascular morbidity
Icosapent ethyl ↓ LDL-C 5%, and mortality and the risk of pancreatitis has not been
whereas omega-3-acid ethyl esters determined in patients with severe hypertriglyceridemia.
↑ LDL-C 45% In patients with paroxysmal or persistent AF, therapy with
omega-3-acid ethyl esters may be associated with increased
frequency of symptomatic AF or flutter, especially within the
first 2 to 3 months after initiation.
The most common adverse events in patients receiving omega-3
fatty acids included arthralgia (2.3%), eructation (4%),
dyspepsia (3%), and taste perversion (4%). Patients may also
experience constipation, gastrointestinal disorders, vomiting,
rash, or pruritus.
Omega-3 fatty acids should be used with caution in nursing
mothers and should only be used in pregnant women if the
benefits of treatment outweigh the potential risk of fetal harm.
Abbreviations: AF = atrial fibrillation; ALT = alanine aminotransferase; AR = adverse reaction; AST = aspartate aminotransferase; apo =
apolipoprotein; eGFR = estimated glomerular filtration rate; FDA = U.S. Food and Drug Administration; GI = gastrointestinal; HDL-C
= high-density lipoprotein cholesterol; HMG-CoA = hydroxymethylglutaryl-coenzyme A; LDL-C = low-density lipoprotein cholester-
ol; LDLR = low-density lipoprotein receptor; MTP = microsomal triglyceride transfer protein; REMS = Risk Evaluation and Mitigation
Strategies; subQ = subcutaneous; TC = total cholesterol; TG = triglycerides; VLDL-C, very low-density lipoprotein cholesterol
a Percentage of change varies depending on baseline lipid variables and dosages. Statin potency and dosages vary.
b Most frequent or serious; See prescribing information for complete contraindications, warnings, precautions, and side effects.
c Results vary. Gemfibrozil has been shown to decrease, have no effect on, or increase fibrinogen depending on the study.
d Results vary. Gemfibrozil has been shown to have no effect on or increase homocysteine.
CPG for Managing Dyslidemia and Prevention of CVD, Endocr Pract. 2017;23(No. 4) 495

Omega-3 Fish Oil Special Considerations: Women

• R63. Prescription omega-3 oil, 2 to 4 g daily, should • R72. Women should be evaluated for their ASCVD
be used to treat severe hypertriglyceridemia (TG >500 risk and be treated with pharmacotherapy if life-
mg/dL). Dietary supplements are not FDA-approved style intervention is insufficient (Grade C; BEL 4;
for treatment of hypertriglyceridemia and generally upgraded due to potential benefit).
are not recommended for this purpose. (Grade A;
BEL 1). • R73. Hormone replacement therapy for the treatment
of dyslipidemia in postmenopausal women is not rec-
Niacin ommended (Grade A; BEL 1).

• R64. Niacin therapy is recommended principally as an Special Considerations: Children and Adolescents
adjunct for reducing TG (Grade A; BEL 1).
• R74. Pharmacotherapy is recommended for chil-
• R65. Niacin therapy should not be used in individu- dren and adolescents older than 10 years who do not
als aggressively treated with statin due to absence respond sufficiently to lifestyle modification, particu-
of additional benefits with well-controlled LDL-C larly for those satisfying the following criteria (Grade
(Grade A; BEL 1). D; BEL 4):
• LDL-C ≥190 mg/dL
Bile Acid Sequestrants • LDL-C ≥160 mg/dL and the presence of 2 or more
cardiovascular risk factors, even after vigorous
• R66. Bile acid sequestrants may be considered for intervention
reducing LDL-C and apo B and modestly increasing • Family history of premature ASCVD (before 55
HDL-C, but they may increase TG (Grade A; BEL 1). years of age), or
• Having overweight, obesity, or other elements of
Cholesterol Absorption Inhibitors insulin resistance syndrome

• R67. Ezetimibe may be considered as monotherapy 3Q3.3. Follow-up and Monitoring


in reducing LDL-C and apo B, especially in statin-
intolerant individuals (Grade B; BEL 2). • R75. Reassess individuals’ lipid status 6 weeks after
therapy initiation and again at 6-week intervals until
• R68. Ezetimibe can be used in combination with the treatment goal is achieved (Grade D; BEL 4).
statins to further reduce both LDL-C and ASCVD risk
(Grade A; BEL 1). • R76. While on stable lipid therapy, individuals
should be tested at 6- to 12-month intervals (Grade
PCSK9 Inhibitors D; BEL 4).

• R69. Proprotein convertase subtilisin/kexin type 9 • R77. While on stable lipid therapy, the specific inter-
(PCSK9) inhibitors should be considered for use in val of testing should depend on individual adherence
combination with statin therapy for LDL-C lowering to therapy and lipid profile consistency; if adher-
in individuals with FH (Grade A; BEL 1). ence is a concern or the lipid profile is unstable, the
individual will probably benefit from more frequent
• R70. PCSK9 inhibitors should be considered in assessment (Grade C; BEL 4; upgraded due to
patients with clinical cardiovascular disease who are potential benefit).
unable to reach LDL-C/non-HDL-C goals with maxi-
mally tolerated statin therapy. They should not be used • R78. More frequent lipid status evaluation is recom-
as monotherapy except in statin-intolerant individuals mended in situations such as deterioration of diabetes
(Grade A; BEL 1). control, use of a new drug known to affect lipid levels,
progression of atherothrombotic disease, considerable
Combination Therapy weight gain, unexpected adverse change in any lipid
parameter, development of a new ASCVD risk factor,
• R71. Combination therapy of lipid-lowering agents or convincing new clinical trial evidence or guidelines
should be considered when the LDL-C/non-HDL-C that suggest stricter lipid goals (Grade C; BEL 4;
level is markedly increased and monotherapy (usually upgraded due to potential benefit).
with a statin) does not achieve the therapeutic goal
(Grade A; BEL 1).
496 CPG for Managing Dyslidemia and Prevention of CVD, Endocr Pract. 2017;23(No. 4)

• R79. Liver transaminase levels should be measured egy to achieve LDL-C goals, especially with price
before and 3 months after niacin or fibric acid treat- decreases for generic ezetimibe (Grade A; BEL 1).
ment initiation because most liver abnormalities occur
within 3 months of treatment initiation. Liver trans- • R87. Bile acid sequestrants are generally not cost-
aminase levels should be measured periodically there- effective alternatives to statin therapy despite generic
after (e.g., semiannually or annually) (Grade C; BEL availability; this is due to their low LDL-C lowering
4; upgraded due to potential benefit). efficacy compared to statins (Grade B; BEL 2).

• R80. Creatine kinase levels should be assessed and Supportive material, supplemental informa-
the statin discontinued, at least temporarily, when an tion, additional tables and figures, and a complete list
individual reports clinically significant myalgias or of references are published online in the Appendix-
muscle weakness on statin therapy (Grade C; BEL 4; Evidence Base accessible at http://journals.aace.com.
upgraded due to potential benefit).
ACKNOWLEDGMENT
3Q4. IS TREATMENT OF DYSLIPIDEMIA
AND PREVENTION OF ATHEROSCLEROTIC We acknowledge the medical writing assistance of
CARDIOVASCULAR DISEASE COST-EFFECTIVE? Caitlin Rothermel, MA, MPH.
AACE recognizes the importance of providing contin-
• R81. Nonpharmacologic interventions such as dietary ued education to its members, which may require finan-
management (Grade A; BEL 1) and smoking cessa- cial support from an outside entity through unrestricted
tion are the most cost-effective options available for educational grants. Outside support will not be used for
ASCVD prevention (Grade A; BEL 2, upgraded due the development and/or writing of AACE consensus state-
to potential health benefit). ments/conference proceedings, white papers, or guidelines.
Outside support may be accepted for the administration/
• R82. When nonpharmacologic interventions fail, phar- logistical support of a consensus conference and for the
macologic intervention is a recommended cost-effective dissemination and distribution of the final written paper.
option for primary and secondary intervention among The content of these documents is developed solely by
individuals at moderate to high risk (Grade B; BEL 2). AACE members and, as always, will remain free of any
outside entity influence.
• R83. Among otherwise healthy individuals at lower
risk, the cost-effectiveness of primary pharmacologic DISCLOSURES
intervention varies on the basis of age and sex (with
this approach being least cost-effective among women Chair
at low risk) (Grade C; BEL 3). Dr. Paul S. Jellinger reports that he has received
speaker honoraria from BI-Lilly, AstraZeneca, Novo
Nordisk, Merck, and Amgen.
• R84. Statins have proven cost-effective in both sec-
ondary and primary prevention of ASCVD events in Task Force Members
individuals at moderate to high risk, or in individuals Dr. Donald A. Smith reports that he has received
at low risk whose LDL-C levels are very high (≥190 research grant support from Sanofi Regeneron and Amgen.
mg/dL) (Grade B; BEL 2). Dr. Yehuda Handelsman reports that he is a consul-
tant for Amarin, Amgen, AstraZeneca, Boehringer
• R85. Treatment with fibrates has been found to be Ingelheim (BI), Janssen, Eli Lilly, Eisai, Intarcia, Merck,
cost-effective as both monotherapy and combination Novo Nordisk, Sanofi, and Regeneron. He is a speaker for
therapy for lowering TG and raising HDL-C (Grade Amarin, Amgen, AstraZeneca, BI-Lilly, Janssen, Novo
D; BEL 4), but not in reducing cardiovascular events, Nordisk, Sanofi, and Regeneron. Dr. Handelsman has
except in individuals with TG concentrations greater received research grant support from Amgen, AstraZeneca,
than 200 mg/dL and HDL-C concentrations less than BI, Esperion, Grifols, Hamni, GSK, Lexicon, Merck, Novo
40 mg/dL (Grade D; BEL 4). Nordisk, and Sanofi.
Dr. David S. H. Bell reports that he is a consultant
• R86. Ezetimibe, co-administered with statin therapy and speaker for AstraZeneca, Takeda, Janssen, and Novo
in individuals unable to meet target LDL-C levels, Nordisk.
has not been evaluated for cost-effectiveness in the Dr. Zachary T. Bloomgarden reports that he is a
U.S. Based on studies from Canada and the United consultant for AstraZeneca, Johnson & Johnson, Merck,
Kingdom, ezetimibe may be a cost-effective strat- Intarcia, and Novartis. He is also a speaker for Merck,
CPG for Managing Dyslidemia and Prevention of CVD, Endocr Pract. 2017;23(No. 4) 497

AstraZeneca, and Johnson & Johnson. He is a shareholder REFERENCES


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Medtronic. Association of Clinical Endocrinologists Medical
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er honoraria from Roche and Bayer and research grant Lancet. 2010;376:1670-1681.
support from Sanofi and Eli Lilly.

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